Concise Paediatrics

Second Edition

Edited by

Rachel U Sidwell MBChB oA MFRCP MRcPcH

Dermatology Registrar
Chelsea and Westminster Hospital
London, UK

Mike A Thomson MBChB ocH FRCP FRCPCH

Consultant Paediatric Gastroenterologist
Sheffield Children's Hospital Foundation NHS Trust
Sheffield, UK
'

The ROYAL
SOCIETY if
MEDICINE
PRESS Limited

i
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j .

Contributors ...................... ....... .. .... .. .......... .... ... .. ..... .. .. .... ......... .. .. ... .. ... .. ... ..... .. ... .. .vii
Preface ..... .. ....... .. ...... ..... ... ..... ..... ... ...... ...... ..... ... .. .. ..... .... ..... .. ........ ..... ..... ..... .......... ix

1. Genetics .... ...... ...... .. .. .... .. .. ...... .. .... .... ... ..... ..... ...... ...... ....... ... ..... ... ... .... ...... .. .... .. 1
2. Immunology ... ... ... ............. ........... ........ ... .. .. .......... .. ... .. ...... .. ... ....... ... ... .... .... ..... 21
3. Infectious diseases. ....... ..... .. ....... ...... ..... .. .... ... ... ... ..... ... .. ... ..... .. .. .. ... .. . .. ... ..... ... .. 41
4. Cardiology ........ ... ..... ..... ..... .... ... ..... .. .. ....... .... ........... .... .... .. .... .. .... ... .... ..... .... .. ... 76
5. Ear, nose and throat disorders ........... .. ... ... .... .. .. .. ... .. .... .. .. .. .. ... ...... ...... .. . .' .. ........ .... 114

6. Respiratory disorders ....... .... ... .... .. ..... ..... .......... ...... ... ... .... ....... ..... ... ... ...... .. ..... ... 126
7. Gastrointestinal disorde rs .... .. .. ..... .. ..... .... .. .......... .. .... .. .. ... .. ... ... ...... ... ... ...... ...... ... 141
8. Liver disorders ...... ....... ... .... ..... .... .. .... .... .... .. ..... ..... .......... .. .. ... ..... ... .. ..... ... ... ..... 17 4
....__
9. Renal disorders ... .... ... ....... ... .. .. ... ... ..... .... ...... .. ... .... ...... .. ... .. ... ..... .... .. .. ........... ... 199
10. Endocrinology, growth and puberty.·.... .. ...... ...... .. ....... .. .. ............ .... .... .. .. .. ... .. .... ..... 233 .

11. Metabolic disorders: .... ..... ... ... .... ..... .... ..... ... ...... ..... .. .. .... ... ... ..... .... ....... ... .. ... ...... 272
12. Dermatology .... .... ..... .. .... .. ... .. .. ....... .. ... ... ........ .. ... ..... ..... .. .. ....... .. .... ... ... ..... .... .. 289
13. Rheumatic and musculoskeletal disorders .... .. .. ... .. .... ... .. .... .. .... .. ... ......... ... ... .... .. .. .. ... 3JO'
14. Neurological and neuromuscula r disorders ... .... .. ...... .... .. ..... .... ...... ...... ........ ...... ... ..... 328
15. Ophthalmology .. ........ ................. ... .... ......... ..... ....... ... .... ... .. ...... .... ....... ... .... ...... 373
16. Haematology ....... .... .... .... ... .......... ... .. .. .. .. ... .. ... .. ... ....... ... .. .... ...... .... ...... .. ... ... ... 386
----..
17. Oncology.... ...... ... .... .... ... ...... ..... ... ... .. ........ .. .... .. .. ..... ..... .......... ...... ..... .. .. ..... .... 417
~- Neonatology ... .... .......... ...... .. ...... .. ... .. ... ... ... ..... .... ........... ... .... ... .... .. .. ... ..... .. .... 442
19. Surgical conditions ......... ....... .... .. .. .... .. .... .. .. ..... .. .......... .... ... .. .. .. ...... ...... .. ..... .. .. 479
20. Emergencies, accjdents, non-accidental injury and the law ............. .. .. ... ... .... ... .... .. ...... 503
' ~,

Index.. .... ... ..... .. ..... ... .... ... ..... .. .. ... .. .... ... ...... ... ..... .... ......... .. ...... ... ...... ...... ..... ..... ... 52 7

v
Chapters are shown in italics

Siobhan Carr MRCP MSc FRCPCH

Consultant Respiratory Paediatrician, St Bartholomew's and The Royal London Hospitals, London, UK
Respiratory disorders
Robert ( Coombes BSc FRCPCH
Consultant Neonatal Paediatrician, Sheffield Children's Hospital NHS Trust, Sheffield, UK
Neonatology
Peter Cuckow FRCS (Paed)
Consultant Paediatric Urological Surgeon, Great Ormond Street Hospital for Children NHS Trust and University Col-
lege Hospital, London, UK
Surgical conditions
Claire Daniel BSc FRCOphth
Consultant Ophthalmologist, Moorfields Eye Hospital NHS Foundation Trust, London, UK
Ophthalmology
James SA Green LLM FRCS (Ural)
Consultant Urological Surgeon, Whipps Cross University Hospital, London, UK
Surgical conditions; Emergencies, accidents, non-accidental injury and the law
Ian MHann MD FRCP FRCPCH FRCPath
Professor of Paediatric Haematology and Oncology, Great Ormond Street Hospital for Children NHS Trust and UCL
Institute of Child Health, London, UK
Oncology
John I Harper MD FRCP FRCPCH
Professor of Paediatric Dermatology, Great Ormond Street Hospital for Children NHS Trust, London, UK
Dermatology
Paul T Heath FRACP FRCPCH
Consultant in Paediatric Infectious Diseases, St George's Healthcare NHS Trust, London, UK
Infectious diseases

Nigel Klein BSc MRCP PhD

Professor of Immunology and Infectious Diseases, Great Ormond Street Hospital for Children NHS Trust and UCL
Institute of Child Health, London, UK
Immunology
Melissa Mlees MRCP DCH MSc MD FRACP
Consultant in Clinical Genetics and Honorary Senior Lecturer, Great Ormond Street Hospital for Children NHS Trust
and UCL Institute of Child Health, London, UK
Genetics
vii
Ahmed F Massoud MRCP MRCPCH MD
Consultant Paediatrician and Endocrinologist, Northwick Park Hospital, London, UK
Endocrinology, growth and puberty

Anthony J Mikalski FRCPCH PhD

Consultant Paediatric Oncologist, Great Ormond Street Hospital for Children NHS Trust, London, UK
Oncology

Mike Potter MA PhD FRCP FRCPath

Consultant Paediatric Haematologist, The Royal Marsden NHS Foundation Trust, London, UK
Haematology

Robert J Sawdy BSc MRCOG PhD

Consultant Obstetrician and Specialist in Maternal and Fetal Medicine, Poole Hospital NHS Foundation Trust, Poole, UK
Neonatology

Rod CScott ChB PhD MRCP MRCPCH

Senior Lecturer in Paediatric Neurology, Great Ormond Street Hospital for Children NHS Trust, London, UK
Neurological and neuromuscular disorders

Rachel U Sidwell MBChB DA MFRCP MRCPCH

Dermatology Registrar, Chelsea and Westminster Hospital, London, UK
All chapters

Mike A Thomson MBChB ocH FRCP FRCPCH

Consultant Paediatric Gastroenterologist, Sheffield Children's Hospital Foundation NHS Trust, Sheffield, UK
Gastrointestinal disorders; Liver disorders; Emergendes, accidents, non-acddental injury and the law

Michael Waring sse FRCS (ORL -HNS)

Consultant Otolaryngologist, St Bartholomew's and The Royal London Hospitals, London, UK
Ear, nose and throat disorders

Nick Wilkinson MBChB MRCP MRCPCH OM

Consultant Paediatric Rheumatologist, Nuffield Orthopaedic Centre NHS Trust, Oxford, UK
Rheumatic and musculoskeletal disorders

Callum J Wilson DCH Dip D&G FRACP

Metabolic Consultant, Starship Children's Health, Aukland, New Zealand
Metabolic disorders

Paul JD Winyard MA MRCP MRCPCH PhD

Senior Lecturer in Paediatric Clinical Science, Great Ormond Street Hospital for Children NHS Trust and UCL Insitute
of Child Health, London, UK
Renal disorders

Robert WM Yates sse FRCP

Consultant Paediatric Cardiologist, Great Ormond Street Hospital for Children NHS Trust, London, UK
Cardiology

Vlll
 Following feedback, this fully revised, second edition of Concise Paediatrics retains the ethos of the popular and sue
cessful first edition: to provide a succinct, easy-to-access reference work, filling the gap between larger paediatri1
reference works and undergraduate books, the latter of which often do not contain enough detail. Each chapter ha~
been extensively updated and there are new chapters on ENT and ophthalmology. The editors have tried to retain <
pithy and user-friendly style, using many lists, boxes and .annotated diagrams for ease of learning. Concise Paediatrics
Second Edition is particularly focused on those contemplating MRCPCH and DCH higher examinations, but, as well a~
being useful for medical students, it is also a useful quick reference for practitioners and for those more advanced ir
their training. This book aims to provide thorough background knowledge of the subject and will help to give inspira·
. tion for further exploration in the field of paediatrics.
We would like to thank all those who helped with this book. In particular we are indebted to the contributing author~
and specialists for providing valuable, up-to-date knowledge and experience, which add to the quality of the book. J
big thank you also to Rachel's husband, James Green, and to her father, Duncan Sidwell for their support. Finally, WE
would like to thank Peter Richardson, Sarah Ogden, Mark Sanderson and the team at the Royal Society of MedicinE
Press for all their help.
Best of luck!
Rachel and Mike

lX
'
• Clinical application of genetics • Single gene defects (Mendelian inheritance)
• Basic cell genetics • Factors affecting inheritance patterns
• Mutations • Multifactorial inheritance
• Techniques for DNA analysis and mutation detection • Dysmorphology
• Chromosomal disorders

CLINICAL APPLICATION OF GENETICS

Genetics is a rapidly advancing and fascinating field of medicine, which has particular relevance in paediatrics.
Increasingly, medical genetics is becoming central to our understanding of many diseases, and not just rare disorders.
A large proportion of paediatric admissions are due to genetic diseases, as are a large proportion (50%) of paediatric
deaths.

GENETIC COUNSELLING
This involves:
• Making or confirming a diagnosis
• Discussing the natural history of the disorder and relevant management
• Discussing risks to other family members of developing or passing on the disorder
• Options for screening and prenatal diagnosis

GENETIC SCREENING
Genetic screening is the search in a population for individuals possessing certain genotypes (variations of a specific
gene) that:
• Are known to be associated with disease or predisposition to disease, or
• May lead to disease in their offspring
Disorders such as thalassaemia are amenable to population screening <JS the test can be performed by a buccal smear
or blood test; the carrier frequency is common in specific populations; gene carriers themselves are not at increased
risk of disease; and a .specific prenatal test can be offered to couples identified to be at risk.

1
Genetic carrier testing is the search in at-risk individuals for a specific genotype known to be associated with disease
in that family.

PRENATAL DIAGNOSIS
This involves both screening tests that give a probability of disease and diagnostic tests that give a definite
diagnosis.
• Screening tests include the antenatal nuchal ultrasound scan (USS), which identifies a pregnancy at increased
risk of Down syndrome, and then definitive testing via a chorionic villus biopsy (CVS) or amniocentesis may be
offered.
• Diagnostic tests include DNA analysis of a fetal sample for DNA changes known to be associated with disease in
that family, e.g. analysis of the cystic fibrosis gene in a CVS sample, where both parents are known to be carriers
of the disorder.

Reasons for antenatal testing

1. To reassure parents in a nQrmal pregnancy
2. To identify an affected fetus.in a high-risk family
3. To allow parents to make an informed decision about continuation of the pregnancy where an anomaly i,s
identified
4. To enable optimal medical management (in utero and after birth), e.g. to arrange forthe baby with a
congenital cardiac anomaly to be born in a hospital where the cardiologist;is aware and able to manage the
·problem ·.·

Prenatal screening and diagnostic tests

Prenatal screening tests
• Nuch<1l~l~rC;l~9.1:lnd ·,s'canc;(tJSSY
• r~tat')artoma'fY~trss11>~'
··•· Materrrat~~btood,~sa mpli ng%for" a..•FP;·,'~"·h.G@i;*

Testing of genetic disorders in at-risk families

• Heterozygotlts'creehin~f'in at-risk families, e.g. cy~tif:,.fibr'O'sis g~ng4q_oaly~jp
• Pre~symptoinatictesting in adult-onset disorders, e.g. Huntingtomdisease, breast,.r'!Q~§r
• Carriei<te'stin~fTO'f'aFiisk'·relative·s in X::::Linked-ed.isorders, e.g. Duchen.ne.fiiJUs£uliu; dystmp~y
• Family~histoty""ofth'rdrilcfs'b'mal·"disord~r, e.g. translocation {

GENE THERAPY
This is the treatment of genetic disease via genetic alteration of the genome of cells of individuals with a genetic
disease. Although this is an exciting area which may in the future provide treatment for genetic disorders, success to
date has been limited. Many clinical trials are in progress. Most techniques involve inserting a functioning normal gene
into somatic cells to programme the cell to produce the normal gene product.
Currently gene therapy is being used in somatic cells and not in germline cells (which could result in the future
generation being affected).

2
 Diseases in which gene therapy is being investigated

BASIC CELL GENETICS

· The gene is the basic unit of inheritance. Humans are estimated .to· have around 30 000 structural genes, i.e. that code
for proteins. Genes are made of deoxyribonucleic acid (DNA) and are organized within chromosomes in the cell.
Somatic celts Contain 22 pairs of autosomes 46 chromosomes altogether
(Diploid) (One pair of sex chromosomes)
Gametes Contain 22 autosomes. '
23 chromosomes altogether
(Haploid) (One sex chromosome)

DNA ,COM IWSITIO N

DNA is a double helix composed of;
1. Sugar-phosphate backbone · (the pentose sugar deoxyribose
and a phosphate group)
2. Nitrogenous base .
Pyrimidines: Cytosine (C) and thymidine (T)
Purines: Adenine (A) and guanine (G,)

A always pairs with T. }

C always pairs with G Complementary base pairing

• The sugar-phosphate backbone has a 5' and a 3' end

• A nucleotid~ = a unit of one base, one deoxyribose. and one
phosphate grqup
3' 5'
• The DNA is coiled tightly to make up chromosomes,
• The gene sequence is made of exons (.code for proteins) inter- 8 Adenine
spaced with introns .
~Thymine
• Three bases make up a codon, which codes for one amino aGid
(via the genetic-code) ~Guanine
• The sequence of amino acids determines the protein prodi:Jct @Cytosine
Figure 1.1 Structure of DNA
DNA REPLICATION
This occurs in a sequence:
1. DNA helix splits to form two single strands
2. New complementary base pairs, i.e. Cwith G, and T with A, are added to the single strands at the 3' end (so
the new DNA replication grows from 5' to 3'). DNA polymerase enzyme adds the new nucleotides.
NB: Along a gene, the 5' direction is 'upstream' and the 3' direction is 'downstream'.

3
Forming proteins from DNA
1. Transcription. The DNA sequence is transcribed into messenger RNA (mRNA). (mRNA is a single strand like DNA
but with a uracil (U) base replacing all the T bases, and a ribose sugar instead of a deoxyribose sugar.) RNA
polymerase initiates this process. All the introns are removed, so the mRNA is made only of exons. The mRNA
then moves from the nucleus to the cytoplasm.
2. Translation. The mRNA is translated into a protein in the ribosomes (organelles in the cytoplasm) . Transfer
RNA (tRNA) attaches to the mRNA. Each tRNA is a clover shape with a three base pair (anticodon) at one
end, which attaches to the mRNA, and a three base pair at the other which codes for one amino acid (via the
genetic code). Thus a sequence of amino acids is formed which will form a protein.

YHE CELL CYCLE

New cells are constantly created. The cell cycle is a continuum of the cell's life, made up of:
1. Interphase. Most of the cell's life, replication of DNA and cell contents occur here
2. Division. The cell divides into two: Diploid cell creation: Mitosis (nuclear division)
Cytokinesis (cytoplasmic division)
Haploid cell creation : Meiosis
NB: After the S phase of the cell cycle, the DNA has already replicated, so the cell contains two identical copies of
each of the 46 chromosomes. The identical copies are joined together at a centromere and are called sister chroma-
tids, making up_ one chromosome. Because the chromosomes are studied in metaphase of mitosis when they are most
condensed, we actually always look at DNA that has replicated, the sister chromatids joined together and appearing
as 46 separate chromosome bodies.

Short arm 'p'

Division

Long arm 'q'

Interphase

Sister
chromatids

Figure 1.2 The cell cycle Figure 1.3 Chromosome (composed of two
identical chromatids). There are two copies of this
chromosome in each cell (one from the mother and
one from the father).

MUTATIONS
A mutation is a change in the DNA sequence within a specific gene which leads to an alteration of gene function.
• Mutations in germ line cells (cells that produce gametes) generally result in genetic diseases

4
 • Mutations in somatic cells (normal body cells) may result in cancer (if they occur early on in the developing
zygote, they may result in mosaics)
Genes differ among individuals due to polymorphisms, and differing sequences for the same gene are called alleles.
If someone has the same allele on both members of a chromosome pair, they are homozygous. If the alleles have
different gene sequences, the person is heterozygous.
A locus is the position of a gene on a chromosome.
The genotype is the alleles present at a given Locus.
A polymorphism is a variation in DNA sequence found with a frequency of at least 1% in the normal population.

TYPES OF SINGLE GENE MUTATION

These are not visible under the microscope and are studied by molecular genetic techniques. Examples of single gene
mutations:
• Point mutation. One base pair is substituted by another. They may cause one amino acid to change to another
(missense mutation) which may alter the structure of the protein product, or produce a stop codon (nonsense
mutation) where no protein product may be produced
• Insertions or deletions of one or more base pairs. The most common cystic fibrosis mutation, D508, is a 3 base-
pair deletion at position 508 of the CFTR gene. Since codons are made of 3 base pairs, alterations in base pairs
not in a multiple of three can exert their effect by altering all the downstream codons, and therefore the amino
acid sequence (frameshift mutation)
• Whole gene duplications, e.g. Charcot-Marie-Tooth disease (three copies of PMP22 encoding myelin)
• Splice site mutations. These result in abnormal splicing of introns and exons thus altering the mRNA
• Expanded repeats. Some genes are coded by triplet repeats, where the gene sequence is made up by a repetitive
pattern of the same 3 base-pairs. An increase in the normal tandem repeat can lead to an alteration in the gene
product, e.g. Fragile Xsyndrome

CAUSES Of MUTATIONS
• Spontaneous mutations (occur naturally" during DNA replication)
• Induced mutations (by mutagens): Ionizing radiation, e.g. X-rays
Non-ionizing radiation, e.g. UV light
Chemicals, e.g. nitrogen mustard, aflatoxin Bl
• Defective DNA repair is seen in certain diseases, which consequently have a high rate of tumour formation, e.g.
xeroderma pigmentosa, Fanconi anaemia, ataxia telangiectasia, Bloom syndrome.
'

Bloom syndrome
Autosomal recessive, chromosome 15q defect. A syndrome involving increased number of chromosomal breaks, with a
sensitivity to UV radiation and increased risk of malignancy.
Features include:
Skin Butterfly distribution facial rash of telangiectasia and erythema with sun exposure
Bullae on lips, hands and forearms
Dysmorphism Malar hypoplasia
Short stature
Syndactyly, polydactyly, short lower limbs
Immunity Low antibody levels (IgG, IgM and IgA), recurrent infections

5
TECHNIQUES FOR DNA ANALYSIS AND MUTATION DETECTION

CYTOGENETIC TECHNIQUES
Karyotype and chromosome banding
A karyotype is an ordered display of the chromosomes, which are studied during the metaphase part of mitosis.
Staining techniques bring out the chromosome bands that may be viewed under the light microscope. Structural
chromosome rearrangements may be identified.
Normal karyotypes: 46, XX (female)
46, XY (male)

Fluorescent in situ hybridization (FISH)

This is a technique using fluorescently-labelled DNA probes that are hybridized with a specific DNA sequence within
the chromosome region being studied. They are then viewed under a fluorescence microscope to detect submicroscopic
deletions, e.g. in Williams syndrome, and duplications, e.g. in Pelizaeus Merzbacher disease, and to define chromosome
rearrangements, e.g. translocations.

~~OLECUlAR GENETIC TECHNIQUES

Polymerase chain reaction (PCR)
This is a technique to replicate a short specific DNA sequence, making millions of copies, suitable for analysis.
1. Double-stranded DNA is denatured to single strands by heating
2. Primers are added and the DNA cooled to enable the primers to anneal to the single DNA strands. (The primers
are selected because they will attach next to the region of interest on the DNA)
3. DNA polymerase is added so the primers are extended along the target DNA, and thus two extra copies are
made
The cycle is repeated, with doubling of the DNA occurring at each repeat cycle.

Restriction fragment length polymorphisms (RFLPs)

These are varying length fragments of DNA that are used to detect DNA polymorphisms in individuals. Bacterial
enzymes known as restriction enzymes, e.g. EcoR1, cut the DNA at recognized sequences known as restriction sites. If
a polymorphism or mutation exists within the DNA sequence cut by the restriction enzyme, the DNA will not be cut at
this point and the DNA length will vary from the expected length and may be detected by gel electrophoresis. Once a
variation is detected, DNA sequencing of the DNA region will determine the precise gene change.

Southern blotting
Atechnique to detect relatively large mutations (insertions, deletions and rearrangements) by separating and ordering
fragments of DNA. Test DNA is digested by restriction enzymes, e.g. EcoR1, into RFLPs, these fragments are separated
by size with gel electrophoresis. The DNA is transferred to a nylon membrane and a labelled probe is hybridized to the
DNA fragments which show up as dark bands.

DNA sequencing
This is determination of the actual orde( of nucleotides of a strand of DNA. PCR is first used to amplify the region of
test DNA, which is then sequenced using automated methods with fluorescent labels and laser detection. Mutations
are detected by comparing this sequence to the DNA sequence of an unaffected individual.

6
 DNA chips
This is a quick, accurate computer-based method to detect mutations. DNA chips are computer chips that contain
arrays of different oligonucleotides. The oligonucleotides consist of both normal DNA sequences and those that
contain known genetic mutations. Fluorescently-labelled test DNA is hybridized to the DNA chips, and it is observed
whether it hybridizes to normal or to mutated oligonucleotides.

GENE ~1APPING TECHNIQUES

Linkage analysis
This is the use of DNA markers to track a gene through a family and to help map a gene. Using linkage analysis, a
specific chromosomal region is identified in which the gene is located (the region may contain several million DNA
base pairs).
Closely located pieces of DNA (linked DNA) are less likely to be separated by the crossing over process in meiosis and
thus are more likely to be inherited together. Linkage analysis is a complex process based on probabilities. The princi-
ple is that the chromosomes of a family with an inherited disease are marked with many DNA markers. A DNA marker
that is near the disease allele will generally be inherited with the disease allele, the linkage is detected and thus the
region containing the gene is identified.

Candidate genes
Once a chromosome region has been identified by linkage analysis, the genes in this area are determined (either by
sequencing or using databases) and candidate genes are analysed to see if they are the gene responsible for the
disorder in question. A gene may be a candidate for a disease either because of its position on the chromosome or
because it is known to act in a way that could cause the condition. Identified candidate genes are then sequenced to
see if a mutation in them gives rise to the disease.

CHROMOSOMAL DISORDERS
Chromosomal disorders are abnormalities in the:
• Number, e.g. trisomy or
• Structure (chromosome rearrangements)
of chromosomes which are large enough to be viewed under the light microscope. The phenotype results from an excess
or deficiency of genes rather than from a mutation in a specific gene.

ABNORMALITIES OF CHROMOSOIVJE NUMBER

r9tyf>:Uiia§ is extra whole sets of chromosomes: Triploidy (fig,XXX) } Both lethal in humans
Tetraploidy (92,XXXX)
AQgypJ(i'
.....
j~~As missing or extra individual chromosomes:
,-_-..,;:,.
Monosomy (only one copy of a particular chromosome)
Trisomy (three copies of a particular chromosome)
N9]!af~Jilfiailfri\Nlthe commo nest cause of aneuploidy and is the failure of chromosomes to separate (dis-join:
normally during meiosis.

7
Down syndrome (trisomy 21)
This is the most common autosomal trisomy.

Clinical features
General Hyp,g~QJlJ~ (floppy baby), relatively smalL stature, hyp~rflJ~?<ible:joints
CNS Developmentat:detay, Alzheimer (later)
Craniofacial B.rachy_cephalyJ mild;emicroceRQ.~ly
Upstanting'-JYalf}ebraFfis'sJ:t'res (Mongolian slant to eyes), ell1£~J1truc4qlds, ffiY9Ri~~ acquired cataracts .
Btus1!1idd·g~R9.~~;, (speckled irises)
- ~mf!1lv,~£!f~, mi~~El:Jl~&ftD9.~lQ;;s, gJu~);~,~r~ ~!lJalb.ogs,gl
Protrudtngtr.to.ogu~, denta1~chYP.9R1il2i~
ShQEbn~~&.,~, (ri~k~J>J'"i!skilJJ,tpa~al subluxatioJJ with anae·s.tb~t.ics)
Hands and feet ShQ.i&~Wil:9tiJS, 5.tbRTIJ119~PGlimtdA~~B'~ly, si.rrg~Jj~J!lle~~~~$e (NB: 'Pl~§~~~~~R,!I!Ml?$:~f,(!,l~nnaJ:~pQ,RJ,Jla­
tion), wid~-,;:9.2:REh~~m,n~l~!:send~?,mhtQ.t!~s~sandab.:gap)
Cardiac Coog~J.Jj;tca,~b"~q,[;l:~qj;~l~it~~"'-(M%): ·AY~,Q,ilVr5D!ilf21MwASU. t Va lv.efipr,Qk~J?S,e > .g~Y~E:!?F~
Respiratory InGr:~~~@.e.~~~,gtiQ!!§~~
Blood I ncreaS'e'tl:t;-nt~i'Oent~e"'''i'\'!leu ka'emia
Endocrine Increa·S'e'tl'filfEi'ae'fftl:!~f.:i'llS'poflly-ro1dis m
Skin Loo.se,neGk'<folds (infant), dry.oskin, fo~liculitis., ;n,:ado.l~s<;~Jits,
Hair Soft, fine. St!'aig_pJ,d?;H,Q,i.8-;;0'!ir.,,
Genitalia Srna~lc:R~nis and test1cular,-vplume. Inf:e.r;tility· ~JJnlf!lOil:"'

Mechanisms of tn'somy 21
1. ~,QIJJcqj,~J.~m_c_tig n (99%) 4.
Karyptype: 41:t.~:X,..t?.J~

This occurs where two chromosome

~lS•;o;do not< separ.ate:~z~fNIJJ~i.Qsis. The
ex~ra <:;hromesome.ois,:mater:nahjq.90%i PARENTS ([]) ( [ ] ) Chcomowme21e
of cases and the inoidem;e:cAnereases
/ \ No;-disjun\tion
wi th1j:m,~t.trXE"'~1;.~~.$.:;, ,
After having a child with Down syn-
drome the risk of recurrence is 1:'200
under-?:JSo~years~and'fo'twree~tneWage­
GAMETES (I) 0 ([]) 0 Not viable

specifio,raterif" over-: 35-;y~~f~. \ /Fertilization

OFFSPRING @
Trisomy 21

Figure 1.4 Non-disjunction

8
 PARENTS Translocation
carrier

GAMETES

OFFSPRING

Normal
® -
-
-'

Translocation Trisomy 14
@ .
.

Trisomy21
carrier Not viable Down syndrome

Figure 1.5 Robertsonian translocation

2.Robertsonian translocation ~-4'l'&)~%\\,

Common karyotype: 4~X4Y,l4,4rli~ +t {14q21q)

Here:za%ichromos-ome ';c21' <is' fral1slociifed · onta''anothenv£~bLG.!lJQ~gmJ~
4

61'4, ~l~n<21 or ·22)• Thisl' mayg:ar:J~~l:"@ Sc;~~;c;f!:~-Y

m~;~tg,ti.on,~JJJ!t-;;in~il ':q\.!F~Jt~r-jofthese cases one-oHhe-;epareoJ::S., w,iJbhctve a balanced transtoc;ation (see p. J1)
The risk of recurrence is:
• 'l.OT-J.:§~/~- ifJhe~ mPth.~r: is. a .tr.an,s .l9cation . carrier,
• 2.•:5fLo:jf,tf!eAather:"isca,translocation "carrier
• l.QQ.:'/o:'ioif,.I',1:P.9repJ;,;has-J he ,translocation 21:21,
• < ·,;}f/o y:lt~l)eithen paren't'll'asJa•;t ransloeation \
3~Mo.saicism-.'{<l%)

These·tchildren.-have.;some·'normaL cells and sbme trisomy:·2'ic;Gells.

l(aryotype: ·4-7,XY+2-1/46;X:Y;:ie. 47-;XY+21/A6;XY,
This:.:re:sultsf.fl'l:Htlmon';djsjp!J~tiqn occurnngxduring :m.i!Q,~j?,nCJ.fter;:;fertilization,

Edwards syndrome (trisomy 18)

Karyotype: 47,XY,+18

Clinical features
General Low birthweight, fetal inactivity, single umbilical artery, skeletal muscle and adipose hypoplasii
mental deficiency
Craniofacial Narrow bifrontal diameter, short palpebral fissures, low-set abnormal ears, small mouth, mien
gnathia, epicanthic folds, cleft lip and/or palate
9
Hands and feet Overlapping of index finger over 3rd and 5th finger over 4th
Clenched hand, small nails, rocker-bottom feet
Trunk and pelvis Short sternum, small nipples, inguinal or umbilical hernia, small pelvis
Genitalia Cryptorchidism (male)
Cardiac VSD, ASD, PDA, bicuspid aortic and/or pulmonary valves
Other organs Right lung malsegmentation or absence, renal and gastrointestinal abnormalities
50% die within the first week, and only 5-10% survive the first year. Recurrence risk is low unless parental transloca-
tion is present.

Pataw~syridrome (trisomy;:J3)
Karyotype: A7,:XYi+13'

Clinical features
General Low:b_irtb .weight, siQgJ~~HD:t9.llj,~f!~, artery '
CNS Holo'j5rosencephaly with varying degrees of inc.ompJ.e;tE!for~br?i.n :deyelopf11ent,
Setzgres~ seve.re::mentahtetardation ·· - ·
Craniofacial WJ~gg~fontar:r.elles, m5GIPP.bih.9Jmia, coJobp.(JJ9S:l re.ti!V!~·dY~pta~i~
Cleft,;:JiPJ andjor deft.;;palate''f
Abn0J:..rna l<.low~s~tcea rS>
Skin Haci~t'o£ottipital'fscalp.'·. defect!!
Hands and feet Sittgte:t;patmaNcrease;Yp:olydactyly
Cardiac· ( 8G 0
'o~WS'()t,
,.. <:-_ .:-t!.J_
.- , BDA
.
2
, ~A3UF'?
Genitalia ·,~·eyptarchidisr;n (male), qJGRJQ!l~ter::~t~f,IJ.~ (female)
Most of these children ·die~Witli'in'the';·:firsf:rrl'olltb (around 80%). Rest;~Ir.~pq~~sri_~~f!~.~t~.lll9.l~ l!Q}essffon"e"'ohtneft5are:n:~:&-1b9s i
a batafftf-etl'~atriff:l:8lo 1fafiom.
7

Turnercsy-.:idrome (monosomy ofthe ,X·chromosom~) I

I
Karyotype: 45;XO; .I
i

Clinical features
I
General
CNS
Short stature, loose neck folds in infant?
Mild developmental delay, hearing impairme11t l
Gonads Ovariartdysgenesi.s with hypoplasia or absence of germinal elements (90%)
Lymph vessels
Craniofacial
Congenital·lymphoedema (puffy fingers and toes)
Abnormal ears:,(often prominent), narrow maxilla, small mandible
I
·I
Short webbed neck, low posterior hairline
Skeletal Broad chest,}'Vith widely spaced nipple~
Cubitus valgus "·
I
Nails Narrow tiyperconveX\ nails
Skin Multiple pigmented naevi)
Renal Horseshoe.kidney, dot.Jble renal pelvi~
Cardiac Bicuspid aortic valve{(30%), coarctation of the aorta,(10%), aortic stenosis, mitral valve prolap~e

These children may be given growth hormone, and oestrogen replacement (if necessary) at adolescence.
iI
This is generally a sporadic event and the paternal sex chromosome is the most likely one to be missing. NB: Mosaicism
is not uncommon and results in milder manifestations.
I

10
I
I
Klinefelter syndrome
J<a ryotype: 47 ,XX'f
Estimated to affect 1:500 males.

Clinical features
Features are very variable. This syndrome may be identified as an incidental finding, or may present with behavioural
difficulties or as infertility in an adult.
Skeletal Tall and slim, Long Limbs, loW upper: lower segment ratio
Genitalia Relatively small penis and testes in childhood, most enter puberty normally
Primary infertility secondary to azoospermia, reduced secondary sexual characteristics, gynaeco~
mastia (33%}
CNS Mild learning problems
Testosterone therapy may be given if deficient.

47,XYY syndrome
Incidence 1:840 males, though seldom detected as most are phenotypically normal.

Clinical features
CNS Learning difficulties, poor fine motor coordination, speech delay common
Behavioural problems (hyperactivity, temper tantrums)
Growth Accelerated growth in mid-childhood
Craniofacial Prominent glabella, Large ears
Skin Nodulocystic teenage acne
Skeletal Long fingers and toes, mild pectus excavatum

CHROfv10SOME REARRANGEMENTS
These are partial chromosome abnormalities, and may result from a number of causes.

This is the interchange of genetic material between non-homologous chromosomes. There are two types:
• Re-cipi'ocah:translotations. Two breaks on different chromosomes occur and so genetic material is exchanged
betwe'en the two chromosomes. A<carrier.:. of:;a .-balanced:J~:ansloc"ti.Q!l is g~ually:;cofmoxmaL pbenbtype ~be·cali!se
theyrh§y,e~-· ~he.,normabchronwsorne : compl~ment. However, their offspring may have an unbalanced translocation,
resuWJ19•;jr;r·a, pa rtiaLtrisomy.· ocmonosomy;e. g.:6ptrisomy, :.4p. mon,o5{)myi
• RobeJ:1s,onjaiJJr<m.sloQatjqn (results in altered chromosome numbers - see Down·:; syndrome). The long arms of
t~~A>it~8H{;VtQf:J,QlBm,~;?WJi"t.~"~tY:~:~ :~Jq~.~ther t.C?., JD?:~~;;:9D~.:t8;B~,~r~PJZlJl,,B,¥,g~[.~ and,At(t~ix~§.hg!t-NQJ~. ,e.t~~ts~r:~i!ii~
only occurs between chromosomes 13, 14, 15, 21 and 22 because tnese are acrocentric (have very small short
arms that contain no essential genetic material.) It can result in Down syndrome for the offspring of a carrier of
the Robertsonian translocation

Deletions
- ... . ~-

Deletion of a portion of the chromosome occurs, e.g. cri,dU''ChaLsyndrome:(46,XY;;de,l[5R]) . Microdeletions (smaller

deletions now visible microscopically using new techniques such as high-resolution banding and FISH, or by molecular
techniques) include Williamssynq~ome (chromosome 7~) and DiGeorge ~yndrp_me (chromo,some 22, .s~e p.llO).

11
Cri ·du chat syndrome,' (deletion 5p syndrome)
This is caused by a partiaVdeletion.ofthe short .arrtrofchrotnosome'"5.

Clinical features
General LowdJirth'Weight, slow ;growth, cat~like - cryi
CNS Hypotonia, men.t-C!hrg~~xdatiqn
Craniofacial Mitrote:phaly, hypettetorism, ep.i!;C!nthicd olds, down.:::s:lanting· pplebrah fisw(es, abnormal low-set
ear:~ ,,

Hands Singl~'pa.lmar cr~ase ~1%)

Cardiac Va riaR,~~:;fOJlgeoitC1tb.eart,~jseps.e.,( 30%)

V:/iifiams syndrome
This is due to a microdeletion of the clirornoscimal region 7q11.23 induding:the eta:stir\Ygene.

Clinical features
Craniofacial Media.~·, gyebrow ,.flare,~ depressed masal· bridge, epj~anthic~fo,~ds
Blue eyes, stel~ate;. pat.t~r!\ iris;, p~norb5ti!LJI.Il.l.o~s.?
Promin'i:~rltHips.,tfish -shaped)
CNS MeptC~ hretardat,ion, fderu:ily~,maDJWft 'cacktai Lpacty~~:speeqt
Hyp,exsensitiv.ity.:toK<:i'urtd
Skeletal ShoJrt'&stature, hyJlap.l.a~:tiW:~tJaj~, s gJ},Ji~'l§, kyp!;].@,§;i&-mjg};p.,~kiiD.il~B;t:jpJls
Cardiac Sypravahm~aJi~il?.ct=Jf<:&);0JJ&~j~, P~,Q;~:!t..K{g~9'R~:~!JJ;S~~"~e;~f£~J,Y ste nosis, VS:IJ!, ASQ, rehahart;~cy ~tenosis
Renal Nephro:calmnos,ls, pelvre~kldney, urethratlfstenosl;S

Duplications
Three copies of a portion of the chromosome are present, e.g. Charcot-Marie-Tooth disease.

SINGLE GENE DEFECTS (MENDELIAN INHERITANCE)

Single gene traits ·are also called Mendelian traits,, after Gregor Mendel the 19th century Austrian monk who formed
some basic genetic principles from experiments with peas. The inheritance of single gene disorders is based on the
principles that genes occur in pairs (alleles), only one allele from each parent is passed onto the offspring, and an
allele may act dominantly or in a recessive manner. There are many factors and exceptions that complicate this
pattern .
A pedigree of family members is constructed to understand the inheritance of a particular condition.

12
 0 or 9 Normal female 0=0 Consanguineous mating

D U
~
or Normal male
Mating with two offspring
() Sex unknown

• and • or • Affected individual

dO Dizygotic twins

• Index case

~
/
Monozygotic twins

() IJ }
•
and
~
Heterozygote (carrier)
in autosomal recessive inheritance
oro Abortion or stillbirth

Female heterozygote (carrier) 0 Dead

in X-linked inheritance

0--0 Mating

Figure 1.6 Basic pedigree symbols

AUTOSOMAL DOMINANT AND AUTOSOMAL RECESSIVE INHERITANCE

13
 Affected Unaffected Carrier Carrier
parent parent parent parent
Aa aa Aa Aa

Aa Aa aa aa AA Aa aA aa
Affected Carrier Carrier Unaffected
Affected Unaffected
50% 50% 25% 50% 25%

Figure 1. 7 Autosomal dominant inheritance Figure 1.8 Autosomal recessive inheritance

Marfan syndrome
I
Au:tosomahdominank·mutations in fibrillin (FBN1) gene on chromosome 15q21.1. There is a very wide variability of
~- !
expression, and multiple mutations exist so screening cannot be performed. Linkage analysis can be used in families !
with multiple ·members affected to identify probable carriers. I
Clinical features
Skeletal Tall, thin habitus, muscle hypotonia and joint Laxity
- -' I
Decreased upper:lower segment ratio
Arachnodactyly, pes planus, pectus excavatum, scoliosis, kyphosis D t_, I
II
High arched palate =. '('
Eyes Upward lens subluxation, myopia, retinal detachment ( ·I
Cardiovascular Dilatation of ascending aorta, dissecting aortic aneurysm, mitral valve prolapse
i
The cardiac complications are the commonest cause of death.

Noonan syndrome
!
I

Autosomal;.: dominant condition, often ·spora·die~

Clinical features
CNS ~ti ld:"me-ntal!ireta-rdattCin~-~ 25%)
I
Craniofacial Pto.sis, epicanthjc-,,fo.lds, bypertelorism, downslan.ting palpeb rq~t:fissures, stra'DiSmus, nystagmus,
lowrnasal"'b.Eidge, low,~s.~k9J~JJ.P.J.lTJ,g1.,,§grs, promineo.tA.lPP.,eJ..lip
Low, poste-lior•rrairline, shor;t. N{gb.bJ~d~o.eek
Skeletal Sho~s-tatare, shie~d"'ehes~ R,~&J;J!~~i;!.Y;i!~.UJJJ, pg,c:tJI.s~£arinatum, cubitussYalgu.?
Cardiac P.ulmonary,Nalv,e~ten.QS:is, cardiqm,yp,~,aJ;hy, ~RDA rNSQ, ASHit-i'•
Branthilstenosi ~{)f'f.J)ulmonary¥artedest<&
Genitalia Smalb:penis, q:yptor,£hjdism:~~\)
Other Bleeding•aiatlfe'sis"'tf1J~to¥ar,va'ne~of,;,defe~ts"':'\

Diseases'caused by.genesortthe X chromosome areXMnked;iand are ·usually recessive. TheYchromosome. is•·.vecy", >IJl~,\~
anct·:contai ns.few ,knownige'fiesi'~
14
I
 Xinactivation
This is a random inactivatibncinfemales :·ofone of the. XthrornQsprnes.in . eqyp\GglL~ The inactivated chromosome is a
dense ·c;hromattn mass called ·a! Barrl"body.{The theory of x:iri'ad1Vation is the Lyom·hypothesis. <
This explains why X-linked disorders are variably expressed in the female (because females have X-mosaicism).

Carrier female Normal male

Xx XY

XX )(y XX XY
Carrier Affected Normal Normal
female male female male

25% 25% 25% 25%

Figure 1.9 X-linked recessive inheritance

X-LINKED DOMINANT DISORDERS

· These are uncommon. The disorder may be lethal in males and seen only in females (who have one normal Xchromo-
some which modifies expression of disease), e.g. incontinentia pigmentii.

MITOCHONDRIAL DISORDERS
Mitochondria contain their own chromosomes which are maternally derived. A few diseases are the result of mito-
chondrial mutations. These have (not strictly Mendelian) inheritance through the maternal line. Examples are the
mitochondrial myopathies, e.g. MELAS and MERRF (see p. 285 metabolic chapter) .

FACTORS AFFECTING INHERITANCE PATTERNS

•"'~N'ewmutation;- This is frequent in some conditions, e.g. achondroplasia. No previous family history of disease is
seen (especially significant in autosomal dominant disorders)
• 'G'e'fffi'fine'mosaifis'm. A mutation that affects all or some of the germ cells of one parent. Thus a condition that
may appear as a one-off mutation recurs in subsequent siblings
• Imp rffftirrgran d:;uni parenta Ldi.somy
• Premutatio'il'~
• Reduced pen·etrante. Some individuals who have inherited the disease do not manifest it phenotypically, e.g.
retinoblastoma. They can transmit the gene to the next generation
• Variable expressiOn. Some individuals manifest the gene mildly and some severely, e.g. tuberose sclerosis
•"Non::·paternity. The genetic picture is confused because the apparent father is not the biological father (relatively
common)

15
 • Anticipation. This is the development of more severe expression of disease through successive generations. It is
seen in diseases caused by genes with trinucleotide repeats. The number of repeats increases through generations
and correlates with severity of disease

Examples of diseases associated with trinucleotide repeat expansions

Disease Repeat sequence Parent in .which expansion'occUrs :
Myotonic dystrophy CTG Either parent
Congenital form via mother
Fragile Xsyndrome CGG Mother
Huntington disease CAG Father > mother

Some diseases are caused by an expansion in the number of triplet repeats seen within the gene. Triplet repeats are
found at many places across the genome and the normal number of repeats may vary between individuals. However, a
repeat number above a certain size may make the gene unstable (premutation) and more likely to expand further, to a
size that interferes with the function of the gene (full mutation). An example of premutation is fragile Xsyndrome.

Fragile X syndrome (FRAXA)

Learning difficulties (Milder in females)

Dysmorphic facies Large ears, long face
Other Macro-orchidism (large testicular volume), hypermobile joints

ueneocs
~ J "

• An X-linked dominant condition with premutation and expansion occurring via the mother
• Seen in approximately 1:1250 males and 1:2500 females
• The term fragile Xcomes from the fact that the Xchromosomes have a fragile site and may develop breaks when
cultured in a medium deficient in folic acid
• The gene for fragile Xsyndrome (FMRl) contains a CGG repeat at one end
• Normal individuals have 5-50 copies of this repeat, those with fragile-X syndrome have >200-1000 repeats (a
full mutation) ·
• People with an intermediate number of repeats (50-200) carry a premutation and are seen in normal transmit-
ting males and their female offspring
• An expansion in the number of repeats occurs when a premutation is passed through the female line, resulting in
a larger premutation or in the full mutation size
• Expansions from the premutation to the full mutation do not occur in male transmission. This explains why pre-
mutation carrier males do not give the disease to their daughters but the daughters' children may be affected and
this becomes more likely through successive generations
• Most males with a full mutation will have the clinical signs of the condition. About one-third of females with a
full mutation will be clinically affected. (The lower penetrance in females is thought to be due to Xinactivation
in females)

Genomic imprinting is the differential activation of genes depending on which parent they were inherited from.
Examples are Prader-Willi, Angelman syndrome and Beckwith-Wiedemann syndromes.

16
l
 ....
Chromosome 15s Chromosome 15s

;' Y' ·~'.f

II ii ii ~-:-:'
-',':
-:•..··
i{
.
p

.. . . ·~ ;; ••••
I )Deletion at 15q 11-1/i

(a) new mutation

';(j II
(b) uniparental disomy

Figure 1.10 Imprinting

Prader-Willi and Angelman syndromes

Genetics
• Both disorders result from loss of a gene at chromosome 15q11-13.
• Failure to inherit the active gene causes the syndrome.
• Failure to inherit the paternal copy ---7 Prader-Wi lli (paternal deletion or maternal UPD)
• Failure to inherit the maternal copy ---7 Angelman syndrome (maternal deletion or paternal UPD)
The absenc:e of the active gene may result from :
1. New mutation. Normal parental chromosomes. Gene deletion from one parent
2. Uniparental disomy. Normal parental chromosomes. The child inherits both copies from one parent. Thus the
normal number of copies is present but there is an effective deletion of the copy from one of the parents.
The resulting syndrome depends on which copy is missing

Beckwith-Wiedemann syndrome
Autosomal dominant variable expression and incomplete penetrance. A minority are caused by paternal uniparental
disomy (two copies inherited from the father), with Beckwith-Wiedermann syndrome resulting from over-expression
of the gene product.
Gene located at 11p15.5, with the maternal copy normally inactivated (imprinted). Imprinting occurs in the insulin-
like growth factor 2 (IGF2 ) gene on chromosome 11. IGF2 is active only in the paternal copy, i.e. imprinted in the
maternal copy. Therefore a double dose of IGF2 will occur with inheritance of both paternal copies, or loss of maternal
imprint (so the !Jl<1{efllal gene is activated). The high levels of IGF2 are thought to result in the clinical features.
~(ltfJ( 11.&-.
17
Clinical features
Pregnancy Polyhydramnions, large for gestational age
Growth Macrosomia, thick subcutaneous tissue, large muscle mass
Advanced bone age when infantile
Craniofacial Ma~roglossia, prominent eyes, port wine stain central forehead and upper eyelids
Ear creases on ear lobule
Organ Large kidneys, fetal adrenocortical enlargement, pancreatic hyperplasia, hepatosplenomegaly, large
ovaries, cliteromegaly, cardiomegaly
Other Infantile hypoglycaemia, neonatal polycythaemia, Wilms tumour, hepatoblastoma (5-10% risk),
hemihypertophy, umbilical hernia, omphalocoele

MULTIFACTORIAl INHERITANCE
Characteristics affected by both genetic and environmental factors are multifactorial. Many quantitative traits are
multifactorial, e.g~ blood pressure, height, and are distributed in a symmetrical (Gaussian) fashion.
Many diseases are inherited in a multifactorial fashion and are present only if a liability threshold is reached, e.g.
pyloric stenosis, cleft lip and palate, neural tube defects.
Recurrence risks for these diseases are based on empiric data, e.g.:
Risk of cleft lip± cleft palate is 1:700 live births
Recurrence risk after one affected child is 3-4%
Recurrence risk after two affected children is around 10%

DYSMORPHOLOGY
This is the study of abnormal physical development (morphogenesis) occurring during embryogenesis, resulting in
congenital defects. There are four pathogenic processes.

1. Malformation
A primary defect resulting from intrinsic abnormal development during embryogenesis, e.g. polydactyly, cleft lip.
Causes include:
• Chromosomal abnormalities
• Single gene defects
• Multifactorial

2. Dysplasia
A primary defect involving abnormal organization of cells into tissues, e.g. haemangioma.

18
3. Deformation
A secondary alteration of a previously normally formed body part by mechanical forces. These can be extrinsic or
intrinsic. Causes include:
Extrinsic: Oligohydramnios
Abnormal presentation, e.g. congenital dislocation of the hip
Multiple pregnancy
Uterine abnormalities
Intrinsic Congenital muscular dystrophy
Congenital skeletal defects
Arthrogryphosis is a picture of prenatal joint contractu res resulting from a variety of causes including fetal crowding
(oligohydramnios, twins), external constraints (uterine abnormalities) and intrinsic neuromuscular, skeletal or con-
nective
-
tissue defects.
.
4. Disruption
Asecondary defect resulting from extrinsic breakdown of an originally normal developmental process. Causes include:
• Teratogens
• Intrauterine infection
• Maternal disease
• Limb defect resulting from a vascular event

TERATOGEN$
Teratogens are agents external to the fetus that induce structural malformations, growth deficiency and/or functional
alterations during prenatal development.

Human teratogens

19
 .· . .>:
·.· ··.

. . . .

Limbhypopl~sia, earabnormatities
Uterine abno/malities; ·vaginal ..
adenocarcinoma, male infertility
Fet~~(attoh~l syndr~ine: . ..
(Rare i~ thE! UK) · ·· ., . .· . • . . ·..·
Craniofacial: Long philtrum., flat nasatbridge
Miclfaci~l hypoplasia, micrdgnathia
'· Uptorned ·nose, ~ar defo'fhiities _·'. ·
· Eye malfonnations, clefflip and palate .
CNS: .. Microcephaly and developmental delay · ·
Growth 'retardation ···
Cafdi<tc; "r~~al andlimbabhormalities···:'';o,: </·: . ;·:;< :-:

MATERNAl ILLNESS AND ASSOCIATE D Il\1 PACT ON THE INFANT

FURTHER READING
Connor M, Ferguson-Smith MEssential Medical Genetics, 5th edn. Oxford: Blackwell Science, 1997
Jones KL Smith's Recognizable Patterns of Human Malformations, 6th edn. Philadelphia: WB Saunders, 2005
Larson WJ Essentials of Human Embryology, Churchill Livingstone, New York, 1998
Sadler TW Langman's Medical Embryology, 10th edn. New York: Lippincott, Williams & Wilkins, 2006

20
• Components of the immune system • Inherited immunodeficiencies
• Clinical features in immunodeficiency • Acquired immunodeficiency

COMPONENTS OF THE IMMUNE SYSTEM

The immune system is subdivided into innate and specific responses, though there is much interaction between the
two.

INNATE IMMUNITY
This involves the elements of the immune system that produce an immediate, non-specific response. The main
components involved are:

Phagocytes
Mononuclear phagocytes Monocytes (blood), macrophages (tissues), Kupfer cells (liver)
Polymorphonuclear granulocytes Neutrophils (granulocytes) (95%)
(PMNs) Eosinophils (2-5%)
• These \ells employ phagocytosis (cellular ingestion) of foreign material
• Opsonization (coating the antigen with antibody and complement) helps ingestion and killing
• Neutrophils live 2-3 days only. They have granules containing antibiotic proteins, enzymes, e.g. lysozyme, and lactoferrin
• Particularly active against bacteria and fungi
• Eosinophils produce cytotoxic granules, which are released onto the surface of large organisms (they can employ
phagocytosis). Active against large parasitic infections

Other cells
Basophils and mast cells Involved in inflammation, parasite immunity and immediate hypersensitivity
Stimulated by antigens (with IgE) to degranulate and release vasoactive
substances including histamine
Basophils are in the circulation and mast cells in the tissues
Antigen presenting cells (APCs) Present antigens to B and T cells
Platelets Involved in inflammation and blood clotting
Endothelial cells Involved in the distribution of leucocytes

21
Complement
The complement system involves> 20 glycoproteins which are activated in a cascade.
There are three pathways of activation:
1 and 2. Classical (and lectin) pathway. Activation via Clq + immune complex (specific immunity). (Lectin is
antibody independent)
3. Alternative pathway. Activation via microorganism surface and factors B, D and then properdin (innate immunity)
All three result in activation of C3 (to C3a and C3b), and then the final common pathway (5 to (9. Involved in eradica-
tion of organisms (via opsonization, activation of leucocytes and target cell lysis), inflammation and immunoregula-
tion (self from non-self).

Soluble mediators
These soluble messengers mediate inflammation and promote uptake by phagocytosis (opsonization). They signal their
target cells to divide, activate or focus on an area of the body.
Cytokines (those produced by lymphocytes are lymphokines):
Interferons (IFNs) Viral infections. INF-a, INF-~, INF-y
Interleukins (Ils) IL-1 to IL -17. Many functions, direct cells to differentiate and divide
Colony stimulating factors (CSFs) E.g. G-CSF (granulocyte-colony stimulating factor)
GM-CSF- differentiation and division of stem cells
Others E.g. Tumour necrosis factors (TNF-a, TNF-~), transforming growth factor-~ (TGF-~),

Antibodies - see below.

Acute phase proteins, e.g.
C-reactive protein (CRP)

Fe Fab

(a)

lgA lgD lgE lgG lgM

~~
_, ~'(~
~
-'tt-
lgA IgO lgE lgG lgM
RMM (Daltons) 160000 180000 190 000 150 000 950000
380 000 (slgA)
Adult Puberty 6 years 1 year
Figure 2.1 (a) Antibody concentration
composition. (b)
Immunoglobulin structure (b)

22
SPECIFIC H4MUNITY
This system involves lymphoid tissue and circulating leucocytes that mount a specific response to an antigen. The
main lymphoid organs are:
Primary lymphoid tissue- bone marrow and fetal liver (make B cells), thymus (make T cells)._
Secondary lymphoid tissue - lymph nodes, spleen and mucosal-associated lymphoid tissue MALT, e.g. tonsils, Peyer's
patches.
Leucocytes have molecules on their surface known as clusters of differentiation {CD), identified using monoclonal
antibodies, which are used for identifying subpopulations.

T Lymphocytes
T-Helper cells (TH) CD4 on their surface. See antigens with MHC class II molecules
Thl subset: Secrete IL -2 and IFN-y
Cytotoxicity and inflammation (protect against intracellular organisms, e.g. viruses,
bacteria, parasites)
Th2 subset: Secrete IL-4, IL-5, IL-6, IL-10
Stimulate B cells (protect against free::_living organisms, i.e. humoral immunity)
T-Cytotoxic cells (TC) CD8 on their surface. See antigens with MHC class I molecules
Kill other cells
Down-regulate immune responses.

B Lymphocytes (5-15%)
These produce immunoglobulins (antibodies) and have these on their surface. When activated they become plasma cells which
make antibody. Carry markers CD19, CD20, CD22 and CD72-78. Carry MHC Class II antigens for interactions with T cells.

Antibodies
These are serum glycoproteins that are specific to particular antigens. The type of heavy chain determines the class.

Natural killer (NK) cells (15%)

CD56 and CD16 surface markings.
Eliminate tumour and virus-infected cells using cytotoxic means.
Lymphokine-activated killer (LAK) cells are cells (NK and certain T cells) that have been activated by IL-2 and
particularly target tumour cells.

23
IMMUNE ACTIVATWN AND INTERACTION
The mechanisms of activation and interaction are integral to the immune system and involve:

Antigen presenting cells

• Langerhans' cells (skin), interdigitating cells (IDCs; lymph node) and germinal centre dendritic cells (GCDC; lymph
nodes) - present to Th cells. (These have class II MHCs)
• Follicular dendritic cells (FDCs) (Lymph nodes, spleen, MALT)- present to B cells
• Macrophages
• B cells - present to T cells

Activation ofT and B cells

T and B cells are activated by binding to their specific antigens.
· B cells - Bind to native antigens but many need T cells to become activated (many activated B cells then become
plasma cells).
T cells - Recognize antigen in association with MHC molecules on antigen-presenting cells.

HUMAN LEUCOCYTE ANTIGENS (HlA)

The HLA molecules are encoded for by a set of genes known as the major histocompatibility complex (MHC) on the
short arm of chromosome 6.
The MHC genes code for HLA antigens (cell surface glycoproteins) which are present on all tissues and help to identify
self from non-self. There are two classes of molecules:
1. Class I HLA-A, B, and C- on all cells except erythrocytes and trop hoblast cells
2. Class II HLA-DP, DO and DR- on Tand B cells, monocytes and dendritic cells; indudble on endothelial and epithelial cells
HLA antigens are important in organ transplantation, where they need to be matched.
Several diseases are associated with specific HLA types (which are being subclassified):

DR4
B8, DR3,
DR7; DQw2 .·

24
HYPERSENSITIVITY REACTIONS

Skin tests
Type I (pn'ck test) A wheal and flare develop within 20 min and resolve in 2 h
Type III (intradermal A wheal develops over hours (maximal at 5- 7 h) and resolves over 24 h (Arthus
or SC injection) reaction)
Type IV (intradermal An indurated area develops within 2- 4 days and resolves over several days
or patch test)

Urticaria and angio-oedema

This is swelling of the skin and mucosa due to capillary leakage. Mechanism may be immunologically- (IgE or
complement) or non-immunologically mediated (direct mast cell release, prostaglandin inhibitors). There is release of
histamine± bradykinin causing vasodi latation.

Clinical features
Urtican'a Intermittent skin wheals, may itch, last 12-14 h (dermal swelling from leaking capillaries),
recurrent crops may occur. Chronic urticaria if lasts > 6 weeks
Angio-oedema Swelling mouth, eyes, genitalia, GIT, upper respiratory tract (submucosal and subcutaneous involvement)

Causes
Cause is not often found.
Ingestion Foods, e.g. cow's milk, drugs
Contact Insects, plants

25
Infections Viral, bacterial, parasitic
Physical Cold, sun, heat, mechanical force
Cholinergic urticaria Sweating (exercise, hot water, anxiety)
Systemic disease Leukaemia, collagen-vascular disease
Genetic Hereditary angie-oedema (see p. 25), urticaria pigmentosa

Management
• Self-limiting disease, usually resolves over weeks or months
• Avoid known triggers
• Antihistamines (H1 ± H2-receptor blockers)
• Adrenaline (severe reaction, anaphylaxis)

Atopy
Atopic individuals have the following :
• A predisposition to form IgE-mediated (type 1) reactions to com mon environ mental allergens
• Susceptibility to asthma, hay fever (allergic conju nctivitis+ rhi nitis) and ato pic eczema
• A family history of atopy
Seep. 131 (asthma) and p. 291 (atopic dermatitis).

INFECTIONS ASSOCIATED WITH SPECIFIC IMMUNODEFICIENCIES

CLINICAL FEATURES IN IMMUNODEFICIENCY

HISTORY
Infections Frequent, unusual severity, opportunistic, invo lvi ng multiple sites, poor respo nse to
therapy, atypica l symptoms and signs

26
 Unusual organisms
Recurrent skin infections, abscesses, sinopulmonary infections, periodontitis, chronic candidiasis
Autoimmune features Arthropathy, rash
Family history Neonatal deaths (particularly male)
Immunodeficiency, parental tonsillectomy
Consanguinuity
Other Adverse reaction to vaccines, rashes
Persistent diarrhoea, prolonged wound healing

EXAMINATION
Faltering growth
Dysmorphism
Lymphoid tissue May be absent or enlarged, e.g. lymph nodes, tonsils, thymus·
Skin Eczema, petechiae, infections, granulomas, telangiectasia
Hepatosplenomegaly
Eyes Retinal abnormalities, conjunctival telangiectasiae
CNS Ataxia

INVESTIGATIONS
Initial
FBC and film Neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets (count and
appearance)
Immunoglobulins IgG, IgM, IgA, IgD, IgE
IgG subclasses
Antibody response to vaccines E.g. diphtheria, tetanus, Hib, polio
Isohaemagglutinins (IgM to red cell antigen)
Complement C3, C4, CH100, THC (total haemolytic complement)
Neutrophil junction tests Nitroblue tetrazolium dye reduction (N BT test)
Lymphocyte subsets
HIV testing
Ultrasound scan Thymus, liver, spleen

Specific
Cell mediated
Quantitative T cell subsets (CD3, CD4, CDS, CD4:CD8 ratio, etc.)
NK cells (CD16 and CD56)
Monocytes (CD14)
Functional
General Mitogen, e.g. phytohaemagglutinin stimulation (PHA) anti-CD3
Specific Antigen specific assays
E.g. Candida, PPD stimulation
Mixed lymphocyte reaction
Response to IL-2 stimulation
Class II expression (DR expression)
Activation status (CD25, IL-2 receptor)
Adenosine deaminas.e (ADA) purine nucleotide phosphorylase (PNP) enzyme activity
Surface expression of CD40 ligand and (03 intensity

27
Humoral
Quantitative B cell markers (CD19, CD20)
Immunoglobulins (IgA, IgG, IgM, Ig Eand IgG subclasses 1-4)
Functional Isohaemaggluti nins
Response to vaccines, e.g. diphtheria, Hib, polio

0
1 haanr•vt
I . . ·. e,
_; L· ~ ~
. ..,I

Adhesion molecule expression CD15s (LAD2), CD18 (LAD1)

Neutrophil function tests Mobility and chemotaxis (rarely done)
Phagocytosis- chemiluminescence
Phagocyte enzyme analysis - cytochrome gp 92 phox, cytosolic proteins

TREATMEN·rs AVAILABLE
Infection treatment Treatment of individual infections
Prophylactic long-term antibiotics and antivirals
Monoclonal antibodies against organism and target cell, e.g. B cells in EBV
infections
Immune component replacement Immunoglobulin infusions
Cure Stem cell transplant
Gene therapy, e.g. gamma chain deficient SCIDS and X-linked CGD

INHERITED IMMUNODEFICIENCIES
Classification of diseases in immunology is complex and changing; therefo re, they may appear elsewhere classified
slightly differently. It is best to concentrate on differentiating the individual diseases rather than their classification.

PREDOMINANTLY B CELt DISORDERS

X-linked agammaglobulinaemia (XlA, Bruton XLA}
X-linked recessive. Presents at 6 months-2 years.
Immune defect Very low or absent B cells
IgA, IgM, IgG, IgD, IgE all low
Underlying defect Mutation in the Bruton tyrosine kinase (btk) gene at Xq22.3-22 causing absence of B cell's
cytoplasmic tyrosine kinase
Pre-B to Bcell transformation is defective

Clinical fea tures

• Recurrent bacterial infections after 6 months of age when maternal immunoglobulins have gone
• Unusual enterovirus infections (chronic meningoencephalitis)
• Tonsils, adenoids and lymph nodes small or absent

Management
Gamma-globulin (IVIG) infusions 3-4 weekly (IV or SC).

Common variable immunodeficiency (CVID)

· Immune defect Abnormal B cell function (normal or reduced B cell numbers)
Low IgA, IgG 6 IgM

28
 Abnormal T cell function in one-third (thus the disease could be considered a combined
defect)
Underlying defect Unknown

Clinical features
Usually present later in life (in 2nd or 3rd decades).
Sinopulmonary infections
Other infections Gastrointestinal (giardia, campylobacter)
Chronic enteroviral meningoencephalitis
Splenomegaly (Diffuse lymphadenopathy may also occur)
GI tract Follicular lymph node hyperplasia, malabsorption, weight loss, diarrhoea
Malignancies Lymphomas, gastrointestinal malignancies
Autoimmune associations Pernicious; anaemia, haemolytic anaemia, thrombocytopenia, leucopenia

~- ft1anagernent
Immunoglobulin replacement.

Selective IgA deficiency

Incidence 1:500 Caucasians, variable inheritance.
Associations HLA-B8, DR3
Autoimmune disease, e.g. RA, SLE, coeliac disease, thyroiditis
Immune defect Low or absent IgA
Sometimes IgG 2 and IgG 4 subclass deficiency also (20%)
Underlying defect Impaired switching or maturational failure of IgA-producing lymphocytes

Clinical features
• Asymptomatic
• Respiratory infections (URTI, sinusitis, wheeze, polysaccharide infections)
• Chronic diarrhoea
• I Type III hypersensitivity
Management
Specific th'erapy for infections. NB: Transfusion reactions more common.

Transient hypogammaglobulinaemia of infancy

'
Immune defect Slow maturation of antibody production
Low IgG 6 IgA before 6 months

Clinical features
• More common in preterm infants
• Recurrent respiratory tract infections in infancy
• Spontaneous improvement with age

Management
Usually none required.
29
IgG subclass deficiency
Immune defect Low IgG subclasses (normal total levels of IgG)
IgG 2 deficiency (most common type in children) often have low IgA levels
IgG 3 most common in adults
Underlying defect Defect of isotype differentiation

Clinical features
• Variable, usually mild
• Frequent infections
• Increased allergy
• Encapsulated bacterial infections if IgG 2 deficiency

Management
• Prophylactic antibiotics
• Intravenous immunoglobulin (occasionally)

Duncan syndrome (X-linked lymphoproliferative syndrome)

Immune defect Inadequate immune response to EBV and other defects
Underlying defect Unknown. Gene defect at Xq26

Clinical features
• Susceptibility to EBV infection
• Abnormal immune response leading to liver necrosis, aplastic crisis and lymphoproliferative disease
• If they survive primary infection, they develop hypogammaglobulinaemia and B lymphomas

Management
• Intravenous immunoglobulin and antibiotics
• Stem cell transplant

PR EDOMINANTLYT CELL DISORDERS

22q11 Microdeletion syndrome {DiGeorge anomaly)

The autosomal dominant 22q11 microdeletion syndrome (DiGeorge anomaly) is caused by microdeletions of chromo-
some 22q, and includes the velocardiofacial (Shprintzen) syndrome.
Immune defect One or more of: Decreased numbers and function ofT cells
Reduced PHA
Specific antibody deficiency

II
Underlying defect 4th branchial arch (3rd and 4th pharyngeal pouches) malformation
Microdeletions of chromosome 22q11

Clinical features
The features result from fourth branchial arch development defect (3rd and 4th pharyngeal pouches).
Thymus
Parathyroid
Aplasia or hypoplasia cellular immunity defect
Hypoplasia/absence, hypoparathyroidism, Ca -1, neonatal seizures, tetany, cataracts I
Cardiac Aortic arch anomalies (right-sided aortic arch, interrupted aortic arch, truncus arteriosus, VSD,
PDA, TOF)

30
lI
CNS Learning difficulties
Growth Short stature
Oesophagus Atresia
Dysmorphism Short palpebral fissures, low-set notched ears, long maxilla, micrognathia, bifid uvula, short
philtrum, absent adenoids, cleft palate, prominent nose
Injections Respiratory, diarrhoea, candida (severity varies, infections are not usually a presenting feature
and immunodefi.ciency may correct over time)

Management
Thymus transplant and stem cell transplant if necessary.

Chronic mucocutaneous candidiasis

Immune defect Impaired cell-mediated immunity to candida
Negative skin tests to candida
Underlying defect Unknown

Clinical features
Chronic candidiasis Skin, nails and mucous membranes, not systemic infection
Others Hypoparathyroidism, autoimmune disorders

Management
Antifungal therapy.

COMBINED IMMUNODEFICIENCIES
Severe_ combined immunodeficiency (SCID)
This comprises various syndromes, which have the following basic characteristics. The definition of SCID is based on
the severity of the condition and presence of typical features. SCID is further distinguished on the basis of patho-
genesis (where known). SCID must be differentiated from AIDS.

Immunological
Absence or impaired function ofT and/or B cells from birth . There are two groups of SCID:
1. T- B- SCID (lack T and B lymphocytes) - RAG-1 or RAG-2 gene mutations
2. T- B+ SCID (lack T cells, normal number of B cells) - profound lymphopenia, hypogammaglobulinaemia, very
small thymus

Clinical features
• Severe faltering growth
• Absent lymphoid tissue
• Diarrhoea
• Infections - pneumonia, otitis media, sepsis, cutaneous infections, opportunistic
• GvH symptoms - features similar to graft versus host disease in the neonatal period

Management
Death occurs < 2 years unless given stem cell transplant or gene therapy.

31
Causes
X-linked (50%) T- B+
Defective yc-chain of IL-2, 4, 7, 9 and 15
Autosomal recessive T- B+
Jak 3 mutation (intracellular kinase)
Omenn syndrome T cell infiltration of tissues
Hypereosinophilia, erythroderma, picture of GVH D
RAG-1/-2 deficiency T- 8-
NK cells normal or t
Mutations in RAG-1 or RAG-2 genes
Autosomal recessive
Adenosine deaminase T- B-
deficiency (ADA) (20%) Autosomal recessive, chromosome 20q13
Gene therapy currently being developed
Purine nucleoside T (reduced), B (less affected)
phosphorylase (PNP) Autosomal recessive, chromosome 14q13
deficiency (4%) Neurological abnormalities (two-thirds)
Autoimmune disease (one-third)
MHC class II deficiency Failure of antigen presentation
Heterogeneous condition
CD4 lymphocytes particularly impaired

Wiskott-Aldrich syndrome
X-linked recessive (boys only).
Immune defect Impaired cell-mediated immunity, progressive T lymphocyte .,[_
Impaired antibody production (normal initially, then IgM 1-)
Isohaemagglutinins .,[_
Underlying defect Abnormal microvilli on T cells
WASP gene on Xpll

Clinical features
Platelets Small size, thrombocytopenic purpura over skin (normal megakaryocytes)
Eczema Severe
Infections Pneumonia, otitis media, meningitis
HSV, VZV, PCP, encapsulated orgal)isms, e.g. pneumococcus
Malignancies Lymphoma
Autoimmune JIA, haemolytic anaemia, vasculitis, glomerulonephritis

Management
These children will die < 2 years without stem cell transplant.

Ataxia telangiectasia
Autosomal recessive.
Immune defeCt Impaired cell-mediated immunity (T cell numbers and function 1-)
Impaired antibody production (IgA very low, IgE 1, IgG 2 and IgG 4 1)
Underlying defect Abnormal DNA repair especially chromosomes 7 and 14
Mutations in ATM gene, chromosome 11q23.1

32
I
Additional CEA i, a -FP i, fatty liver changes
Cells have an extreme hypersensitivity to ionizing radiation (frequent somatic mutations)

Clinical features
Cerebellar ataxia Progressive
Telangiectasia Occulocutaneous, particularly on ear lobes and conjunctival sclera
Injections Chronic sinopulmonary
Malignancy Lymphomas, adenocarcinomas
Endocrine Hypogonadism (ovaries or testes), glucose intolerance

Management
Supportive.

X-linked immunodeficiency with hyper IgM

Immune defect Impaired antibody formation, low IgA and IgG
IgM normal or i, absent germinal centres
Recurrent neutropenia and thrombocytopenia
Underlying defect Absent CD40 ligand on T cells (B cells need this to switch isotypes)

Clinical features
• Recurrent respiratory infection (URTI, LTRI, PCP)
• Autoimmune features may be present

Management
Gammaglobulin infusions.

Hyper IgE. (Job syndrome)

Immune defect Possible immune dysregulation of IgE
Very high IgE (> 1000), impaired neutrophil locomotion
T cell abnormalities
Underlying defect Unknown

Clinical features
Eczema infections Staphylococcal abscesses in lung, skin, joints

Management
1. Antibiotic prophylaxis (penicillin)
2. Gammaglobulin infusions if deficient
3. Drainage of abscesses

NEUTROPHIL DISORDERS
Chronic granulomatous disease (CGD)
Immune defect Failure of superoxide production (therefore inability to kill)
Underlying defect Defective cytochrome b558 (the enzymatic unit of NADPH oxidase) from a defect in one of its
subunits. Absent gp91phox (X-linked, 66%) . Absence of p22phox (autosomal recessive, 33%)

33
Clinical features
Infections Recurrent abscesses of bone, lung, liver, lymph nodes, gastrointestinal tract
Aspergillus infection
Granulomas GIT, liver, spleen, skin, lung, bone
Other Gingival hyperplasia, cervical lymphadenopathy, hepatosplenomegaly
n · .
u;agnos1s
• NBT test (failure to reduce nitroblue tetrazolium)
• Biopsy granuloma
• Hypergammaglobulinaemia
• Radiology - liver/spleen CT scan, bone scan, CXR

Management
• Treat acute infection with antibiotics and neutrophil transfusions
• Long-term therapy withy-interferon and prophylactic antibiotics
• Gene therapy for X-linked disease in development

Chediak-Higashi syndrome
Immune defect Giant granules in all nucleated cells
Neutropenia, granulocyte mobility and chemotaxis defects
NK cell cytotoxicity defective
Underlying defect Cytoskeletal microtubule defect
Autosomal recessive

Clinical features
Infections Recurrent, bacterial (skin, respiratory, abscesses)
Albi.nism Partial occulocutaneous
Photophobia, nystagmus
Neurological CNS and peripheral nerve lesions
Accelerated phase of disease can occur with Epstein- Barr virus infection resembling familial lymphohistiocytosis
(FLH), leading to pancytopenia, hepatosplenomegaly and death.

Diagnosis
• Neutrophil analysis (giant granules)
• Giant melanosomes in melanocytes
• Bleeding time prolonged due to platelet aggregation defects

Management
• Treatment of acute infections
• Stem cell transplant
I
Shwachman-Diamond syndrome (see p. 151)
Immune defect Cyclical neutropenia, defective neutrophil mobility and chemotaxis I
Underlying defect Unknown
Autosomal recessive

34
IJ
;I
Clinical features
• Cyclical neutropenia
• Exocrine pancreatic failure (steatorrhoea)
• Metaphyseal dysostosis (short stature)
• Anaemia, thrombocytopenia (variable)

Management
Supportive, pancreatic exocrine supplements, GMCSF.

Leucocyte adhesion defects (LAD)

Immune defect Abnormal leucocyte adhesion
Peripheral neutrophils I
Underlying defect Absence of CD18 (LADl) resulting in LFAl, C3b or p150 deficiency
Autosomal recessive

Clinical features
Infections Skin, necrotic ulcers, periodontal infections
Fistulae Intestinal or perianal

Management
• Aggressive use of antibiotics and antifungals
• BMT

COMPLEMENT DEFICIENCIES
Congenital deficiencies of almost all the complement components have been found, and of complement control proteins.
Two niajor patterns of infection exist:
1. Encapsulated bacteria - deficiencies of (2, (3, C4 and C1q (complement components); deficiencies of factor H
or I (complement control proteins)
2. Neisseria[ infections - deficiencies of the lytic pathway (C5-9) (complement components)

Hereditary angioedema
This is due' to Cl esterase inhibitor deficiency or defectiveness. Activation of C1 leads to uncontrolled Cl activity,
breakdown of (2 and C4 and release of kinin (vasoactive peptide) from C2. The disease manifests as episodes of non-
pitting oedema (with no itch, urticaria or redness) lasting 2- 3 days. Laryngeal involvement may cause respiratory
obstruction, and intestinal wall swelling can cause abdominal pain, vomiting and diarrhoea . Stress, surgery or exercise
may trigger attacks. Treatment is with hydrocortisone± adrenaline, FFP or purified inhibitor in acute attack. Danazol
for long-term. Autosomal dominant acquired form exists.

ACQUIRED IMMUNODEFICIENCY

CAUSES
Immunoglobulin deficiency
• Lymphoproliferative disease, e.g. CLL
• Bone marrow aplasia, hypersplenism

35
 • Protein loss: Protein-losing enteropathy
Burns
Nephrotic syndrome
Malnutrition states

Cell-mediated immunodeficiency
• Drugs, e.g. cyclosporin, cyclophosphamide, steroids, azathioprine, tacrolimus
• Lymphoproliferative disease, e.g. lymphoma
• Bone marrow aplasia, hypersplenism
• HIV infection

HIV (human immunodeficiency virus) is in the lentivi rus group of retroviruses. Retroviruses contain the enzyme
reverse transcriptase, which enables viral RNA to be incorporated into host cell DNA. There are two main types: HIV-1
(widespread) and HIV-2 (West Africa) .
The cellular receptor for the virus is the CD4 molecule, which is found on T helper cells (Th1 subset), the cells most
affected by the disease. The CD4 cell numbers decline and the host develops a profound immunodeficiency, encourag-
ing opportunistic infections.

Transmission .
Mode of transmission:
• Vertical transmission (mother to child, the majority of childhood HIV): Prenatally
Intrapartum
Postnatally throug h breastfeeding
• Via mucous membranes during sexual intercourse (NB: sexual abuse)
• Blood transmission directly into the circulation, e.g. IV drug abusers
The overall vertical transmission rate estimates vary from 15% to 30% (see below).

Diagnosis
There are various techniques to detect HIV:
• Virus detection by PCR (rapid, sensitive and
specific) or viral culture (slower)
• Viral p24 antigen - present shortly after infec-
gp 120
gp 41
(envelope)
l
gp 160

tion until8-10 weeks. Can reappear as disease

becomes worse
• Detection of IgG antibody to envelop compo-
p17, matrix
nents (gp 120 and subunits). There is a win-
dow of< 3 months after infection before this
becomes positive. These antibodies cross the
Protease
placenta, therefore all infants of HIV-posi-
tive mothers possess them, whether they are
infected or not. The antibody disappears by
around 12-18 months if infant is not infected Lipid layer
• Detection of IgG antibody to p24, present early
in infection only
Figure 2.2 Structure of HIV

36
Repeat testing by PCR during the first few months should be done on all infants at risk to be sure of not missing an
infected infant and to confirm a positive test.

Clinical manifestations
Infants are generally asymptomatic in the neonatal period. Two patterns of disease are seen:
1. Early-onset AIDS-defining symptoms (within a few months) (25%)
2. Late-onset AIDS-defining symptoms (around 8 years) (75%)
The disease develops more rapidly in children than in adults and opportunistic infections occur more frequently
early in the disease. In addition to multiple infections, particular presentations in childhood include faltering
growth, lymphocytic interstitial pneumonitis (LIP) and HIV encephalopathy. The disease criteria were revised in
1994, as below.

CDC 1994 classification for HIV disease in children < 13 years

This involves the four clinical categories listed below and three immunological categories based on the CD4 T
lymphocyte counts at different ages.

~ ' 2ofthffoltowing symptoms: .

• ·lymphadenopathy (>0.5 ern at >2 sites)
• Hepatomegaly
• Splerwmegaly
• Parotitis
• Dermatitis
• ReciJrtent of persistentURTis (> 3 episodes/year) ·

Any condition listed in the 1987 suryeillancecase definition ofAIDS except

LIP. Exa~ples i~clude : . . . _· -_.·. _·•· .. .
• Oesophageal or pulmonary candidiasismultiple or recurrent serious
..bad:eriai'infecfiohs'(any.comb1iiatlon. ofat-least two cuttiire-proveri
infectiqns Within a 2-year period; iricluding·septicaemia, pneumonia,_
. meningitis) ....· ; .; ' ·•. '
• PneuniOcystis jeimi (formerly carini1) pneumonia · ·
• Progressive multifocalleucoencephalopathy
• Kaposi sarcoma

37
Falten'ng growth
This may be apparent in the first few months of life. HIV with faltering growth is a differential diagnosis of SCID. It
occurs due to a combination of factors:
• Reduced intake (appetite poor, HIV encephalopathy)
• Malabsorption (GI infections, HIV enteropathy)
• Increased metabolic requirements (recurrent infections)

Lyn:phocytic interstitial pneumonitis

This is a chronic lung disease of uncertain aetio logy seen in 40-50% of vertically infected children.
Clinical features are variable. Patients may be asymptomatic, diagnosed on CXR or have features of respiratory distress
including dyspnoea and hypoxia.
CXR findings Diffuse, interstitial reticulonodular infiltrate
Hilar or mediastinal lymphadenopathy may be present
Management is symptomatic only. Steroids may reduce oxygen dependency.

Hit! encephalopathy'
This is common in HIV-infected children. It presents as motor and language developmental delay, and an acquired
microcephaly may occur. Brain imagin_g studies (CT/MRI) may demonstrate cortical atrophy, basal ganglia calcification,
ventricular enlargement and white matter abnormalities.

Opportunistic infections
Protozoa

Pneumocystis jejuni (carinil) pneumonia (PCP)

Pnemocystisjejuni (formerly carinii) is an extracellular protozoan which causes opportunistic infection in immunocom-
promised individuals. It is an AIDS-defining illness. It often presents at 3 months of age in severely affected infants.
Clinical features:
• Hypoxia often more severe than expected from chest examination findings
• Persistent non-productive cough
• Dyspnoea
• High fever
Investigations:
CXR Diffuse perihilar bilateral 'butterfly' shadowing, ground glass appearance, cavities
May be normal
Bronchoalveolar lavage Immunofluorescence staining with monoclonal antibodies
Management:
Pneumonia High -dose co-trimoxazole (Septrin) IV/orally or pentamidine IV for 21 days
Prophylaxis Low-dose co-trimoxazole orally or pentamidine nebulizers monthly

Toxoplasmosis
Toxoplasma gondii Cerebral abscesses, encephalitis (more common in adults)
Diagnosis CT or MRI scan
Positive IgG antibody to toxoplasmosis
Treatment Long-term pyrimethamine +sulphonamide

38
Cryptosporidiosis
Cryptosporidium parvum Severe secretory diarrhoea, abdominal pain, bowel wall cysts, sclerosing cholangitis
Diagnosis Stool specimens (cysts), small bowel biopsy
Treatment Supportive, Paromamycin

Fungi
Candida
Candida albicans Oropharyngeal (> 70% symptomatic children)
Oesophageal (dysphagia), vulvovaginal, disseminated (rare)
Treatment Chronic antifungal therapy, e.g. fluconazole
IV amphotericin B may be needed

Cryptococcus
Cryptococcus neoformans Meningitis (atypical presentation), pneumonia
Diagnosis CSF (India ink staining, antigen titres, culture)
Serum (organism culture)
Treatment _ Long-term fluconazole

Viruses
Many viruses can cause unusually severe disease in HIV-infected children. These include VZV (severe primary disease,
recurrent zoster), RSV and adenovirus (severe pneumonitis), measles (pneumonitis and encephalitis), CMV and HSV
(as below).

Cytomegalovirus (CMV)
Retinitis Decreased acuity, floaters, orbital pain
'Pizza-pie' appearance of haemorrhages and exudate on ophthalmoscopy
Treatment with gancyclovir IV
Colitis Bloody diarrhoea, fever, toxic dilatation, ulcers, hepatitis, sclerosing cholangitis
Diagnosis on colonoscopy and biopsy ('owl's eye' cytoplasmic inclusion bodies)
Treatment with gancyclovir IV
Other Pneumonitis, hepatitis, pancreatitis, adrenal insufficiency

Herpes simplex virus (HSV)

HSV 1 and '2 Extensive oral and genital ulceration
Diagnosis Clinical, virus isolation from ulcers, serology
Treatment Acyclovir IV (NB: Resistance problems)

Bacteria
Recurrent serious bacterial infections are seen, as dysregulation of B cell function occurs in HIV. Of particular note is
atypical mycobacterial infection, e.g. Mycobacterium avium intracellulare.

Tumours
Less common in children than adults.

l<aposi sarcoma
This is a tumour of vascular endothelial cells associated with HHV-8 and appears as purple lesions. It commonly involves
skin, gut, lymphatics and lung. Treatment is with antiretrovirals, radiotherapy (if local) or chemotherapy (if disseminated).

39
Lymphoma
Non-Hodgkin B cell lymphoma, primary CNS lymphoma. Poor response to therapy unless it occurs when immuno-
suppression is mild.

HIV therapy
A multidisciplinary team approach is used to manage the physical and emotional needs of these children and their
families.
Currently Septrin prophylaxis is given until the child is shown to be HIV negative. If HIV positive, Septrin is continued
until 12 months of age and then treatment is given according to the CD4 count and viral load. Combinations of drugs
are used : the specific recommendations frequently change due to rapid therapeutic developments. Viral load and CD4
cell count are used as monitors of therapy.
. .
Dr~g . Side-effect · . . · ,
·~:u:c.t~~~ide'·all~to9'ues (rel/erse'transhi pta~·~, 1ri~i bitors) i .•. t : ~'"::. ·. . . _
· ..;,,. .~ -·,

Zido~udire. (AZTv}~aiido~JC"\ ;< .: ;.;"·.Nal1sea·i;abdp.minal;P<lin, headach·e, -insoin:nia .· .

de6xythymjdine) · · · ·•·...·. ; Bone111arr()wsuppression, rieyttopenia, myopathy
6i;d~~~}ii~6sine(r)bi) . . Gastroinlesti~~l diftJ'rbance, pancreatit\{p~ripheral
~n9. di9i9~ycitidir1~ (DDC) ne~ropathy. ·

Reduction of vertical transmission

Pregnant women with HIV infection have a transmission risk (untreated) of approximately 15-30%. ~easures to reduce
transmission to < 5% include:
• Antiretroviral therapy during pregnancy and delivery
• Antiretroviral therapy during delivery only if unable to administer during pregnancy
• Elective Caesarean section
• Avoid invasive fetal procedures, e.g. fetal scalp electrodes and blood sampling
• Avoid breastfeeding (the WHO advises breastfeeding continue in developing countries to prevent malnutrition)
• Oral AZT to infant for the first 4- 6 weeks

FURTHER Rf.J.\DING
Primary Immunodeficiency Diseases, Report of a WHO Scientific Group Clinical and Experimental Immunology 1997 109
(Suppl1):1-28
Raitt IM, Brostoff J, Male DImmunology, 6th edn. Philadelphia: Mosby, 2001

40
• Vaccination • Bacterial infections
• The febrile child • Protozoal infections
• The seriously unwell child - • Fungal infections
• Viral infections • Helminthic infections

VACCINATION

IMMUNIZATION SCHEDULE

41
VACCINES

Contraindications to vaccination
All vaccines
1. Acute febrile illness - temporary contraindication. NB: Mild infection without fever or systemic upset is not a
contraindication
2. Anaphylactic reaction to previous dose

Live vaccines
1. Immunosuppressed or on immunosuppressive treatment
2. On prednisolone (oral/rectal) 2 mg/kg/day for at least 1 week or 1 mgjkg/day for at least 1 month
3. Lower dose of prolonged steroids or in combination with immunosuppressives, to discuss with immunologist
4. Impaired cell-mediated immunity (antibody deficiency is a contraindication to oral polio vaccine)

HIV-positive children
These may receive all standard vaccines in the schedule except BCG. Inactivated polio vaccine may be used instead of
live vaccine in symptomatic individuals.

Pertussis vaccine
In children with an evolving neurological problem, immunization is deferred until the condition is stable.

THE FEBRILE CHILD

The majority of children with a fever will have a self-limiting viral infection; however, it is important to distinguish
and treat those children with a more serious cause.

42
Management of a febrile child includes a thorough history and examination to help elucidate the cause. There is no
single clinical or laboratory finding that distinguishes viral from bacterial infection so it is necessary to develop an
impression of the child as a whole and frequently to reassess the child.
Fevers can be divided into:
1. Fever with localizing signs
2. Fever without localizing signs

IMPORTANT POINTS IN THE HISTORY

• Contact with infectious diseases
• Travel
• Contact with animals and insects
• Dietary history, e.g.-unpasturized milk consumption - listeria, brucellosis
• Age (age-related infections)
• Immunization status
• Season
• Immunocompromised state, e.g. chemotherapy patient, HIV patient, congenital immunodeficiency_

IMPORTANT POINTS IN THE EXA~HNATION

• General clinical state and vital signs (see below)

• Degree of fever
• Rash
• Lymphadenopathy, hepatosplenomegaly
• Heart murmur
• Localizing signs, e.g. tonsillar exudate, joint or bone tenderness
• Features of immunodeficiency (see p. 26)

MANAGEMENT
Fever with localizing signs Treat and investigate as appropriate for the condition
Fever without localizing signs • It is important not to miss a bacteraemic illness. Features suggestive of bacteraemia
are outlined (see below); however, these are non-specific and none is diagnostic
• Remember infections are dynamic. A child who has mild fever and looks well may
be at the early stages of a septicaemic illness. Regular review (by family, primary
or secondary health care workers) is imperative
• Children who are clinically ill are investigated (with CRP and FBC; blood, throat and
urine, stool± CSF cultures) and then either commenced empirically on antibiotics,
or observed with antibiotics only given if exact cause of illness is found, or sepsis
is apparent
• If a fever persists > a few days with no cause found, causes of prolonged fever
should be looked for (see below) . In particular, consider Kawasaki disease

Features suggestive of an unwell child

(Not necessarily a bacterial infection, but think of it in this context.)
NB: These features have low sensitivity and specificity.

43
Colour
Capillar-y·refilLtime
:.::.· ·. ·. ·.· :

·Periphe:ne$
Tone . .

Respons1~erie~s·· ·
wee
ESR, CRP el~vated .

Causes of prolonged fever

Viral infections CMV, EBV, human herpes virus 6, HIV
Bacterial infections TB, leptospirosis, brucellosis, spirochaetes, salmonella, bacterial endocarditis,
osteomyelitis, abscesses
Other infections Malaria, toxoplasmosis, chlamydia, rickettsia, fungal infections
Non-infectious causes Kawasaki disease, collagen vascular disease, malignancies, drugs, inflammatory bowel
disease, familial Mediterranean fever

THE SERIOUSLY UNWELL CHILD

If a pathogen manages to break through the host's first line of defence and invades the blood stream, and if the host
does not rapidly resolve the infection, bacterial proliferation can ensue and this results in a systemic host inflamma-
tory response, which together with the virulent properties of the invading organism cause the features of sepsis.
In septic shock there is persistent hypotension despite adequate fluid resuscitation and/or hypoperfusion even after
adequate inotrope or pressor support. '

Primary site~ Bloodstream·~ Bacterial • Systemic host response }

of invasion t t proliferation Septic
child
Restricted by host Resolved by ----t•~ Virulent properties of
primary defence host microorganism
mechanisms
~------------------------------------------------------- -- -- ---------------

Figure 3.1 Pathway of sepsis

44
Main causes

Clinical features
• The clinical features depend upon the organism, child's age and pre-existing health and duration of the illness
• Early bacteraemia can be difficult to assess. Therefore it is essential frequently to reassess the situation
• Non-specific early features : Lethargy, irritability, hypotonia, poor feeding, mottled skin, nausea and vomiting
• Cardiovascular features : tachycardia/bradycardia, poor peripheral perfusion, prolonged capillary refill time,
peripheral oedema, decreased urine output
• Other organs: respiratory, gastrointestinal, neurological derangement
• Rash : petechial, erythroderma, mucosal erythema and oedema (toxic shock syndrome, see p. 58)

Causes of petechial rash

Management
Initially there is a small number of invading organisms, but these multiply (often Logarithmically) resulting in rapid
clinical deterioration. Therefore the most important management is recognition of sepsis as early as possible and initia-
tion of antibiotics and supportive treatment. Frequent reassessment is therefore imperative.
Investigations Source of infection: Blood cultures
Urine microscopy and culture
Other samples, e.g . throat swab
Lumbar puncture if suspected meningeal involvement
Other indicators of infection: WCC, inflammatory markers
Other: FBC, coagulation profile, U&E, creatinine, glucose, LFTs, blood gas
Treatment Initial resuscitation as necessary
Appropriate antibiotic therapy as soon as possible
Supportive measures for septic shock
Adjuvant therapy: new treatments administering antagonists of host-derived inflammatory
mediators are being developed

45
MENINGITIS
This is an acute infection with an inflammatory process involving the meninges, and may be bacterial, viral, fungal
or other microbial.

Most common causes of bacterial meningitis

Causes of viral meningitis

• Enteroviruses (> 80%, especially coxsackie and echovirus)
• Adenovirus
• Mumps
• EBV, CMV, VZV, HSV
• HIV

Clinical features
Sudden onset and rapid deterioration are seen in meningococcal meningitis.
Neonate Non-specific features, lethargy, apnoea, poor feeding, temperature instability, respiratory
distress, high-pitched cry, seizures, -bulging fontanelle, shock, rash (occasionally)
Infant Fever, lethargy, irritability, poor feeding, vomiting
Bulging fontanelle, shock, seizures, coma, rash
Older child Fever, headache, drowsiness, shock, seizures (late), papilloedema (rare)
(> 18 months) Meningeal irritation: Headache, neck stiffness, photophobia
Kernig sign (pain on lower leg extension, with hip flexed)
Brudzinski sign (involuntary flexion of knees and hips with neck flexion)
Rash Petechial rash seen classically in meningococcal infection (can also be seen in pneumococcal and
Haemophilus influenzae infections)

Investigations
Blood Glucose, blood gases, FBC, clotting profile, U&E, creatinine, CRP
Bacterial cultures
Bacterial PCR
Viral (PCR)
Viral serology, bacterial serology, e.g. N. meningitidis
CSF Microscopy, culture, protein, glucose, bacterial antigens, viral and bacterial PCR
Throat and stool M, C& S and viral culture
Urine Rapid antigen tests
CXR

46
~·

Typical lumbar puncture findings

Contraindications to lumbar puncture

• ICP I (focal or prolonged seizures, impaired consciousness, papilloedema, focal neurological signs)
• Cardiopulmonary compromise (sepsis)
• Local skin infection overlying LP site
• Coagulopathy

Management
Bacten"al meningitis
Antibiotics IV therapy to commence immediately. Do not delay for LP
Choice depends on likely pathogen, generally third-generation cephalosporin, e.g.
ceftriaxone, for 7-10 days
Add ampicillin if< 3 months to cover listeria
Rifampicin 2 days following treatment of meningococcal disease (if antibiotic other than
ceftriaxone used)
Dexamethasone Only of proven benefit in H. influenzae meningitis but generally administered in all
bacterial meningitis
Supportive measures Initial resuscitation with oxygen and IV fluids
Monitoring of neurological status
Intubation and ventilation if necessary and circulatory support (fluids, inotropes, CVP) as
needed

Viral meningitis
Less severe infection, full recovery usual, enterovirus in the majority. Treat as bacterial if in doubt until culture result
at 48 h. Aciclovir for HSV or VZV infection.

Complications
SIADH Common complication, monitor plasma and urine electrolytes, and osmolality
Cerebral Abscess, infarction, subdural effusion, hydrocephalus
Deafness Due to VIIIth nerve vasculitis
Meningococcal disease This may present as septicaemia (worse prognosis) or meningitis, with rapid
deterioration
Purpuric rash, may lead to necrotic areas
Haemophilus influenzae Reduced incidence due to H. influenzae (Hib) vaccine. Subdurals common
Pneumococcal meningitis High mortality (10%) and morbidity (30% neurological sequelae)

47
TB meningitis (see p. 66)
Unusual features Chronic presentation, vague headache, anorexia, vomiting . Focal neurological signs, seizures,
cortical blindness
Investigations Mantoux or Heaf test (NB: May be negative)
CXR (changes in 50%)
CT brain (oedema, infarction, hydrocephalus, abscess, tuberculoma)
CSF, gastric aspirate and early morning urine for microscopy, PCR and TB culture
Management Commence on suspicion, 12 months of antituberculous therapy (rifampicin, isoniazid,
pyrazinamide, ±ethambutol). Consider steroids

Partially treated bacterial meningitis

The picture may be confused, with culture-negative CSF but leucocytosis. Rapid antigen tests ± PCR may be useful. If
concerned, treat as bacterial.

Prevention for contacts

Contacts Meningococcal H. influenzae: all close contacts given 2 days oral rifampicin and 4 days oral
rifampicin if there is an unvaccinated child < 4 years in household
Vaccination Hib vaccine all children
Meningococcal vaccine currently available to groups A, C, Yand W135 only

Prognosis
• Mortality of bacterial meningitis 5-10% with treatment
• Neurological impairment in survivors> 10%

ENCEPHALITIS
An inflammation of the brain parenchyma, which may be due to:
• Direct viral invasion
• Secondary to post-infectious due to immune response or slow virus infection, e.g. SSPE
Viral encephalitis and meningitis are caused by the same organisms and form a continuum .

Viral encephalitis

48
Clinical features
• Insidious onset compared to bacterial meningitis
· • Fever, headache, lethargy, behavioural change, meningeal irritation (uncommon in young infants), decreased
consciousness, seizures
• Focal neurology, features of ICP I
• Neurological sequelae common (cognitive and motor deficits, epilepsy, behavioural changes)

Investigations
Samples As for bacterial meningitis
In particular, blood serology (including viral, mycoplasma raised specific IgM, or increase in IgG
in paired sera), viral cultures (blood, urine, stool, throat and CSF) and PCR for specific pathogens
Imaging MRI
Other EEG

Management
• Supportive care (shock, ICP I treatment)
• Antiviral agents (intravenous)
• Treat with antibiotics as for bacterial meningitis until viral aetiology confirmed/bacterial cultures negative

VIRAL INFECTIONS
DNA VIRUSES

Herpes simplex virus (HSV)

Transmission Direct contact
Incubation 2-15 days

Two types of HSV exist:

HSV-1 Transmitted mainly via saliva and the cause of most childhood infections

49
 , .. ·
'! : ,;," · · ··:
. -:·· .

HSV-2 Transmitted mainly via genital secretions or via vaginal delivery and the primary cause of genital herpes.
Dormancy in sacral ganglia
(NB: The two forms of HSV infections overlap.)
Primary infection causes a severe vesicular rash wherever the primary inoculation was:
• Mouth infection (gingivostomatitis). The most common primary infection. If severe, swallowing is painful and
NG or intravenous fluids may be required. Fever for 2-3 days, then ulceration, healing in 1 week. Peak age 1-3
years. Dormancy in trigeminal ganglia
• Skin infection, e.g. herpetic Whitlow (infection on finger)
• Eye infection (keratoconjunctivitis) can result in corneal scarring. Ophthalmological review is important
Recurrent disease is triggered by stress, illness, sun exposure. Local recurrence generating from dormancy:
• Herpes labial is (cold sore) - the most common site
• Herpes genitalis

Diagnosis
Usually clinical.
. .
Vesicle fluid Electron microscopy (EM), immunofluorescence, viral culture
Blood Serology
CSF PCR

Treatment
Aciclovir IV in severe disease (neonates, immunocompromised, eczema herpeticum, encephalitis, ophthalmic disease)
Oral treatment considered in some cases
Topical to cold sores
Eye drops (ocular infection)

Varicella zoster virus (VZV)

This produces two diseases.

Varicella (chicken pox)

Transmission Airborne or contact
Incubation 14-21 days, infectious 48 h pre-rasn to 5 days after onset of rash
Clinical features Mild prodromal illness with fever 2-3 days (not in young children)
Peak age 2-8 years
Rash: face, scalp and trunk, spreads centrifugally
Macules -7 papules -7 vesicles -7 pustules -7 crusts. All stages are seen at once on the skin

50
Complications Superinfection of the skin - crusts, pustules, prolonged fever. May develop toxic shock
syndrome (Staphylococcus aureus or Streptococcus pyogenes)
Encephalitis- acute truncal cerebellar ataxia (post-infectious). Recovery good
Purpura fulminans - a vasculitis in skin and subcutaneous tissues
Pneumonia - common in adults (30%), CXR dramatic
Other- Sepsis, thrombocytopenia, DIC, hepatitis, Reye syndrome, arthritis, pancreatitis,
nephritis, stroke
Immunocompromised - severe disseminated haemorrhagic disease, high mortality
Congenital injection This can produce severe malformations, with limb deformities

Zoster (shingles)
This occurs from reactivation of dormant VZV, from the dorsal root or cranial ganglia. Triggered by immunocompromise,
though commonly seen in normal children. Lesions identical to varicella, itchy and slightly painful in children, anc
usually restricted to < 3 dermatomes. Infection of the geniculate ganglion causes ear pin na vesicles and facial nervE
palsy(= Ramsay-Hunt syndrome).

Diagnosis
Clinical diagnosis Vesicle fluid- electron microscopy, immunofluorescence, viral culture (difficult)
Serology CSF- PCR

Treatment
Chicken pox No treatment required in uncomplicated cases
IV aciclovir if complications or immunocompromised
Shingles Aciclovir (oral or IV, dependent on severity and site)
Neonatal Maternal infection 5 days predelivery to 2 days post: give ZIG to infant. If infant develops
vesicles, treat with IV aciclovir

Prophylaxis
Zoster immunoglobulin (ZIG), i.e. passive immunization is given to:
1. Immunocompromised children exposed to VZV, e.g. stem cell transplant patients, congenital immunodeficiency
on immunosuppressives or high dose steroids in previous 3 months
2. Neonates (as above)
VZV vaccine exists but is currently not routinely used in the UK.
'
Cytomegalovirus (CMV)
Transmission Close contact (saliva, breast milk, genital secretions)
Transplacental
Blood (NB: An important pathogen in organ transpla nt)
Most children are infected when toddlers, and hatf of adults have positive serology (IgG to CMV).

Clinical features
Healthy individuals Asymptomatic (usually)
Similar clinical picture to EBV (but tonsillitis less obvious)
Immunocompromised Severe infection including encephalitis, retinitis, pneumonitis, gastrointestinal infection,
atypical lymphocytes, hepatitis
Congenital injection Seep. 449

51
Serology Primary infection (IgM), latent infection (IgG)
Urine For CMV DEAFF (signifies active replication)
CMV PCR On blood and other secretions
Blood count Lymphocytosis with atypical lymphocytes. Sometimes neut ropenia
Tissues Intranuclear 'owl's eye' inclusions on microscopy, direct imm unofluorescence, viral culture

Treatrnent
None in healthy individuals. Ganciclovir, foscarnet or cidofovir IV if immunocomp romised.

Epstein-Barr virus (EBV)

This produces infectious mononucleosis (glandular fever) . The virus infects t he B lymphocytes.
Transmission Aerosol, saliva
Incubation 20-30 days

• Often asymptomatic in young children . Classical picture in adolescents

• Fever, headache, tonsillopharyngitis, palatal petechjae, generalized lymp hadenopathy
• Maculopapular rash . Bright red rash in 90% if ampicillin given
• Splenomegaly (tender), hepatitis, hepatomegaly
• Arthropathy
• Thrombocytopenia, haemolytic anaemia, a.typicallymphocytes, mononuclea r cells
• May produce depression and malaise for months

Complications
• Meningitis, encephalitis
• Myocarditis
• Myelitis, Guillain-Barre syndrome
• Mesenteric adenitis
• Splenic rupture
Burkitt lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease in the immunocompromised are thought
to be caused by EBV infection (see p. 52).

Diagnosis
• Atypical lymphocytes in the blood
• Monos pot test positive (heterophile antibodies to horse RBCs, unreliable < 5 years due to false negatives)
• Positive Paul-Bunnell reaction positive (IgM antibodies that aggluti nate sheep RBCs. Non-specific. False positives:
leukaemia, non-Hodgkin lymphoma, hepatitis)
• EBV IgM may be detected (75-90% by end of third week)
• EBV VCA (EBV viral capsid antigen) } Ant.1gens for sero logy
• EBV NA (EBV nuclear antigen)
• EBV PCR

52
' .,·
F
Treatment
Not usually required except in the rare cases of lymphoproliferation where monoclonal antibodies to the B cell antigen
CD20 are used.

Roseola infantum (exanthem subitum, HHV6)

Almost all children are infected with this during infancy. Roseola infantum is the cause of approximately one-third o1
febrile convulsions in children < 2 years of age.
Transmission Droplet
Incubation 9- 10 days

Clinical fea~ures
• High fever and malaise
• Cervical lymphadenopathy
• Few days later red macular rash over face, trunk and arms 1-2 days
• Red papules on the palate
• Febrile convulsions
• Sudden improvement after the rash
• Rarely: meningitis, encephalitis, hepatitis
• One-third of children asymptomatic
There is no specific treatment

Parvovirus 819
This virus attacks the erythroid precursors, and leads to transient arrest of erythropoiesis.
Transmission Respiratory route, blood, vertical transmission
Incubation Variable

Clinical features
It produces various clinical features:
1. Slapped cheek disease (erythema infectiosum, Fifth disease) :
Incubation 4-21 days
Seen in school-age children, most commonly in spring
Fever, malaise, myalgia
Then after 1 week: very red cheeks, macular erythema over trunk and limbs with central clearing of the lesions,
resulting in a lacy pattern which may recur over weeks
2. Asymptomatic infection - common
3. Arthropathy- usually transient, older children may develop arthritis
4. Immunocompromised - chronic infection with anaemia
5. Transient aplastic crisis - occurs in children in states of chronic haemolysis, e.g. sickle cell disease,
thalassaemia, spherocytosis
6. Congenital infection -severe anaemia with hydrops fetalis.

53
RNA VIRUSES

NB: Poliovirus, coxsackie A and B, echovirus and enterovirus are all in the genus Enteroviruses.

Hand, foot and mouth disease

Organisms Coxsackie A (A16) and B, enterovirus (71)
Transmission Faecal-oral, droplet, direct contact

Clinical features
• Mild disease lasting a week, mostly in pre-school children
• Fever with vesicles in the oropharynx, palms and soles
• Maculopapular rash also on palms, soles and buttocks
• In X-linked agammaglobulinaemia (XLA) enteroviruses can cause extensive cerebral infections

Rubella (German measles)

Transmission Droplet, winter and spring
Incubation 14--21 days. Infectious <7 days from onset of rash

54
( ..
i '
Clinical features
< 5 years Usually asymptomatic
> 5 years Prodrome of conjunctivitis, low grade fever, cervical lymphadenopathy (suboccipital and
postauricular)
Forcheimer spots (palatal petechiae)
Splenomegaly
< 7 days fine pink maculopapular rash on face, then body, lasting 3-5 days

Complications
• Arthritis (small joints)
• Myocarditis
• Thrombocytopenia
• Encephalitis
• Congenital rubella syndrome (seep. 451)

Diagnosis
Viral culture Throat swab, urine
Serology Rubella-specific IgM levels and rising antibody titre (acute and convalescent samples)

Management
• No treatment usually necessary
• Vaccination (contraindicated during pregnancy)

Measles
A potentially serious illness, whose incidence is rising again as the MMR vaccine uptake is poor. Avaccine coverage oi
> 90% is required to prevent epidemics.

-Transmission Droplet (coughing, sneezing)

Incubation 7-14days
Infectious from pre-eruptive stage until 1 week after onset of rash

Clinical features
Pre-eruptive stage Unwell, high fever, conjunctivitis, cough, coryza
Koplik spots (pathognomonic small white spots on labial mucosa and gums around 2nd molar).
2-3 days later:
Eruptive stage Fine red maculopapular rash behind ears and on face, progressing to whole body
NB: EEG abnormalities seen in 50%

Complications
• Common in malnourished children with vitamin A deficiency (developing countries)
• Otitis media
• Secondary bacterial pneumonia bronchitis
• Hepatitis, myocarditis, diarrhoea
• Post-measles blindness secondary to keratitis (seen in developing countries)
• Encephalomyelitis (post-infectious)
• Subacute sclerosing pan-encephalitis (SSPE) (a rare progressive dementia occurring several years after measles
infection in< 1:100 000 cases) This is not caused by vaccine strains (seep. 358)

55
Investigations
Viral isolation Immunofluorescence (CSF, serum, nasal secretions)
Viral culture Throat swab
Serology Serum, CSF, saliva (anti-measles IgM)

Treatment
• Symptomatic only
• Human pooled immunoglobulin and ribavirin can be given< 6 days of exposure (immunocompromised, < 3 years)
• MMR immunization

Mumps
Transmission Droplet, direct contact, winter and spring
Incubation 14-21 days, infectious for 6 days pre-9 days post parotid swelling appears
rt · . I r ,
dlrJICOL Jearures
• Prodrome of fever, anorexia, headache, earache. Usually asymptomatic
• Painful salivary gland swelling- bilateral (usually) or unilateral, parotid 60%, parotid and submandibular 10%
• Irismus may occur

Complications
• Meningeal signs (10%), encephalitis (1:5000), transient hearing loss
• Epididymo-orchitis (20% after puberty), pancreatitis, oophoritis, myocarditis, arthritis, mastitis, hepatitis

Investigations
Viral isolation/culture Urine, saliva, throat swab, CSF (meningism)
Serology Rise in antibody titre ('5' antigen early and 'V' antigen later, for life).

Rabies
Transmission Saliva (animal bite)
Incubation 1-3 months (average 10 days)
The rabies virus enters through the bite wound, replicates in local muscle, travels up the peripheral nerves to the brain
and replicates further. Then it travels via autonomic nerves to the salivary glands, lungs, kidneys, etc.

Clinical features
Initial Pain at site of wound, fever, headache
Furious rabies Anxiety, hallucinations, hyperexcitability with visual and auditory stimuli
Hydrophobia (50%), aerophobia (pathognomonic)
Sympathetic overactivity, cardiac arrhythmias, convulsions
Death< 10-14 days
Dumb rabies Symmetrical ascending paralysis with areflexia

Diagnosis
Rabies antigen Salivary secretion, corneal impressions or skin sections (using fluorescent antibodies)
Postmortem Negri bodies in cerebellum and hippocampus

Treatment
1. Clean the wound
2. Local antiserum (rabies immunoglobulin) around wound

56
 3. Postexposure vaccine, human diploid cell strain vaccine (HDCSV) IM on days 0, 3, 7, 14 and 28
4. Symptomatic treatment with quiet, dark environment, sedation and analgesia

Prophylaxis
Rabies vaccine HDCSV IM two or three doses.

BACTERIAL INFECTIONS

GRAfV1-POSITIVE AND -NEGATIVE COCCI

STAPHYLOCOCCAL INFECTIONS
Staphylococci are part of the normal flora of skin, upper respiratory tract and gastrointestinal tract.

57
Toxic shock syndrome
This severe infection is due to exotoxins, e.g. toxic shock syndrome toxin-1 (TSST-1) usually from Staph. aureus. The
focus of infection is usually minor, e.g. a boil. There is an association with tampon use.

!Jjognostic features
• Fever::: 38.9°(
• Conjunctivitis
• Patchy then diffuse tender pale red rash followed by desquamation
• Hypotension
• Vomiting and diarrhoea
• Toxic effects in other systems (::: 3 required for diagnosis): myalgia, renal impairment, thrombocytopenia, drowsi-
ness, mucous membrane involvement
Anti-TSST-1 antibodies are positive. Management is mostly supportive, with IV antibiotics, cardiovascular support,
IPPV and renal dialysis as necessary. IVIG may be considered.
Streptococcal TSS is similar and often due to a deep-seated streptococcal infection.

STREPTOCOCCAL INfECIIONS

Cardiac
Renal

Scarlet fever
This is due to a strain of Group A ~- haemolytic streptococci producing an erythrogenic exotoxin in individuals with
no neutralizing antibodies. The entry site is usually the pharynx (after tonsillitis).
Transmission Contact, droplets
Incubation 2-4 days post-streptococcal pharyngitis

• Fever, headache, sore throat, rigors, vomiting, anorexia

• 'White strawberry tongue' (white coating, red papillae), then
• 'Strawberry tongue' (bright red)

58
 • Flushed cheeks with circumoral pallor. Erythematous, coarse rash (feels like sandpaper) commencing on the neck,
spreading to the rest of the body (face, palms and soles usually involved), desquamation after 5 days
• School-age children

Diagnosis
• Throat swab (positive culture)
• ASOT (antistreptolysin 0 toxin) and anti-DNAse B present

Management
Oral penicillin for 10 days (erythromycin if penicillin allergic).

PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal

infections)
• Onset or symptom exacerbation of obsessive- compulsive disorder and/or tic disorders following Group A~-haemo­
lytic streptococcal infection (scarlet fever or streptococcal sore throat)
• Symptoms episodic

GRA~1-POSITIVE AND -NEGATIVE BACilli

59
Bacteria . Disease

G~~~r~ent~ritis
s. ·enteritidis < Enterocolitis,_food poisoning
S; _typhi Typhoid/paratyphoid .feVer
5. paratyphi Qsteomy~lit:K · ·
. __:_;·· ~:- · ::- :- ,- ,->·:_~'- . - ~·: ?' ' __:
Gastroenteritis
Gastritis (see p. 151)

. ... . ...
_ __ -; ·.
- -;•:--'
__.. _ _ ..·. -, .
__ __ . : ."

. . - ··_>;·: _ .··.··'·

Gastroerit~litis ·.· ··• ..... · ·...•...·.. · ·

Ga~tHtis:(seep~ · 151) .··. ·. ;

D!Prl'fHERIA
Organisms Corynebacterium diphtheriae, types mitis (mild disease), intermedius and gravis
Exposure of the bacteria to bacteriophage - results in 'toxin production and disease. The toxin has:
• Subunit A- produces clinical disease
• Subunit B - transports the toxin to target receptors
Transmission Droplets, fomites
Incubation 2-7 days

Clinical features
Local Thick grey membrane over tonsils, progressing to husky voice, dyspnoea and respiratory
obstruction
Systemic Fever, tachycardia, irritability
'Bull-neck' from lymphadenopathy
Other Day 10 acute myocarditis (usually fatal)
Myocarditis weeks later
Neurological, e.g. palatal paralysis, cranial nerve palsies, peripheral neuropathy.
Recovery usual
Cutaneous diphtheria (Cutaneous ulcers with covering membrane) seen in burns patients

Diagnosis
Clinical diagnosis and organism culture.

Managernent
• Antitoxin IV (NB: Only neutralizes unfixed toxin, anaphylaxis risk)
• Antibiotics IV, e.g. penicillin
• Supportive therapy as needed

USTERWSIS
Listeriosis (due to Listeria monocytogenes) can be severe in pregnant mothers, neonates and immunocompromised
individuals.

60
 Transmission Ingestion of unpasturized soft cheese, pate, raw vegetables and chicken
Diseases seen Neonates - pneumonia, meningitis, septicaemia (see p. 46)
Pregnancy - miscarriage
Immunocompromised - meningitis, septicaemia

Diagnosis
Blood or CSF culture.

Treatment
Antibiotics, e.g. ampicillin and gentamicin.

THAN US
Clostn"dium tetani produces disease via tetanospasmin (neurotoxin) .
.f
Transmission Direct contact onto open wound
Incubation 4-21 days

Clinical features
Generalized tetanus Malaise, trismus, risus sardonicus (fixed smile) within 42-72 h spasms, opisthotonus,
autonomic dysfunction
Localized tetanus Wound site pain and stiffness
Cephalic tetanus This occurs from entry via the middle ear, mortality nearly 100%
Tetanus neonatorum Features as for generalized disease, entry via umbilical stump, mortality nearly 100%

Diagnosis
Clinical.

Management
• Wound debridement, IV penicillin, antitetanus immunoglobulin IM
• Control of spasms, e.g. diazepam and systemic support as necessary

Tetanus immunization recommendations

61
GRAM-NEGATIVE BACilU
Cat scratch disease
Common worldwide infection due to Bartonella henselae.
Transmission: Scratch or contact from cat (especially kitten) , sometimes a dog
50% no history of scratch obtained
September-February mostly
Incubation: 3- 30 days

con1•ca I jearures
~ ~· r '

• Inoculation pustule/papule (lasts days-months)

• Conjunctivitis
• Regional lymphadenopathy (2-4 months)
• Well child (50%)
• Malaise, low-grade fever (50%)
• Other symptoms unusual (maculopapular rash, splenomegaly, hepatitis, th ro mbocytopenia, en cephalopathy with
convulsions)

Diagnosis
• History and primary inoculation site found
• Serology for B. henselae

Treatment
• Spontaneous recovery common
• Azithromicin effective for severe disease

Brucellosis
Brucella endotoxin produces disease symptoms.
Organism Brucella melitensis
Transmission Ingestion of raw milk (cows, goats, camels)
Also abraded skin, respiratory tract and genital tract entry
Incubation 1-3 weeks

Clinical features
Acute brucellosis Fever, headache, malaise, night sweats
Hepatomegaly, lymphadenopathy, splenomegaly (if severe), arthritis (33%, large joints,
oligoarticular), endocarditis, osteomyelitis, epididymitis, meni ngoencephalitis
Chronic brucellosis Tiredness, episodes of fever, depression, splenomegaly

Diagnosis
• Blood cultures (50% positive during acute phase)
• Serological tests (titre rise over 4 weeks, raised IgG)

Trealmen t
Cotrimoxazole high dose.

62
Typhoid fever
Organism Salmonella typhi
Transmission Ingestion food contaminated from faeces (humans only reservoir)
Common in Asia, Africa, S. America
Incubation 10-14 days

Clinical features
Week 1 Fever, malaise, sore throat, headache, abdominal pain, confused
Toxic child with relative bradycardia
Week 2 'Rose spots' (pink macules) on chest and upper abdomen
Splenomegaly (75%), toxic, confused, hepatomegaly (30%)
Week 3 Complications: seizures, pneumonia, myocarditis, gastrointestinal haemorrhage and perforation,
meningitis, peripheral neuropathy, haemolytic anaemia, glomerulonephritis, renal failure, osteomyelitis
Week 4 Recovery

Diagnosis
• Blood cultures (80% positive during week 1, 30% during week 3)
• Stool cultures (more positives after 2nd week)
• Urine cultures (positive with bacteraemia)
• Widal test (high titre of 0 antigens)
• Anaemia and leucopenia

Treatment
This depends on age and clinical severity. If unwell, IV antibiotics are given, e.g. cephalosporin or oral ciprofloxacin
if appropriate.
Carrier state - chronic carriers excrete sa lmonella for> 1 year (gallbladder often the focus) and may be treated with
4 weeks of antibiotic and, if .ineffective, cholecystectomy.
Paratyphoid fever is a similar, milder illness caused by 5. paratyphi A, B or C. Treatment is co-trimoxazole for 2 weeks.

OTHER BACTERIA

63
Mycoplasma
Mycoplasma pneumoniae is unusual in that it is the smallest organism that can survive outside a host cell
and has no cell wall. The most common condition it causes is a bronchopneumonia in school-age children and
adolescents.
Transmission Droplet
Incubation 10-14 days

Ciin ical features

Bronchopneumonia Gradual onset mild URTI, then persistent cough, fever, malaise, headache, wheeze
Young school-age children. Resolves within 3-4 weeks.
Other features Skin rashes (maculopapular erythematous, vesicular) common
Vomiting, diarrhoea, arthralgia, myalgia (common)
Bullous myringitis, haemolytic anaemia, Stevens-Johnson syndrome
Hepatitis, pancreatitis, splenomegaly
Aseptic meningitis, encephalitis, cerebellar ataxia, Guillain-Barre syndrome

Blood Serology (specific IgM antibody)

Cold agglutinins (in 50%)
CXR Diffuse patchy shadowing, often looks unexpectedly severe

Tre atrnent
Erythromycin 2 weeks.

Tuberculosis
Infective agent Usually Mycobacterium tuberculosis (an acid- and alcohol-fast bacillus).
• TB is on the increase in the UK, particularly London as a result of the widespread migration of people from Asia
and Africa ·
• The clinical features depend greatly on the host reaction. If there is a good immune response the infection
is locally contained and can become dormant. Small numbers of organisms may spread via the bloodstream
and infect other organs. If there is a poor immune response the infection becomes overwhelming and dissemi-
nated
• In children, tuberculosis is usually a primary infection (rarely becoming disseminated), whereas in adults it is
usually a reactivation of previous pulmonary infection
• The amount of TB organisms in primary TB in children is vel}' small
• The lung manifestations are mostly due to a marked delayed hypersensitivity reaction
• Children are usually infected from an adult with active pulmonary TB
• Children with primary TB are generally not infectious

Primary infection
Asymptomatic pulmonary TB infection
• A primary complex develops: a small local lung parenchymal area of TB infection and regional lymph node
involvement
• This is asymptomatic

64
 • On CXR the lymph nodes are usually visible but not the TB focus
• The MantouxjHeaf test may become positive (in which case anti-TB medication should be given)
• It becomes dormant and goes fibrotic. The lung focus may calcify over a couple of years and may then be visible
on the CXR
• NB: This can reactivate later in life and develop into highly infectious 'open' pulmonary TB, and should therefore
be treated
Symptomatic primary pulmonary TB
• Enlargement of the primary complex (in around 50% of children), i.e. local lung reaction+ regional lymph nodes,
visible on CXR (the lymph nodes but not the lung TB focus)
• Child becomes symptomatic after 4-8 weeks when the immune system responds : wheeze, cough, dyspnoea, fever,
anorexia, weight loss
• Local pulmonary complications can occur from: Obstruction of a bronchus (due to lymph nodes) - cough,
localized wheeze
Rupture into a bronchus - bronchopneumonia, bronchitis
Rupture into pleural cavity- pleural effusion
• This is treated with anti-TB medication
• It may become dormant (and may reactivate later) going fibrotic, and calcifying over a couple of years when the
lung focus is visible on the CXR
• Small numbers of bacilli may escape into the bloodstream and lodge in other sites where they can cause abscesses
or spontaneously become dormant, e.g. the kidney
• Sometimes this primary infection is not contained by the immune system and spreads (see below)
• NB: It is the immune response mounted by the child that is primarily responsible for the lung manifestations.
Only a few organisms may be present, but release of organisms with rupture causes a marked hypersensitivity
reaction, as delayed hypersensitivity to TB has developed by this time (4-8 weeks post-infection)

Massive JB spread (acute miliary TB)

• TB will rarely enter the bloodstream (from the primary infection - lung or other, or from reactivation of dormant
TB)
• This can result in a few tubercles that can lodge in other organs, e.g. kidney, and spontaneously become dormant,
or form a local abscess
• Or it can result in disseminated TB, which has a high mortality if untreated
• Disseminated infection is more likely in children < 4 years, with malnutrition and immunosuppression
Features of disseminated TB:
Acute miliary TB. Acutely unwell, fever, weight loss, hepatosplenomegaly, lymphadenopathy, widespread internal
organ infection including: :
• TB pericarditis - a constrictive pericarditis
• Renal TB
• Bones and joints - osteomyelitis, infective arthritis
'Mi liary' picture on CXR, i.e. scattered white dots throughout the lung fields

65
 TB meningitis A slow, insidious onset of meningitis
Night sweats, weight loss, malaise
Symptoms of meningeal irritation occur later

Late reactivation
Dormant TB (post-asymptomatic or symptomatic) can reactivate any time, usually during intercurrent illness or
immunosuppression, causing post primary TB. This can be:
- • Disseminated TB (as above)
• Open 'pulmonary' TB which is very infectious. This generally occurs in adults, with an approximate life-long risk
of 5-10%

Diagnosis
TB is an elusive disease. There are two main forms of investigation:
1. Direct detection of bacilli (microscopy, PCR)
2. Assessment of host immunity
Ideally all TB would be diagnosed by visualization of the bacteria; however, this is rarely the case. More frequently
diagnosis is made through a combination of radiological findings and evidence of host immunity to the organism.

Immunological tests ·
The immunological test is the Mantoux test.
• Atest of delayed hypersensitivity to tuberculin using an intradermal injection of purified protein derivative (PPD)
of tuberculin on the forearm
• The presence of induration is measured at 48- 72 h
• A positive Mantoux is> 10 mm induration (indicating active infection)
• Interpretation is however variable depending on the individual estimated risk of TB
Other immunological investigations are being developed such as interferon-r release from T cells in response to myco-
bacterial antigens.

Direct detection of organisms

Brorichostopy ....· . •. . . . .·
Coughed up .sputum( older child) •··.

66
 PRIMARY TB INFEffiON

Asymptomatic
and contained
Usually lung Usually lung
(primary complex only) (Primary complex enlarges)
May be other sites May be other sites, e.g. bone, gut, skin
Symptoms due to immune reaction at 6-8 weeks
Further symptoms possible from local pulmonary complications

Few numbers escape to Large numbers in bloodstream

bloodstream and lodge Overwhelming infection
Treated Treated elsewhere, e.g . kidney -Miliary TB
if Mantoux positive - TB abscesses
- May spontaneously become
dormant or be treated

t
Treated Treated
Die

Treated or becomes dormant

t

Post-primary TB

t
Pulmonary TB Disseminated TB

Figure 3'.2 Management of primary TB infection

Management
1. Mantoux positive but no other evidence of disease: isoniazid or rifampicin + pyrazinamide for 3-6 months (two
agents given if concern about multiresistance)
2. Evidence of infection in addition to a positive ,Mantoux test:
For pulmonary disease - 6 months combination therapy
For disseminated disease- 12 months therapy
Combination therapy is used with various combinations of isoniazid, rifampicin, pyrazinamide and
ethambutol
67
 Prevention
• Vaccination with the BCG (Bacille Calmette-Guerin, a live attenuated strain) gives up to 75% protection.
• This is now recommended for neonates in high-risk groups, i.e. most infants in London, and Asian and African
populations, and at 10- 14 years to tuberculin test-negative children

Isoniazid Increased effects in slow acetylators

Skin rashes and hepatoxicity (rare in children)
Psychosis rarely occurs (due to pyridoxine deficiency)
Rifampicin Liver enzyme inducer
Pink/orange secretions, 4-8 h
Skin rashes, gastrointestinal upset and hepatotoxicity (rare)
Pyrazinamide Skin rashes, gastrointestinal upset and hepatotoxicity
.· ness,' ' blurre~ _ vision, sc?tc>~a) . _. :
·· _ lmological opim _with vi"s[¥·ac'uity ass,essln'ent must be done
.. in< 7~8 y~ars asyoung ' chlldr~ n. "rjot ca pable :of_reporting vi

Leprosy
Organism Mycobacterium leprae. Acid and alcohol- fast, weekly Gram-positive bacilli
Transmission Uncertain
Incubation Months-years
Found in Asia, Africa, the USA and Russia. The clinical disease is dependent on the immune status
of the individual.

· Tuberculoid leprosy (TL) Good immune response mounted

A single hypopigmented skin lesion wit h decreased sensation , central atrophy and a
thickened, tender nerve
Lepromatous leprosy (LL) Poor cell-mediated immunity
Many florid skin lesions
All internal organs may be involved
Nasal snuffles, saddle nose deformity, leonine facies, hoarse voice, fingers disappear,
peripheral neuropathy
Intermediate forms Borderline leprosy, indeterminate leprosy, ne uritic leprosy (nerve lesion only)

Investigations
Clinical diagnosis
Organism isolation Acid-fast bacilli found in skin or nasal mucosa smears
NB: Organism cannot be cultured in artificial media
Culture In mouse foot pad
Lepromin test This is a measure of host resistance to disease. Dead bacilli are injected intradermally

rreatment
Multidrug regimens, e.g. dapsone, rifampicin and clofazimine, for at least 2 years.

68
Syphilis
Organism Treponema pallidum
Transmission Sexual contact, transplacentally (congenital syphilis, see p. 452)
Incubation 10-90 days

Clinical features
Early stages Primary (3 weeks) Painless hard chancre, regional lymphadenopathy
Secondary (4- 10 weeks) Fever, malaise, sore throat, arthralgia, myalgia
Maculopapular, itchy rash, mucosal ulcers
Condylomata lata (perianal plaque warts)
Late stages Tertiary (years) Gummas (granulomatous ulcers) in bones, liver, testes
CNS disease (meningovascular involvement, general paralysis of the
insane, tabes dorsalis)
Cardiac disease (aortitis, aortic regurgitation)

Diagnosis
Dark ground microscopy From chancres or mucous ulcers
Serology VORL (Venerea l Disease Reference Laboratory) :
• Positive 3 weeks of infection, negative 6 months after treatment
• Fa lse positive: EBV, hepatitis, mycoplasma, malignancy, autoimmune disease
TPHA (T. pallidum haemagglutination assay). Specific for treponema, remains positive
FTA-ABS (fluorescent treponema antibodies). Specific for treponema

Treatment
This is dependent on the stage. Penicillin is given via the IM route (long-acting) for some stages or IV route, e.g. for
CNS disease.

Lyme disease
Organism Borellia burgdotferi
Transmission Ixodid ticks on deer (or sheep, cattle, dogs or squirrels), Europe, the USA, Australia, Asia
Incubation 7-30 days

Clinical features
Within days Erythema chronicum migrans (painless, red annular rash slowly enlarging) from site of tick bite
Headache, conjunctivitis, malaise, fever, arthralgia, myalgia, lymphadenopathy
Weeks to months later CNS 15% (meningoencephalitis, cranial and peripheral nerve palsies, especially VIIth nerve palsy)
Cardiac 10% (myocarditis, heart block)
Recurrent arthritis (oligoarticular, episodic, often the knee with erosion of bone and cartilage)
Other (myelitis, hepatitis, hepatosplenomegaly)

Diagnosis
This is a clinical diagnosis.
Organism isolab"on Serum, CSF, skin biopsy (difficult)
Serology IgM antibodies in CSF and serum may be positive after 3-6 weeks

Treatment
For early general symptoms, oral antibiotics (amoxicillin or erythromycin if< 9 years, doxycycline if> 9 years). If CNS
or articular involvement, give ceftriaxone.

69
Typhus
Organism Rikettsiae (small bacteria that multiply intracellularly and cause a vasculitis)
Transmission Human lice (epidemic), rat flea (endemic) in tropical areas
Incubation 1-3 weeks

Clinical features
Epidemic typhus:
Week 1 Profound malaise, high fever, severe headache, orbital pain, conjunctivitis. Measles-type rash on day 5,
becoming purpun"c
Week 2 Meningoencephalitis, myocarditis, pneumonia, splenomegaly, gangrene of peripheries, renal failure; death
may occur
Week 3 Slow recovery
NB: Recurrence years later= Brill-Zinsser disease (from lymph node storage) .
Endemic typhus- similar but milder disease

Serology.

Treatrnen t
Oral tetracycline.

Rocky Mountain spotted fever

Organism Rikettsia n"kettsii
Transmission Tick on dogs and rodents in America
Incubation 1- 2 weeks
Clinical features As for epidemic typhus. NB: Crusted papule at bite site
Diagnosis Serology
Treatment ·retracycli ne

PROTOZOAL INFECTIONS

70
Malaria
Malaria is found in all countries between latitude 40 Nand 30 S, and there are four species: Plasmodium vivax, P. ovate,
P. malan·ae and P. falciparum.
Transmission Anopheles mosquitos
Incubation 18 days-6 weeks Pl. malan"ae
10-14 days All others

1. Injection of parasite
Female mosquito

/
SPOROZOITES - - - - - ,

2. Multipli~tion
the liver
in 1
Multiplication in the liver
I Hypnozoites (latent)
(not Pl. falciparun)
Schizont
t
Merozoites
\ 5. Mosquito
fertilization in
3. RBC Invasion
stomach and
\ sporozoites formed
Trophozoites
\
Schizont

~
MEROZOITES
/
4. GAMETOCYTES
(person infective)
RBCrupture ~

Figure 3.3 Malaria parasite lifecycle

Clinical features
General
Intermittent fevers Due to schizont rupture:
• Cold stage {lh - 1 h, vasoconstriction, rapid temperature rise, patient feels cold)
• Hot stage (2- 6 h, patient feels hot, delirium)
• Sweating stage (profuse sweating, patient sleeps)
Other Anaemia, splenomegaly, hepatomegaly
P. vivax and P. ovale Mild disease, young RBCs and reticulocytes only affected. NB: Relapses and difficult to
eradicate due to latent phase
P. malan"ae Mild, chronic course, growth retardation, massive splenomegaly, old RBCs only affected.
Nephrotic syndrome may occur
P. falciparum Most severe form, all RBCs affected and become sticky to endothelium, causing vascular
occlusion and ischaemic organ damage (brain, kidneys, liver, gastrointestinal tract)
Worse if high parasitaemia (> 2%)
Complications:
• Cerebral malaria, fits, hyperpyrexia
• Acute renal failure (Blackwater fever)
71
 • Shock, metabolic acidosis, DIC, jaundice
• Severe anaemia
• Hypoglycaemia, splenic rupture
Diaanosis
Thin and thick peripheral blood smears (parasites seen with staining). Three negative smears on three successive days
required to declare malaria-free. NB: Consider malaria in any febrile child returning from an endemic area.

Treatrnent
Acute attack Disease-type specific oral medication given and because resistance is increasing, up-to-date
therapy advice should be obtained from the malaria reference laboratory
In severe disease (< 2% RBCs) IV quinine infusion and intensive care as necessary
If infective species unknown or mixed, initial treatment as for Falciparum malan"ae
Eradication Primaquine for 2- 3 weeks after acute treatment (NB: Not if G6PD deficiency present)
(for P. vivax and P. ova/e)

Prevention
Prophylaxis Drugs taken 2 weeks prior to entering malaria area and for 6 weeks after return. Resistance
affects choice of drugs, so up-to-date advice should be obtained
Drugs used (sometimes in combination) are: chloroquine (weekly), proguanil (daily),
maloprim (weekly), mefloquine (weekly), doxycycline (daily, not if< 12 years old)
Natural protection This is present in people with: Duffy-negative blood group (P. vivax), HbS and (partial) G6PD,
thalassaemia, PK deficiency (P. faldparum)

Amoebiasis
Organism Entamoeba histolytica
Transmission Faecal-oral (cysts transferred). Tropics and sub-tropics

Clinical features
In the intestine, trophozoites emerge from the cysts and multiply in the colon producing symptoms:
Amoebic colitis Colonic mucosa invaded, ulcers, bloody diarrhoea, amoebic granulomas (10%). Acute amoebic
dysentery may occur
Hepatitis Travel of trophozoites via portal vein
Amoebic 'anchovy sauce' liver abscesses, high mortality
Asymptomatic cyst carn"er

Diagnosis
'Hot' stools Trophozoites and cysts seen
Serology Amoebic fluorescent antibody titre (FAT) positive in symptomatic disease
Liver USS Abscess
Liver function Alkaline phosphatase - (in liver abscess)

Treatment
Metronidazole orally. Drainage of liver abscesses.

Giardiasis
Organism Giardia Iamblia
Transmission Faecal- oral, spreads easily in nurseries and institutions

72
Clinical features
Asymptomatic carrier
Gastroenteritis Abdominal pain, watery diarrhoea, vomiting
If prolonged: malabsorption, steatorrhoea, weight loss, growth retardation

Diagnosis
Isolation

Treatment
'Hot' stool (trophozoites and cysts) (20% pick up rate only)
-
Metronidazole orally for 5-7 days (20% resistance rate).

Toxoplasmosis
r·~
Organism Toxoplasma gondii (intracellular protozoan) >'-..J'--
\..1.Jv'\.
Transmission Faecal-oral from cat faeces, sheep, pigs or goats
/~,v/'" 4~- ·~\.\
Clinical features v OJ c-/..~1./
(_j ~
This may present as: 'If<_ ..~ "-
1. Lymphadenopathy ~ ~~
2. Acute febrile illness with Lymphadenopathy \(}--'\\' \
3. Immunocompromised - headache, neck stiffness (ICP I), intracerebral Lesions, acute febrile i~lness, ,o\ ~\.--
hepatosplenomegaly, chorioretinitis, sore throat \(~ · \
4. Congenital infection - classical triad of choreoretinitis, hydrocephalus and cerebral calcification (see p. 449)

Diagnosis
Serology- rising antibody titre, IgM.

Treatment
None if mild disease. Pyrimethamine and sulphadiazine in severe disease and pregnancy.

FUNGAl INFECTIONS

73
HELMINTHIC INFECTIONS

INTESTINAl NEMATODE INFECTIONS

74
FURTHER READI NG
Department of Health Immunisation Against Infectious Disease, Manual on Immunisation Practices in the UK, HMSC
London, 1997 · ·
Feigin RD, Cherry JD Textbook of Pediatric Infectious Diseases, 5th ed n. Philadelphia: WB Saunders, Philadelphia
2003
Isaacs D, Moxon REA Practical Approach to Paediatric Infectious Diseases. Edinburgh: Churchill Livingstone, 1996
Long SS, Pickering LK, Prober CG Principles and Practice of Pediatric Infectious Diseases, 3rd edn . Philadelphia : W
Saunders, 2007
I

75
• Physiology • Structural congenital heart disease
• The ECG • Duct-dependent circulations
• Cardiac positions • Arrhythmias
• Innocent murmurs • Rheumatic fever
• Heart failure • Infective endocarditis
• Eisenmenger reaction • Myocarditis
• Teratogens and maternal disorders associated with CHD • Cardiomyopathy
• Inherited conditions associated with CHD • Pericarditis

76
PHYSIOLOGY

FETAL CIRCUlATION
Pulmonary artery

Superior vena cava - - - - -- f

Aorta

Lung Lung

Ductus arteriosus

Pulmonary vein

+ - - - - Descending aorta

Right ventricle ------1'--+------'~~­

lnferior v e n a - - - -- -+
caval return

Hepatic portal vein _ _ __ - - - - - - - h - J r - - - - - Oxygenated blood

to inferior vena cava
via the ductus venosus

Internal iliac arteries

Oxygenation in
the placenta
Umbilical arteries

Figure 4.1 Fetal circulation

77
CARDIAC CYCLE
120

Ol
I
E
E

Atrial systole R

p
_ _ _ _ _!\_
ECG
T
Ventricular diastole
s
Figure 4.2 Cardiac cycle: * = ejection click; t = opening snap

HEART SOU NOS

First heart sound (51)
Loud 51 seen with: High cardiac output state, e.g.: Anxiety
Exercise
Fever
Thin chest
Thyrotoxicosis
Vasodilatation
Mitral stenosis
Soft 51 seen with: Obesity
Emphysema
Impaired left ventricular function

Second heart sound (A2 P2)

Soft P2 (Fig. 4.38) Stenotic pulmonary valve, e.g. Fallot
Loud P2 (Fig. 4.3C) Pulmonary hypertension
Normal splitting (Fig. 4.30) Children
Young adults
Wide mobile splitting (Fig. 4.3E) Pulmonary stenosis
Pulmonary hypertension
RBBB
78
Reversed splitting (Fig. 4.3F) Aortic stenosis
LBBB
HOCM
Wide fixed splitting (Fig. 4.3G) ASD

A Normal
I ~~
81 A2 P2

B Soft P2
~ ~-
u
81 A2 P2

C Loud P2
S1 A2 P2
EXPIRATION INSPIRATION
D Normal splitting
I ~ ~~
E Wide mobile splitting ~
~I ~I
F Reversed splitting
I I~ d
G Wide fixed splitting
~ ~I ~I
Figure 4.3 Heart sounds

Third heart sound (53)

Due to rapid ventricular filling.

Causes ,
• Normal (in children, athletes and pregnancy)
• Increased left ventricular stroke volume (aortic regurgitation, mitral regurgitation)
• Restrictive ventricular filling (constrictive pericarditis, restrictive cardiomyopathy)
• Ischaemic heart disease

Fourth heart sound (54)

Due to forceful atrial contraction.

Causes
• HOCM
• Long-standing hypertension
• Ischaemic heart disease

79
JUGW.. AR VENOUS PU LSE (JVP)

a = atrial systole
a x1 atrium begins to relax
c onset of ventricular contraction
v atrial filling in ventricular systole
X atrial relaxation commencing
y y tricuspid valve opens and
ventricle relaxes

Figure 4.4 Jugular venous pulse

Changes in the JVP

.-_· c~·~strictiv~- peri~-arditis··

Tricuspid regurgitatlon .

NOHMAl VITAl SHiNS - AGE RELATED

Ref: Duke J, Rosenberg SG Anesthesia Secrets, Hanley & Belfus, Mosby, 1996.

80
,-

CARDIAC CATHETERiZATION DATA

Key

B = Blood pres~ure
Q = Oxygen saturations

Figure 4.5 Cardiac catheterization data

CXR SILHOUEITE
CARDIAC SCARS
:Scar · Cause . Left brachial pulse .
Left _tho-racotomy (only) PDA ligatior1 .<;· ~ _ :: :·;;
Blalock.:Tauss1g shunt · . · ·- . ..
Coarct~tion repaif(left.subclavian flap)
Pulmonary.artery: ba'ndi ng '.
Non~tardia-c . . -~>. --.>_)> ··.. ,: N
Right!. s(at6ckiTa~~sig shunt N
NOrl ~-C-iiidlat' -.·- --· -. -._ N
Median sternotomy Any ~o~recti~ri N

THE ECG
R

QT
Figure 4. 7 ECG

RATE
The heart rate varies with age (outlined above). It is calculated by noting the number of large squares between QRS
complexes:
1 large square = 300/min
2 large squares= 150/min
3 large squares= 100/min
4 large squares= 75/min
5 large squares= 60/min
NB. 5 large squares= 1 s, 1 large square= 0.2 s

82
AXIS
The cardiac axis is the average direction of spread of the depolarization wave through the ventricles (as seen from thE
front) and it changes from right and anterior in infants to left and posterior in adults.

(-30)
. \

AVL \
I
-30" I
\

(180)
+ + 180. f-"-'-~----"-=-;.*'---:'-'-':-~'7':;--':-:1 0. I
\
\

(+90) -+----
Figure 4.8 Cardiac axis

The axis can be derived by noting the direction of the QRS complexes in leads I, II and III. It can also be estimated
by observing the direction in leads I and AVF (though this is less accurate).
The axis may be normal, left axis deviation (LAD) or right axis deviation (RAD). A superior axis is seen when the S
wave > R wave in AVF.

Normal Left axis Right axis

axis deviation deviation

LEAD I l- J_

LEAD II J_
LEAD Ill
+
t
Figure 4.9 Calculating the cardiac axis

83
Normal in children Primum ASD Primum ASD
RVH LVH AVSD
RBBB LBBB Tricuspid atresia
Secundum ASD AVSD Noonan syndrome
Double inlet left ventricle
Familial
Myocarditis

HEART BLOC!(

FIRST DEGREE BLOCK

p p

SECOND DEGREE BLOCK

1. Mobitz type I (Wenkebach)
p p p p

The PR interval gradually increases until

it does not conduct to the ventricles

2. Mobitz type II
p p p
pt--
The P waves that do not conduct to the
ventricles are not preceded by a gradual
PR prolongation
3. 2:1 AV block
p p p p p

THIRD DEGREE (COMPLETE) BLOCK

p p p p p p

No relation between P waves and QRS complexes

Figure 4.10 Heart block

84
BUNDLE BRANCH BLOCK
Right bundle branch block (RBBB) (Fig. 4.11a) A. RBBB B. LBBB

The left ventricle and septum are activated normally and the right v,
ventricle has a slower conduction spreading from left to right. ECG
features include:
I
• QRS complex is prolonged 1....-. AI J

• An RSR pattern in the right precordial leads

\ \V

Left bundle branch block (LB BB) (Fig. 4.11b) RSR(W) M pattern
The septum depolarizes from right to left and the left ventricle relies
pattern in V1 in v6
on late transmission of the activation wave. ECG features include: Figure 4.11 (a) Right bundle branch block.
• QRS complex prolonged (b) Left bundle branch block
• Lead Vl negative and V5-V6 mostly positive with an Mpattern
NB: With complete LBBB or RBBB, ventricular hypertrophy and ischaemia changes cannot be interpreted from the
ECG.

VENTRICULAR HYPERTROPHY

Left ventricular hypertrophy (LVH) (Fig. 4.12a)

This is difficult to predict accurately from the ECG and so it is best to have a combination of criteria, which include:
• R wave amplitude in V5-V6 higher than the 98th centile for age (NB: voltage criteria for LVH are not very exact)
• 5 wave in Vl
• Lateral t wave inversion (strain pattern, in V5-V6 and II, III and AVF)
• LAD

A. LVH B.RVH

v,

-J
""
v- "'
I

(a) In V5 or V6 there is a tall R wave (a) In V1 the height of the R wave

(>25 mm in adults) is > the depth of the S wave

v, ./'- 0 v6

r-

(b) In V1 or V2 there is a deepS wave (b) In V6 there is a deepS wave

Figure 4.12 (a) Left ventricular hypertrophy. (b) Right ventricular hypertrophy

85
Right ventricular hypertrophy (RVH) (Fig. 4.12b)
ECG features include:
• Rwave amplitude in Vl > 98th centi le for age
• Abnormal T wave direction in Vl (NB: the T wave direction changes with age: it is upright in newborns, negative
> 7 days of age, then becomes positive again in adolescents and adults)
• S wave depth in V6 is lower than the 98th centile for age
• In marked RVH the Rwave is big and the T wave inverted (a strain pattern)

I~
\
\1
v

Figure 4.13 Effects of hyper- and hypo-kalaemia on the ECG

CARDIAC POSTIONS
The classification of the normal and abnormal cardiac positions involves looking at the visceroatrial situs and the
apex of the heart.

VISCEtWAHUAl SITUS
Situs solitus Viscera normal, lungs normal, atria normal
Situs inversus Viscera reversed, lungs reversed, atria reversed
Situs ambiguous (isomen"sm) Asplenia syndrome (right isomerism)
No spleen, central liver, two right Lungs
Polysplenia syndrome (left isomerism)
Multiple small spleens, no intrahepatic portion of IVC
Bilateral left lungs
NB: Isomerism (right worse than left) is usually associated with severe congenital heart disease.

86
APEX Of THE HEART
Laevocardia Normal (apex points to the left)
Dextrocardia Apex points to the right
The following combinations are associated with severe congenital heart disease:
• Situs solitus + dextrocardia
• Situs inversus + laevocardia

ECG in dextrocardia
The p waves are negative in lead I and reflect the position of the atria. The chest leads V1-V6 show right ventricular
complexes.

ECG in dextrocardia

II
f--+----+--l----1
Ill
f--+----+-t----1
VR VL VF 1--+--+--l----1

A
I v
'

~nr
~

,( 11
v '

Figure 4.14 ECG in dextrocardia

INNOCENT MURMURS
These are heard in 30% of children. There are two types:
Ejection murmur
I
Due to turbulent flow in the outflow tracts from the heart
A buzzing or blowing quality in the 2nd- 4th left intercostal space
Venous hum Due to turbulent flow in the head and neck veins
A continuous low-pitched rumble heard beneath the clavicles
Disappears with compression of ipsilateral jugular veins or on lying down

Specific features
• Soft
• Change with altered patient position
• More pronounced if child tachycardic
• Child asymptomatic
• Normal examination: Normal heart sounds
No thrill or radiation
Normal pulses
• Normal CXR and ECG

87
 .•. ,

;_ :-.

HEART FAilURE
. . . .
~~~ ~~ '

Sweatin~g · 'TachypJt()~a; -irtercostal ahd subcostaL recession

Po~r feediri~- ·
. . . - .- -·· .
· : Tachyiardil
_·:-_ · . . ·:_:·::·,._._._

Faltering groV-ith Cardi~megaly ·

Sh()rtriess ofbreath. (SOB) .

' - . '
Hepatb_rneg~ly
Recurre~t· ch~~t infections Gallop rhyth m/murmur/muffled heart sounds
.
A9dominal p~iri (big ·liver)
.

Centr~l cyanosis

.cd6Cp~-B~h·eAe~ ._ . . .
(NB: Hi'rtgsofi'ellsound clear in children/neonates)

CXR
Prominent pulmonary markings and cardiomegaly. NB: An important exception is with infradiaphragmatic TAPVD where
the heart size is normal and therefore this can appear like primary lung disease.

Management
Sit patient up
Give oxygen
Diuretics E.g. frusemide (with potassiu m supplements), spironolactone (reduce preload and afterload)
Inotropes For acute heart failure use IV dobutamine (peripherally) or dopamine (centrally)
If less severe, oral digoxin may be used
Vasodilators E.g. captopril and hydralazine (reduce afterload)
Intubation and If necessary
ventilation

EISENMENGER REACTION
This is when persistently increased pulmonary blood flow leads to increased pulmonary artery vascular resistance,
pulmonary hypertension and, eventually, reversal of a previous left-to-right shunt. When this is due specifically to a
VSD, it is called Eisenmenger syndrome.
The Eisenmenger reaction is becoming rarer as the diagnosis of CHD improves and there is earlier management.

Causes
VSD, AVSD, PDA, ASD (rare) and any other condition with a communication between PA and the aorta.

Clinical features
• Progressively worsening cyanosis, malaise, dsypnoea and haemoptysis
• Right ventricular heave
• Loud P2

88
ECG
o RVH
• P wave tall and spiked

CXR
• Prominent pulmonary artery with peripheral tapering of pulmonary vessels
• Cardiomegaly
• May be normal

Management
Medical Symptomatic treatment (oxygen, calcium channel blockers)
Surgical Heart-lung transplant or bilateral lung transplant with repair of the cardiac defect

TERATOGEN$ AND MATERNAL DISORDERS ASSOCIATED WITH CHD

89
INHERITED CONDITIONS ASSOCIATED WITH CHD

··... : .... . · :

Patau·syndrcmie
-rtN~·kr · $yJ1dro"~e
-ch~o~6sO'me
. . . . . . .-· .. ..
·
n. microdeletion.

STRUCTURAL CONGENITAL HEART DISEASE

The incidence of structural congenital heart disease is 8 in 1000. Recurrence risk is 3% if one child affected, 10% if
two children affected and 25% if three children affected.
It can be divided into acyanotic conditions and cyanotic conditions. If CHD is suspected the child should be inves-
tigated with a CXR and ECG initially, then an echocardiogram with Doppler ultrasound to outline the defect(s).
Cardiac catheterization may be used for presurgical evaluation, evaluation of pulmonary vascular resistance, to moni-
tor progress after surgical intervention and as a therapeutic tool in interventional cardiac catheterization, e.g. balloon
dilatation, embolization and closure of intracardiac defects.

ACYANOTIC CONGHHTAL HEART DISEASE

Ventricular septal defect {VSD)
This comprises 32% of CHD, being the most common form . There are several types of VSD that may be classified as:
• Inlet
• Muscular
• Perimembranous
• Outlet
• Doubly committed
The symptoms and signs depend on the size of the hole and any other cardiac defects present. Large ones and outlet
VSDs are less likely to close spontaneously.

90
i
!

Murmur

lv\NvV1AI
\%{
81 A2 P2

Figure 4.15 Ventricular septal defect

Clinical features
• Asymptomatic murmur
• Features of cardiac failure
• Recurrent chest infections
• Endocarditis
• Cyanosis (Eisenmenger syndrome) may develop 'at 10-20 years (only in untreated large VSDs)

Signs
Murmur Loud pansystolic murmur
Lower left sternal edge (LSE)
Parasternal thrill
± Mid-diastolic apical murmur (due to increased mitral flow) if large defect (smaller holes may
have shorter, louder murmurs)
Heart sounds Loud PZ if pulmonary hypertension

ECG
Normal or LVH (RVH if pulmonary hypertension).

CXR
• Cardiomegaly and increased pulmonary vascular markings
• May be normal
NB: Important findings in pulmonary hypertension:
' on the ECG
• RVH
• Loud PZ

Management
Treat cardiac failure if present: oxygen, sitting up, diuretics (frusemide, spironolactone, ACE inhibitors, thiazides), digoxin.
Surgical repair is required in < 10% as most will dose spontaneously during the first few years of life. Repair is needed if:
• Severe symptoms with failure to thrive
• Pulmonary hypertension develops
• Aortic regurgitation develops
• Persistent significant shunting > 10 years of age

91
 Atrial septal defect {ASD)
There are two types of ASD: ostium secundum and ostium primum.

Ostium secundum
This is the most common form of ASD and involves a defect(s) in the atrial septum. The defects may be single or multiple.
Associations Holt- Oram syndrome
Clinical features Asymptomatic (commonly)
Heart failure (rare until adult life)
Atrial arrhythmias (onset at 30-40 years)
Signs Murmur:
• Ejection systolic
• Upper LSE (due to increased RV outflow)
• ± Mid-diastolic tricuspid flow murmur at the lower LSE (due to increased tricuspid flow)
Heart sounds: fixed wide splitting of the second heart sound
ECG RAD )
Partial RBBB (in 90%) NB: All right
RVH
CXR Cardiomegaly, large pulmonary artel'J', straight left heart border and increased pulmonary
vascular markings
Management Elective ?Urgical or transcatheter device closure performed at 3-5 years (earlier if necessary) if
child is symptomatic. Small defects will usually close spontaneously

Ostium secundum atrial septum defect

Murmur

S1 A2 P2

lAD INMw- I Fixed

Figure 4.16 Atria l septal defect

. .
0st1UlTI pr;rnurn
Here there is failure of development of the septum primum (which divides the mitral and tricuspid valves) and usually
also a cleft in the anterior leaflet of the mitral valve.
Associations Down syndrome and Ellis-van Crevald syndrome
Clinical features Many asymptomatic (if small defect)
Heart failure and recurrent pneumonias (severity depending on A-V valve regu rgitation)
Signs As for ostium secundum with a mitral regurgitation murmur (apical, pansystolic)

92
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _.._~------------------------------------------------------------------
 ECG LAD or superior axis
Partial RBBB
RVH
Management Surgical repair is always required

Atrioventicular septal defect (AVSD)

Association - common in Down syndrome
Atrioventricular septal defect (also known as A-V canal defect or endocardial cushion Atrioventricular defect
defect) is a severe form of CH D where there is a contiguous atrial and ventricular
septal defect and defects of the mitral and tricuspid valves. (There are variable
degrees of severity of AVSD.)

Clinical features
Usually severe with early development of heart failure, recurre-nt pneumoilias, falter-
it ing growth and pulmonary hypertension due to the large left-to-right shunt across
both the atria and the ventricles. Some right-to-left shunting may also occur.

ECG
LAD or superior axis and biventricular hypertrophy.

CXR
Large heart with pulmonary plethora Figure 4.17 Atrioventricular
septal defect
Management
Repair is usually needed within 6 months to prevent the development of pulmonary hypertension.

Patent ductus arteriosus (PDA)

Associations Sick premature neonates
Maternal warfarin and phenyto jn therapy-
Congenital rubella
Commoner in girls

Clinical features and signs

Preterm infants Systolic murmur at the left sternal edge
' Collapsing pulse (visible brachial artery)
Heart failure
Older children Continuous murmur beneath
the left clavicle, 'machinery
murmur' (continuous because
the PA pressure is always lower
than the aortic pressure)
Collapsing pulse,
'waterhammer pulse' (systolic Murmur
pressure = twice the diastolic S1 A2 P2
pressure). If severe there is . ,. -~

heart failure and eventually -

~
--~

,;.,
.
.

pulmonary hypertension ~

Figure 4.18 Patent ductus arteriosus

93
rrr
Ll.U

• Usually normal
• May show LVH (or RVH if pulmonary hypertension)
• Indistinguishable from VSD

[){l?

• Increased pulmonary vascular markings

• May be normal

Neonate Fluid restrict

Indomethacin if< 34 weeks' gestation and within 3 weeks of birth (check renal function, platelets
and predisposition to NEC)
Surgical ligation if failure of medical management
Older child Transcatheter device occlusion or surgical ligation
NB: PDA must be closed even if asymptomatic because of the risk of endocarditis.

Pulmonpry stenosis (PS)

Associations Noonan syndrome
Maternal warfarin therapy

Clinical features
• Usually asymptomatic
• Right heart failure
• Arrhythmias (later in life)
NB: In neonates critical pulmonary stenosis presents as a duct-dependent circulation with cyanosis.

Signs
Murmur Ejection systolic
Upper left intercostal space Murmur

Heart sounds
No carotid radiation
No carotid thrill
Right ventricular heave
Ejection click
1.!~··
·~
..
.~::.·.
.·.•
.:
2p
-·· I
2

If severe: delayed P2 and soft P2 EC == Ejection click

Figure 4.19 Pulmonary stenosis

RVH.

CXR
Post-stenotic dilatation of the pulmonary artery.

Monoaement
_,

If the pressure gradient across the pulmonary valve is > 50 mmHg, found on Doppler scan, e.g. right ventricular
pressure 70, pulmonary artery pressure 20, or there is severe pulmonary valve thickening, then transvenous balloon
dilatation may be necessary. Surgical valvotomy is performed if balloon dilatation is unsuccessful.
In critical neonatal PS, emergency balloon valvuloplasty or surgical valvotomy is performed.

94
 Aortic stenosis (AS)
This is usually anatomically a bicuspid aortic valve.
Associations Aortic incompetence
Coarctation of the aorta
Mitral stenosis
Williams syndrome is supravalvular aortic stenosis with hypercalcaemia, elfin facies, mental retardation (see p. 12).

Clinical features
Neonate Severe heart failure
Duct-dependent circulation
Older child Asymptomatic murmur
Thrill on the chest
Decreased exercise tolerance
1- Chest pain, syncope
Endocarditis
Sudden death

Signs
Murmur Ejection systolic
Aortic area
Radiation to the neck
Carotid thrill
Heart sounds Paradoxical splitting of second heart sound and soft A2
Apical ejection click (due to opening of deformed aortic valve)
Slow rising
plateau pulse Murmur

ECG
LVH.

CXR Figure 4.20 Aortic stenosis

Post-stenotic aortic dilatation.

Management
Neonate Valvotomy (balloon or surgical), then valve replacement
later on
Older child If symptomatic or resting pressure gradient across aortic valve
>50 mmHg, then valvotomy (balloon or surgical) is required

Coarctation of the aorta

The descending aorta is constricted at any point between the transverse arch and the
iliac bifurcation, but usually just distal to the left subclavian artery. Male > female 2:1.
Associations Bicuspid aortic valve (40%)
Mitral valve anomaly (10%)
VSD
Turner syndrome
Berry aneurysm Figure 4.21 Coarctation of the aorta

95
Clinical features
This may present early or late.
Early Circulatory collapse in the first week (duct-dependent circulation)
Late Asymptomatic murmur discovered
Hypertension (in the upper limbs only), weak pulses in legs
Heart failure
Subarachnoid haemorrhage (Berry aneurysm or SBE)

• Femoral pulses weak or absent(± left radial pulse)

• Four-limb blood pressure measurements show BP higher in right arm (± left arm) than legs
• Radiofemoral delay may be observed in older children
• Murmur: Ejection systolic
Between the shoulder blades

ECG
• RVH in neonates (because the right ventricle is systemic in the fetus)
• LVH in older children

CXl?
• May be normal
• Cardiomegaly with increased pulmonary vascular markings
• Rib notching (due to collaterals developing beneath the ribs)> 8 years of age

Management
Unstable neonates to be stabilized as for duct-dependent circulation (PGE 2, ventilation and inotropes as necessary). Sur-
gical repair with an end-to-end repair or a left subclavian flap procedure. A left thoracotomy is used. The left subclavian
flap procedure leaves the child with an absent left radial pulse. Recoi~rctation rate is approximately 5% . Mortality< 2%.
Balloon dilatation has been used successfully in older children.

Interrupted aortic arch

This is a form of severe coarctation where there is complete interruption of the aorta.
Associations VSD
Chromosome 22 microdeletion (these can also have t runcus arteriosus)

Clinical features
These present as neonates with features of a duct-dependent circulation.

Management
Complete correction is required within days of birth. The operative mortality is around 20%.

CYANOTIC CONGENITAL HEART DISEASE

In cyanotic CHD there is central cyanosis, manifested as a blue-coloured tongue, which occurs when capillary
deoxygenated haemoglobin is > 3 g/dl (100 ml) of blood. It can be difficult to detect clinically in the presence of
anaemia.

96
Causes of central cyanosis
• Lung disease
• Cardiac disease
• Persistent pulmonary hypertension of the newborn (PPHN)
• Methaemoglobinaemia

Cyanotic congenital heart disease results from:

1. Right-to-left shunting with decreased pulmonary blood flow, e.g. TOF, TA, PA, Ebstein anomaly, or
2. Abnormal blood mixing with normal or increased pulmonary blood flow, e.g. TGA, TAPVD, double inlet ventricle,
hypoplastic left heart

Complications
• Metabolic acidosis .(occurs when Pa0 2 < 40 mmHg). Treated with sodium bicarbonate
• Increased affinity for oxygen (because the oxyhaemoglobin dissociation curve shifts to the left)
• Polycythaemia, which may lead to thrombosis, embolism, haemorrhage and abscess formation
• Necrotizing enterocolitis

Nitrogen washout test

This test is used to distinguish cardiac from respiratory causes of central cyanosis. The baby is given > 90% oxygen·
to breath for 10 min.
• If the Pa0 2 rises to> 100 mmHg (14 kPa) the cause is respiratory or a central disorder
• If there is no change in the Pa0 2 or a small rise but it remains< 100 mmHg (14 kPa) the cause is cardiac or it is
PPHN

Prostaglandin (PGE2)
This is a relatively specific ductal smooth muscle relaxant. It is used as an emergency measure in duct-dependent
circulations. It is given as an intravenous infusion. · ·
The common side-effects are: hypotension, fever, apnoea (dose related) and jitteri ness.

Methaemoglobinaemia
Iron in haemoglobin is usually in the ferrous form (for both oxygenated and deoxygenated Hb ). In methaemoglobin
(MetHb) iron is in the ferric form, non-functional and brown in colour. Normally methaemoglobin accounts for< 2%
of total body haemoglobin.

Causes
• Cor1genital - autosomal recessive enzyme deficiencies
• Nitrites
• Nitrobenzi ne
• Aniline dyes

Clinical features
• Cyanosis with normal or only slightly reduced oxygen saturations
• Cardiac and respiratory distress on exertion

Investigatiohs
• Nitrogen washouttest (Pa0 2 rises)

97
 • Shaken blood turns brown
• Oxygen saturations are 80-100%
• Spectrophotometry of blood reveals MetHb

,IV!anagement options
1. Reducing agents (IV) - methylene blue or ascorbic acid
2. Exchange transfusion
3. Reducing agents (orally) - methylene blue or ascorbic acid

Tetralogy of Fallot (TOF)

This is the most common congenital cyanotic heart condition . The cyanosis results from right-to-left shunting.
Associations Down syndrome
22q microdeletion (DiGeorge) syndrome
CHARGE syndrome
VACTERL syndrome

Murmur

Figure 4.22 Tetralogy of Fallot

Anatomical features
• Malaligned VSD
• RV outflow obstruction (valvular+ infundibular stenosis)
• Overriding aorta
• RV hypertrophy

Clinical presentations
• Cyanosis present in the first few days of life (rare)
• Murmur detected in first 2-3 months of life
• Hypercyanotic spells (late infancy) due to infundibular spasm:
Occur in the morning and on crying
Cyanosis ur pallor
Acidosis
Child assumes squatting position (increases pulmonary blood flo w by increasing systemic vascular resistance)
Murmur becomes inaudible (due to no flow through pulmonary valve)

98
... _
Management
1. Put child in knee-chest position and hold them over one shoulder with their knees bent, and reassure them
(increases systemic vascular resistance and therefore pulmonary flow)
2. IV fluids
3. Morphine
4. Propranolol IV (decreases infundibular spasm and peripheral resistance)
5. Bicarbonate, then as necessary: IPPV (paralysed, therefore decreased oxygen demand)
Noradrenaline (increases systemic vascular resistance and so increases
pulmonary flow)
Emergency surgery

Complications
Cerebral thrombosis, endocarditis, heart failure, myocardial infarction, brain abscess.

Signs
Murmur Ejection systolic
Upper left sternal edge (due to flow through pulmonary artery)
Heart sounds Single second heart sou nd
Cyanosis
Clubbing

ECG
• RAD
• RVH

CXR
• Small boot-shaped heart: 'coeur en sabot'
• Prominent pulmonary artery bay
• Right-sided aortic arch (30%)
• Pulmonary oligaemia

Management
1. Palliative early surgery in the first few months of life if symptomatic with a modified Blalock-Taussig shunt (side
to-side anastomosis of subclavian artery to pulmonary artery)
2. Corrective surgery at 4-12 months of age (patch closure of the VSD and relief of the obstruction of the RVOT
1by removing muscle bundles, pulmonary valvotomy or outflow tract patch). Mortality of total correction is

approximately 2%. Long -term problems are those of pulmonary regurgitation

NB: In a classical Blalock-Taussig shunt the subclavian artery is anastomosed to the pulmonary artery (child is lef
with an absent right radial pulse).

Tricuspid atresia
Clinical features
• Cyanosis usually present at birth and increases with age as pulmonary flow decreases
• Systolic murmur at LSE
• Single second heart sound

99
 • Superior axis or LAD
• Tall P wave in V2
NB: Severe cyanosis + superior axis - 1. Absence of tricuspid valve
can only be TA. 2. ASD
3. VSD
4. Small, non-functional right ventricle

Small heart with pulmonary oligaemia.

1. Initial palliation with a Blalock- Figure 4.23 Tricuspid atresia

Taussig shunt if too little
pulmonary flow, or pulmonary
band if too much pulmonary
artery flow
2. Definitive palliation (usually at 2- 5 years) with the Fontan procedure (SVC and IVC connected to pulmonary
artery) . Long-term problems are due to a single effective ventricle and concern of atrial arrhythmias
developing

Double inlet ventricle

Here both atria empty into a single ventricle. The ventricle may be left, right or indeterminate. Both the aorta and the
pulmonary artery arise from this ventricle.

The degree of cyanosis depends on the pulmonary blood flow :

If pulmonary flow is high Relatively pink with severe heart failure and eventually Eisenmenger reaction
If pulmonary flow is low Severe cyanosis and no heart failure

Cardiomegaly with either pulmonary plethora or oligaemia.

Manogement
1. Initial palliation with pulmonary artery banding (if no stenosis) or aortopulmonary shunt (if stenosis)
2. Then a bidirectional Glenn shunt (SVC to PA) at 4- 12 months.
3. A modified Fontan procedure is performed for later surgical management at 1.5-3 years

Ebstein anomaly
• Abnormal tricuspid valve, leaflets adherent to ventricle wall (anterior cusp most normal)
• Distally displaced TV
• Atrialization of right ventricle
o ASD
• Functional pulmonary atresia
• WPW syndrome type B

100
'·;
Clinical featurP.s
.• Cyanosis
• Failure to thrive
• SVT, extrasystoles
• May be asymptomatic, especially if mild anatomical abnormalities

Signs
• Soft, long systolic murmur (due to tricuspid regurgitation)
• Diastolic murmurs, extra heart sounds

ECG
• RBBB, RAD
Figure 4.24 Ebstein anomaly
• WPW (negative deflection of 8 wave)
• Tall P waves, long PR interval

CXR
• Massive 'box cardiomegaly' and pulmonary oligaemia
• May be normal

Management
Neonate Consider pulmonary vasodilatation (with 02, prostacyclin or nitric oxide); if unsuccessful, the
duct is opened using PGE 2
Older child Control of SVTs and cardiac failure medically
Tricuspid repair or replacement with closure of the ASD and ablation of the WPW pathway (this
procedure is delayed as long as possible)

Hypoplastic left heart

This involves underdevelopment of the left side of the heart:
• Small left ventricle
• Small mitral valve
• Aortic valve atresia
• Small ascending aorta

Clinical features
Duct-dependent systemic circulation on closure of the ductus arteriosus in the first week of life, i.e. cyanosis, collapse,
acidosis and impalpable peripheral pulses.
I

Management
Norwood procedure - a series of surgical procedures to rebuild the aorta and use the right ventricle as a systemic
ventricle.

Pulmonary atresia
This may be:
1. Complete atresia of the pulmonary valve± VSD with <l PDA or collateral vessels and variable pulmonary arteries
2. Complete atresia of lhe pulmonary valve, no VSD, a PDA, hypoplastic right heart and good pulmonary arteries
supplied by the duct. This type is totally duct dependent

101
 -- ·-1

Clinical features and signs

• Early neonatal cyanosis (duct-dependent circulation)
• No murmurs at the front, continuous murmur at the back (from collaterals
in those with a VSD)
• Single second heart sound

ECG
RAH + RVH.

CXN
• Prominent right atrium (both types)
• Those with a VSD: right-sided aortic arch (30%) and 'coeur en sabot' Figure 4.25 Pulmonary atresia
finding
• Pulmonary oligaemia

I'VItnnaaeJ-r•e~~
"' ' I ·::'} . I . Ill

• Emergency neonatal treatment with PGE 2 if duct dependent

• Pulmonary valvotomy or outflow patch ±a Blalock- Taussig-type shunt as a neonate
• Formation of a systemic-pulmonary connection when older
• Fontan operation in those with hypoplastic right heart

Total anomalous pulmonary venous drainage (TAPVD)

All the pulmonary veins drain into the right atrium instead of the left atrium . There are three types:
1. Supracardiac - drainage of pulmonary veins to SVC
2. Cardiac - drainage to right atrium and coronary sinus
3. Infracardiac - drainage below the diaphragm to the IV(, ductus venosus and portal vein . This type is always
associated with obstruction to pulmonary venous return

Right
atrium

Right
atrium

Supracardiac Cardiac lnfracardiac

Figure 4.26 Total anomalous pulmonary venous drainage .

102
There is mixing of blood between right and left sides at the:
• Patent foramen ovate
• Ductus arteriosus
• ASD

Clinical features and signs

There are two presentations.
If obstruction present (type 3)Severe cyanosis as a neonate
Respiratory distress
Hepatomegaly
No murmurs 'Snowman'-shaped
heart
No obstruction (types 1 and 2) Mild cyanosis
Cardiac failure Figure 4.27 'Snowman'-shaped heart
Recurrent chest infections
Pulmonary hypertension

ECG
Normal or RVH.

CXR
1. Infracardiac - small heart and hazy lung fields
2. Supracardiac - big supracardiac shadow (classic 'snowman' appearance)

Management
1. If obstructive type, emergency prostaglandin infusion in neonates, then urgent cardiac surgery
2. Elective surgical correction in infancy (pulmonary venous trunk connected to left atrium)

Transposition of the great arteries (TGA)

Association Maternal diabetes
There are two parallel circulations. Survival is due to mixing of blood at the:
• Ductus arteriosus
• Foramen ovate
• ASD'
• VSD

Clinic;al features and signs

• Cyanosis within hours (on
closure of DA and FO)
• Acidosis
• Mild tachycardia
• No murmur (there may be a
systolic murmur from increased
pulmonary flow)
• Single second heart sound
'Egg on side'-shaped
heart
Figure 4.28 Transposition of the great arteries

103
ECG
Normal.

CXR
• 'Egg on side' appearance of heart
• Increased pulmonary markings

Management
1. Emergency neonatal prostaglandin (PGE 1) infusion
2. Atrial balloon septostomy (Rashkind)
3. Corrective surgery with anatomical correction (aterial switch procedure) within a few weeks of birth

DUCT-DEPENDENT CIRCULATIONS
These are circulations that depend on the ductus arteriosus to maintain pulmonary or systemic blood flow, and
deterioration occurs when the duct closes in the first week.

ARRHYTHMIAS

SUPRAVtNT!UCULAR TAOiYGUUJH\ (SVT)

This is the commonest arrhythmia in children. It is a re-entry tachycardia causing premature reactivation of the atria .
In neonates the rate is > 220 bpm, and in older children > 180 bpm.

Wolff-Parkinson-White syndrome (WPW)

A congenital condition caused by an abnormal connection between the atria and the ventricle (an accessory pathway).
The features are:
• 8 Wave
• Short PR interval
• Wide QRS complexes 8wave
There are two types: ~
Type a Activation of the left ventricle via the accessory pathway (most common)
Type b Activation of the right ventricle via the accessory pathway (occurs in Figure 4.29 Wolff-Parkinson-White
Ebstein anomaly) syndrome

104
:' :c; The tachycardia may be stopped by IV adenosine, oral digoxin or oral flecainide. Flecainide reduces the recurrence risk
of tachycardias.

Clinical presentation of SVT

Older child Palpitations, dizziness, chest pain, collapse
Infant Poor cardiac output, cardiac failure
In utero Fetal tachyarrhthymia which can cause IUD or hydrops fetalis

Investigation
• ECG (particularly of the tachycardia, recording the response to adenosine if possible)
• It is helpful to do an echocardiogram to exclude structural CH D

Management
1. Vagal stimulation:
Diving reflex: Babies Immerse head and face in basin of ice-cold water for 5 seconds
Older child: Place polythene bag full of ice-cold water on face for 15 seconds
Unilateral carotid sinus massage (older children only)
2. Adenosine - treatment of choice, given by rapid IV bolus
3. Synchronized DC cardioversion (1-2 Jjkg). Anaesthetize or sedate the child (first line if child severely ill,
otherwise use if drugs fail)
4. Other drugs that may be used are: Amioderone
Flecainide - IV over 15 min
Digoxin -oral or IV (slow acting)
Maintenance therapy to prevent recurrence may be required and this can be achieved with either flecainide, pro-
pranolol, digoxin or amiodarone. NB: Stop maintenance when > 1 year of age as 90% will have no further attacks.

Adenosine
Adenosine is an endogenous purine nucleotide. The half-life is very short (3-6 s). It acts to block A-V conduction. The
side-effects are common and unpleasant.
• Dyspnoea, flushing, nausea
• Chest pain (this is not angina, though feels the same)
• Bradycardia (therefore do not use in the presence of sinus node disease)
• Heart block
• Atrial and ventricular premature beats
• If inhaled, bronchoconstriction (therefore do not use in asthmatics)
The antidote is aminophylline.

VENTRICULAR TACHYCARDIA (VT)

This is the occurrence of three or more ventricular beats in a row at a rate of at least 120/min.

Causes
• Metabolic- calcium, magnesium, potassium imbalances
• Long QT syndrome
• HOCM
• Infantile VT
• Postcardiac surgery
105
Management
• Adenosine to make the diagnosis if necessary
• DC cardioversion
• IV lignocaine or IV amiodarone
NB: It can be hard to distinguish VT from SVT (see below). If unsure whether it is VT or SVT, always treat as VT.

CONGENITAl COMPlHt HEMU BLOCK

This is associated with:
• Maternal connective tissue disease - SLE and Sjogren syndrome (maternal anti-Rho antibodies cause atrophy and
fibrosis of the AV node)
• Structural CHD (in 15% of cases): AVSD
Congenitally corrected TGA

Clinical presentation and management

• In utero: fetal bradycardia, hydrops fetalis or fetal death
• Neonatal bradycardia and heart failure
• Investigations include a 24-h ECG (as it may be intermittent)
• Treatment with the placement of a pacemaker is necessary if symptomatic or if the daytime pulse rate is < 60/min
in an infant or< 50/rriin in an older child

PROLONGED QT SYNDROME (TOHSADES DE POINTES)

Torsades de pointes is an arrhythmia usually of short duration . The ECG has a prolonged QT between the tachycardias. The
arrhythmia usually spontaneously reverts to sinus rhythm; however, it can convert to VF and result in sudden death.

Figure 4.30 Torsades de pointes

106
causes of prolonged QT interval
Congenital Jervell-Lang-Neilson:
• Autoso mal recessive
• Long QT plus congenital deafness. Suffer repeat drop attacks
• Triggering factors: fear, excitement, exercise
• May be misdiagnosed as epilepsy
Romano-Ward:
• Autosomal dominant
• Isolated prolonged QT. Prognosis better than Jervell-Lang-Neilson
Acquired Electrolyte disturbances - hypercalcaemia, hypomagnesaemia
Drugs - amiodarone, quinidine, sotalol, MAOis, tricyclics, erythromycin
Poisoning - organophosphates
Low-protein diets
Anorexia nervosa
Any cause of a bradycardia - myxoedema, complete heart block, head injury

Management
Congenital ~-blockers (mortality reduced from around 80% to 6%)
Other antiarrhythmic drugs
Left stellate ganglionectomy
Implantable defibrillator if future treatment required
Acquired Isoprenaline IV (this is contraindicated in congenital types)
Pacing wire if associated heart block

RHEUMATIC FEVER
This is an inflammatory disease occurring in response to Group A ~-haemolytic streptococcal (GAS) infection. It is
now rare in the UK due to antibiotics. A streptococcal infection (usually sore throat or scarlet fever) is followed 2- 6
weeks later by a polyarthritis, fever and malaise, and cardiac symptoms (the exact symptoms depending on the organs
involved). The diagnosis is made on the basis of the Duckett Jones criteria. Two major criteria or one major and two
minor criteria are needed to make the diagnosis.

107
 ' ,\... ··.

Investigations
• Evidence of recent streptococcal infection (ASOT raised, blood cultures, throat cultures, serology, recent scarlet
fever)
• Investigation of symptoms and signs (FBC, U&E, creatinine), acute phase proteins, ECG, CXR, echocardiogram)

Management
• Bed rest (when active fever, carditis or arthritis is present)
• High-dose aspirin
• Steroids
• Treat heart failure
• Benzathine penicillin intramuscularly or oral penicillin course
• Then lifelong penicillin prophylaxis (monthly IM or daily oral penicillin)

Long-term complications
Mitral stenosis ± aortic stenosis.

INFECTIVE ENDOCARDITIS
This is infection of the endocardium, which occurs particularly with congenital heart disease (especially cyanotic)
and on previously damaged or prosthetic valves. A high-velocity flow is needed to damage the endocardium. It can be
acute (rare) or subacute (SBE).

Infecting organisms
• a-Haemolytic streptococcus (Strep. vin"dans) (50% of SBE)
• Staphylococcus aureus (50% of acute endocarditis, occurs with central lines and postcardiac surgery)
• Enterococcus faecalis
• Staphylococcus epidermidis (central lines, postcardiac surgery)
• Candida albicans (central lines, immunosuppressed)
• Aspergillus, brucella, histoplasma, Coxiella burnetii (Q fever) (all rare)

Clinical features
These may be subtle, therefore always think of SBE in a patient with a known cardiac defect who is unwell.
• Sustained fever, night sweats, malaise
• Development of new cardiac murmur ..
• Persistence of fever after acut~ illness (in the acute form)
• Splenomegaly and splenic rub
• Small vascular lesions: Splinter haemorrhages
Roth spots (retinal haemorrhages)
Janeway lesions (erythematous macules on thenar and hypothenar eminences)
Osler's nodes (hard, painful embolic swellings on toes, fingers, soles and palms)
• Major embolic phenomena - cerebral, coronary, pulmonary and peripheral arterial
• Renal lesions - haematuria, focal glomerulosclerosis, renal failure
• Clubbing
• Arthritis of major joints

Investigations
Blood tests Serial blood cultures (at least three sets, more if negative)
FBC (anaemia almost invariably)

108
!' L ESR and CRP (i), immunoglobulins
C3 (low due to immune complex formation)
Serology (chlamydia, candida, coxiella and brucella) if culture negative
Urine Microscopic haematuria and proteinuria
CXR and ECG
Echocardiogram Looking for vegetations

Management
1. 4-6 weeks of antibiotic therapy with suitable antibiotic (initially IV for 2 weeks)
2. Antibiotic prophylaxis in the future for procedures
3. Surgery (if extensive valve damage, cardiac failure, vegetations or embolization)
NB: 'At-risk' individuals should receive prophylactic antibiotics for certain procedures.

MYOCARDITIS
This is an inflammation of the heart, with necrosis and fibrosis, causing serious weakening of the heart muscle witt
cardiac and respiratory failure. May become chronic.

Causes
Infectious Viral (most common cause in children) -coxsackie B, adenovirus
Bacterial- diphtheria, rikettsia
Fungal
Parasitic
Toxic E.g. pneumonia, sepsis, drugs
Connective tissue
disease
Idiopathic

Clinical features
• Cardiac failure - tachycardia, weak pulses, respiratory distress
• Arrhythmias
• Sudden death
• Asymptomatic (in adolescents)

Investigations
CXR , Gross cardiomegaly, pulmonary plethora
ECG Arrhythmias
Bloods Cardiac enzymes (CK i, LDH I, troponin i)
Viral serology (specific IgM i), PCR
Echocardiography Poor ventricular function, large heart, pericardia[ effusion

Management
Most cases of mild inflammation will resolve spontaneously but in a proportion irreversible devastating damage is
done to the heart.
Supportive Cardiac failure, arrhythmias management, ECMO may be necessary
Cardiac transplant If refractory heart failure
109
CARDIOMYOPATHY

This is a disease involving dysfunction of the cardiomyocytes, resulting in dilatation and impaired function of the left
± right ventricle. Most cases are idiopathic.

Associations
Genetic diseases Familial, mitochondrial abnormalities, Friedreich ataxia, carnitine deficiency, muscular
dystrophy, Fabrey disease, Refsum disease, Pompe disease
Infections Post-viral myocarditis, e.g. coxsackie, echovirus, sepsis, diphtheria, rheumatic fever, HIV,
trypanosomiasis (Chagas disease)
Nutn"tion Selenium deficiency, e.g. TPN, short bowel syndrome, Keshan disease, thiamine, or calcium
deficiency, iron overload, severe chronic anaemia
Toxins E.g. doxorubicin, cyclophosphamide, adriamycin

Clinical features
• Heart failure (tachycardia, cardiomegaly, raised JVP, third and fourth heart sounds present)
• Arrhythmias
• Embolism

Investigations
CXR Cardiomegaly and pulmonary plethora
ECG lVH, non-specific T wave abnormalities
Echocardiogram large baggy heart (poorly contracting with atrial and ventricular dilatation)
Reduced ejection fraction, mitral and tricuspid regurgitation
Cardiac biopsy (rarely) Fibrosis, myocardiocyte hypertrophy and white cell infiltration (often unhelpful)
Other If indicated to detect the cause: metabolic screen, nutritional bloods and genetic screening

Treatment
1. Treatment of cardiac failure and arrhythmias, and anticoagulants (aspirin or warfarin)
2. Cardiac transplant if needed

This is characterized by hypertrophy of the interventricular septum and left ventricular wall, in the absence of a cardiac
or systemic cause. left ventricular outflow tract obstruction may be present.

Associations/causes
• Maternal IDDM (transient)
• Premature infants receiving steroids for lung disease (transient)
• Neurofibromatosis, mucopolysaccharidoses
• Autosomal dominant in some cases
In some of the familial cases mutations have been found in chromosome 14, cardiac ~-myosin heavy chain (~-MCG)
defect.

Clinical features
• Syncope, angina
• Arrhythmias (AF and VF) ·

110
 • Sudden death (60-70%)
• Family history of sudden death

Signs
• Murmur: Ejection systolic (due to left ventricular outflow obstruction) mid-diastolic
± pan-systolic (mitral regurgitation)
• Fourth heart sound (palpable = double apex beat)
• Left ventricular failure

Investigations
Echocardiogram
24-h ECG VT or VF (treat with amiodarone fi rst li ne)
AF (dangerous as they are dependent on atrial contraction)
ECG Long 0 waves (due to thick interventricular septum )
LVH, non-specific T wave changes
Electron microscopy (EM) 'Myocardial disarray'
CXR Cardiomegaly, prominent left ventricle

Treatment
1. Amiodarone
2. ~-blockers
3. Cardiac pacing (causes an LBBB)
4. Surgical resection of the septum if significant LV outflow obstructio n

PERICARDITIS

ACUTE PERICARDITIS
This is inflammation of the pericardium .

Causes
• Coxsackie virus
• Staphylococcus, Haemophilus influenzae, TB
• Rheumatic fever, malignancy, e.g. Hodgkin disease

Symptoms
Chest pain Substernal, sharp, radiating to the neck
Worse on lying flat and respiration
Better on sitting forward

Signs Raised ST segment, concave upwards

• Pericardia[ friction rub
• Fever

Investigations
• ECG: ST elevation, concave upwards
T inversion
• Cardiac enzymes elevated (if associated myoca rditis) Figure 4.31 ECG in pericarditis

111
 :,
· ~.

Treatment
• Anti -inflammatory drugs
• Drainage if indicated (always in post~viral pericarditis)

All cases of acute pericarditis eventually develop a pericardial effusion.

Clinical features (if significant)

• Decreased cardiac output, impalpable apex beat
• Soft heart sounds, friction rub (quiet)
• Pulsus paradoxicus (BP decreases on inspiration)
• Kusmaul's sign (neck veins distend on inspiration)
• Raised JVP with Friedreich's sign (steep y descent)

Investigations
ECG Small voltages
CXR Large, globular heart
Echocardiogram Diagnostic

Treatment
Pericardiocentesis with pericardia[ window formation if indicated.

CONSTRJ.CHVE P'ERIC!HHHnS

Causes
• TB
• Acute pericarditis
• Haemopericardium

Clinical features
• Cardiac failure - dyspnoea, sweatiness, hepatosplenomegaly
• Decreased ventricular filling - pulsus paradoxus, Kusmaul's sign, Friedreich's sign
• Atrial fibrillation (30%)
• Pericardia[ knock (loud third heart sound)

Investigations
CXR Small heart with calcification
ECG Low voltage ORS complexes and T wave inversion
Echocardiogram Thick pericardium

Treatment
Surgery (pericardiectomy- removal of pericardium).

Archer N, Burch MPaediatric Cardiology - An Introduction. London: Chapman & Hall, 1998

112
;;" Emmanouitides GC, Allen HD, Reimenschneider TA, Gutgesell HP, eds Clinical Synopsis of Moss and Adams' Heart DiseasE
in Infants, Children and Adolescents. Baltimore: Williams & Wilkins, Baltimore, 1998
Park MD, Guntheroth WG How to Read Pediatric ECGs, 4th edn. Philadelphia: Mosby, 2006
Trusler GA, Freedom RM, Mawson JB, Yoo S, eds Congenital Heart Disease: Textbook of Angiocardiography. New York:
Futura Publishing Company, 1997

.1

113
• Ears • Throat

• Nose

EARS

!-!IEARING TESTS

Causes for concern regarding hearing in newborns

• Family history of deafness
• Craniofacial malformations
• Birthweight < 1500 g
• Neonatal meningitis
• Severe perinatal asphyxia
• Potentially toxic levels of ototoxic drugs

114
 • Neonatal jaundice requiring exchange transfusion
• Congenital infection, e.g. rubella, CMV, toxoplasmosis
• Parental concern

Tuning fork hearing tests

These tests may be used on older children to distinguish sensorineural hearing loss from conductive hearing loss.
Beware - they are not always reliable.
Rinne test Tuning fork held in front of the ear (air conduction) and then firmly on the mastoid process (bone
conduction) :
• Rinne positive = heard louder in front of the ear - normal or sensorineural hearing loss
• Rinne negative= heard louder on the mastoid process- conductive hearing loss
Weber test Tuning fork held on the forehead in the midline. A conductive loss in one ear results in the sound
being referred to that ear and heard as a louder sound

Possible test results

HEARING LOSS
Mild hearing loss 25- 35 dB
Moderate hearing loss 40-60 dB
Severe hearing loss 60-90 Db
Profound hearing loss > 90 dB

115
Audiograrns
Hearing loss may be conductive (common in children) or sensorineural (uncommon).

Severity of hearing loss

-20
0 Threshold sound
0(/)
m 20
2- ] Mild (25-35 dB)
Qj
40
~
>
Ol
JModerate (40-60 dB)
c 60 ~---T~+-~~-r~+-·--;---1

f-l~--t-~+---t~-+~-t----t~-1] Severe (60-90 dB)

·;:::
Cll
(j)
I 80

100
1--1-----i-~+---+----+-~+----+·----ill Profound (>90 dB)
Normal speech range
120 250 500 1000 2000 4000 8000
(a) Frequency (Hz)

. -20 I

-10 I I
0
A
~ /T A T
0(/) 20
10
. n, *, '()
m 30
1-< )-~-Q /~?""''"' '
.........-¥
2- 40
Qj
50
r--f-1 I I
Air conduction 0 Right
>
~ 60
Ol
I I I X Left
c
·;:::
70
Cll
(j)
80 Bone conduction A Right or left
I 90 1 - - unmasked
100 I
110 I J -~
120 iTi
125 250 500 1000 2000 4000 8000
(b) Frequency (Hz)
-20 I
IT
-10
0
I
I
I I
I
I l
i
I i
~
10
0 20 - -
en 30
r--+-I I
I

I
I
jl
I
I
L 1

2- 40
Qj I
> 50
Q)
60 I
Ol
c 70
I
·;:::
Cll
QJ
80 I I
I 90 1 - \ '
100 r--- I
~y, I
110
120
~~ ',~
125 250 500 1000 2000 4000 8000
(c) Frequency (Hz)

Figure 5.1 Audiograms. (a) Normal hearing speech range. (b) Bilateral conductive
hearing loss. (c) Bilateral profound sensorineural hearing loss

116
 EAR CONDITIONS

Acute otitis media (AOM)

This is infection of the middle ear.

Causes
Viral RSV, rhinovirus
Bacterial Streptococcus pneumoniae, Haemophilus influenzae, Moxarel/a catarrhalis, Group A ~-hae molytic
streptococcus, Streptococcus pyogenes
Frequently a bacterial infection will follow an initial viral infection.

Clinical features
• Earache (not in 20%)
• Fever
-: ·~.
• URTI
• Hearing loss

Signs
Injected tympanic membrane (TM), bulging TM, loss of light reflex, perforated TM, discharge. Middle ear effusion post-
infection in most children for 2-3 weeks.

Management
1. Analgesia and antipyretics for 24 h; if no improvement, commence oral antibiotics
2. Oral antibiotics
3. Myringotomy and drainage very rarely required

Glue ear (otitis media with effusion)

Glue ear occurs after acute otitis media when fluid persists for> 8 weeks without signs of inflammation. Incidence and
prevalence are high but the majority of effusions resolve spontaneously. The initial infection may not be noticed.
Associations Down syndrome, cleft palate and other craniofacial abnormalities
IgG subclass deficiency, food allergies

Clinical features
• Conductive hearing loss, earache
• Speech and learning difficulties, behavioural difficulties

Signs
• Retracted TM, loss of light reflex, bubbles and fluid levels on the TM
• There may be a normal-looking drum
• Rinne test negative (if> 5 years)
• Tympanometry usually shows a flat (type B) response
• Pure tone audiometry shows a conductive hearing loss

Management
1. Initial observation for spontaneous resolution, 'watchful waiting' for 3 months
2. Trial of antibiotics may benefit a few children, e.g . 6 weeks of low dose co-amoxiclav

117
 .. ..,

3. Grommet insertion
4. Adenoidectomy may be combined with grommets (leads to higher resolution rates)

Chronic otitis media (COM)

This is chronic disease of the middle ear, and is subdivided into different conditions depending on where the perfora-
tion lies and whether it is active.

-
COM classification (synonym) - Otoscopic abnormalities - ·

Perforation of the central tympanic membrane is a 'safe' perforation, and may be active, i.e. discharging, or inactive
when the only sign is the perforation. There is conductive deafness and in long-standing cases a coexistent sensory
loss. This can heal spontaneously leaving tympanosclerosis. ·
Perforation of the margin of the tympanic membrane (squamous epithelia) or pars tensa that has retained squamous
epithelia is an 'unsafe' perforation, and become an active cholesteatoma.

Cholesteatoma
A potentially serious condition in which squamous epithelial debris, granulation tissue and pus develop in the middle
ear and progress to damage neighbouring structures. Treatment is nearly always surgical.

Complications
Extracranial VIIth nerve palsy, suppurative labyrinthitis, perimastoid abscess
Intracranial Extradural, subdural and intracerebral abscess, meningitis, sigmoid sinus thrombosis and
hydrocephalus

Otitis externa
This is relatively uncommon in children. It comprises an infected, oedematous external auditory canal and usually
presents as a discharging ear which then becomes painful (unlike otitis media which is initially painful and then
may discharge). Treatment is with aural toilet and topical antibiotics given as eardrops or impregnated onto a
wick.

118
 Acute mastoiditis
Clinical features
This is a serious condition, usually following AOM which presents with similar symptoms plus swelling and tenderness
in the postauricular region.

Investigations
Blood tests FBC (neutrophilia), blood cultures
CTscan (If diagnosis uncertain) Opacification of the mastoid air cell system with breakdown of bony septa

Treatment
Admit immediately for IV antibiotics and analgesia. Surgical exploration and mastoidectomy are performed in cases
that fail to resolve with medical therapy or are advanced in presentation .

:J Complications
The concern with this condition is the development of brain abscess, meningitis or venous sinus thrombosis.

NOSE

Rhinitis
This is divided into allergic rhinitis (where known allergens trigger the symptoms) and non-allergic rhinitis. The
symptoms are very similar.

Clinical features
• Persistently runny nose, clear disch9rge, occasionally becoming purulent
• Sneezing and itchy nose
• Nasal obstruction
"' • Mouth breather, hyponasal speech
• Family history of atopy

Signs and investigations

• Nasa~ mucosa pale and purple (normally pink)
• Serum IgE (1} and RAST tests may be done (allergic rhinitis)
• Postnasal space X-ray if concern about enlarged adenoids

Differential diagnosis
• Adenoidal hypertrophy
• Foreign body (unilateral)

Management
• Allergen avoidance
• Topical steroids (nasal drops or spray)
• Decongestants for short-term(< 1 week) usage for acute exacerbations, e.g. ephedrine, xylometazoline
• Antihistamines (nasal or systemic)
• Mast cell stabilizers, e.g. disodium chromoglycate
• Check for nasal foreign body (if unilateral discharge)

119
Epistaxis
This is a common problem in childhood, usually involving bleeding from Little's area of the nasal septum (the bit
they pick!). Immediate management involves applying pressure to the soft part of the nose; vasoconstrictors such as
xylometazoline (paediatric otrivine) will usually arrest bleeding if this fails.
Very rarely epistaxis is persistent: a nasal pack can be inserted (with admission) if this fails. If recurrent nose bleeds
are occurring, underlying defects of coagulation, hypertension and neoplasms should be excluded. Cauterization of
Little's area can be carried out if necessary.

Common cold (nasopharyngitis)

Causes
Rhinoviruses, coronaviruses, RSV.

Clinical features
• Snuffles, nasal discharge, sneezing
• Mouth breathing, headache, fever, malaise, anorexia, sore th roat

Management
• Rest, oral fluids, simple analgesics
• For infants, sali-ne nasal drops help clear the nose

Sinusitis
Sinusitis is rare in children. Infection of the sinuses in children usually involves the ethmoid and maxillary sinuses as
the frontal sinuses are not fully developed. The serious complication of subperiosteal abscess or orbital cellulitis
may be the presentation.

Ciinical features
• Purulent nasal discharge, fever, local tenderness and pain
• Postnasal drip and chronic cough in chronic sinusitis

Blood tests FBC and blood cultures (if acutely unwell)

Sinus CT Opaque maxillary sinuses (or X-ray - less frequently requested)

Management
• Broad-spectrum antibiotics (IV if acutely unwell)
• Nasal decongestion, e.g. xylometazoline
• Intranasal steroid drops
• Steam inhalations
If orbital cellulitis is present, an ophthalmologist must be involved to assess and help make the differentiation
between pre- and post-septal cellulitis, and an ENT surgeon should also be involved. A CT of the sinuses will show
sinus involvement as well as intraorbital complications necessitating surgical intervention.
Progression of orbital cellulitis:
• Pre-septal
• Post-septal
o Subperiosteal abscess

120
 • Orbital abscess
• Cavernous sinus thrombosis

t:J~1~f~~~fY't~tdMii'~i~i~.
'Y"r~rrl1paired globe mobility
{/~ ·Decreased colour vision
§\+.Proptosis ·

THROAT

STRIDOR
.
.f
Stridor is a harsh sound caused by upper airway obstruction. Associated hoarse voice or cry, barking cough, tracheal
tug or sternal recession, dyspnoea, tachycardia, tachypnoea, cyanosis (if severe) and agitation progressing to drowsi-
ness may be seen.
• Inspiratory stridor is caused by extrathoracic obstruction
• Expiratory stridor is caused by intrathoracic obstruction
• Stridor arising from the subglottis and cervical trachea is often biphasic

Causes

LARYNGOMALACIA {flOPPY LARYNX)

• Acommon condition in neonates where soft laryngeal cartilage collapses on inspiration or an elongated epiglottis
flops into the larynx resulting in stridor
• Stridor worse on crying, agitation or lying supine
• Diagnosis clinical or by direct laryngoscopy
• Develops in first few days of life and usually resolves by 1 year (occasionally 2 years)
• Gastro-oesophageal-laryngo-respiratory reflux (GOLR) may prolong or exacerbate it

121
CROUP (ACUTE LARYNGOTRACHEOBRONCHITlS)
This is the commonest cause of acute stridor in children. It is a viral condition caused by parainfluenza virus, respira-
tory syncytial virus (RSV) or rhinovirus. The child's already small airway is narrowed by secretions and oedema.

Clinical presentation
• Usual age 1-2 years
• Stridor, mild fever, hoarse voice, barking cough and little constitutional disturbance. Worse in evening and over-
night. Sometimes viral croup can deteriorate into a much more severe condition

Management
1. Calm atmosphere with avoidance of unnecessary blood tests, direct airway vision and neck X-rays which may
frighten the child, making the condition worse
2. Humidified oxygen as necessary (keep oxygen saturations > 92%)
3. Steroids as nebulizer (budesonide 1 mg 12 hourly) or oral dexamethasone 12 hourly
4. Racemic epinephrine (adrenaline) nebulizer 1 ml1/1000 if necessary (NB: Rebound increased stridor common
30-45 min later)
5. Intubation and IPPV are needed in approximately 1% of children and tracheostomy very rarely

Indications for IPPV

• Drowsiness due to hypoxia
• Tiring
• Rapid deterioration

Recurrent (spasmodic) croup

• Recurrent episodes of sudden onset at night of inspiratory stridor and croupy cough
• Most common in infants 1-3 years old
• Responds to inhaled steroids in acute phase
• Thought to be related to bronchial hyper-reactivity/reflux (GORL)

Bacterial tracheitis (pseudomembranous croup)

An uncommon condition usually caused by Staphylococcus aureus. The child is unwell for 2-3 days and is usually
severely unwell on presentation. Soft hoarse voice, quiet cough and soft stridor. Intubation with IPPV for several days
is usually required together with antibiotic therapy.

ACUTE EPIGLOTITIS
This is an infection usually caused by Haemophilus influenzae type b. It presents between 1 and 7 years (peak 2-3
years). It has become much less common since the introduction of the Hib vaccine.

Clinical presentation
• Toxic child
• Drooling, no cough, stridor, high fever and a short history (usually< 6 h)
• Muffled voice, pain in throat

Management
• Immediate involvement of senior ENT surgeon and anaesthetist
• Transfer to intensive care or high-dependency setting with intubation equipment and anaesthetist, paediatrician
and ENT surgeon

122
U. • Intubation with IPPV for 1-3 days electively or in response to hypoxia
• Antibiotic therapy, e.g. cefuroxime, IV for 5 days
· • Rifampicin prophylaxis for contacts

Low grade
Lg~g~h of history · Few days
dr&a!ing · No
c&ti~h · Barking
Hoarse Muffled
Common Rare
1-3 years 2-7 years

PHARYNGITIS
This is a common infection usually caused by a virus (adenovirus or para-influenza virus) or, more rarely, a bacteri<
(Group A streptococcus).

Clinical features
• Sore throat. nasal congestion, fever
• Oropharyngeal inflammation (red throat)

Treatment
Symptomatic treatment with antipyretics and plenty of fluids, and antibiotics if bacterial infection is suspected .

Differential diagnoses
• Infectious mononucleosis, measles, scarlet fever, diphtheria, chronic adenoiditis, HIV
• Presentation of acute leukaemia or lymphoma

ACU"{E TONSILITIS

Clinical features
• Sore throat, fever, malaise, bad breath
• Red tonsils sometimes with pus
• Cervical lymphadenopathy

Investigations
• Throat swab
• FBC and Monospot test
It can be difficult to distinguish bacterial (usually Streptococcus pneumoniae) from viral tonsillitis.
123
 ··-···----------------- - - - - -- ---

Management
• Analgesics, antipyretics and plenty of fluids
• Antibiotics may be required (penicillin V as first-line management- usually streptococcal if bacterial)

Complications
• Quinsy (peritonsillar abscess)- surgical drainage required
• Post-streptococcal complications (see p. 58)
• Obstructive sleep apnoea syndrome

TonsilLE~ctomy indications · - :\
At lea sf six attacks of tcinsilliti~ per.year for? years·
Three attacks per year over a number ofyears for the older child
.,- - ._·-_ . . . :·.:. : _· .

Obstructive sleep apnOea syndrol}le is a strong indi2abon ,< _y ,

OBSTHUCT!VE SLHP APNOEA SYNDROlV!E

This is upper airway obstruction with periods of desaturation. It is usually due to adenotonsillar hypertrophy. Children
with certain craniofacial abnormalities are more at risk. Children with sickle cell disease are particularly affected due
to a lower resting oxygen saturation and propensity to precipitate a sickle crisis. There is a spectrum of disease from
mild and intermittent, e.g. with a URTI, to marked desaturation.

Clinical features
During sleeping Snoring with apnoeas of> 10 s as the child struggles for breath
Mouth breathing
Frequent awakenings
Unusual sleeping postures
Daytime Sleepiness, morning headaches
Learning problems and behavioural change

Complications
In extreme cases prolonged periods of hypoxia and hypercapnoea can cause ventricular hypertrophy, hypertension,
polycythaemia and eventually cor pulmonale.

Investigations
• ENT examination
• X-ray postnasal space
• Sleep studies if diagnosis is in doubt or chi ld at high risk. In practice not all children require sleep studies

Treatment
Adenotonsillectomy is usually curative.

CLEFT LIP AND PALATE

Incidence 1:1000 babies, polygenic inheritance. Subsequent pregnancy risk 5%.

124
Associations ,
, • Older mothers
• Syndromes, e.g. Patau syndrome
• Drugs, e.g. maternal anticonvulsant therapy, alcohol
They may be unilateral or bilateral and isolated or combined.

Problems
• Inability to feed
• Choking episodes
• Otitis media with effusion
• Speech problems

Management
A multidisciplinary approach involving plastic surgeons, ENT surgeons, geneticists, paediatricians, speech therapists,
audiologists, orthodontists. Special feeding teats, speech therapy.
Surgical repair Lip may be repaired early (first week of life), though some surgeons prefer to wait until
infant is 3 months old
Palate usually repaired at several months of age

Pierre-Robin sequence
Asequence of:
• Midline cleft of soft palate
• Micrognathia
• Glossoptosis (posterior displacement of the tongue)
These result in difficulty with feeding and Up!Jer airway obstruction.
Management includes:
• Nasopharyngeal airway
• Special feeding teat
• Surgical repair of palate (mandible grows)

125
 · -..,

• Physiology • Causes of chronic cough

• Congenital malformations • Infection
• Causes of wheeze • Cystic fibrosis
• Bronchiolitis • Bronchiectasis
• Inhalation of a foreign body • Immotile cilia syndrome
• Aspiration (acute and recurrent) • a1-Antitrypsin deficiency
• Asthma • Pulmonary fibrosis
• Viral-induced wheeze • Sarcoidosis

PHYSIOLOGY 700 Gentile

97

Peak respiratory flow rate (PEFR)

The PEFR is a useful and very simple lung function test. It
varies with height, sex, age and ethnic group. It also varies
during the day, being lowest in the early morning, and
with exercise, being low shortly after moderate exercise.
It is used to assess asthma severity by comparing a child's
PEFR to normal corrected PEFR and to the individual child's
normal PEFR. Height (em)

Figure 6.1 Peak flow readings

126
~;.

'
Spirometry 6 1FEV 1
Normal (adult)

Spirometry provides timed measurements of expired

I
1
1
~o "
" " _.
-- -- ••• - - - - - - - - - - - - - · FVC
Obstructive
volumes from the lung. It enables obstructive and ' I
restrictive lung conditions to be differentiated. # I

I
I
Q)
I
E I Restrictive
::l
0
>

0
Time (seconds)

Figure 6.2 Spirometry

..
·>

Lung volumes ·
Methods of measuring the lung volumes:
Y.

• Helium dilution
• Nitrogen washout
• Whole-body plethysmography

Volumes Capacities

Values in adult males

IRV
IC

TV
c
·u
Cll
D.
Cll
-
>-
·u
Cll
D.
IRV (inspiratory reserve volume)
TV (tidal volume)
= 2-31
= 0.51
u ro ERV (expiratory reserve volume) = 11
()

]§ Ol
RV (residual volume) = 1.51
c
ERV > .2
VC (vital capacity)
FRC (functional residual capacity)
= 4.51

--- -- ---- .
FRC ~ ---
1-
IC (inspiratory capacity)
TLC (total lung capacity)
= 2.51
= 3.51
= 5.5-Q.O I
RV
--- 1--------------------- - - - ---- -
Figure 6.3 Lung volumes and capacities

127
Transfer factor
This measures the rate at which a gas will transfer from the alveoli into the blood. It is a function of both the
membrane-diffusing capacity and pulmonary vascular components, which together refl.ect the alveolar-capillary unit
function . Carbon monoxide is used to measure this. Normal diffusing capacity (Dco) is 25-30 mljmin/mmHg.

Flow-volume curves
These are constructed from spirometric data and are used to locate the site of an airway obstruction .

Fixed obstruction Extrathoracic obstruction Intra thoracic obstruction

intra or extra thoracic (variable) (variable)

Exp.
flow

Insp.
flow

(a) (b) (c)

Figure 6.4 Flow-volume curves

CONGENITAL MALFORMATIONS
• Laryngomalacia (seep. 121)
• Trachea-oesophageal fistula (see p. 479)
• Congenital Lobar emphysema
• Bronchogenic cyst. These are usually asymptomatic at birth and present when secondarily infected or they enlarge in
size and compromise an adjacent airway. There is an air-fluid level on CXR and treatment is with surgical excision
• Cystic adenomatoid malformation (CAM lung). This is the second most common congenital lung malformation after
congenital lobar emphysema. Asingle lobe of one lung is enlarged and cystic, and usually causes mediastinaL shift
with compression of the other lung. It presents with neonatal respiratory distress, a pneumothorax or recurrent
respiratory infections. It may be seen on CXR and CT scan of the thorax. Management is surgical
128
 CAUSES OF WHEEZE

,~, BRONCHIOLITIS
This is a common condition usually presenting between 1 and 9 months. It is due to the respiratory syncytial virus (RSV
in 80% of cases, and otherwise to adenovirus types 3, 7 and 21, para-influenza virus, rhinovirus or influenza viruses.

Clinical features
• Coryza, cough, dyspnoea, tachypnoea, wheeze
• Worsening for first 5 days then resolution over next 2 weeks
• Feeding difficulties (secondary to breathing difficulties), poor intake, vomiting
• Apnoea in small babies
• Secondary bacterial chest infection can develop

Signs
• Tachypnoea, tachycardia, intercostal, subcostal and suprasternal recession
• Inspiratory crackles, wheeze
• Low grade fever, and if severe cyanosis

Investigations
Nasopharyngeal aspirate (NPA) Immunofluorescence test for RSV antibodies
CXR (Only if severe or bacterial superinfection suspected)
Hyperinflation (horizontal ribs and flattened diaphragm)
Patchy atelectasis (often RU L), peribronchial thickening
Blood tests Paired antibody titres (for RSV)
Viral culture

Treatment
• Oxygen via nasal prongs or head box
• IV fluids as necessary with NG feeding in recovery phase
• CPAP or intubation with IPPV if deterioration with exhaustion or persistent apnoeas
• Bronchodilators advocated in some centres, these cause short-term improvement in a minority and must be
monitored for efficacy
• Antibiotic therapy if secondary bacterial pneumonia suspected
• Ribavirin via SPAG machine for infants who are very unwell or at risk of severe disease, e.g. BPD, CHD, CF,
immunodeficiency or< 6 weeks old
• ECMO if above management is failing

129
Complications
• Bronchiolitis obliterans - severe persistent airways damage (usually with adenovirus)
• Macleod syndrome - persistent overdistension of one lung

INHALATION OF A FOREIGN BODY {FB)

Clinical features
Acute episode Acute coughing or choking episode followed by
Stridor (in upper airways), or
Wheeze (in lungs)
Positive history of small object inhaled
Chronic symptoms Respiratory infection not resolving
Recurrent lobar pneumonias involving the same lobe
Persistent wheeze ,

Investigations
CXR FB radio-opaque only in 10- 15% of cases. NB: Peanuts are radiolucent
Collapse distal to FB
FB side may be hyperinflated
Inspiratory (both sides equal) and expiratory film (FB side lung hyperinflated)

Management
Removal of FB using rigid bronchoscopy under general anaesthesia.

ASPIRATION (ACUTE ANO RECURRENT)

Causes
Acute Infants with acute viral illness exacerbating existing gastro-oesophageat reflux
Depressed gag reflex
Reduced state of consciousness
Recurrent Neurological swallowing disorder, e.g. cerebral patsy
Gastro-oesophageat reflux
Oesophageal incoordination
Structural anomaly, e.g. trachea-oesophageal fistula

Clinical features
• Cough, stridor and wheeze
• Pneumonia

Investigations
CXR Consolidation
More than one lobe may be involved
Features of collapse in recurrent aspiration
Other To elucidate cause, e.g. reflux investigations
130
Management
Treat acute infection/ then identify and treat underlying cause.

ASTHMA
This is an endemic condition affecting up to 1:10. It is a chronic inflammatory disease of the airways characterized by:
• Reversible bronchoconstriction
• Mucosal oedema
• Excessive mucus production
Associations Atopic conditions (33% have eczema/ 50% have allergic rhinitis± conjunctivitis)

Chronic clinical features

• Recurrent wheeze }
• Difficulty in breathing Both often with exercise
• Nocturnal wheeze with cough
• In long-standing disease there may be chest hyperinflation/ pectus carinatum (pigeon chest) and Harrison sulci
(a permanent groove in the chest wall at the insertion of the diaphragm)

Clinical features of an exacerbation .

• Dyspnoea
• Expiratory wheeze (crackles in younger children)
• Respiratory distress (tachypnoea/ recession/ tachycardia/ cyanosis)

Features of a life-threatening attack

• Unable to speak or feed
• Central cyanosis
• Exhaustion/confusion/decreasing level of consciousness
• Silent chest on auscultation (due to minimal air entry)
• Peak flow ~ 30% of predicted
• Hypotension - pulsus paradoxus (fall of inspiratory systolic BP > 10 mmHg from expiratory systolic BP)

Management
Acute attack
• Oxygen
• B-agonist either 10 puffs from an MDI via spacer device or nebulized/ as frequently as necessary (initially 15 minutely)

131
 • Ipatropium bromide 6 hourly
• Systemic steroids (oral prednisolone 1-2 mgjkg [max. dose 40 mg] or IV hydrocortisone)
• If severe attack, may then need:
• IV infusion or bolus of salbutamol or aminophylline infusion (if on oral theophylline no loading dose)
• Intubation and ventilation if deterioration in general condition, i.e. peak flow, blood gases, drowsiness or tiring,
despite above measures

This is outlined in the British Guidelines on Asthma Management (summarized below). The lowest step to control the
asthma should be used. Management should be reviewed every 3-6 months and a step down in treatment is possible
if control is sustained for> 3 months. ~-Agonists are used as relievers on all of the steps.
NB: A short course of steroids is usually required to treat an acute exacerbation.

Children under 5 years

Step 1 Step 2 Step 3 Step 4
Mild intermittent Regular preventer Add-on therapy Persistent poor canto/
Occasional inhaled Add 2-5 years Refer to respiratory
~- agonist Consider leucotriene paediatrician
Inhaled steroid receptor antagonist
200-400 jlgjday* (LRA)
(or LRA if inhaled
steroid cannot be < 2 years
used) consider step 4
·.--·-· ·.· ·_.

: s~hool children
Step 1 Step 2 Step 3 Step 4 Step 5
Mild intermittent Regular preventer Add-on therapy Persistent poor . Frequent or ~ontjnuous
asthma therapy control . use oforal ~teroids }
Occasfonal ~-agonist Add inhaled steroids Add Increase inhaled Use dailysteroid . •.·
inhaled (200- 400 jlgjday*) 1. long-acting steroids to 800 11g/ tablet in lowest dose
(or other prevention ~-agonist (LABA) day* to maintain 'control •
drug if inhaled
steroid cannot be .· . 2. Assess control:
used) · :- LABk benefit, but
still poor control,
ensure 400 jlg/day'
inhaled steroids -
LABA'nd iesponse,
stbp LABA>eh'sure
. 400 ~g)day· inhaled ·.
steroids ·. .·.
Trial other therapies,
e.g. theophylline
SR, leukotriene
antagonist
*Beclomethasone equivalent. : . . . . . . .. . . . ..
· Ref: British:Guideline-o~ the Mana~~meilt :(JfAsth-ni'a Th6r~x May:. 63 Suppl 4: .iv
- ·. , : . ;. ·. - " .
/' - ~_ .. .,:.:.._ ...:.··.::· __;
_ . ,_, .
__ --~- :··-·: ;, . •' . ·. ·· ..

132
 -·. . : ,; .·

Asthma medications

st~r;fds·- · ____ ," .. . __ .

. m'matory
_. ·
.
effect
.. ..
on
.'
ai'r
'
wayst
.
st:eroid
: .
side-effects
'· •,
minimal
. ·-
unless high dose
.
inhaled
,·
.
.
or oral steroids given .

MDI; dry powder

· MDI; dry powde(neb sol
. MDI,-dry powder, neb sol

. .
Sodium cromoglycate _MDI, dry poyJder, neb sol
Necrodomil · MDI
3.-.'Methyl xanthin~~ ._-- _ ·· - ' . _ . -_ _- _- -
sr'()richoditatqrs;sriloqth.muscle relaxer. Narrow m~rginbetween toxicity (arrhythmias, convulsions)and "
therapeutic dose. :, . :... ·.: ,<~ > -· · ·. •· : · - ---- -- · · - -· -. ' · _·. ·· ·
_, _.
_

Aminophylline Tabs; injection

Theop]lylline · Tabs, caps, syrup
:,.-·: .

4.t [eukotriene receptor antagonists - _ -

Blocks effect of cysteinylleukotrienes in the airways, Additive effect with corticosteroids.
Monteleukast Tabs

Delivery devices
There are many different devices and routes for the medications suitable for different ages of child, and the most
convenient and appropriate is chosen for each child.

133
 .. •. ... ,.. ..

• It 1s most important the parents and child are taught how to use the equipment properly
• The best device to use for all children and adu lts is an MDI with spacer
• Some older children prefer for practical reasons to use dry powder devices
• Methods of dispersing medication to the lungs: Metered dose inhaler (MDI) with or without spacer
Dry powder inhaler, e.g. turbohaler and accuhaler
Nebulizer
• Two spacer devices exist. By increasing the distance, these slow the aerosol, allowing propellants to evaporate.
This reduces the size of the droplets which helps inhalation and traps larger non-respirable particles in the
chamber. Also, they reduce the need for coordination between drug release and inhalation . They connect with
different medications:
1. Nebuhaler- terbutaline, budesonide
2. Volumatic- salbutamol, beclomethasone, fluticasone, ipatropium bromide

VIRAL-INDUCED WHEEZE
• Wheeze only with concurrent URTI
• Usually found in pre-school children
• Individuals are often non-atopic and symptoms resolve by school age
• Management as for acute asthma attack, dependent on severity. Acute bronchodilators when symptoms occur;
short course oral steroids may be necessary

PERSISTENT WHEEZE IN INFANCY

• Recurrent episodes of wheeze in infants, sometimes following viral infections
• Usually these children have small airways (boys, child of smoking mother)
• Some resolve in first few years, others go on to become asthmatic

CAUSES OF CHRONIC COUGH

INFECTION

PNEUMONIA
A common disease of childhood caused by many pathogens.

Clinical features
• Respiratory distress symptoms and signs
• Fever (> 38.SOC) and malaise
• Abdominal pain ·

134
Causes
Newborn Group B P-haemolytic streptococcus, Escherichia coli, Listeria monocytogenes, Chlamydia
trachomatis, Staphylococcus aureus, CMV
Infants RSV, adenovirus, influenza viruses, parainfluenza, Streptococcus pneumoniae,
Staphylococcus aureus, Haemophilus influenzae
Children Streptococcus pneumoniae, Mycoplasma pneumonia, Haemophilus influenzae,
Staphylococcus aureus, TB
Jmmunocompromised As for children plus Pneumocystis carinii, atypical TB

Investigations
This is a clinical diagnosis
CXR Lobar pneumonia (dense consolidation) or bronchopneumonia (patchy)
Blood tests Blood cultures, FBC, blood gas ifUJlwell
Oropharyngeal For viral immunofluorescence, M, C& S
suction specimen
Sputum M, C & S

Management
It is not p_ossible to distinguish between viral and bacterial pneumonia clinically or on CXR, and therefore it is always
treated with antibiotics.
1. Humidified oxygen as needed to keep saturation > 92%. Use head box, nasal cannulae, or face mask
2. Therapy with appropriate antibiotic

Complications
• Pneumococcal pneumonia - meningitis, pleural effusion
• Staphylococcal pneumonia- empyema, lung abscess, pneumothorax

PERTUSSIS (WHOOPING COUGH)

This is an infection caused by the Gram-negative coccobacillus, Bordatella pertussis. It is a notifiable disease.

Clinical features
Usually o~curs ~ 5 years of age
Transmission Droplet
Incubqtion period 7- 14 days
Catarrhal stage 1- 2 weeks. Runny nose, conjunctivitis, malaise, highly infectious
Paroxysmal stage Paroxysms of coughing causing inspiratory whoop and vomiting. The severe coughing can
cause conjunctival petechiae and epistaxis. Severe in young babies. Infants may have no
whoop, but apnoea followi ng coughing spasms. May last up to 3 months (usually 2 weeks)
Convalescence 1-2 weeks. Resolution of symptoms

Investigations
Aclinical diagnosis, confirmed by:
Per nasal swab PCR and culture
FBC Lymphocytosis

135
Management
• Isolate child and give supportive care
• Erythromycin early in disease and for contacts
• Prevention by immunization

Complications
• Lobar pneumonia (causes 90% of deaths)
• Atelectasis, bronchiectasis (late sequela)
• Apnoea, cerebral anoxia with convulsions in young infants
• Rectal prolapse, inguinal hernia, phrenulum tear, periorbital petechiae, subconjunctival haemorrhage (from
coughing spasms)

CYSTIC FIBROSIS
• Autosomal recessive disorder. Highest prevalence in Northern Europeans: carrier rate 1:25, 1:2500 affected
• Chloride (with passive movement of sodium and water) is poorly secreted, resulting in viscid secretions
• Due to a defect in CFTR (cystic fibrosis transmembrane regulator) protein, which is a chloride channel
• CFTR protein located on chromosome 7. Over 1000 mut§tions found. Loss of phenylalanine at position 508
(DF508) in 75% of UK cases
• The two main problems are: Recurrent chest infections causing chronic lung damage (bronchiectasis)
· Malabsorption (due to reduced pancreatic enzymes) causing faltering growth

Clinical features
General Faltering growth
Respiratory Recurrent infections classically in the following order: Staphyloccocus aureus, Haemophilus
influenzae, Pseudomonas aeruginosa, Cepacia
Restrictive (and obstructive component in one-third) lung disorder
Chronic lung damage (bronchiectasis, lobar collapse, pneumothorax)
Nasal polyps, sinusitis
Cardiovascular Right heart failure (late feature secondary to severe lung disease)
Pancreas Decreased pancreatic enzymes in 85% (lipase, amylase, proteases), causing steatorrhoea
CFRD (CF-related diabetes) - increasing incidence with age (one-third of adults)
Liver Fatty infi ltrate, cholesterol gallstones, cirrhosis, pericholangitis, portal hypertension
Gut Meconium ileus (15% present with this - soon after birth with delayed passage of meconium
and bowel obstruction. Relieved either surgically or with Gastrograffin enema), meconium ileus
equivalent
Rectal prolapse (> 18 months) - resolves rapidly on starting enzyme replacement
Hepatosplenomegaly, pubertal delay
Intussusception, constipation
Joints Cystic fibrosis -related arthropathy
Reproductive Males infertile (as vas deferens are absent)

Neonatal presentations
• Meconium ileus
• Prolonged neonatal jaundice
• Recurrent chest infections
• Malabsorption with diarrhoea or steatorrhoea
• Faltering growth .

136
Examination findings
General Poor growth and nutritional state
Finger clubbing, finger prick marks (from monitoring IDDM)
Respiratory Hyperinflation, scoliosis, Portacath (NB: Auscultation may be normal if post physiotherapy)
Cardiovascular Right heart failure
Abdominal Hepatosplenomegaly, faecal masses, pubertal delay, jaundice, caput medusae, surgical scars, e.g.
from meconium ileus, liver transplant, gastrostomy
ENT Nasal polyps
Joints Swelling (cystic fibrosis-related arthropathy)
CXR findings Bronchial wall thickening } All become more marked
Hyperinflation with flattened diaphragms with increasing disease
Ring and line shadows, mottling severity

Diagnosis
This is usually suspected on the basis of failure to thrive and recurrent chest infections.
Sweat test Gold standard. Two tests needed, with ~ 100 mg sweat, pilocarpine used
In CF, hjgh chloride (> 60 mmoljL) is diagnostic, sodium also high
Immune-reactive trypsin (IRT) i. Used < 3 months of age. May be performed on Guthrie test
Gene analysis PCR technique looking for common mutations. This is possible on the Guthrie test.
Also antenatally to screen for maternal mutations for risk of having CF child
Stool With pancreatic insufficiency elastase is low, chymotrypsin absent and high fat
content
Electrolytes Unwell children have hypokalaemic alkalosis secondary to sodium and potassium
loss in the sweat. Known as pseudo-Bartter syndrome

Management
Aims of management are to ensure optimal physical and emotional growth, and delay the progress of the pulmonary
disease.
Lung disease Physiotherapy often twice daily (more as necessary)
Antibiotics (long-term or pulsed as prophylaxis)
May be nebulized
Intercurrent infections treated as necessary
Bronchodilators (useful in 30%)
Oxygen at night at home if necessary
Gastrointestinal disease Oral pancreatic enzymes, e.g. Creon®, Pancrease®
Optimum nutrition: High-calorie, high-protein diet
Vitamins, bile acids (ursodeoxycholic acid)
Salt required in hot weather and for babies

137
Other treatments Mucolytics, e.g. DNase therapy or hypertonic saline
Heart-lung transplantation in end-stage disease
Treatment for complications, e.g. insulin for CFRD
Gene therapy is still in development

Regular review
• General growth and development
• Respiratory pathogens
• Frequency and severity of chest infections and lung function
• Nutrition and gastrointestinal symptoms
• Development of diabetes, liver or joint disease
• Psychosocial problems (school progress, etc.)
• Fertility and genetic counselling

BRONCHIECTASIS
This is a condition of permanent dilatation of the bronchi . It may be localized or diffuse. There are inflamed bronchial
walls, decreased mucociliary transport and recurrent bacterial infections.

Causes
• Severe pneumonia
• Post-whooping cough, measles and TB
• Inhaled foreign body
• Cystic fibrosis
• IgA deficiency IgG subclass deficiency
• Primary ciliary dyskinesia

CLinicaL features
• Chronic productive cough
• Haemoptysis
• Dyspnoea and clubbing after time

Investigations
CXR Hyperinflation and peribronchial thickening of affected area
CT scan thorax Dilated bronchi and thickened walls

Management
• Postural drainage
• Antibiotics (for acute infections or prophylaxis)
• Bronchodilators
• Surgical resection of affected lobe if necessary and possible

IMMOTILE CILIA SYNDROME

Agroup of inherited conditions caused by an absence of dynein arms (ATPase) on the cilia, which results in defective
or absent cilia action. The defective cilia affect the lungs, nose, ears and sperm ducts. First described as Kartagener
syndrome (situs inversus, chronic sinusitis and immotile cilia).

138
.. ~

. Clinical features
• Neonatal respiratory distress
• Chronic sinusitis
• Otitis media (conductive hearing loss)
• Chronic productive cough ±wheeze
• Males infertile (sperm motility poor)

Diagnosis
• Ultrastructural changes of dynein arms on the cilia (gold standard)
• Nasal mucosal scrapings - motility decreased
• Mucociliary clearance -time to taste saccharine placed on inferior nasal turbinates (prolonged)
• Liver function tests - obstructive picture
• CXR and CT scan as for bronchiectasis

Management
As for bronchiectasis with ENT involvement.

a 1-ANTITRYPSIN DEFICIENCY
The lung disease in cx 1-antitrypsin deficiency generally presents as emphysema at 30-50 years of age, though younger
presentation occurs. Hyperinflation is seen on CXR. Management is with aggressive treatment of infections, vaccina-
tion for pneumococcus and influenza, bronchodilators if necessary and advice against smoking.

PULMONARY FIBROSIS
This is a rare condition resulting in 'honeycomb' lung seen on CXR. Progression to respiratory failure is inevitable.

Causes

Management
Supportive, with steroids to alleviate symptoms.

SARCOIDOSIS
A multisystem granulomatous disease, uncommon in children, most usually seen in young adults.

Clinical features
Very variable depending on the organs involved and the severity. Organs involved include:

Lungs Parenchymal infiltrates, miliary nodules, restrictive lung changes

Hilar and paratracheallymphadenopathy
Eyes Uveitis, iritis

139
Joints Arthritis
Other Skin rashes, peripheral lymphadenopathy, liver involvement
Hypercalcaemia may lead to renal damage

Clinical presentation
Young child Cough, fatigue, weight loss, anaemia, bone and joint pain
Older child Maculopapular erythematous rash, uveitis, arthritis and minimal lung involvement

Investigations
Biopsy Of involved area (non-caseating, granulomatous lesions)
Serum ESR i
Ca i
ACE (angiotensin-converting enzyme) t a measure of disease activity
Urine Hypercalciuria
Lung function tests Restrictive defect
CXR/CT scan Perihilar lymphadenopathy, parenchymal infiltrates

Management
• Regular assessment for lung, renaL eye and other involvement
• Supportive and symptomatic treatment. Steroids may be used
• Prognosis is very variable

British Thoracic Society. The British Guidelines on Asthma Management. Thorax 1997 Vol 52: Suppl 1, 1-21
Chernick V, Boat TF, Wilmott RW, Bush A Kendig's Disorders of the Respiratory Tract in Children, 7th edn. Philadelphia: ·
WB Saunders, 2006

140
 • Physiology • Constipation
• Upper gastrointestinal conditions • Pancreatitis
• Malabsorption • Gastrointestinal tract bleeding
• Gastroenteritis • Gastrointestinal tract tumours
• Diarrhoea • Faltering growth
• Chronic abdominal pain • Nutritional disorders
• Peptic ulcer • Eating disorders
• Inflammatory bowel disease

PHYSIOLOGY

OESOPHAGUS

The oesophagus propels food along with normal peristaltic waves, which are disturbed in motility disorders. It has
two sphincters:
Upper oesophageal sphincter (UOS) Normally closed by the cricopharyngeus muscle
Lower oesophageal sphincter (LOS) A high resting tone to prevent reflux of gastric contents
Composed of oesophagea l smooth muscle, under vagal and hormonal control
Intra-abdominal oesophagus also acts as a physiological valve
STOMACH
Function Food reservoir, mixes food, produces acid, emulsifies fats, intrinsic factor secretion and minimal
absorption
Gastrin (hormone)
Released with Antral distension
Amino acids in antrum
Vagal nerve stimulation
pH> 1.5

141
Acb"ons Release of gastric acid, pepsin, IF
Gastric emptying
Pancreatic bicarbonate release

Vagus nerve

Pepsinogen

Parietal cells
Gastric acid
Intrinsic factor
Mucosal cells
Mucus
G cells
Gastrin

Figure 7.1 The stomach

PANCHEAS

Proenzymes Trypsinogen, chymotrysinogens, 2. a-cells Glucagon

proami no peptidase, ·procarboxypeptidases, 3. D-cells Somatostatin . .·.·•···.
co-lipase 4. pp-cells Pancreatic polypeptide ·

DUODENUM AND JEJUNUM

Function Digestion, absorption, hormone production and defence organ
Produces 2 L of fluid/day, made from:
• Brunner's glands - bicarbonate juice
• Panneth cells - watery juice
• Enterocytes - digestive enzymes and absorption

142
''
,·-:.:
' principal gastrointestinal polypeptide hormones
Pancreatic bicarbonate release 1'
Delays gastric emptying, inhibits gastric acid and pepsin secretion
~/ Cholecystokinin- Pancreatic enzyme and bicarbonate release 1', gallbladder contraction,
, pancreozymin (CCK-PZ) inhibits gastric emptying
!' Gastric inhibitory peptide (GIP) Insulin secretion 1', inhibits gastric acid secretion
l· Motilin Increases bowel motility
Gastrin Action as above (p. 141)
J Pancreatic polypeptide (PP) Inhibits pancreatic secretion
Gallbladder relaxation
' Somatostatin Inhibits secretion and action of many hormones
' Vasoactive intestinal Intestinal and pancreatic secretion 1', inhibits gastric acid and pepsin
peptide (VIP) secretion.
' Substance P Increases small bowel motility

Digestive enzymes
Amylase, lactase, sucrase, maltase, isomaltase, lipases and enterokinase.
Absorption
• Passive - water, salts, folic acid, vitamins B and C
• Active - amino acids and monosaccharides
• Released from micelles then passive -fatty acids, cholesterol, monoglycerides, vitamins A, D, E, K

ILEUM
Function is absorption (though this occurs mainly in the jejunum and duodenum), with bile salts and vitamin B11
absorbed in the terminal ileum.

Bile acids
Function Digestion of fats
Bile contains Bile acids, cholesterol, phospholipids, bile pigments (bilirubin and biliverdin) and protein
Primary bile acids Cholic acid
Chenodeoxycholic acid
Secondary bile acids Deoxycholic acid
} From breakdown of primary acids
Lithocholic acid

143
ENTHWHEPATIC CIRCULATION
This occurs 6-8 times a day. It is increased by parasympathetic stimulation, gastrin and secretin and decreased by
sympathetic stimulation and cholestyramine.

salt pool

6--8 cycles
per day

~
Faecal loss
(1 0-20% of pool
per day)
terminal ileum

Figure 7.2 The enterohepatic circulation

Function Absorption of water, sodium and chloride (passive and active)

Secretion of potassium, bicarbonate and mucus
Stool is 70% water.

UPPER GASTROINTESTINAL CONDITIONS

This is the passage of gastric contents involuntarily into the oesophagus. It is the result of an incompetent lower
oesophageal sphincter, usually secondary to immaturity.
Associations Cerebral palsy
Hiatus hernia
Thoracic stomach
Coeliac disease
Raised intracranial pressure
UTis
Fabricated or induced illness

Clinical features
• Vomiting at end of feeds (±altered blood)
• Crying, food refusal, poor sleeping, irritability
• Usually resolves spontaneously by 12-18 months of age

144
 ..
.:)
Complications
o Faltering growth
• Oesophagitis ± oesophagea l stricture
• Apnoea, ALTE, SIDS
• Aspiration, wheezing, hoarseness, recurrent chest infections
• Iron-deficiency anaemia
• Seizure-like events, torticollis

Investigations
These are necessary only if there is failure to resolve with simple measures or the reflux is complicated. The investiga-
tions complement each other.
Oesophageal pH measurement %of time pH< 4.0 in 24 h: >10%' =abnormal if< 1 year old;
> 6% = abnormal if> 1 year old
.J' Barium swallow and meal Looking for malrotation, hiatus hernia, oesophageal stricture
Endoscopy Looking for oesophagitis, stricture, enteropathy
Other investigations CXR
Urine M, C& S
Hb and iron studies
Faecal occult bloods
Remember raised intracranial pressure may cause reflux

Management
Position Nurse on side, 30° head up
Thi~ken feeds Add thickeners, e.g. Carobel, Nestargal, or use prethickened feeds, e.g. Enfamil AR, SMA
Staydown
Change feeds Consider changing feeds to hydrolysate, e.g. Nutramigen, Pregestamil, Peptijunior, or
elemental amino acid-based (Neocate) · ·
Drugs Antacid, e.g. Gaviscon Infant
Prokinetic, e.g. domperidone
H2 blocker, e.g. ranitidine
Proton pump inhibitor, e.g . omeprazole
Surgery If medical management fails over a 3-month period, consider an antireflux procedure, e.g.
Nissen fundoplication, but only if life-threatening reflux as it normally resolves spontaneously
by 12- 18 months of age

POSStTTING
This is small-volume vomits that occur during or between feeds. The infant will be thriving and there is no cause for
concern. Management is with reassurance.

HIATUS HERNIA
i
This is herniation of the stomach through the oesophageal hiatus and may be of the sliding type (gastro-oesophageal
junction slides into the thorax) or para-oesophageal (a portion of the stomach herniates beside the gastro-
oesophageal junction).

145
 -l

Compt\c(3tion ':~f fu[ld_oplication (Nissen) .

~Upper
,.. .. .
·:.
abdomi. naLpair(
' . .
comrnon-symptom
,._ .. , ,- .· -
·;

Management
• Antireflux medication Gastro- _
• Surgery if necessary (rarely so) oesophageal
junction
~

Gastro-
oesophageal
junction
Ia\ lb\
Figure 7.3 Types of hiatus hernia. (a) Sliding hiatus hernia.
(b) Para-oesophageal hiatus-hernia

CAUSES OF VOMITING

Acute infectionjocculfirifection e.g. UTI

Metabolic disorder, e.g. IDDM . ·.
Drugs or deliberate poisoning
CNS disease, e.g. migraine, ICP
Psychogenic, e.g. anorexia nervosa, bulimia
Severe illness

146
 MALABSORPTION
Malabsorption may be generalized or specific where individual transport mechanisms or enzymes are defective.
Generalized malabsorption presents with faltering growth and steatorrhoea. Specific malabsorption may present
with different features.

CAUSES OF MALABSORPTION

Generalized
Gut Short gut syndrome, blind loop syndrome, chronic infection (giardiasis, immunodeficiency), coeliac
disease, food intolerance, e.g. cow's milk protein
Diffuse mucosal lesions, e.g. congenital microvillous atrophy
Pancreas Cystic fibrosis, chronic pancreatitis, Shwachman-Diamond syndrome
Liver Cholestasis of any cause, e.g. biliary atresia
.;;
Specific
Protein Amino acid transport defects, e.g. Hartnup disease, cysteinuria
Carbohydrate Disaccharidase deficiencies, e.g. lactase, sucrase-isomaltase
Glucose-galactose malabsorption
Fat Ab~talipoproteinaemia
Elements Chloride diarrhoea, acrodermatitis enteropathica (zinc)
Vitamins Juvenile pernicious anaemia (B 12 )

INVESTIGATIONS
The list is exhaustive and therefore investigations must be symptom led. Some investigations to consider are:
Bloods FBC, iron studies, bicarbonate, U&Es, creatinine, plasma lipids
Coeliac screen, CF genotype
Stool Electrolytes, fats, reducing substances
Microscopy and culture (cysts, parasites)
Faecal elastase (-1- in pancreatic insufficiency) and a. 1-antitrypsin (i in protein-losing
enteropathy)
Sweat test Cystic fibrosis
Radiology AXR, CXR, barium studies
Endoscopy With duodenaljjejunal biopsies and duodenal juice microscopy
Breath tests Lactose, sucrose and lactulose breath tests (the latter for bacterial overgrowth)

FOOD INTOLERANCES
I

Dietary protein intolerance (cow's milk protein intolerance)

This is most commonly due to cow's milk protein (CMP) intolerance. Other protein intolerances occur to soya, fish,
wheat and eggs.
Associations Atopy
IgA deficiency

Clinical features
• Diarrhoea, vomiting, failure to thrive
• Recurrent mouth ulcers, allergic pancolitis

147
 • History of contact allergy or anaphylaxis (rare) to cow's milk, family history of reaction to foods
• Atopic history (eczema, asthma)

Diagnosis may be established by:

• Trial of cow's milk protein elimination diet without biopsy, or
• Small intestinal biopsy- patchy partial villous atrophy, eosinophils in lamina propria
• Other investigations: IgE t eosinophilia

l~o nagen1 ent

Elimination diet using casein-hydrolysate based formula . Breast feeding mothers need to avoid cow's milk and soya
protein.
NB: 35-40% of children with CMP sensitivity also have soya sensitivity and need a CMP and soya-free diet e.g.
Nutramigen, Pregestamil, Peptijunior or, increasingly commonly, elemental amino-acid based milk (Neocate). 50% of
children recover by 1 year of age and most of the rest by 2 years.

Post-gastroenteritis intolerance
This is a transient condition, occurring after acute gastroenteritis and resulting in persistent diarrhoea (> 14 days).
They have usually developed a temporary intolerance to lactose secondary to CMP sensitization and villous damage.
Diagnosis is on the history and presence of reducing substances in the stool (positive Clinitest). Test for glucose in
the stool (Clinistix) is negative. The condition usually resolves after 2-3 days on a lactose-free diet.

Lactose intolerance
Lactase, the enzyme necessary for digesting lactose -(the sugar in milk), appears late in fetal life and falls after age 3.
40% of Orientals have late-onset (classically age 10-14 years old) lactose intolerance.

Causes
• Transient post-gastroenteritis
• Primary lactase deficiency (very rare)
• Late-onset lactase deficiency (common)

l~il.tli·~,J 1 fea,_,,~,..,s
.. ' LL t J . Ll- /L.

After ingestion of lactose: explosive watery diarrhoea, abdominal distension, flatulence, loud audible bowel sounds.

Investigations
• Stool chromatography positive for lactose, i.e. > 1% present
• Lactose hydrogen breath test

fvi:;nnao;·p.:>r]f-
. . . . .,.;.,.;\,..-/ ......, ·-

• Lactose-free formula feed for infants

• Milk-free diet with calcium supplements for older children

148
 Nutramigen Casein hydrolysate (hydrolysed protein t() peptides of< 15 amino acids)
Pregestamil Casein hydrolysate (hydrolysed protein to peptides of< 15 amino acids)
Peptijunior Partial whey hydrolysate (contains somepeptides > 15 amino acids)
Neocate Amino acids

SUCRASE-ISOMALTASE DEFICIENCY
Autosomal recessive, rare. This is a congenital enzyme deficiency of the disaccharidases sucrase and isomaltase and is
worth considering as adifferential diagnosis in 'toddler's diarrhoea'.
Symptoms are of diarrhoea and bloating. The sugars (sucrose and isomaltase) may be seen in stool chromatography.
These are not reducing sugars. Enzyme assays show the specific deficiencies and hydrogen breath test is positive after
sucrose ingestion. Management is with dietary sucros~ restriction.

GLUCOSE-GAlACTOSE.MALABSORPTION
Autosomal recessive. This is due to a congenital deficiency of the glucose galactose transport sites. The condition
presents with severe diarrhoea, bloating and dehydration. Management is with glucose and a galactose-free diet, using
fructose-containing formula.

COELIAC DISEASE
Adietary gliadin intolerance resulting in small bowel mucosal damage. Gliadin, a fraction of the protein gluten is in
wheat, barley, oats (marginally) and rye.
Associations HLA-B8 DR3, DR7, DQW2.
Presentation is usually with the introduction of dietary gluten at around 4-6 months of age.

Clinical features
• Faltering growth, anorexia, vomiting, diarrhoea
• Irrita,ble, unhappy
• Abdominal pain, rectal prolapse, smelly stools
• Signs of pallor, abdominal distension, clubbing and malabsorption
NB: Increasingly a more subtle presentation occurs with, for instance, poor height and weight for the familial context,
e.g. parents may be on goth percentiles whilst the child may be on the 25th centiles. Without appreciation of the paren-
tal heights, the child's diagnosis of coeliac disease may be missed as they fall within population normal percentiles.
Many adults have coeliac disease but are unaware of their diagnosis, e.g. common cause of male infertility.

Associations/other features
• Malabsorption
• Dermatitis herpetiformis: Very itchy vesicles on extensor surfaces. Improves on a gluten-free diet
IgA Abs in normal and perilesional skin but not active lesions
Treatment is with dapsone until diet effective
(All children with dermatitis herpetiformis have coeliac disease)

149
 • Selective IgA deficiency
• IDDM
e Intestinal lymphoma
• Later life: osteopoenia and general increase in bowel carcinoma incidence

Investigations
IgA anti-endomysia! and (With total IgA level because in the 1 in 200 or so individuals who have a low
tissue trans-glutaminase lgA there may be false-negative serological results as these antibodies are IgA
Abs antibodies, i.e. these antibodies are not seen in IgA-deficient individuals.) Anti-gliadin
antibodies are now not considered specific enough for a serologically secure diagnosis
Jejunal biopsy Gold standard
Total or subtotal villous atrophy seen on small bowel biopsy by endoscopy
Gluten challenge Now only necessary in children diagnosed under 2 years of age -transient gluten enter-
opathy may occur under this age but coeliac disease is diagnosed as a life-long condition
after 2 years of age.
Other findings include Anaemia (dimorphic blood film from iron and folate deficiency)
Hypoalbuminaemia

Management
Lifetime gluten-free diet. (This reduces risk of complications such as intestinal lymphoma.)

Causes of villous atrophy on jejunal biopsy

This is a group of disorders involving dilatation of the intestinal lymphatic vessels with leakage of lymph into the
intestine and peritoneal cavity.
Associations Noonan and Turner syndromes

Causes
Congenital
Acquired Lymphatic obstruction from abdominal or thoracic surgery, malrotation, right heart failure or constrictive .~

pericarditis, post-Fontan cardiac surgery

Clinical features
• Fat malabsorption with steatorrhoea and features of vitamin E deficiency
• Protein-losing enteropathy (oedema, chylous ascites, hypoalbuminaemia and hypogammaglobulinaemia)

150
 , ." \ .
. . ·,. .

Diagnostic investigations
• Small bowel biopsy- distorted villi with dilated lacteals
• Faecal u1-antitrypsin i due to protein-losing enteropathy

Management
High-protein, low long chain (LCT) triglycerides, high medium chain triglyceride (MCT) diet.

ABHALIPOPROTEINAEMIA
Autosomal recessive. Severe fat malabsorption with neuropathy secondary to vitamin Edeficiency. Underlying deficienc
of microsomal triglyceride transfer protein in the small bowel.

Clinical features
Gastrointestinal Faltering growth, steatorrhoea, abdominal distension
Neurological (After age 10 years) Ataxia (spinocerebellar degeneration), loss of proprioception and vibratior
sense, peripheral neuropathy and retinitis pigmentosa
Mental retardation and regression

Investigations
• Decreasea cholesterol and triglycerides and no vitamin E in serum
• Acanthocytes in the blood (spiky red cells)
• Jejunal biopsy (fat accumulation in intestinal cells) ofr O~

Management
Special diet with increased MCTs and supplements of fat-soluble vitamins (A, D, Eand K).

51-iWACHMAN-DIAMOND SYNDROME
An inherited autosomal recessive condition, 1:50 000 births, female > male, 2:1. Caused by mutation (pseudogenE
i' copy) in the SBDS gene on chromosome 7q11.
The syndrome involves:
• Pancreatic exocrine insufficiency (with subsequent malabsorption)
• Haematological dysfunction: Neutropaenia - often cyclic, progression to myeloid arrest can occur
Neutrophil chemotactic defects
Thrombocytopaenia {70%), anaemia (50%)
High HbF
• S~eletal abnormalities: Metaphyseal dysostosis
Short stature and faltering growth
Management is with pancreatic enzyme replacement therapy and steroids or androgens. Average survival time is 35
years. Stem cell transplant and GCSF have been used.

GASTROENTERITIS
Causes
Viral Rotavirus (winter epidemics, cause in 60% < 2 years old in winter)
Norwalk virus, adenovirus {40 and 41), astrovirus

151
 --, ~~,

Bacterial Staphylococcus (exotoxin)

Watery diarrhoea Enterotoxigenic E. coli (ETEC, traveller's diarrhoea)
Vibrio cholerae
Bloody diarrhoea Enteroinvasive f. coli (EIEC)
Enterohaemorrhagic E. coli (EHEC)
Shigella, Campylobader jejuni,Salmonella enteritidis, yersinia
Protozoal Giardia, cryptosporidium, amoebiasis

Clinical features
• Acute-onset vomiting and diarrhoea
• Abdominal pain and distension
• Mild pyrexia
• Invasive bacterial infection - unwell, high fever, blood and mucoid stool

Differential diagnosis
Acute infection Septicaemia, meningitis, UTI, respiratory infection
Surgical Intussusception, appendicitis
Metabolic Diabetic ketoacidosis
Other Reye syndrome, coeliac disease

Examination findings
• Assess child for dehydration, which is difficult to do accurately (see below). Below 5% dehydration usually there
are no obvious clinical findings. Dehydration is usually hyponatraemic or isotonic.
• Other possible findings: Acidosis - hyperpnoea
Potassium depletion - hypotonia, weakness
Hypocalcaemia - neuromuscular irritability
Hypoglycaemia - lethargy, coma, convulsions

Dehydration assessment

- .

Thr~ady, v~ry tachycardic

Normal -. Norm~l'or low
Urine output Reduced R~duced/absent

152
Hypernatraemic dehydration
• Unusual and potentially serious
• Irritable with doughy skin and relatively good circulation
• Water shifts from intracellular to extracellular and therefore the signs of extracellular fluid loss are reduced
• Rehydration should be slow (over 48 h) to avoid rapid brain rehydration and subsequent raised intracranial
pressure

Investigations
These depend on the clinical state of the child.
Stool Virology, M, C &S, PCR, 'hot stool' for cysts and ova
Bloods FBC, haematocrit, U&Es, creatinine, glucose, capillary blood gas
Plasma and urine osmolality as necessary

Management
Mild< 5% Oral rehydration therapy (ORT) for 24 h or until diarrhoea settles, then milk and light diet
ORT fluid contains glucose and sodium because they are absorbed across even a damaged
mucosa by a joint mechanism and water absorption follows by osmosis NB: Breast feeding
can continue with initial ORT
Moderate/severe > 5% Admit
If the CRT >3 s or acidotic breathing is apparent, IV rehydration is necessary
If in shock: IV volume expansion with 20-30 mljkg 0.9% saline. Then rehydrate over 24 h

Maintenance fluid calculation

w~f§llF ,.
o;Jd'kg 100-126··~ l/k~f24?h'(2 ~i/kglh) .··.

...........,.
10- 20 kg 1000 ml + 50 mljkg(24h (2 mljkgjh) for each kg >10
1500 ml + 20 mljkg/24 h (1 ml(kg/h) for each kg >20

153
Complications
Renal Oliguria (i.e.< 200 mljm 2/day or< 0.5 mlfkg/h)
NB: If prerenal renal failure: Urine osmolality> 500
Urine Na < 10 mmoljl
Urine urea > 250 mmoljl
Urine:plasma osmolality ratio > 1.3
Management of oliguria: urgent IV volume re-expansion. If no recovery of renal function, then
give minimal maintenance fluid plus losses only, with no potassium. Dialysis is necessary if the
fluid, electrolyte or acid- base status does not correct. Recovery is seen with the polyuric phase
of acute tubular necrosis
Renal vein thrombosis (haematuria + renal mass, see p. 216)
Haemolytic uraemic syndrome (seep. 217)
Pulmonary oedema From fluid overload
Convulsions Several possible causes: hypernatraemia, hypoglycaemia, febrile convulsions, other electrolyte
disturbance and cerebral haemorrhage
Check blood glucose, U&Es, Mg, Ca and cranial USS and treat accordingly
Prolonged diarrhoea Diarrhoea > 14 days (see p. 155)

DIARRHOEA
The pathogenesis of most episodes of diarrhoea can be explained by osmotic, secretory or motility disorders or a com-
bination of these. In osmotic diarrhoea the underlying mechanism is a high osmotic load of intra-luminal content,
and in secretory diarrhoea the mechanism is active chloride secretion.

Motility disorders
Increased motility A decreased transit time results in diarrhoea
Causes include IBS, post-vagotomy and dumping syndrome
Decreased motility Bacterial overgrowth results in diarrhoea
Causes include intestinal pseudo-obstruction

Combined mechanisms
This occurs with mucosal invasion, resulting in inflammation, decreased colonic reabsorption and increased motility.
This is seen in dysentery from bacterial infection, e.g. salmonella, and amoebicinfection.
A decreased surface area results in both osmotic and motility disorders, as seen in short bowel syndrome.

154
 Causes

TODDLER'S DIARRHOEA
Achronic diarrhoea up to 4- 5 years of age, with loose stools at a frequency of 3- 6 per day, normal growth and nothing
abnormal on examination. The cause is not clearly understood and may be due to decreased gut transit time leading
to colonic bacterial degradation of partially digested foods and subsequent release of secretagogues.
Management is with reassurance and dietary changes (i fat, l fibre, l juice) to increase gut transit time. The.condition
usually resolves spontaneously by 3 years.

~' CHRONIC DIARRHOEA

Prolonged diarrhoea may be due to any of the above ca uses and the child will quickly become malnourished.

Investigations
Stool M, C & S, reducing substances, fats and electrolytes
Faecal elastase (pancreatic insufficiency)
Bloods FBC (immunodeficiency), electrolytes, ESR, CRP
Coeliac screen (anti-endomysia[ IgA, tissue transglutaminase and total IgA)
AXR and CXR (Obstruction, bronchiectasis)
Sweat test (Cystic fibrosis)
Trial off oral feeds (Secretory or osmotic diarrhoea)
Endoscopy With small biopsy and duodenal juice culture (enteropathy, infection)

Management
Nutritional support while the diagnosis is being arrived at. A hypoallergenic modular feed with supplementation, e.g.
Neocate, can be tried first. If enteral feeds fail, then a period of TPN will be necessary.
A trial of metronidazole for 5-7 days may be considered (as giardia is only detected in stool specimens in 20% of
cases).

155
CHRONIC ABDOMINAl PAIN

CAUSES
Psychiatric Psychogenic recurrent abdominal pain
Abdominal Constipation, food intolerance (including lactose intolerance), IBD, coeliac disease, Meckel
diverticulum, abdominal TB, peptic ulcer, irritable bowel syndrome
Pancreas/liver Chronic pancreatitis, cystic fibrosis, cholecystitis, chronic hepatitis
Renal UTI, pyelonephritis, renal calculi
Metabolic IDDM, porphyria, lead poisoning
CNS Migraine
Other Referred testicular pain, ovarian pain, sickle cell crisis

This is a very common condition. In order to arrive at this diagnosis, a thorough history and examination must be
done. It is defined as> 3 episodes of life-altering pain per week for 3 months (Apley's criteria).

Features
• Pain para-umbilical and worse on waking
• No signs or symptoms of organic abdominal pathology
• Growth normal and good health otherwise
• Girls > boys
• Most commonly age 6-9 years (school-age symptom)
• High achiever personality (doing well at school, anxious)

Features that suggest an organic cause

. R~in:; · ; . Ldc~tiieO away fro in the .urn bi lie us .·. . .·

:fft·>~! i.~;.<··_!·:.,- 3) W~kib'9' · chi.L~ "afhi9ht · ·- · · ··· · · <· --• ·•·· ·-··
R~diatesto back, legs or shoulders

;r~J,~t;;~.h~Ji~u'"' ·· ·
'ch'jld
. ..
··~
urn.Ve(((fev~r,
,• ·•. :· . .. .. ..
--
weight. . loss,
·_ ·. ': ·.
:
faltering ·,

Management
Thorough history and examination Pain: site, nature, timing, recurrence rate
Aggravating facto rs (? related to school)
Vomiting, weight loss, bowel habit, urinary problems, headache
Ask parent(s) and child what they think the cause is
Take thorough social history (family life, school life)
Any necessary investigations to An MSU should be done to exclude a urinary tract infection
exclude organic disease Other investigations only if indicated, e.g. FBC, ESR, CRP, AXR, endoscopy, etc.
Treatment Explain that although a psychosomatic cause, the pain is real
Reassure parents, child and teachers that no organic cause was found. This can
result in the symptoms improving
Try to avoid medications as these imply there may be something organic
Rapid recovery is seen in 50%, slow recovery in 25%, and continuation of
symptoms in 25%

156
NB: Other common recurrent pain syndromes are headache and limb pain.

Organic causes of Recurrent Abdominal Pain

PEPTIC ULCER
Duodenal ulcers are seen in children with gastric ulcers being very rare.
Zollinger-Ellison syndrome - multiple ulcers due to a gastrin-secreting tumour (see p. 259).

Association Helicobacter pylori infection accounts for 90% of duodenal ulcers in childhood (can be asymptomatic or
cause chronic gastritis or peptic ulceration)
Clinical features
• Intermittent abdominal pain, worse at night
• Nausea, vomiting
• Iron-deficiency anaemia, gastrointestinal bleeding
Investigations
I

• Endoscopy with biopsies

• CLO test on biopsy specimen to detect H. pylori; H. pylori makes urease, which changes the colour in the agar
Management
• H2 antagonists or proton pump inhibitor, e.g. omeprazole
• H. pylori eradication therapy: omeprazole and a combination of two of amoxycillin, clarythromicin and metronida-
zole for 1- 2 weeks - bismuth and tetracyclines are not used under the age of 12 years

INFLAMMATORY BOWEL DISEASE

CROHN'S DISEASE
Adisease of chronic inflammation of the bowel, involving any part from the mouth to the anus, classically the terminal
ileum, and the rectum is often spared. Incidence increasing, male= female.

157
Differential diagnosis
• Gastrointestinal TB
• Infectious enteropathies, esp. Yersinia ileitis
• Small bowel lymphoma

Clinical features
Gastrointestinal Abdominal pain, diarrhoea, anorexia, aphthous ulcers
Abdominal mass, perianal lesions (tags, abscess, fistulae), stricture and fistulae common
Systemic features Fever, malaise, weight loss, anaemia, nutritional deficiencies, growth retardation,
amenorrhoea (primary or secondary)
Extra-abdominal features See p. 159

Investigations
Bloods FBC, iron studies, folate, 812, ESR, CRP, LFTs, serum proteins (l)
Yersinia serology
Stool microscopy and culture Enterocolitides (salmonella, shigella, campylobacter, Entamoeba histolytica)
Plain AXR Partial small bowel obstruction, thumb-printing colon wall
Barium meal and Cobblestone appearance (linear ulcers), deep fissures
follow-through Strictures and fistulae common, discontinuous disease with normal'skip' lesions
Upper endoscopy and
ileocolonoscopy with biopsies
Histology of lesions Non-caseating granulomas, transmural inflammation, patchy involvement

Management options
Polymeric elemental diets Effective as initial therapy instead of steroids. Give exclusive polymeric enteral
nutrition, e.g. Modulin IBD, for 8 weeks orally or via NG tube, as tolerated.
Steroids Oral or IV. High dose for 3-4 weeks, then alternate days and reduce as able
Aminosalicylates Sulphasalazine, mesalazine or olsalazine for colon disease
Delayed-release 5-ASA (Asacol) for terminal small bowel disease
Azathioprine Often now as first line, previously if steroid dependent or not responding
Metronidazole or ciprofloxacin If fistulae or perianal disease
Tacrolimusjpabecrolimus paste For perianal disease
TPN Rarely necessary temporarily
Surgery Reserved for special indications as recurrence risk high
Resection of disease unresponsive to medical therapy (wide resection margin with
right sub-total hemicolectomy)
Abscess, perforation, obstruction, bleeding

UlCERATIVE COLITIS
This is a chronic inflammatory disease of the colon with ulceration, classically involving large bowel from the rectum
upwards. Small bowel may be involved. Incidence: male= female.

Differential diagnosis
• Crohn colitis
• Amoebic colitis
• Bacillary dysentery

158
Clinical features
Gastrointestinal Diarrhoea with blood and mucus
General Anaemia (iron loss from bleeding), growth retardation (malabsorption rare)
Extra-abdominal features See below

Investigations
Blood tests FBC (Hb 1, leucocytosis), iron studies, B12 , LFTs, ESR, CRP, albumin (.l.)
AXR Decreased haustrations
Dilated colon, NB: Toxic megacolon is colon width > 2.5 vertebrae
Double contrast Continuous pathology, 'collar button ulcers', 'lead pipe' (smooth) colon,
barium (air) enema backwash ileitis, double contour
Ileo-colonoscopy with biopsies
Histology of lesions Mucosal involvement only, gland destruction, crypt abscesses, decreased goblet-cells,
pseudo-polyps, friability, ulceration

Management options
Aminosalicylates Oral, e.g. sulphasalazine, mesalazine, olsalazine. For mild colitis and prevention of
relapses
Enemas Aminosalicylate or steroid for proctitis
Steroids Oral or intravenous at 1- 2 mgjkg/day (maximum dose 40 mg) for cases unresponsive
to aminosalicylates
Other drugs Azathioprine, 6-MP, cyclosporin, tacrolimus, metronidazole may be used in steroid-
dependent or uncontrolled disease
TPN In preparation for surgery
Surgery Colectomy is performed for fulminant disease unresponsive to medical therapy or
pancolitis of> 10 years' duration

Complications
• Toxic megacolon
• Fulminating colitis
• Colon cancer (long term), therefore regular colonoscopy after> 10 years' active disease

Extra-abdominal features of Crohn's disease and ulcerative colitis

There are many extra-abdominal features associated with inflammatory bowel disease. Some are more common in
Crohn's disease and others in ulcerative colitis.

159
'crohn's . ut~erative colitis· . · 8oth equally_ · · · .
(most commonly) . . ·. . (most commonly) . . ·. . .. . .·
ErYthema
.- ..,,
riodosi.InT
·-·-· .-.
··
.. ..
· Pyoderma gangrenosum Uveitis
..
P~riph,~ral. arthritis . Ankylosing spondylitis Conjunctivitis .
Aphthous ulcers Sclerosing cholangitis Fatty liver
Clubbing .· . Chronic active hepatitis Cholangiocarcinoma
Episcleritis Cirrhosis
Renal stones( oxalate; uric acid)
Gallstones

CONSTIPATION
This is a difficulty, delay or pain in defecation. When prolonged, there is overflow diarrhoea due to liquid faeces escap-
ing around a hard lump of faeces in the rectum (rectal faecalith).
NB: Important differential is Hirschsprung disease.

Causes
Non-organic Coercive potty training in a defiant toddler, lack of privacy
Organic Intake - low-residue diet, dehydration
Gut- Hirschsprung disease, stricture
Metabolic- hypothyroidism, cystic fibrosis, hypercalcaemia
Neuromuscular - cerebral palsy, spinal cord lesions, myotonic dystrophy, absent abdominal wall
muscles
Drugs - narcotics, antidepressants

Complications
Short-term constipation This quickly resolves with fluids and stool softeners, usually with no sequelae
Long-term constipation Acquired megacolon (decreased sensation of a full rectum)
Anal fissures
Overflow incontinence
Behavioural problems (fear of defecation, embarrassment of overflow)

Clinical findings
Hard faeces on abdominal examination.
PR Not always necessary
Faecal mass, soiled anal region, sacral tuft (spina bifida occulta)
Sphincter tone (J. in simple constipation, i in Hirschsprung disease)
AXR Loaded with faeces
Gut transit study

160
Management
1. Positive reinforcement
2. Increase fluids and fibre intake
3. Oral medications: Softener, e.g. lactulose, paraffin oil (also acts as mild stimulant and prevents water
reabsorption by coating colonic pits- no fat-soluble vitamin malabsorption has been seen
with this therapy)
Non-absorbed laxative irrigative, e.g. Movicol- non-absorbed polyethylene glycol solution
with added electrolytes. NB: Dispensed in adult and paediatric strengths- adult version is
twice as strong
Stimulant, e.g. Senekot, sodium picosulphate
Bulking agent, e.g. Fybogel
4. Enema if necessary for disimpaction, e.g. phosphate enema
5. Anal fissure treatment with local topical a~aesthetic cream and/or GTN ointment

HIRSCHSPRUNG DISEASE
Incidence: 1:5000. Polygenic inheritance, 3-5% recurrence. RET oncogene.
Associations Down syndrome
Lawrence-Moon - Beidel syndrome
Waardenburg syndrome
This disease is due to the absence of parasympathetic ganglia in Auerbach's and Meissner's plexi. The unopposec
sympathetic activity results in hypertonus of the affected segment of bowel. The disease occurs from the recturr
upwards.
There are two types:
Short aganglionic segment Common, male> female
Long aganglionic segment Rare, male = female, familial

Presentation
Neonatal (> 80%) Acute obstruction, Hirschprung colitis
Older child Chronic constipation, history of delayed passage of meconium (> 48 h), faltering growth

Investigations
AXR Constipation
Barium enema Narrow aganglionic segment, dilated proximal segment
Rectal biopsy Rectal suction biopsy (mucosa + submucosa) or full thickness biopsy - surgical
transanal
Anorectal manometry Failure of internal sphincter pressure to drop with rectal distension
Histology of affected bowel Acetylcholinesterase staining shows increased number of hypertrophied nerve bundles
that stain positively for acetylcholinesterase

Management
This is surgical, with an immediate definitive repair or a temporary neonatal colostomy with definitive repair at 3-6
months of age. Definitive repai.r is with direct resection and anastomosis or an endorectal pull-through.
Ultra-short segment disease can be treated with anal dilatation and partial sphincterotomy.

161
 l
'· ' ···.

FAECAL SOILING
Faecal soiling is involuntary soiling. Normal bowel control is achieved by around 2 years (girls are quicker than
boys).
Soiling by day: Boys> girl (2:1)
1-2% 5-12 year olds
Faecal soiling occurs when there is:
• Faecal retention with overflow incontinence. This can happen:
After an episode of diarrhoea, then anal fissure causing painful defecation and constipation
Due to psychological stress coinciding with toi let training, resulting in refusal to sit on potty
Due to other disease, e.g. Hirschsprung disease, hypothyroidism
If the rectum is chronically obstructed with faeces it may enlarge to form a mega rectum . Children with mega rectum
may not sense faecal matter in the rectum, and have diminished urgency to defecate
• Neurological damage with failure to establish bowel control, e.g. cerebral palsy, learning difficulties
• Stress- normal bowel control but soiling in response to stress only
NB: Important to exclude Hirschsprung disease, which is present from birth . If this is suspected, then full investiga-
tion is necessary (seep. 161).
Encopresis is the voluntary passage of faeces in an otherwise healthy child beyond the usual age for toilet training.
It is due to non-organic causes.

Management
• Comprehensive history including gastrointestinal and social
• Abdominal (including rectal) and neurological examination
• Plain AXR: faecal retention
• Empty bowel of impacted faeces: microenemas, manual disempaction
• High fibre diet and stool softeners (for soft painless stools)
For encopresis, psychotherapy (child and family therapy) including a behaviour modification programme (positive
reinforcement, defined periods of toilet training, remove fear of the toilet, remove control battle between parents and
child).

PANCREATITIS

ACUTE PANCREATITIS
This involves inflammation of the pancreas with autodigestion, localized necrosis and haemorrhage. Complications
can be severe.

Causes
• Biliary sludging
• Congenital abnormalities
• Blunt abdominal trauma
• Viral infection - mumps, varicella, measles, EBV, coxsackie virus
• Iatrogenic- total parenteral nutrition, steroids, azathioprine
• Diseases associated- HUS, Kawasaki disease, stem cell transplant brain tumour, metabolic disease such as
isovaleric acidaemia

162
Clinical features
• Abdominal pain (epigastric, radiating straight through to the back), nausea, vomiting, fever
• Tender abdomen, guarding, absent or obstructed bowel sounds, abdominal mass
• Acute haemorrhagic pancreatitis: Very unwell, shocked, jaundiced
Cullen sign (bluish periumbilical region)
Grey Turner sign (bluish flanks)
50% mortality with DIC, renal failure, RDS
Sepsis, gastrointestinal bleeding

Investigations
Serum amylase > 500 IU/L seen in first 72 h (and/or i serum lipase)
Other bloods FBC (leucocytosis), glucose (i), Ca (l),
Clotting screen (prolonged clotting), LFTs (i)
CXR Left pleural effusion, atelectasis
AXR Ileus, ascites, pseudocyst, pancreatic calcification (in recurrent disease)
USS andjor CT abdomen Oedematous pancreas, abscess, pseudocyst

Management
1. Analgesia
2. Keep NBM with intravenous fluids and nasogastric suctioning until amylase normal. Treat shock if necessary
3. Fluid and electrolyte balance with careful monitoring
4. Surgical drainage if abscess or pseudocyst
5. Possible place for octreotide

CHRONIC PANCREATITIS
Causes
Hereditary Autosomal dominant. Progressively more severe attacks
Congenital pancreatic or Hyperlipidaemia, cystic fibrosis, Wilson disease
biliary ductal anomalies
Predisposing disorders Cystinuria, hyperparathyroidism, cystinosis, isovaleric acidaemia, a 1-antitrypsin disease,
ascans

Complications
Pancreatic pseudocysts, calcifications and pancreatic insufficiency.

Investigations
As for acute pancreatitis.
Also check:
• Sweat test and genotype for hereditary pancreatitis
• Stools for ascaris (rare cause), amino and organic acid screen
• ERCP (necessary prior to any surgery), although MRCP may now be preferable as without a therapeutic intention
ERCP has a risk-benefit which may not be preferable (5% risk of inducing acute pancreatitis due to the
procedure itself, even without any pre-disposing pathology)

163
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ---- - - - - - - - - - - - - --- - - - - - - - -

Management
Endoscopic treatment with sphincterotomy, pancreatic or biliary endoprostheses and stone extraction is possible as
necessary.

GASTROINTESTINAL TRACT BLEEDING

This has many causes, the frequency of which depends on the age of the child.

Causes

Clinical presentations
• Haematemesis- fresh blood or 'coffee grounds' (altered by gastric juices)
• Melaena (altered blood per rectum) ~ tarry smelly stool
• Fresh rectal bleeding
• Massive bleeding with collapse
• Small bleeds with iron -deficiency anaemia

Investigations and management

1. Assess circulation and resuscitate if necessary
2. Bloods - FBC, clotting studies, iron studies
3. Faecal occult bloods
4. Endoscopy- this is the emergency management also. Oesophageal banding for varices. (Sclerotherapy is
outdated, and insertion of a Sengstaken-Blakemore tube only in extremis.) Wireless capsule endoscopy is
now considered a viable diagnostic alternative in the context of occult or obscure GI bleeding thought to be
emanating from the small bowel
5. Laparotomy andjor mesenteric angiography if necessary

164
GASTROINTESTINAL TRACT TUMOURS

JUVENILE COLONIC POLYPS

These occur in 3-4% of the population in the colon only. Symptoms usually occur between 2 and 10 years. Uncommon
> 15 years. They are usually benign hamartomas (unless they have an adenomatous element).

Presentation
Bright red rectal bleeding, autolysis, prolapse of a polyp, anaemia, abdominal pain (unusual).

Diagnosis
Rectal examination, colonoscopy with polyp removal, barium enema.

FAMILIAL POLYPOSIS SYNDROMES

Familial adenomatous polyposis coli (FAP)
Autosomal dominant, incidence 1:8000, pre-malignant condition. The APC (adenomatous polyposis coli) gene has
been identified on the long arm of chromosome 5; many different mutations rnay occur within this gene, resulting in
FAP.
Multiple adenomas on the distal bowel (100-1000), onset < 10 years. Annual colonoscopy needed after age 10 and
pan-colectomy after 10 years of disease (usually late teens or early 20s).

Congenital hypertrophy of the retinal pigment epithelium (Cl-ll?PE)

Seen in association with APC gene mutations (55-75%). When present, CHRPE lesions are an early clinical marker for
familial polyposis coli and may be used in risk assessment.

Turcot syndrome
• APC gene defects
• Primary medulloblastoma
• Multiple colorectal polyposis

Gardner syndrome
• APC gene defect
• Multiple colorectal polyps
• Soft tissue and bone tumours (especially the mandible)
• Extracolonic cancers

165
Peutz-Jegher syndrome
Autosomal dominant, 50% new mutations.
Syndrome of:
• Mucosal pigmentation (freckles) of lips and gums
• Stomach and small bowel hamartomas
• Malignant tumours (not of the GI tract) develop in 50% of patients

ENDOOUNE TUMOURS
APUDomas These hormone-secreting tumours arise from APUD cells (neural crest cell
derivatives of the gastroenteropancreatic endocrine system) . They are:
• Carcinoid
• VIPomas, gastrinoma (see p. 259), somatostatinoma
• Mastocytoma (see p. 299)
• Medullary carcinoma thyroid
Neurogenic tumours Ganglioneuroma
Phaeochromocytoma (see p. 242)
NB: APUD = amine precursor uptake and decarboxylation

Carcinoid tumours
These tumours of the intestine usually arise in the appendix in children . They are benign or low-grade malignancy and .
when symptomatic present as appendicitis. Tumours elsewhere in the GI tract are likely to metastasize. They produce :
the carcinoid syndrome, the result of serotonin {5-HT) and other ho rmone production, when metastatic. ;

Carcinoid syndrome

Clinical features
• All have liver metastases
• Intestinal hypermobility, with watery diarrhoea and abdominal pain
• Bluish-red facial flushing with telangiectasia
• Bronchoconstriction
• Tricuspid incompetence or pulmonary stenosis

Diagnosis
• Urine 5HIAA 1' (serotonin metabolite)
• Plasma serotonin i
• Bradykinin, histamine, tachykinins and/or prostaglandins i
Management
• Resection of primary tumour if possible
• Octreotride (somatostatin analogue) inhibits release of gut hormones

FALTERING GROWTH
This is the failure to gain adequate weight or achieve adequate growth during infancy at a normal rate for age. At least
two growth measurements needed 3-6 months apart, showing the child falls across two major centiles.

166
CAUSES

MEDICAL MANAGEMENT

History
Include:
• Heights of parents and siblings
• Family history, e.g. atopy
• Pregnancy history, e.g. smoking
• Birth history, e.g. gestation and birthweight
• Dietary assessment
• Social report

Examination
Weight, height± head circumference, general examination and developmental assessment.

167
Investigations
The sequence and extent of these is dictated by the clinical history and examination.

NUTRITIONAL DISORDERS

Malnutrition is categorized based on wasting (weight for height ratios), indicating short-term effects, and stunting
(height for age and sex ratios), indicating long-term effects, using standard scores. Traditionally it has been classified
into marasmus, kwashiorkor and marasmic kwashiorkor.

Marasmus
This is a mixed deficiency of both protein and calories, resulting in non-oedematous malnutrition. Decreased weight
for age and sex ratios (<60% of the mean average).
,- .
teo.wres
• Hungry, emaciated child
• Loose, wrinkled skin, 'old man' appearance, decreased skin turgor
• Muscle atrophy and little subcutaneous fat
• Thin sparse hair, hair colour changes unusual
• Hypothermia, bradycardia, hypotension (basal metabolic rate J,)
• Listlessness

Kwashiorkor
This malnutrition results in oedema which is due to unknown causes, though it has historically been attributed to a
disproportionately Low protein intake compared with calorie intake. There is a near normal weight for age ratio (weight
for age and sex ratio< 80%) and oedema.

Features
• Lethargy, miserable, no appetite
• Oedema - hypoalbuminaemic, overall 'fatness' appearance, moon face
• Hepatomegaly (fatty infiltration)
• Skin lesions (flaking paint rash, ulcers, fissures, pellagra-type rash)
• Thin, red hair and darkened skin
• Cardiomegaly
• Infections, secondary immunodeficiency

Marasmic kwashiorkor (mixed type)

A combined type exists where there are features of both marasmus and kwashiorkor, with a weight for age and sex
ratio of< 60% with oedema.

Management of malnutrition
1. Initial rehydration with oral rehydration salts solution (or IV if in shock)
2. Dilute milk for 5 days, increasing volume gradually to 150 mljkgjday. Look for and treat hypoglycaemia,
hypothermia, infection, electrolyte imbalance and micronutrient deficiency
3. High -energy feeds as strength builds up. NB: If feeds are too strong too early, hepatomegaly and a slower
recovery result

168
 --·-·-----···------·---- -·· ------- -------·---- - - - --

Figure 7.4 Child with severe malnutrition showing a lack of subcutaneous fat stores and muscle wasting

ACRODERMATITIS ENTEROPATHICA (ZINC DEFICIENCY)

Jhis is 9 disorder of zinc deficiency of various causes.

Causes
Inherited form Autosomal recessive, rare.
Due to defective intestinal absorption of zinc
Acquired transient neonatal form Due to nutritional zinc deficiency from:
• Breast-fed infants in mothers with low zinc levels
• Premature infants with prolonged TPN
• Infants with malabsorption (including cystic fibrosis)

Clinical features
Skin Persistent well demarcated eczematous or psoriaform rash
Symmetrical distribution
Perioral, perineum, flexures, eyes, cheeks and nose
Dystrophic nails, glossitis and stomatitis
Hair Red with areas of alopecia
Eyes Photophobia, conjunctivitis, blepharitis, corneal dystrophy
Growth Faltering growth _
Others Irritability, delayed wound healing, chronic diarrhoea, recurrent bacterial and candida infections
The inherited form develops when weaned from the breast (as breast milk contains a zinc-binding protein and therefore
helps zinc absorption) or earlier if bottle fed.

169
Diagnosis
• low plasma z1nc level (< 50 }lg/ml)
• Alkaline phosphatase also low (a zinc-dependent enzyme)

Management
Oral zinc supplementation with monitoring of plasma levels.

SCURVY (VITAMIN C [ASCORBIC ACID] DEFICIENCY)

Ascorbic acid is a reducing agent involved in collagen synthesis. It is found in fruit and vegetables, oxidized by heat
and leaks into water.

Deficiency features
• Perifollicular haemorrhages, follicular hyperkeratosis and 'corkscrew' hair on back, arms and legs
• Spontaneous bruising and bleeding with subperiosteal haemorrhages of long bones
• Swollen, spongy gums
• Delayed wound healing
• Irritability
• Muscle pain and weakness, pseudoparalysis of the Legs
• Anaemia
Diagnosis is made by checking plasma ascorbic acid levels or giving a trial of vitamin C. Management is with oral
vitamin C1 g/day.

PELlAGRA (NIACIN DEFICIENCY)

Alack of niacin (nicotinamide) results in this condition. Niacin forms part of the enzymes NAD (nicotinamide adenine
dinucleotidase) and NADP (nicotinamide adenine dinucleotide phosphatase) . It is found in fish and meat and in small
amount in cereals. Niacin can be made from tryptophan (found in milk and eggs).

Features of deficiency
Dermatitis Erythema on sun-exposed areas ('Casals' necklace' on the neck), hyperkeratosis, ulcers, progressing to
atrophy. Red tongue and angular stomatitis
Dementia Tremor, depression, encephalopathy, psychosis
Diarrhoea Also constipation
Management is with oral nicotinamide or vitamin B complex therapy.
Other causes include:
• Isoniazid (causes B6 deficiency, needed for nicotinamide manufacture)
• Generalized malabsorption, low-protein diets
• Hartnup disease (tryptophan not absorbed)
• Phaeochromocytoma, carcinoid (metabolism of niacin altered)

170
,-_1_:

VITAfv\IN A DEFICIENCY
Vitamin A (retinol) is found in milk, eggs, liver and green vegetables. Deficiency occurs with dietary deficiency (rare),
fat malabsorption, liver disease.

Clinical features
Eyes Night blindness, xerophthalmia, photophobia, keratomalacia and blindness
Developmental delay
Growth retardation
Skin Follicular hyperkeratosifi, dry and scaly
Diagnosis can be confirmed with low vitamin A levels. Management is with oral vitamin A.

BERIBERI (THIAMINE DEFICIENCY)

, Thiamine (vitamin 81) is a cofactor for many enzyme reactions. It is found in most foods, especially legumes. Defi-
ciency occurs with dietary deficiency, e.g. polished rice-only diet, alcoholics, and babies breast fed by a deficient
mother. Clinical features involve cardiac and neurological problems.
Cardiac features Dilated heart with cardiac fail~re and oedema
(wet beriberi) Tachycardia, tachypnoea, hepatomegaly, QT prolongation
Neurological features Slow onset
(dry beriberi) Symmetrical polyneuropathy, commencing with lower limbs (absent lower limb tendon reflexes,
paraesthesias, loss of vibration sense)
CNS involvement (Wernicke-Korsakoff syndrome):
• Occular Nystagmus, papilloedema, lateral rectus palsies
Conjugate gaze palsies, fixed pupils, ptosis, optic atrophy
• Ataxia Cerebellar signs
• Confusion Irritability, amnesia, apathy and coma
Diagnosis is based on a rapid clinical response to therapy. Management is with IV or IM thiamine if in cardiac failu re.
Otherwise, oral thiamine is given to the mother and child. ·

EATING DISORDERS

ANOREXIA NERVOSA
I
This is predominantly a disorder of Western adolescent girls. Girls> boys, 10:1. Complex family dynamics involved.

Diagnostic criteria
• ' of becoming obese
Fear
• Disturbance of perception of body size, shape and weight
• Refusal to maintain body weight over the age/height minimum (via calorie restriction, obsessive exercise,
.vomiting, laxatives)
• Amenorrhoea
The typical psychological profile includes: overachiever, poor self-esteem, strong-willed, distrustful, uncommunica·
tive, depression, irritability, obsessional (obsessive thoughts of food and body shape in particula r) and distorted bod)
image. Family dysfunction with overprotection, conflict avoidance and control battles over food.

171
Physical features
Bodyweight Below expected for age/height
Skin Dry skin, rashes, fine lanugo hair on body and face
Cardiac Bradycardia, BP l with pronounced postural drop, long QT interval, arrhythmias (may cause sudden
death)
Hormones GH l T3 l, rT3 l hypothalamic-pituitary-ovarian disorders (amenorrhoea, LH and FSH l)
Loss of diurnal variation in cortisol
Electrolyte Disturbances, e.g. Kland hypochloraemic alkalosis due to vomiting
Other Hypothermia, constipation, cool peripheries, slowly relaxing reflexes

Management
A combination of expert psychotherapy and nutritional rehabilitation (at home or in hospital) is necessary.
The prognosis is best if treated early, otherwise long-term eating problems are common with a mortality of up to 10%
in adulthood.

BULIMIA
This is also predominantly a disorder of adolescent girls, and is more common than anorexia nervosa.

Clinical features
• Episodic high-calorie binge eating
• Followed by self-induced vomiting, laxative abuse and/or episodes of fasting
• Weight is usually normal or mildly overweight
• Teeth enamel erosion, salivary gland enlargement and cheilosis (from recurrent vomiting)
• Electrolyte and cardiac abnormalities as in anorexia nervosa may occur
The diagnosis is made from the history.
Management is with specialist psychotherapy.

OBESITY
Obesity is defined as a body mass index (BMI) >85th percentile. BMI > 35 = morbid obesity. The International Obesity
Task Force (IOTF) has developed specific BMI centile charts.
This is a problem of increasing incidence in the UK.

Causes
Intake and exercise balance A combination of excessive and poor quality nutrition and inadequate exercise
Overfeeding in infants may be secondary to maternal anxiety or postnatal
depression
Bottle-fed infants more likely to become obese
Other causes Cushing syndrome
Prader-Willi syndrome, Laurence-Moon-Seidel syndrome

172
 Associated problems
• Advanced bone age, increased height (early), early puberty
• Psychological effects (poor self-image, depression)
• Sleep apnoea (severe obesity)
• Obesity throughout life increased
• Long-term effects: hypertension, diabetes, cardiovascular disease
Management of nutritional obesity needs to involve addressing family eating and exercise habits.

FURTHER READING
Walker WA, Hamilton JR, Watkins JB, Durie PR, eds Pediatric Gastrointestinal Disease, 3'd edn. Philadelphia: Mosby,
2000

.-- ~:

173
 -- -~

• Physiology and anatomy • Hepatitis

• Clinical manifestations in liver disease • Portal hypertension
• Jaundice (icterus) • Gallbladder disease
• Metabolic disorders • Liver transplantation
• Congenital hepatic fibrosis

PHYSIOLOGY AND ANATOMY

Protein
Metabolism Principal site of synthesis of all circulating proteins (except y globulins), e.g. albumin,
coagulation factors (except factor VIII), complement system components, carrier proteins
(transferrin, caeruloplasmin), cx.-fetoprotein, and cx. 1-antitrypsin. Factors II, VII, IX and Xare
vitamin Kdependent
Degradation Amino acids are deaminated. Amino acids and ammonia are converted to urea

174
 Liver

Cystic duct ----f--'1"~~ +---------Common hepatic duct

H-::-='----==-----,.-<:----r--r"- Common bile duct
Gall bladder

Figure 8.1 Anatomy of the liver and ducts

Terminal ------..'--'
hepatic
venule

Portal triad - - - - n r
Portal vein radiclesl
Hepatic arteriole
[ Bile ductule

1 = zone 1 Best oxygenated hepatocytes

2 =zone 2 Intermediate oxygenation
3 = zone 3 Least well oxygenated hepatocytes

Figure 8.2 Afunctional liver acinus

Carbohydrate metabolism
Post-prandially, glucose is converted to glycogen and stored, and to fatty acids and transported to adipose tissue
In starvation, glucose is released from glycogen (glycogenolysis) and is synthesized from amino acids, lactate anc
glycerol (gluconeogenesis). Preterm infants have inefficient regulation of this.

lipid metabolism
Synthesis of lipoproteins VLDL and HDL, fatty acid oxidation and cholesterol excretion. Young infants have reducec
capacity for hepatic ketogenesis.

175
 l
Bile
Bile acids Synthesis from cholesterol
Bilirubin metabolism See Figure 8.3
Bile secretion Containing bile acids, water, bilirubin, electrolytes, cholesterol and phospholipids. Neonates
have inefficient ileal reabsorption and hepatic clearance of bile acids from portal blood and
therefore raised serum levels of bile acids

Hormone and drug metabolism

Many hormones are inactivated in the liver or targeted to the liver. Drugs metabolized by enzymes including the P450
system, e.g. alcohol. Newborns have decreased capacity to metabolize certain drugs.

Immunological function
Involving the reticuloendothelial system of the liver. Kupffer cell (macrophages on endothelium) functions include:
• Phagocytosis
• Secretion of interleukins, TNF, collagenase and lysosomal hydrolases

INVESHGAHVE liVER BLOOD TESTS

Laboratory tests examine the function of the liver and also markers of liver cell damage . As the liver has a very large
functional reserve, functional tests alter later in disease.
Albumin · Synthetic function marker
Prothrombin time (PT) Synthetic function marker. Very sensitive (as short half-life)
NB: Must exclude vitamin Kdeficiency as cause of prolonged PT
Bilirubin Raised bilirubin level may be: Conjugated= 'direct' reading, or
Unconjugated ='indirect' reading
Aminotransferases Enzymes in hepatocytes which leak into blood with liver cell damage (also raised in
(transaminases) increased red cell degradation)
Sensitive markers:
1. Aspartate aminotransferase (AST) - mitochondrial enzyme, also in heart, muscle,
kidney, brain
2. Alanine aminotransferase (ALT) - cytosol enzyme, more specific to liver than AST
Alkaline phosphatase In canalicular and sinusoidal membranes. Also in bone, intestine and placenta.
(AlkPh) Isoenzymes used to determine specific origin. Raised in cholestasis, cirrhosis and liver
metastases
y-Glutamyl Microsomal enzyme which increases in cholestasis and is induced by some drugs, e.g.
transpeptidase (yGT) phenytoin, alcohol
Serum proteins Albumin (hypoalbuminaemia as above)
Globulins (hyperglobulinaemia due to decreased phagocytosis of antigens by Kupffer
cells)
Immunoglobulins (raised in chronic disease)
a-Fetoprotein Normally produced by the fetal liver. Seen in teratomas, hepatocellular carcinoma,
hepatitis, chronic liver disease and in pregnancy with fetal neural tube defects

Immunological tests
• Antimitochondrial antibody (/\MA) in primary biliary cirrhosis and autoimmune hepatitis
• Antinuclear (ANA), anti-smooth muscle (ASM) and liver/kidney microsomal (LKMA) antibodies seen in auto-
immune hepatitis
Other biochemical alterations - hypoglycaemia, electrolyte imbalance, hyperammonaemia.

176
CLINICAl MANIFESTATIONS IN liVER DISEASE
Liver disease may be acute or chronic and may manifest with the fo llowing .

ACUTE LIVER DISEASE

• Asymptomatic
• General malaise (fever, anorexia)
• Hypoglycaemia
• Hepatomegaly
• Jaundice
• Pruritis
• Spider naevi and liver palms (rare in acute)
• Encephalopathy, bleeding disorders and renal impairment may occur

CHRONIC LIVER DISEASE

Asymptomatic
Anorexia
Liver size Increased (hepatomegaly), decreased or no change
Jaundice
Pruritis Seen in cholestasis, due to conjugated hype rbilirubinaemia
Other skin changes Palmar erythema, spider naevi (telangiectasia in the distribution of the superior vena
cava, < 5 may still be normal) , xanthomata, purpu ra, clubbing
Portal hypertension An increase in portal venous pressure to> 10-12 mmHg . Caput medusae, varices,
splenomegaly
Asdtes Due to hydrostatic pressure from si nusoida l blockade and hypoalbuminaemia
Encephalopathy Portosystemic encephalopathy (PSE) (a chronic syndrome involving neuropsychiatric
disturbance), drowsiness, fetor hepaticus and liver flap. Due to metabolic abnormalitie ~
Endocrine abnormalities Testicular atrophy, gynaecomastia, parotid enlargement
Renal abnormalities Secondary impairment of renal functio n. Hepatorenal syndrome (renal failure of no
other demonstrable cause in a patient with cirrhosis)
Gastrointestinal bleeding Due to coagulation dysfunction and portal hypertension

FULMINANT HEPATIC FAILURE (FHF)

This is aT( acute clinical syndrome resulting from massive impairment or necrosis of hepatocytes in a patient withoui
pre-existing chronic liver disease. The prognosis is poor with a mortality without transplant of around 70%.

Causes
• '
Hypoxic liver damage
• Viral hepatitis - combined B and Despecially
• Drugs, e.g. paracetamol, sodium valproate
• Metabolic disorders, e.g. Wilson disease, galactosaemia, neonatal haemochromatosis, mitochondrial cytopathy,
tyrosinaemia

Clinical manifestations
• Progressive jaundice, fetor hepaticus, fever, vomiting, abdominal pai n
• Rapid decrease in liver size with no clinical improvement (ominous sign )
• Defective coagulation
• Hypoglycaemia

177
 • Sepsis
• Fluid overload
• Occult gastrointestinal or intracranial bleeding
• Pancreatitis
• Hepatic encephalopathy with cerebral oedema (lethargy, sleep rhythm disturbance, confusion, progressing to
coma)

Poor prognostic features

• Onset of liver failure < 7 days
• ~ 10 years
• Shrinking liver size
• Renal failure
• Paracetamol overdose
• Hypersensitivity reactions of unknown aetiology

Investigations
• PT i
• Transaminases (raised initially, then may decrease with no clinical improvement, indicating little or no function-
ing liver remaining)
• Ammonia i
• Glucose 1
• Hyperbilirubinaemia (conjugated and unconjugated)
• Metabolic acidosis, K1, Na 1
• EEG (monitor of cerebral activity, occult seizures may be present)

Management
The aims of management include close monitoring to prevent complications, maintenance of blood glucose
> 4 mmoljl, support of the cardiovascular, renal and respiratory systems and close monitoring of CNS function.
Liver transplant should be considered early if recovery is considered unlikely.
Specific management includes the following:
• Fluid restriction to 50- 75% maintenance (to avoid ICP i)
• Use colloid to maintain intravascular volume
• Sodium and potassium additives depending on electrolytes
• Maintain blood glucose with IV hypertonic glucose as needed
• Monitor with CVP, MAP, urine output, ICP, blood gases, serum electrolyte and glucose status
Cerebral complications Avoid sedation as this masks encephalopathy
Monitor fori ICP and maintain normal ICP with mannitol, hyperventilation, thiopentone
and haemofiltration as necessary
Convulsions may be occult and EEG or cerebral function monitoring should be performed
if concern exists. Any convulsions are treated, e.g. phenytoin IV, paraldehyde in oil PR,
phenobarbitone IV or thiopentone IV may be required
Renal Nephrotoxic drugs and arterial hypotension should be avoided. Hepatorenal syndrome may
occur
Established renal failure treated with haemofiltration
Sepsis Daily culturing for infection and empirical use of broad-spectrum antibiotics with
antifungals. Aciclovir if herpetic origin suspected
Bleeding Vitamin KIV given daily. Avoid invasive procedures if possible
Respiratory ARDS equivalent may occur

178
Cardiovascular Inotropic support as required. Prostacyclin or N-acetyl cysteine may improve
microcirculation
Gastrointestinal Prophylaxis for stress ulceration with IV ranitidine or omeprazole. GI haemorrhage managed
with blood products and emergency endoscopy as necessary

CIRRHOSIS
This is a histological diagnosis identified by fibrosis and nodule formation with abnormal liver architecture and
results from necrosis of liver cells. It may be macronodular (nodules up to 5 em), micronodular (nodules< 3 mm) or
mixed. Progressive scarring in cirrhosis leads to restricted blood flow with further impairment of liver function and
portal hypertension.

Causes
• Acute viral hepatitis
• Metabolic liver disease, e.g. Wilson disease, tyrosinaemia
• Vena-occlusive disease (especially post stem cell transplant)
• Autoimmune CAH, primary biliary cirrhosis
• Idiopathic
The prognosis is variable and the 5-year survival rate is around 50%, depending on the aetiology.

CAUSES OF HEPATOMEGALY

179
JAUNDICE (ICTERUS)
Serum bilirubin> 35 11moljl is clinically detectable. Jaundice is traditionally classified as pre-hepatic, hepatocellular
and obstructive (cholestatic) but this is inaccurate, as cholestasis occurs in hepatocellular as well as obstructive
jaundice. It may help to consider jaundice as:
1. Haemolytic (prehepatic)
2. Congenital hyperbilirubinaemias (hepatocellular)
3. Cholestatic: Intrahepatic (hepatocellular and/or obstructive)
Extrahepatic (obstructive)

RBC haem Tissue haem proteins

75% 25%

\ I
Biliverdin
t
(1) Bilirubin (Free) Crosses BBB (lipid soluble)
(Unconjugated) Causes kernicterus.
~
(2) Bilirubin-albumin Does not Cross BBB.
(Unconjugated)
!___ _. Liver ---------------t---------------
2: Bilirubin-albumin
0
-~ Uridyl diphosphate glucuronyl
Glucuronate
transferase (UDPGT)
·u
(.)

~ (3) ·conjugated bilirubin Water soluble

0.
<!)
..c (Bilirubin glucuronide)
e
<!)

c
w Bile ---- -----------!---------------
Conjugated bilirubin ------ ---- -- - + Bilirubinuria (Dark urine)
Pathological
(occurs when increased conjugated
Gut --------------- --------------- bilirubin in plasma)
Urine
' - - - - - - Stercobilinogen----+- Urine Urobilinogen (Colourless)

~
Stools
Stercobilin (Coloured)

Figure 8.3 Bilirubin metabolism

HAH'IOlYTIC J;!\UNDICE
• Unconjugated bilirubin i (not water soluble, therefore not in urine) = acholuric jaundice, i.e. no bilirubinuria.
Therefore, urine and stools normal colour
t Urine urobilinogen 1'

180
;_;.

• Transaminases }
• Alkaline phosphatase Normal
• Albumin
Haemolytic features:
• Plasma haptoglobins l
• Lactate dehydrogenase (LDH) 1'
• Reticulocytes 1'
• Bone marrow erythroid hyperplasia
• Spherocytes, red cell fragments, sickle cells may be present
In intravascular haemolysis:
• Haemosiderinuria, haemoglobinuria
• Methaemalbumin
• FDPs 1', haptoglobins l

CHOLESTATH.: JAUNDICE
• Conjugated bilirubin 1' (> 20% total bilirubin)
• Pale stools
• Dark urine (bilirubinuria)
Altered synthetic function and transaminases may sometimes accompany the picture as outlined below.
Intrahepatic may be due to:
• Parenchymal disease (hepatocellular)
• Bile canalicular excretion problem

Additional features

NEONATAL JAUNDICE
Most-neonates develop some jaundice in the first few weeks of life because they have a:
• Relative polycythaemia
• Shortened red cell lifespan (70 days as compared to 120 days in adults)
• Relative immaturity of the liver
Most neonatal jaundice is due to unconjugated bilirubin and is physiological. Conditions involving haemolysis, e.g.
Rhesus disease, excessive neonatal bruising, result in more pronounced jaundice, sometimes severe. Premature infants,
sick neonates and those with low albumin levels are at increased risk.

181
When levels of unconjugated bilirubin are high they exceed the albumin binding capacity of the blood and exist as
free unconjugated bilirubin. This is harmful to the baby. It is lipid soluble, and therefore can cross the blood-brain
barrier where it causes neurotoxicity (known as kernicterus):
Immediate effects Lethargy, irritability, increased tone, opisthotonus
Long-term effects Sensorineural deafness, learning difficulties and choreoathetoid cerebral palsy
Conjugated hyperbilirubinaemia is always pathological, and has many rare causes (see p. 187). Conjugated bilirubin
is not toxic to the brain

Excessive neonatal br~i~iAg, e.g. after ventouse delivery

. Blood groupincompatibility (Rh~sws orABO) ·._ · . ,
. ·Red cell shape abnor;,ality, ei· spheiocytosi~, elliptocytosis -,·? . .·
Red cell riJenibrane instability, ~:g.ii6PD defiCiency, PK defidJncy ·
.... ; -·· .. . - . -;-~:_· · .::_~ -- : _ ~ . . -~--··:· · _, . -~ ~ .· ·'
·.···_;._. -·· .•. _·,·_:·
. · -·

Haemolytic disease Physiological jaundice Breast milk jaundi~e

Congenital infection Prematurity Sepsis •· -
Severe bruising Haemolysis
Sepsis Neonatal hepatitis
Breast milk jaundice Biliary atresia
Hypothyroidism
Haemolytic disease
Galactosaemia

Management
1 Baseline investigations to assess the severity, type and possible cause of jaundice:
SBR
Blood group, Coombs' test and FBC
Bilirubin conjugated and unconjugated fractions (conjugated is < 20% of total in unconjugated
hyperbilirubinaemia, and > 20% in conjugated hyperbilirubinaemia)
Urine (microscopy, culture and sensitivities)
2. H the serum bilirubin (SBR) exceeds a certain level, treatment is commenced with phototherapy (or exchange
transfusion if very rapidly increasing levels). Charts which act as guidelines for the level of bilirubin to
commence phototherapy or exchange transfusion have been developed, and vary for different gestations,
weights and for ill and sick babies

182
Phototherapy does not remove the bilirubin, 390
but works by UV radiation converting the I 360
harmful unconjugated bilirubin into water- ~ 330
soluble bilirubin, which can be excreted by :i. 300
c
the body. .D 270
::J
'-
240
• Whole baby under phototherapy lamp .D
"0 210
24 h/day Q)

• Undressed to increase skin exposed to

co 180
OJ
::J 150
uv ·c:
120
• Eyes are covered to prevent damage 8 fill
Zone of obligatory
(cataracts) ~ 90 '-+---+--1 @0 Indefinite zone
60
• Extra fluid (30 mljkg/day) given to
prevent dehydration £~ II Phototherapy zone
30r---~---+~--,---,----,----,--L~

• Side-effects - loose stools, 0 2 3 4 5 6 7

overheating, dehydration, 'bronze baby Age (days)
syndrome'
Figure 8.4 Phototherapy treatment chart

Exchange transfusion
Repeated small aliquots of the infant's blood are removed via peripheral arterial line, or umbilical artery or vein, and
replaced with 0 Rh negative blood (or infant's ABO type if mother same group) which will not haemolyse.
Complications Acidosis, hypoxia, apnoeas and bradycardias, thrombocytopenia and NEC.

Physiological jaundice
• Seen in 65% of term babies and 80% of premature babies
• Commences after 24 h and lasts 5-7 days
• Due to immature fetal liver, postnatal haemolysis and shorter red cell lifespan in infants
• Keep well hydrated
• Phototherapy is needed if the SBR level is high enough (;3: 350 11moljL on day 3)
• Check regular SBRs

Breast milk jaundice

This is a diagnosis of exclusion that is poorly understood. It lasts for several weeks, requires no treatment, and breast
feeding should continue. The infant should be investigated to rule out other causes.

Haemolytic jaundice due to Rhesus or ABO incompatibility

• This is due to high levels of haemolysis, resulting in too large a bilirubin load for the immature fetal liver
• Jaundice develops within the first 24 h and rapidly rises
• Mixing of blood, with a few fetal red cells entering the maternal circulation, can result in maternal antibodies
developing to the fetal cells if they have a different antigenic component
• This mixing usually occurs at delivery or, if there is a placental bleed, may occur during the pregnancy. The anti-
bodies are therefore usually formed after the first pregnancy, so it is subsequent pregnancies that are affected
• Anti-D injections (as Lhis is the most common form) are therefore given during pregnancy to Rhesus negative
women to 'mop up' any fetal red cells in the maternal circulation and prevent antibodies developing

183
It may be caused by:
Rhesus incompatibility Maternal antibodies to Rhesus C, Dor E antigen (usually anti-D)
Mother is blood group Rhesus negative, the baby Rhesus positive
Antibodies cross the placenta and cause haemolysis in utero
If severe, the infant can become profoundly anaemic and develop hydrops fetalis (see p. 477)
ABO incompab"bility Maternal antibodies to red cell Aor B antigens develop
Mother is group 0, the baby group A, B or AB
Rarer but more severe than Rhesus incompatibility

1. Cord blood is taken for Hb, PCV (to assess severity), fetal blood group, maternal antibodies, Coombs' test and
bilirubin level
2. Phototherapy
3. Regular 6-hourly SBR, Hb and PCV levels
4. Exchange transfusion if the bilirubin level becomes high enough
5. Intrauterine exchange transfusions can be done in fetal medicine units in very severe cases

Neonatal conjugated hyperbilirubinaemia

Causes
1. Extrahepatic bile duct obstruction:
Biliary atresia
Choledochal cyst
2. Intrahepatic disease:
Intrahepatic bile duct obstruction Intrahepatic biliary hypoplasia, e.g. Alagille syndrome
Intrahepatic biliary dilatation (Caroli disease)
Progressive familial intrahepatic cholestasis (PFIC)
Hepatocyte injury Infections:
Hepatitis, e.g. HSV, CMV, enteroviruses, hepatitis B and C
Systemic, e.g. listeria, toxoplasmosis, UTI
Metabolic disease:
Galactosaemia, fructosaemia, tyrosinaemia,
<\-antitrypsin deficiency
Glycogen storage disease
Cystic fibrosis
Peroxisomal disease
Inborn error of bile acid biosynthesis
Other:
Idiopathic neonatal hepatitis
Hypothyroidism
TPN therapy
Chromosomal
Hypoxic-ischaemic damage

184
 NB: 'Neonatal hepatitis syndrome' refers to intrahepatic cholestasis of many causes (idiopathic, infectious hepatitis or
intrahepatic bile duct paucity).

Examination and investigations

Examination Liver and spleen size
Cystic mass below the liver (choledochal cyst)
Skin lesions, purpura, choroidoretinitis (congenital infection)
Cataracts (galactosaemia, hypoparathryroidisrn)
Cutaneous haemangioma (hepatic haemangioma)
Situs inversus (extrahepatic biliary atresia)
Dysmorphic features (trisomy 13, 18 or 21, Alagille syndrome)
Micropenis, optic nerve hypoplasia (septo-optic dysplasia)
Biochemistry Fractionated bilirubin (conjugated> 20% of total is pathological)
LFTs
Blood glucose, U&E, creatinine
',;
Galactose-l-phosphate uridyl transferase
a 1-antitrypsin phenotype
Metabolic screen (urine and serum amino acids, urine-reducing substances)
Sweat test if feasible, IRT, CF genotype
Thyroid function tests
Cholesterol profile
Haematology FBC, prothrombin time, blood group
Infection screen Culture of urine, blood and CSF
Serology for congenital infection and hepatitis B and C, i.e. HBsAg, VDRL, HIV, other specific viral
serology
Urine Succinylacetone (lin tyrosinaemia - suspect if parents consanguineous)
Imaging USS liver and gallbladder (choledochal cyst, biliary tract dilatation)
TOBIDA scan following 3-5 days of phenobarbitone to help distinguish neonatal hepatitis (usually
some excretion) from biliary atresia (no excretion). .
Direct cholangiography at operation
Other systems, e.g. skeletal X-rays, ·echocardiography
Liver biopsy Biliary tract and hepatocellular differentiation (NB: Correct prothrombin time prior to biopsy if
abnormal)

Biliary atresia
Incidence. 1:15 000-20 000 live births. A condition of progres-
sive obliteration of part or all of the extrahepatic biliary ducts
(an obliterative cholangiopathy). This leads to chronic liver
failure and death. It should be suspected if there is prolonged
' beyond 14 days.
jaundice '
)
. I
Clinical manifestations
• Normal at birth
• Jaundice persisting from day 2
• Pale stools and dark urine
• Hepatosplenomegaly with progressive liver disease

Figure 8.5 TOBIDA scan shows no excretion

into the bowel

185
 ··'··'

Investigations
LFTs Often normal enzymes, with conjugated hyperbilirubinaemia
uss May be normal, gallbladder may be absent on fasting USS (should be present)
Fasting TOBIDA Isotope uptake into liver unimpaired, excretion into the intestine absent
radioisotope scan
Liver biopsy Perilobular oedema and fibrosis, proliferation of bile ductules, bile plugs, basic hepatic
architecture intact
Laparotomy with
operative cholangiography
NB: It can be difficult to differentiate biliary atresia (bile duct proliferation present) from neonatal hepatitis
(intrahepatic disease with giant cells present).

Management
1. Kasai procedure (hepatoportoenterostomy): Success rate 80%
Later complications: cholangitis, fat malabsorption, cirrhosis,
portal hypertension
NB: Surgery must be performed < 60 days of life to increase
chances of success
2. Liver transplantation usually necessary at
a later date

Alagille syndrome (arteriohepatic dysplasia)

Autosomal dominant with variable penetrance, incidence 1:100 000 births. Gene mapping is now possible.
Liver Progressive intrahepatic bile duct paucity, pruritis
Facial dysmorphism Broad forehead, hypertelorism, deep-set eyes, long nose, small mandible
Eyes Posterior embryotoxon
CVS Peripheral pulmonary stenosis, tetralogy of Fallot
Skeletal 'Butterfly vertebrae' (vertebral arch defects)
Renal Tubulointerstitial nephropathy
Other Cholesterol 1', tuberous xanthomas

Zellweger syndrome (cerebrohepatorenal syndrome)

Autosomal recessive. Incidence 1:100 000 births. A peroxisomal disorder.
Liver Progressive degeneration, hepatomegaly. Absence of peroxisomes in hepatocytes
Kidneys Progressive degeneration, renal cortical cysts
Neurological Neurological impairment, severe hypotonia, psychomotor retardation
Dysmorphism Abnormal-shaped head, distinctive facies (similar to Down syndrome)
Skeletal Stippled calcification of patellae and greater trochanter (chondrodysplasia punctata)
Eyes Congenital cataracts, hypoplastic, pale optic disc, retinal pigmentary changes

Caroii disease
Autosomal recessive. A congenital cystic dilatation of the intrahepatic bile ducts.
Symptoms are of recurring episodes of acute cholangitis and biliary lithiasis,_ and there is increased risk of cholangio-
carcinoma.
Caroli disease Isolated ductal dilatations
Caroli syndrome Ductal dilatations with congenital hepatic fibrosis and autosomal recessive polycystic kidneys

186
'~.·'!.~..
!' CONGENITAL HYPERBILIRUBINAEMIAS

Autosomal recessive '

HepatocYte secretion of bilirubin glucuronide l
Bilirubin excretion defective .
· Mild conjugatgd hyperbilirubinaemia

._ Usually asymptomatic .
_Pigmentin t.h€diver --7 black liver
~~~?i

_ re~essive) Autosomal recessive . .

l hansfera~e . · . Defi~iencyin uptake and storage of bilirubin
(kernicterus ·
, N~~n~tie~thahge transfusion
<Photqth~ra py.into child hood ·
· .:liyer transplant ·

METABOLIC DISORDERS

WILSON DISEASE (HEPATOLENTICULAR DEGENERATION)

Autosomal recessive. Incidence 1:100 000 births. Gene mapped (ATP7B) to chromosome 13 q14-21.
The underlying problem is a copper transport defect. A defect in the hepatocytes prevents entry of copper into the
caerulopla'smin compartment. Copper therefore accumulates in the liver and then escapes to the circulation and other
organs such as the brain, kidneys and eyes.

Copp~r metabolism
Ingested copper is absorbed in the stomach and small intestine and transported bound to albumin to the liver. In the
liver it is incorporated into caeruloplasmin for transport to the rest of the body. It is excreted into the biliary system
or incorporated into copper storage proteins.

Clinical manifestations
Liver Manifest> 5 years. Subacute or chronic hepa"titis, hepatomegaly± splenomegaly, fulminant hepatic failure,
cirrhosis, portal hypertension, manifestations of chronic liver disease
Brain Manifest > 10 years. Copper deposition in the basal ganglia. Intention tremor, severe 'wing-beat' tremor
later, dysarthria, choreoathetosis, dystonia, behavioural change (bizarre or psychotic), school performance
deterioration. Occasionally behavioural changes may be the only manifestation

187
Kidney Proximal renal tubular acidosis (Fanconi syndrome), renal failure
Blood Haemolysis, may be initial presentation, severe
Cornea Kayser-Fleischer ring is pathognomonic (golden brown ring at periphery of cornea due to deposition in
Descemet membrane)
Others Arthritis, endocrinopathies, e.g. hypoparathyroidism

Diagnostic investigations
Urine 24-h copper excretion I
24-h copper excretion after penicillamine given 11
Serum caeruloplasmin j,
Liver biopsy Characteristic histology and periportal copper deposition present
Serum copper Raised early in disease, may be normal

Management
Symptoms and signs improved with therapy, pre-symptomatic disease treated in relatives.
Copper chelation agents Penicillamine orally. (NB: This is an antimetabolite to vitamin B6, therefore this is also
given)
TETA (triethylene tetra mine dihydrochloride) if penicillamine not tolerated
Copper intake Reduce to < 1 mgjkgjday
Foods high in copper: liver, _nuts, chocolate, shellfish
Liver transplant If fulminant liver disease

Screening
All family members are screened for pre-symptomatic disease:
• Caeruloplasmi n (t)
• Urine copper (I)
• Liver biopsy if diagnosis suspected
Antenatal diagnosis is possible.

Autosomal dominant. 1:300 heterozygotes. Gene (C282Y) on chromosome 6p.

Assodations HLA A3 (72%)
HLA B7 (Australia)
HLA B14 (France)
A disease of excess iron deposition and absorption. The underlying defect is unknown.

Clinical manifestations
Clinical features rare below age 20 years.
Liver Fibrosis, cirrhosis, of which 30% will develop primary hepatocellular carcinoma
Skin Slate-grey discolouration
Pancreas IDDM, 'bronzed diabetes'
Heart Cardiomyopathy, arrhythmias
Endocrine glands Pituitary (failure), growth failure, hypothyroidism, hypoparathyroidism, testicular atrophy
Joints . Chondrocalcinosis (calcium pyrophosphate deposition), asymmetrical, all joints

188
 Investigations
Serum Ferritin 1'
Iron 1'
TIBC (saturated)
Bone marrow Biopsy ( Perls' stain)
Liver biopsy Fibrosis and iron deposition
Liver CT/MRI
Oesferrioxamine test Iron excretion increases with chelation
Investigations to assess individual organ damage:
Liver LFTs, CT/MRI, biopsy
Cardiac CXR, ECG, echocardiogram
Endocrine Pituitary function tests, TFTs, GH, parathyroid, adrenal and gonadal function

Management
• Venesection regularly
• Iron chelation therapy with desferrioxamine subcutaneously five nights a week

Neonatal haemochromatosis
An acquired condition secondary to severe prenatal liver disease. Severe liver dysfunction, with liver transplantation
usually required. Aggressive chelation and an antioxidant regimen can, rarely, avoid the need for liver transplantation.
Diagnosis is most accurate by estimation of extrahepatic iron deposition, e.g. lip biopsy.

Transfusion-induced haemochromatosis
This occurs with multiple chronic transfusions and results in a similar pathology due to the excess iron deposition.
Therefore, chelation therapy must be given.

a 1-ANTITRYPSIN DEFICIENCY
~ Autosomal dominant. Incidence 1:2000-5000 live births. Common in Northern Europeans (1:10 carries a deficiency
gene). Gene located on chromosome 14q31-32.3.
This disease is the result of a deficiency of a 1-antitrypsin in varying degrees of severity. a 1-antitrypsin is a protease
inhibitor (Pi) made by hepatocytes; it is a glycoprotein and accounts for?: 80% of the circulating a 1-globulin.
The disease results in:
• Liver disease - childhood onset
• Lung disease - 20-40 year onset
I

Proteases are inherited as a series of co-do minant alleles (> 20 phenotypes exist). The genetic variants are character-
ized by their electrophoretic mobilities as medium (M), slow (S) and very slow (Z) . Example genotypes are:
PiMM = normal phenotype
PiSS = a 1-AT 60% activity
PiZZ = a 1-AT 15% activity. 1:3400 births. Most clinical disease. 20% have neonatal cholestasis
Pinullnull = not associated with liver·disease. 0% CX 1-AT activity

Clinical. manifestations
Liver Very variable. Neonatal cholestasis, transient jaundice in first few months of life, hepatomegaly±
splenomegaly, childhood cirrhosis

189
Respiratory Emphysema (as for adult)
Skin Persistent cutaneous vasculitis, cold-contact urticaria, acquired angiooedema

Investigations
• Serum at-antitrypsin 1
• Liver biopsy (globules of at-antitrypsin in the periportal cells)
• Pi phenotype
• Parental genotype
Antenatal diagnosis is possible.

Management
• Liver transplant if severe liver disease.
• Lung disease- give danazol (increases at-antitrypsin), enzyme replacement therapy available
• Genetic counselling required for future pregnancies

A syndrome of acute encephalopathy and fatty degeneration of the liver. The incidence has markedly declined over
recent years, due to decreased aspirin use in children and greater recognition of the differential diagnoses. Usual age
4-12 years, mortality 40%.
Associations Aspirin therapy
Viral infections (influenza B, varicella)
Mitochondrial cytopathy

Clinical manifestations
• Prodromal URTI or chicken pox
• 4- 7 days later: Vomiting +++
Encephalopathy
Moderate hepatomegaly, no jaundice, not icteric
± Hypoglycaemia

Clinical staging

Investigations
Blood Ammonia i (> 125 ~g/dl)
AST, ALT, LDH, CK (1)
Glucose (1, in small children especially)
Clotting deranged (PT 1)

190
 Normal analysis, raised ICP
Fatty infiltralion, specific mitochondrial morphology on EM

Management
This is supportive, with correction of hypoglycaemia and coagulation defects, and IPPV intensive care as necessary.
It is important to:
• Control raised ICP
• Make sure the diagnosis is correct

Differential diagnoses
• CNS infections
• Drug ingestion
• Haemorrhagic shock with encephalopathy
• Metabolic disease, e.g. fatty acid oxidation defects, organic acidurias, urea cycle defects

C6NGENITAL HEPATIC FIBROSIS

Autosomal recessive. This is a congenital disease involving:
Liver disease Diffuse fibrosis ± abnormal bile ducts
Hepatosplenomegaly, portal hypertension
Renal disease {75%} Renal tubule ectasia, ARPKD, nephronophthisis

Clinical features
• Hepatosplenomegaly, bleeding from varices
• Cholangitis (when bile duct abnormal)

Investigations
LFTs Alkaline phosphatase i
Other LFTs (AST, ALT, bilirubin, albumin and PT) usually normal
Liver biopsy Needed for the diagnosis

Management
I

Treatment of varices.

HEPATITIS

VIRAL HEPATITIS
This may be caused by the hepatitis viruses, CMV, EBV, HSV, varicella, HIV, rubella, adenovirus, enteroviruses and
arbovi ruses.

Hepatitis A (HAV)
RNA picornavirus, the commonest cause of viral hepatitis.
Transmission Faecal-oral (especially water, seafood, poor sanitation)

191
Clinical features
Incubation (2 weeks) Infective until just after jaundice appears (while faecal HAV excreted)
Prodrome (2 weeks) Ma laise, nausea, vomiting, diarrhoea, headaches (mild in young children)
Jaundice (2-4 weeks) Cholestatic jaundice, mild hepatosplenomegaly, symptoms improving
Rare complications Fulminant hepatic failure, vasculitis, arthritis, myocarditis, renal failure

Investigations

andyrobilinogen (i)

FBC(WtCJwith.relative lymphocytosis, aplastic§nae~ia, .

.... "' ' ?.,,.....,.· ·~· ha~nwlyticanaemj<l) . . ·· · L , ..·.... ·
indicates liver injury)
nnn..-,·'''"' f()r HAV · • ~· ; ----: i

Management
Supportive only. No carrier state.

Prevention
(lgG HAV)
• Passive immunization - standard
immunoglobulin, three months
protection
• Active immunization - vaccine 0 2 3 4 5 6 7 8
available Weeks
t.
Hepatitis B (HBV} Infection

DNA hepadnavirus. Transmission by intra- Incubation Malaise Jaundice Recovery

venous, close contact or vertical
Figure 8.6 HAV serology. (NB: IgG indicates past infection)

Clinical features
HBsAg
These are as for hepatitis Abut more prolonged and severe.

Investigations
As for hepatitis A.
HBcAg}
Core particle
_ HBeAg

Figure 8. 7 HBV particle

192
r.;:--·

v··
[
i
~:· · Specific markers for hepatitis B:

PCR for HBV DNA is also available (indicates continued viral replication)

(a) (b)

HBV DNA,' HBsAg

I HBeAg
ALT Anti-HBc (PCR) I . • ••• • •• • ••• v

HBsAg _ 1, ' (lgM)

I

0 2 3 4 5 6 0 6 10
t Months t Months Years
Infection Infection

Incubation Symptoms Symptoms

Jaundice

Figure 8.8 HBV serology. (a) Acute infection. (b) Chronic carrier

Clinical course
Most make a full recovery.
Fulminant hepatitis {1%) (Anti-HBcAg diagnostic in this situation)
Chronic infection {10%) HBsAg (normal carrier state)
HBeAg (very infectious)
70- 90% asymptomatic carrier ---1 chronic hepatitis, cirrhosis, hepatocellular carcinoma
(few)
10- 30% chronic hepatitis ---1 cirrhosis ---1 hepatocellular carcinoma
Common among infants infected < 1 yea r
Carriers may be treated with pegylated interferon-a and lamivudine which may seroconvert them.

HBs.t\'9 po~itivf " Vaccine withinJ2 hof birth, o·.s ml

Anti-HBeAb 'positive (10 ~g) IM thigh
Repeat doses of vaccine at 1 and 6 months
If mother is: HBsAg positive Vaccine wlthin 12 h of birth, 0.5 ml .
HBeAg positive IM thigh ..
Hepatitis B immune globulin (HBIG) < l h; 200IU, IM, .opposite thigh
Repeat doses of vaccine at 1 and 6 months .

193
Hepatitis C (HCV)
RNA virus with six subtypes. Types I, II and III common in Europe; Type IV is common in the Far East.
Transmission Vertical (uncommon); intravenous, close contact
This causes a mild flu-like illness.
Rare complications are aplastic anaemia, arthritis, agranulocytosis, neurological problems. Chronic liver disease occurs
in 50% --7 cirrhosis (25%) --7 hepatocellular carcinoma (15%).
Diagnosis is with anti-HCV antibody detection (negative untill-3 months after clinical onset)
Pegylated interferon-ex and ribavirin can be given to chronic carriers. No prophylaxis for maternal transmission.

Hepatitis D (HDV)
Hepatitis Dvirus (delta virus) is an incomplete RNA particle enclosed in the HBsAg. It can only replicate in the pres-
ence of hepatitis B infection. Two patterns of infection are seen: super-infection in a person already infected with
HBV and co-infection with HBV. Features are similar but more severe with more fulminant hepatitis occurring than
in other viral hepatitis.

Transmission Percutaneous, close contact, vertical

• Diagnosis is by detecting IgM antibody to HDV
• Chronic infection is very serious as 70% get cirrhosis
• ex-Interferon therapy causes a remission only

Hepatitis E (HEV)
RNA virus.
Transmission Enteral route
Clinical illness is similar to hepatitis A though often more severe. NB. Pregnant women have high rate of fulminant
hepatic failure (20% vs 2% in others infected) and fatality.
• Diagnosis is by HEV RNA detection in serum or stools
• No effective prophylaxis
• No carrier state exists

CHRONIC BEPJ\THIS
This is the presence of hepatic inflammation (manifest by elevated transaminases) for> 6 months. There are two sub-
divisions of chronic hepatitis, distinguished histologically:
Chronic persistent hepatitis Benign, self-limiting usually
Chronic active hepatitis Progressive disease with eventual cirrhosis

194
r
'

The clinical manifestations are variable:

. • Asymptomatic
• Chronic liver disease
• Hepatic failure

Causes
• Persistent viral infection
• Autoimmune
• Drugs, e.g. isoniazid, nitrofurantoin, sulphonamides, dantrolene
• Metabolic, e.g. cystic fibrosis, Wilson disease, haemochromatosis, 0: 1-antitrypsin disease

Chronic persistent hepatitis (CPH)

Usual cause Hepatitis B or C
Histology Inflammation limited to portal triads, no fibrosis or cirrhosis
Clinical manifestations Usually asymptomatic, may have non-specific malaise and mild hepatomegaly. Sometimes
chronic liver disease occurs
InvestigEJtions Transaminases i, bilirubin i
Alkaline phosphatase, albumin, PT all normal
Autoantibodies negative
Liver biopsy essential
Management Interferon-a: may help in hepatitis B or C disease

Chronic active hepatitis {CAH)

Usual cause Hepatitis B or(, autoimmune disease
Histology Inflammatory infiltrates beyond portal areas, 'piece-meal necrosis' of hepatocytes, fibrosis
and necrosis between neighbouring triads, cirrhosis
Clinical manifestations Very variable, ranging from asymptomatic to cirrhosis or hepatic failure
Associations Arthriti.s, rash, nephritis, vasculitis, haemolytic anaemia in autoimmune disease
Investigations Transaminases i, bilirubin i, y-globulins i, PT i
Anaemia, thrombocytopoenia, leucopoenia
ANA i, ASM i, AMA i, LKM (liver-kidney microsomal antibodies) i and IgG i in
autoimmune disease
Liver biopsy essential
Managem,ent Steroids and azathioprine in autoimmune disease
Course of interferon-a injections in hepatitis B or C
Liver transplant in end-stage liver disease

PORTAL HYPERTENSION
This occurs when the portal pressure is elevated~ 10-12 mmHg (normal= 7 mmHg). Increased portal venous pressure
results in collaterals (varices) developing (portosystemic shunting) and a hyperdynamic circulation. These together
can cause varices to rupture and result in GI bleeds. Important sites of collaterals (varices):
• Oesophagus
• Anorectal
• Periumbilical (caput medusae. NB: These flow away from the umbilicus)
• Retroperitoneal
• Perivertebraljperispinal

195
Causes
It is caused by obstructio.n to the portal flow anywhere along the portal system.

- : . . ..
thrombosis: . Hepatocellular:, Hepa~icveirl thrombdsis .
• ~ong. h~patic fiiJ.~qsis . .· (Budd--~hj?ri ,syndrome):
• .Viral hepatitis .·· · . ·• c6ng. ~enous vJeb ·
• Metaboliccirrhosis . . • ;P,olycyth(3eniia .
:-·· '

·• ·. Hepatotoxidty ·. · • . uu.k?~rnia
(TPN) : · . • . Co~~~lopathy
:.;. .,
~.;,.: ;-;-

'· ( M~thbtrex~t~) ·
Biliary)tractdisease: ::· ,..···.,.
·.·~ .Scl~r~~ih~~~~b,t~h·~iti~~ fi~ ): ...
'·'>::· :· .. < ·>·-r '

~;~~~1~~1~lrr't '};T ',:§ic·'··.·

Clinical features
• Bleeding oesophageal varices
• Cutaneous collaterals (periumbilical, inferior abdominal wall)
• Splenomegaly (depending on the site of the obstruction)
• Liver size may be normal, enlarged or small, and there may be signs of underlying liver disease
• Haemorrhagic encephalopathy secondary to massive GI bleed

Investigations
uss Outlining portal vein pathology, direction of flow of the portal system, presence of oesophageal
vances
CT/MRI scan Findings as for USS
Arteriography Can be done from the coeliac axis, superior mesenteric artery or splenic vein
Endoscopy Outlining oesophageal and gastric varices

Management
Emergency Resuscitation (clear fluids and blood)
Treatment of coagulopathy (FFP, vitamin K, platelets)
NG tube
H2 antagonist or proton pump inhibitor intravenously
Other drugs if necessary (octreotide, GTN)

196
 Endoscopy- sclerosis (now virtually never undertaken}, elastic band ligation of varices or
insertion of, in extremis, Sengstaken-Blakemore tube (gastric balloon only) may be required
Elective Endoscopic obliteration (as above)
Portosystemic shunts, e.g. ITPSS (transjugular intrahepatic porto-systemic shunt), REX shunt (but
shunts have complication of encephalopathy)
Liver transplantation (for intrahepatic disease or hepatic vein obstruction)

GALLBLADDER DISEASE
Gallstones are relatively rare in children. They are of the pigment type in 70% of children and cholesterol stones in
ZO%. Conditions associated with gallstone formation include:
• Chronic haemolysis (sickle cell disease, spherocytosis) (pigment stones)
• Crohn disease
• Ileal resection
• Cystic fibrosis
• TPN
• Obesity
• Sick premature infants

Clinical features
• Intolerance of fatty foods
• Recurrent colicky RUQ abdominal pain
• Acute cholecystitis: RUQ pain, tenderness and guarding, fever, jaundice, nausea, vomiting

Investigations
USS liver and gall bladder
Blood LFTs, blood cultures (in acute cholecystitis)

Management
Cholecystectomy (open or laparoscopic, once acute infection subsided)

LIVER TRANSPLANTATION
Orthotopic liver transplant is available for chronic liver disease or acute/subacute liver failure.
Transplant should be considered before irreversible nutritional deficit and growth and developmental delay. Biliary
atresia and metabolic liver disease are common indications in children.
Combined small bowel and liver transplantation is now an effective treatment for short-gut or intestinal failure. How-
'
ever, isolated small bowel transplant is recommended unless end-stage liver dysfunction accompanies bowel disease.

197
 ~-~
I

.,: '

Indications and contraindications for urgent liver transplantation

Complications
Early Renal impairment, hypertension, GI haemorrhage, graft dysfunction, acute rejection
Late Infection (especially bacterial, CMV and PCP), organ rejection, lymphoproliferative disease

Prognosis
80-90% 5-year survival rate for elective transplantation.

FURTHER READING
Kelly DA Diseases of the Liver and Biliary System in Children, znd edn. Oxford: Blackwell Publishing, 2003
Shah N, Thomson MThe liver in intensive care. In: Henderson J, Fleming P, eds, Manual of Paediatn"c Intensive Care.
London: Edward Arnold, 1999

198
• Physiology • Haemolytic uraemic syndrome
• Urinary trad infection • Renal venous thrombosis
• Vesicoureteric reflux • Disorders of tubular function
• Congenital urinary trad obstruction • Congenital structural malformations
• Nocturnal enuresis • Urate metabolism
• Renal calculi • Hypertension
• Nephrotic syndrome • Renal failure
• Glomerulonephritis

PHYSIOLOGY

FUNCTIONS OF THE KIDNEY

• Excretion of waste products
• Regutation of body fluid volume and composition (salt and water [and hence BP] and pH balance)
· • Endocrine and metabolic (renin, prostaglandins, erythropoietin, vitamin D metabolism)
I

GlOMERUlAR FILTRATION

Urine flow x [Urine]

GFR=------ [ ] = concentration of substance
[Plasma]

199
 (Urine Cr x Urine (voljmin)) (Cr = creatinine)
Cr clearance =
Plasma Cr
GFR can be estimated using endogenous substances or by injecting a substance and comparing the rate of urinary
excretion with the plasma concentration. The ideal substance for this estimation is:
1. Not metabolized
2. Freely filtered, i.e. not protein bound
3. Neither secreted nor reabsorbed
4. The concentration in the plasma remains in a steady state during the collection of urine, i.e. rate of
production = rate of clearance
If all these criteria are met then ihe renal clearance = GFR. Substances that may be used for measurement:

Creatinine Commonly used (endogenous), some tubular secretion

Cystatin Endogenous substance
Inulin Gold standard, used for research purposes
Cr EDTA Used for accurate GFR calculation, but does involve radioactivity
Iothalamate Non-radioactive assays possible, multipoint using finger prick blood spots increases accuracy

~{ENJ\l BlOOD flOW (REf)

This is dependent on the BP and the renal vascular resistance. RBF is low at birth and gradually increases to adult
levels (25% of the cardiac output). The RBF remains constant throughout a BP range of 80- 180 mmHg in adults.
The countercurrent mechanism ensures a concentrated environment surrounding the distal collecting duct and thus
water is reabsorbed at this point (the amount dependent on ADH status), resulting in more concentrated urine.

~ENIN--ANG!OTENSIN~ALDOSTERONE SYSTEM
This system is involved in the control of BP. The juxtaglomerular apparatus (JGA) is made up of specialized arteriolar
smooth muscle cells which secrete renin in response to various stimuli. Renin cleaves angiotensin I from angiotensino-
gen, which is then converted to active angiotensin II. This vasoactive substance results directly in vasoconstriction
and also in sodium retention via aldosterone release. These changes mediate an increase in BP and salt and water
retention.

ATRIAL NJ-\TRIUREHC PEPTIDES (ANP)

These are peptides secreted from the cardiac atria in response to increased stretch, increased pressure and increased
osmolality and are involved in cardiovascular and fluid homeostasis. ANP has the following actions:
• GFR i
• Na excretion i
• H20 excretion i
• BP j,
• Renin -1-, aldosterone -1-

200
· _;.:.

EFFERENT ARTERIOLE~ ~AFFERENT ARTERIOLE

GLOMERULUS -(((i)))
PROXIMAL CONVOLUTED TUBULE ---+-

DISTAL CONVOLUTED TUBULE

NaCI
K•
HC0 3 , P04
Active Ca, Uric acid
reabsorption ] Reabsorption
Glucose
Galactose
Amino acids K+
Fructose H+
Passive NH 3•-
reabsorption [ H20+ Urea Drugs
Metabolic pochitis
~;. [ Organic acids
Secretion
w

NaCI, HC0 3 , H20 Reabsorption

LOOP OF HENLE ----+1
K•, W, NH 3 • Secretion
Countercurrent
mechanism

COLLECTING DUCT

Figure 9.1 Schematic diagram of sites of electrolyte absorption and excretion

Angiotensinogen (liver)
Afferent glomerular
arteriole
JGA - - - - Renin _ _,___

Nal
RBFI Angiotensin I
BPI

'e ACE Lungs, heart

--{1.
blood vessels

Peripheral vasoconstriction (seconds)

Angiotensin II
2. Aldosterone (release from _ tNa retention (days)
adrenals) Kloss
: H loss

I
BPI ~---- - - - -------- - ---

Figure 9.2 Renin-angiotensin-aldosterone system

201
ACHl-EASE HOMEOSTASIS
Normal arterial blood gases:
pH 7.35- 7.45
P0 2 10.0- 13.3 kPa (75-100 mmHg)
PC0 2 4.8-6.1 kPa (36-46 mmHg)
HC0 3 23-30 mmoljl
BE ± 2.3 mmoljl

Anion gap
This is used to evaluate acid- base disturbances. It is the apparent disparity between the total cation (+) and the total
anion (-) concentration in the blood. It occurs because some anions are not routinely measured.
Anion gap = [Na] - [Cl + HC0 3]
Normal values are 10-12 mmoljl.
The anion gap is useful in metabolic acidosis when the key distinguishing factor is chloride concentration -this will
be normal or increased, depending on the cause of the acidosis

Acidosis with normal anion gap (chloride! compensates for reduced bicarbonate)
Bicarbonate loss i GIT losses
Renal losses, e.g. proximal RTA, interstitial nephritis, hypoadrenalism
W excretion t E.g. distal RTA

Acidosis with increased anion gap (chloride normal, other acids must be present to explain the
aridr)sir;'-'/i
\.. .- \...

Add increased Lactic acidosis

Ketoacidosis
Inborn errors of metabolism
Unfortunately, chronic renal failure can cause both a normal or increased anion gap acidosis.

mma;ncs

Loop diuretics Inhibit-Na, Kand cl co-transport in the Ototoxicity _

ascending loop of Henle and increas_e
E.g. frusemide Hypochloraemic alkalosis
venous capacitance
K l Mg .!., Na .l
Impaired glucose tolerance
Gout (urates i)
Myalgia
Allergic nephritis
Hypercakiuria, withrenal stone formation
brhephrcidilcin()sis in neonates ..

202
RENAL RADIOLOGICAL INVESTIGATIVE TECHNIQUES

Ultrasound scan (USS)

The standard imaging procedure generates information on renal size and growth, structure and dilatation (which may
be a mark~r of obstruction). No information obtained on renal function.

Intravenous urography (IVU)

I

Used to check detailed anatomy, i.e. renal pelvis, calyces, ureters, stones and obstruction. Contrast is given intra-
venously and is excreted via (and hence outlines) the urinary tract. Rarely needed.

Micturating cystourethrography (MCUG)

Radiolabelled scanning with contrast medium instilled into the bladder via a urethral catheter in place and the urinary
tract is visualized while the infant is voiding . A sensitive technique to detect and grade reflux and outline urethral
obstruction on voiding with the catheter removed. This is a relatively invasive procedure due to the necessity to place
a catheter.

203
Static nuclear medicine scan (DMSA)
Static renal scanning with technetium-labelled 2,3-dimercaptosuccinic acid (DMSA). DMSA is taken up by proximal
tubules and the functional cortical mass is outlined. Normal results range from > 45% one kidney and <55% the other
kidney. The scan is used to detect renal scarring and pyelonephritis (though a single scan cannot differentiate acute
from chronic).

Figure 9.3 A6-year-old girl presenting with urinary incontinence, both daytime
and night-time wetting. Final diagnosis is that of a duplex right kidney with ectopic
opening of the upper moiety ureter below the bladder neck and VUR into the lower
moiety with damage. This is the right posterior oblique projection of the 99 mTc-DMSA
scan showing a defect in the upper pole of the right kidney. In addition, there is
a focal defect on the lateral aspect of the lower portion of the right kidney, better
seen in the oblique projection

Dynamic nuclear medicine

Vascular Filtration Excretion
scanning (DTPA and MAG3)
ph~ ~sre----p-haLs_e_ _
Radioisotope scanning with technetium-
labelled diethylenetria mi nepenta-a ceti c
Acute
acid (DTPA) or mercaptoacetylglycine
obstruction
(MAG3). DTPA and MAG3 are freely fil- c
::J
tered through the glomerulus. In a normal 0
0
scan the isotope is quickly excreted, but QJ
Q.
0
with pathology the excretion is delayed. 0
(/)
Frusemide is then given to differentiate -Impaired function
an obstructed system (where delay con-
tinues) from an unobstructed system.
_ _ _ _....--- Normal kidney
Used to detect rena l blood flow, function
l[__ _ j__ __j__ ___::}======~= Renal artery stenosis
and drainage disorders, and reflux in an 0 5 10 15 20 mins
older child who can control micturition on Radioisotope renogram
demand.
. Figure 9.4 Normal and abnormal DTPA scans

URINARY TRACT INFECTION (UTI)

A UTI can present as acute cystitis, acute pyelonephritis, septicaemia or be picked up as asymptomatic bacteriuria.
Acute pyelonephritis may lead to renal scarring and changes of chronic pyelonephritis. UTI associated with reflux can
cause scarring in a growing kidney and this can lead to hypertension and chronic renal failure.

Causes

Predisposing factors ~- · · comtn~n

.
bacteria · ·. :_- · ·~.< ··... .-:.~:., ·· :: :_- -. <·-:c:_:<~:'-~:·{:~
. .: ..
F~M.~le (3% ' 6fgirt.s·Cf. :1% of boys) ·_ EscHerichiq ·coli · ,. · . ;':>},_>:' :- \:': '•_:··. <~> . .-
-~d~ary· trad •ab~dirnality (SO%) ·Prot~us {b;o..y(particuta:rty,lript~'~h6sphat~ stories)·- -.
.. : ., .~ ·.~

Immunosuppression · PseudOITiohas aerilginosl1 (ccin1f11on in structural abnormalities) _

204
Clinical manifestations
Asymptomatic bacteriuria or:
Infant Sepsis (PUO)
· Faltering growth, gastro-oesophageal reflux
Older child Dysuria, frequency, nocturia, abdominal pain, incontinence of urine, haematuria, smelly urine
Systemic infection (PUO)

Diagnosis
1. Urine sample: Suprapubic aspiration (SPA) -in infants< 1 year. Standard in sick infants
Clean -catch urine - infants. Preferred sample. Three samples collected prior to treatment
Bag urine -infants. Contamination common. Three samples collected prior to treatment
Catheter sample
Midstream urine (MSU) - children > 3 years (or younger with patience or if potty-trained)
Signs of infection (on urinalysis, microscopy and culture):
• Proteinuria, haematuria (dipstick) }
• Pyuria (almost always) (microscopy) Supportive
• Organisms on microscopy (microscopy)
• Single species growth> 105/ml (culture) Diagnostic
2. In unexplained fever and sick infants/children - urine sample, U&Es, creatinine, ESR, CRP, blood cultures
3. Urgent USS if there is a known structural abnormality and co.ncern of obstruction or severe localized flank pain
(looking for obstructed, infected kidney)
NB: Some infants with posterior uretheral valves, i.e. must be boys, can present with an early UTI- usually with sepsis
at 1-2 months of age.

Management
• Antibiotic therapy: If unwelljinfant - intravenous (change if necessary when sensitivities known)
If well child- oral therapy (change if necessary when sensitivities known)
• Optimize hydration
• Commence Further investigation in proven UTI
prophylactic
Proven UTI
antibiotics l
until further USS (and abdo X-ray if stones, obstruction, bladder or spinal anomaly suspected)
investigations IVU if concern on USS (rarely needed)
complete l
• Drainage proce- Prophylactic antibiotics until investigations are complete
dures if required
< 1 year 1- 5 years > 5 years > 5 years
l l If abnormal USS/abdo X-ray Normal USS/
2 months later 2 months later 2 months later AXR
t l t l
DMSA (scars?) DMSA DMSA No further
+ l l investigation
MCUG (reflux/ If abnormal (USS If abnormal
obstruction?) or DMSA) l
Figure 9.5 Further (especially or pyelonephritis MAG-3
investigation in important in or recurrent infection
proven UTI. (This is boys) or FH reflux
a baseline protocol; l
individual units may MCUG (MAG-3 if older or can urinate on demand)
(If pyelonephritis, add DTPA)
vary in the detail)
205
Prevention
• High fluid intake
• Girls to wipe themselves after micturition from front to back
• Empty bladder completely and regularly; may involve double micturition, i.e. empty once and then repeat a few
minutes later
• Avoid constipation

VESICOURETERIC REFLUX (VUR)

This is detected on renal investigation, usually following UTI. It is retrograde flow of urine from the bladder into the
ureters± kidney, due to incompetence at the vesicoureteric junction or abnormality of the whole ureter.
• It is very common (1:50- 100) and usually resolves spontaneously
• It is familial (multifactorial, several loci found)
• 10-15% improvement in reflux per year
Traditional teaching is that reflux can result in renal scarring (reflux nephropathy) because:
1. The renal pelvis is exposed to high pressures (during urination), and
2. The reflux facilitates the passage of bacteria to the renal pelvis
-
However, many of the kidneys are already abnormal at birth because of combined maldevelopment of the lower urinary
tract and kidneys, i.e. urinary tract 'field defect'. 20% of adult ESRF is traditionally said to result from reflux nephropa-
thy, but many of these may have had an underlying developmental defect.

Classification
Grades I- V:
• Grades I and II - spontaneous resolution in 80%
• Grades III and IV - spontaneous resolution in 15%

Management of reflux and renal scarring

1. Long-term prophylactic antibiotic therapy (tri-
methoprim 2 mgjkgjnight). Controversial when
to stop (when reflux resolved, no UTis for a year,
or after the age of 35 when new scarring is very Figure 9.6 Simplest classification is by Scott who divided the
rare) types into those with 1ormal calibre or dilated ureters
2. MSUs if/when symptomatic
4. Consider circumcision in boys if recurrent UTis and tight foreskin
5. Cystoscopic injection of reinforcing material around ureteric orifices in the bladder or surgical re-implantation
of the ureters (old fashioned) if medical management fails (rarely necessary)
6. If bilateral scarring, perform regular renal growth (ultrasound) and function tests (creatinine, GFR)
Reinvestigate regularly in early childhood looking at:
• Renal growth (USS)
• If condition has resolved (MAG3)
• Any new scars (DMSA).
• BP and urinalysis check 6-12 monthly for life

CONGENITAL URINARY TRACT OBSTRUCTION

NB: Ureteral dilatation does not always signify obstruction (congenitally abnormal ureters could be present).

206
congenital obstruction may occur at the sites shown in Figure 9. 7.

Pelviureteric junction -+---.,;;:'f&-

obstruclion (PUJ)

~'---- Vesicoureteric junction

Bladder neck---~~ obstruction (VUJ)
obstruction /---Posterior urethral
valves (PUV) (boys only)

Figure 9.7 Urinary tract obstruction sites

Obstruction results in dilatation of the urinary tract proximal to the obstruction,± hydronephrosis and hydroureter,±
dysplastic or malformed kidneys, often with peripheral cortical cysts. Intrauterine detection of dilatation on antenatal
ultrasound scan is possible.
It is important to assess infants in whom congenital hydronephrosis has been detected in order to check for obstruc-
tion and possible renal damage, and then to treat the cause. These infants are commenced on prophylactic antibiotics
from birth, which may later be discontinued if all investigations are normal.

Antibiotic prophylaxis from birth

Renal USS soon after birth

I
Unilateral obstruction Bilateral obstruction or unilateral
Normal or < 15 mm renal pelvis dilatation > 15 mm pelvic dilatation or dilated ureter
I ---.----'
'-·

Renal USS at 6 weeks

l
U & E, creatinine
Urgent MCUG in males (PUJ I PUV
+ t obstruction?)
Normal Abnormal In females consider ureterocoele

+ t Refer to specialist
Stop antibiotics MCUG + DMSA I DTPA
Consider referral to specialist

Figure 9.8 Management of an infant with antenatal urinary tract obstruction (individual
protocols may vary)

POSTERIOR URETHRAL VALVES (PUV)

This condition is seen in male infants and it is important to recognize it early as prompt surgical treatment can delay/
prevent rapid progression to renal failure (though irreversible damage may have already occ~rred in utero). .
An outflow obstruction in the posterior urethra causes aberrant bladder development with a thick wall and small
capacity. There is bilateral hydronephrosis, there may be associated ureteric and kidney abnormalities and, if severe,
oligohydramnios and the Potter sequence can occur. It may present as sepsis during the first few weeks of life.

207
NOCTURNAL ENURESIS
This is the involuntary passage of urine during sleep.
Incidence (100% at birth, i.e. normal!)
5% at 5 years of age
2-3% at 10 years of age
< 2% at 15 years of age

It may be primary (always present) or secondary (occurs after continence was achieved). It is due to an inability to
wake when the bladder is full, bladder overactivity and/or a high nocturnal urine output.

Causes of pathological nocturnal enuresis

Psychological > 95%
Organic UTI
Constipation
Polyuria, e.g. IDDM, diabetes insipidus, polyuric renal failure
Neurological, e.g. spina bifida
Renal structural abnormality, e.g. ectopic ureter

Initial- investigations and assessment

• History of onset and frequency. Is the child dry during the day? Get parents/child to keep a drinks and toilet
diary
• Diet, stress and nocturnal access to the toilet
• Examination of abdomen, genitalia, spine, neurological assessment and growth
• Urine sample: check for glycosuria, proteinuria, infection and early morning urine osmolality
• BP check
• Renal USS if indicated (± AXR)
NB: The history is most important and guides investigations. Organic causes must be ruled out prior to managing it
as a psychological problem . ·

Management options
• Star charts and reward systems (positive reinforcement)
• Alarm pads (negative reinforcement)
• Behavioural programmes, e.g. retention control during the day to increase bladder capacity
• Drugs (only needed in a very few): Anticholinergics, e.g. oxybutinin
Adrenergics, e.g. ephedrine
ADH analogue (desmopressin) for short-term relief

RENAL CALCULI
Unusual in children (overall incidence 1.5:1000000).

Clinical features
• None
• UTI
• Haematuria, abdominal pain, renal failure (if bilateral)
• Family history

208
Classification

Investigations
Urine M, C& S (NB: proteus)
Urinalysis for pH (distal RTA)
Amino acid screen (cystinuria)
Calcium/creatinine ratios or 24-h collection
Blood Renal function tests (creatinine, HC0 3 especially)
Calcium, phosphate, alkaline phosphatase
PTH if concern of hyperparathyroidism
Imaging AXR, renal USS, IVU
Stone analysis

Management
• High fluid intake
• Alkalinize the urine to pH 7.5 (cystine and uric acid stones)
• Stone removal via lithotripsy or endoscopically
• Treat' cause if possible

NEP~ROTIC SYNDROME
Incidence 1:50000 children. Male> female, 2:1. Typical age 1-6 years.
This condition is characterized by heavy proteinuria and the consequences of hypoalbuminaemia.
Diagnostic triad:
1. Proteinuria > 40 (mg/h/m 2)
2. Hypoalbuminaemia < 25 mg/L
3. Oedema
Hyperlipidaemia (LDL i, triglycerides i) also occurs in most cases.

209
There are three main types of nephrotic syndrome in childhood:
Minimal change disease (85-90%) No changes seen under normal microscope, but podocyte foot process fusion on
EM
Focal segmental glomerulosclerosis Focal because not all glomeruli affected (usua.lly deeper ones) and (10-15%)
segmental because only segments of each glomeruli affected
Membranous nephropathy (1-5%) Associated with hepatitis Band malignancy, e.g. lymphomas
Other types of nephrotic syndrome fall into an overlap pattern with nephritis, where there is marked inflammation in
the glomerulus (hence there will be additional features such as red and white cells ± casts in the urine, secondary to
inflammation). Unlike uncomplicated nephrotic syndrome, it is rare for the plasma albumin to fall below 20 g/dl in
these conditions. Causes include:
• Poststreptococcal glomerulonephritis
• HSP
• Anaphylactoid
• Malaria
• SLE
• Drugs, e.g. penicillamine, and heavy metals

Clinical features
Preceding URTI
General features Lethar~Jy, anorexia, diarrhoea
Hypoalbuminaemia Oedema: Periorbital in mornings (first sign, often misdiagnosed as allergy)
Scrotal, sacral, leg and ankle later in the day
Ascites
Pleural effusions with SOB (uncommon)
Proteinuria Frothy urine (rare)
Hypogammag/obulinaemia Infections (especially encapsulated organisms [pneumococcus])
Abdominal pain, e.g. secondary to peritonitis
Intravascular hypovolaemia (Abdominal pain, circulatory collapse or venous thrombosis)

Initial investigations
Urine Dipstick for proteinuria (+3 or +4)
(May have +3 or +4 blood too because sticks are overly sensitive)
Albumin:creatinine ratio (> 200 mg/mmol)
Na concentration (< 20 mmoljl is an indication of potential hypovolaemia)
Microscopy (0 or minimal cells in uncomplicated nephrotic syndrome; red cells, white cells and casts
in glomerulonephritis)
Selective protein clearance (research only): IgG (large molecule), albumin (small molecule)
Low ratio = selective protein leak. Seen in minimal change disease
Serum FBC, PCV, ESR (i haematocrit or Hb in hypovolaemia, i ESR and WCC in infection)
U&E, creatinine, albumin (< 25 g/L), cholesterol and triglyceride (both i)
Complement factors (3 and C4 (t) (not in minimal change)
ASOT, anti-DNAse B (streptococcal infection)
HBsAg (if membranous GN and from Middle/Far East or at-risk group)
Throat swab (Streptotoccal infection)
Renal biopsy Only if: 1. No response to steroids after 4-6 weeks, or
2. Atypical features at presentation, i.e. high creatinine, hypertension, or < 1 year
of age

210
Management
1. Oral corticosteroids- 60 mg/m 2/day (2 mg/kg/day) for 4 weeks (irrespective of when they go into remission, i.e.
do not shorten the initial course). Then 40 mg/m 2 alternate days for 4 weeks. If no response to steroids consider
renal biopsy
2. Oral penicillin prophylaxis
3. Monitor intravascular volume (see below)
4. Daily weight, electrolytes and albumin and fluid input-output chart
5. Diuretics as needed (in hospital only)
6. Monitor proteinuria at home when recovered to assess for a relapse

Features of intravascular hypovolaemia

Orthostatic hypotension, cool peripheries, oliguria, capillary refill time l abdominal pain, tachycardia, significant
core_:_periphery temperature difference, urine sodium < 20 mmol/L, rising haematocrit.
NB: The BP will not fall in these children until there is severe hypovolaemia due to their compensatory mechanisms;
therefore, the above features must be regularly assessed.
Give albumin if hypovolaemic (4.5% albumin if in shock, 20% albumin 0.5-1 gjkg with diuretics over at least 4 h if
not in shock) .

Complications
• Hypovolaemia (see above)
• Infection: classically pneumococcal peritonitis, although Gram-negative sepsis is becoming commoner due to
penicillin prophylaxis. (Due to low immunoglobulins)
• Intravascular thrombosis - renal vein thrombosis and DVT (due to hypovolaemia, hypercoagulable state with a
low antithrombin III)
• Hypercholesterolaemia
• Acute tubular necrosis - if severe hypovolaemia

Prognosis
Steroid-sensitive disease: 1
h resolve with no relapses
h have occasional relapses
1

1
h have regular relapses
Steroid-resistant disease Alternative immunosuppressive therapy needed, which may include cyslophosphamide
and/or cyclosporin
Up to 50% progress to chronic renal failure
Ifwell, follow-up yearly, checking particularly BP and growth.

'
CONGENITAL NEPHROTIC SYNDROME
This is the development of nephrotic syndrome presenting antenatally or within the first month after birth.

Causes
Genetic Various mutations found
Finnish type (nephrin gene defect, autosomal recessive) . Gene testing available
Denys-Drash syndrome (WTl gene mutation)
Post-infective Congenital syphilis, congenital toxoplasmosis ..

211
Clinical features
• Large oedematous placenta
• Proteinuria
o Clinical deterioration with oedema in the first weeks of life due to the increase in GFR (and therefore protein
excretion)

Management options
1. Supportive therapy until large enough for renal transplantation (> 10 kg)
2. Reduce the GFR with NSAIDs and ACE inhibitors, then unilateral nephrectomy, or bilateral nephrectomy with
dialysis as necessary. Transplant when big enough (> 7-10 kg).
Death may occur from the complications (CRF, peritonitis, respiratory infections and strokes) .

GLOMERULONEPHRITIS
This is a term covering several diseases involving inflammation of the glomerulus. It is often immune-mediated.
There are two major mechanisms of immunological injury:
1. Deposition of circulating antigen-antibody immune complexes (95% of GN)
2. Deposition of antiglomerular basement membrane antibody (anti-GBM, 5% of GN, e.g. Goodpasture syndrome)

1-!ISTOUJGICAl CU\SSIFICAHON OF GLOM ERUU\H PATHOLOGY

This may be asked about in exams.

. . ?P .·.
Type •
Mesa.hgial'2etl·pt0liferation . · . •··••··• · ·····• . : >·· .. · ····
In~·r~membrano~s immune ... , :- .··• ... ·>•·· ··c·,• <>:··
complex deposits · > • • .· ,>_>
C3 stain ()nly . ·.

212
ACUTE NEPHRITIC SYNDROM E
This has four major characteristics:
• Haematuria
• Proteinuria
• Oliguria
• Volume overload leading to hypertension (i circulating volume) and oedema (i extravascular fluid)
Other features are red cell casts and white cells in the urine.

General investigations
Urine Urinalysis (protein, blood, casts)
M, C & S (haematuria, proteinuria, casts, features of infection)
Serum FBC, ESR
U&E, creatinine, LFTs
Complement levels (C3 and C4)
Viral titres and ASOT
HBsAg, ANA
Throat swab M, C & S (features of infection)

Management
This is supportive.
1. Fluid restriction - insensible loss (300-400 mljm 2/day) + urine output
2. Sodium restriction - difficult in children, hence often use 'no added salt' diet
3. Hypertension management, e.g. frusemide to correct volume overload
4. Penicillin if positive throat swab or nephrotic picture, i.e. low albumin
5. Dialysis if necessary, e.g. marked hyperkalaemia

CAUSES OF PROTEINURIA
Proteinuria may be mild or heavy. Microalbuminuria is defined as 20-200 mgjday and is not detectable on dipsticks.
Proteinuria may also be detected by measuring the albumin:creatinine ratio on a spot urine (normal=< 0.1).

213
POST-STREPTOCOCCAL GLOMERULONEPHRITIS
Typically this presents as the nephritic syndrome 6- 10 days after a Group A ~-haemolytic streptococcal URTI or_14-21
days after streptococcal skin infection.

Investigations
General investigations for glomerulonephritis and specifically: anti-streptolysin 0 titre (ASOT) (positive), anti-DNase B
antibodies(!), C3(l), C4 (N), throat swab (M,C & S). Renal biopsy only if atypical, i.e. severe BPi, rising creatinine.

Management
• 10-day course of penicillin if positive throat swab
• Supportive therapy as for nephritic syndrome (NB: steroids unhelpful)

Prognosis
Spontaneous resolution in> 95%. NB. Haematuria can continue for up to a year, but not significant proteinuria.

HEN OCH~SC H ONLEIN PURPURA (HSP)

This is a vasculitic syndrome affecting small vessels. Male> female, 2:1, age 3-10 years. Mostly in late winter and early
summer. Often there is a preceding URTI.

Clinical features
The four classical features are rash, joint involvement, abdominal pain and haematuria.
Rash Often the first sign. Vasculitic (macular, becoming purpuric) . Typically on buttocks, extensor
surfaces of lower limbs and pressure points, e.g. sock line. Recurs over weeks
Joints Non-destructive arthritis of weight-bearing joints (hips, knees, ankles)
Abdominal pain Bloody stool due to intussusception. Pancreatitis, ileus, protein-losing enteropathy, Gibleeding
from vasculitic Lesions
Haematuria Secondary to GN
Renal Glomerulonephritis (focal segmental) in 80%
Oedema Forehead, genitalia, hands and feet, periarticular
Other organs CNS, testis, pancreas, parotids, muscles, lungs (haemoptysis)

214
 Renal disease
• Microscopic haematuria in 80%
• Nephritic syndrome
• Nephrotic syndrome

Investigations
• General investigations for nephritic and/or nephrotic syndrome
• ESR (1}
• IgA (i in > 50%)
• Clotting and platelet screen (may be deranged)

Management
• Treat any suspected infection (particularly streptococcal disease)
• Supportive therapy for arthralgia, rash, fever and malaise
~· • Renal disease: Standard treatment of nephritis or nephrotic syndrome
Renal biopsy if severe hypertension or increasing creatinine
If crescentic disease, plasma exchange is used _
• Abdominal disease - early use of steroids has been used for abdominal pain but is controversial and may mask
signs of intussusception

Prognosis
Generally good, although 5-10% progress to chronic renal disease. Low albumin is a sign of a poor prognosis.

IGA NEPHROPATHY {BERGER NEPHROPATHY)

This condition is not inherited. Male > female, 2:1. A focal segmental glomerulonephritis with IgA deposits in the
mesangium.
. .
Clinical features
• Microscopic haematuria
• Macroscopic haematuria during infections (NB: not after)

Specific investigations
• Compl~ment (normal C3)
~ Serum IgA (i in 20%)
• Renal biopsy

Management
• No specific therapy
• Follow-up for life essential

Prognosis
• End-stage renal failure develops in 25%
• Poor prognosis is associated with BPi and proteinuria

215
SYSTEfvUC LUPUS ERYTHEMATOSUS NEPHRITIS
This is a systemic vasculitis with protean manifestations (see p. 000). Renal disease may involve various types of
nephritis, classified by the WHO into five classes. They include focal and diffuse disease, and proliferate and membra- '
nous disease.
Characteristically both C3 and (4 levels are depressed in active disease, ESR is high and CRP normal. Renal biopsy
should be considered if haematuria and proteinuria develop in SLE.
Immunosuppressive therapy (steroids, cyclophosphamide and plasma exchange if necessary) is used in the manage-
ment.
The renal disease may burn out.

GOODPASTURE DISEASE
Rare before teenage years. This disease may follow a URTI and involves:
• Severe progressive glomerulonephritis
• Pulmonary haemorrhage in smokers (intermittent haemoptysis, anaemia, massive bleeding)
• Antibodies to lung and glomerular basement membrane (GBM)
N15: Goodpasture syndrome is the clinical picture of pulmonary haemorrhage and glomerulonephritis seen in a systemic
disorder, e.g. SLE, PAN.
Diagnosis is confirmed by renal biopsy.
Therapies include immunosuppression, pulsed methylprednisolone and plasmapharesis. Patients may die in the acute
stage of pulmonary haemorrhage or commonly progress to chronic renal failure.

Al?ORT SYNDROME
Ahereditary disease of collagen IV (part of the glomerulus basement membrane). X- linked dominant, autosomal domi-
nimt or spontaneous mutation (20%). Worse in males.

Clinical features
Hereditary nephritis Microscopic haematuria (macroscopic with infections), proteinuria, ESRF (by 20-30 years)
Sensorineural deafness High frequency, progressing to the whole speech range
Ocular defects (15%) Cataracts, anterior lenticonus, macular lesions
The disease generally presents as haematuria and a young patient may show none of the above features. Parents and
siblings of an affected individual should be screened for disease by urine dipstick at least.
Typical'basket weave' appearance (splitting of the BM) on electron microscopy of renal biopsy. Anti-GBM nephritis can
occur in a transplanted kidney in these patients because of immune reaction to 'normal' collagen IV in the transplant.

CAUSES OF 1-lAEMATUfUA

UrinarY'ifactinfectian ·
Glb'm~rtifqn.~p hrftis ·····•·.·· .Al~drt .syndro.nie ·. .
· · . ·· IgAn~phropathy (Berger) ·
Congenitalriwiformations ...· ·...· .
Trauma ' < > ·· ··
Haematologicai ·.Coagulopathy

216
HAEMOLYTIC URAEMIC SYNDROME (HUS)
The commonest cause of acute renal failure in children in the UK. A potentially life-threatening disease involving:
• Acute renal failure
• Microangiopathic haemolytic anaemia
• Thrombocytopaenia

Causes
Diarrhoea-positive HUS
E. coli Verotoxin-producing Escherichia coli 0157 (10% of these infections develop into HUS)
Other bacteria E.g. shigella (shigatoxin), salmonella, campylobacter
Diarrhoea-negative HUS
Familial Poor prognosis if presents < 1 year, recurrent episodes. Complement factor H deficiency
Bacteria/viruses Pneumococcus, coxsackie, echovirus, varicella
Drugs Cyclosporin (post transplant), oral contraceptive pill
Other - SLE, postpartum
The most common causes are diarrhoea-positive disease and familial, the prognosis of the former being much better.
Features and management of diarrhoea-positive disease are outlined.

Clinical features in diarrhoea-positive disease

• Usually < 5 years
• Bloody diarrhoea, may resolve, with 5-10 days later oliguria, pallor, lethargy and petechiae
• NB: Hypertension and hyperkalaemia are major causes of mortality
• Other organ damage - CNS (fits, coma), colitis, pancreatitis
• A high presenting wee is associated with a poor prognosis

Investigations
Serum FBC and film (microangiopathic haemolytic anaemia, platelets -L)
• Coagulation screen (normal)
U&E, creatinine, calcium, phosphate (changes of acute renal failure)
Urine Urinalysis (mild haematuria and mild proteinuria)
Stool M, e& S
Management
Therapy is supportive, as needed.
Fluid status Careful assessment- twice daily weights
Diuretics may be needed
Hyperkalaemia Salbutamol nebulizers or IV, insulin and dextrose, etc.
Dialysis

217
 l l
!

Transfusions Blood and rarely platelets

Cerebral involvement Consider plasma exchange
NB: Long-term follow-up is essential, looking for hypertension and chronic renal failure.

RENAL VENOUS THROMBOSIS

Causes
Neonate/infant Asphyxia, dehydration, sepsis, maternal IDDM
Hypercoagulable state, e.g. proteinS or C deficiency, prothrombotic mutations (factor V Leyden)
Older child Nephrotic syndrome, cyanotic CHD, contrast angiography
Hypercoagulable state

Clinical features
Neonate Gross haematuria and unilateral or bilateral flank masses
Older child Micro/macroscopic haematuria and flank pain
Bilateral thrombosis will also result in acute renal failure.

Investigations
uss IVC (to check extension) and renal (renal en~argement)
Radionucleotide imaging Reduced renal function
Doppler flow studies
Prothrombotic screen (Up to half have inherited procoagulant defect)

Differential diagnoses
Causes of haematuria IgA nephropathy, Alport syndrome, glomerulonephritis
Causes of renal enlargement Cystic kidneys, Wilms tumour, abscess, haematoma, hydronephrosis

Management
Unilateral Supportive therapy with fluids, electrolyte management and treatment of infection
Bilateral Fibrinolytic agents, e.g. heparin, urokinase, TPA

Prognosis
The kidney becomes atrophic and should-be removed if:
• Hypertension develops
• Repeated UTis occur

DISORDERS OF TUBULAR FUNCTION

RENAL TUBULAR ACIDOSIS (RTA)

This is a condition of systemic acidosis caused by renal tubular dysfunction. Three types of RTA exist: types I.. II and
IV (type III was reclassified as a variant of type I).
• Types I and II result in a hypokalaemic hyperchloraemic metabolic acidosis
• Type IV results in a hyperkalaemic hyperchloraemic metabolic acidosis
The urine pH should be measured with a glass electrode within 20 min of collection; dipsticks are not accurate enough.

218
.. t
Ammonium chloride loading can help distinguish between types I and II in mild acidosis by increasing the serur
acidification and accentuating the defect (type II can then acidify the urine).

Type I - distal RTA

This is due to a failure of Wexcretion by the distal tubule (and urine pH cannot be< 5.5). There is a normal anio
gap because chloride is increased to compensate for the acidosis.

Causes
Isolated Autosomal dominant, autosomal recessive, sporadic
Secondary Interstitial nephritis: Obstructive nephropathy
Pyelonephritis
Medullary sponge kidney
Transplant rejection
SLE nephritis, Ehlers-Danlos and Marfan syndrome
Cirrhosis
.:•
Nephrocalcinosis
Sickle cell nephropathy
Toxins: Lithium
Amphotericin B

Biochemical findings
Serum HC0 3 l,K l, Ca J-, Cl i
Metabolic acidosis (Normal anion gap)
Urine pH cannot be <5.5
Hypercalciuria (stones)

Clinical findings
• Growth failure
• Nephrocalcinosis
• Renal stones
• Osteomalacia (no clinical rickets)
• Underlying disease

Management
• Bicarbonate supplements as sodium citrate solution or bicarbonate tablets
• Potassium supplements

Typ~ II- proximal RTA

This is due to a failure of proximal tubular bicarbonate reabsorption. The serum bicarbonate falls until the bicar
bonate threshold is reached (15- 18 mmolfl) where no more HC0 3 loss occurs (because less HC0 3 is filtered and thi
level can all be reabsorbed distally). Because the distal tubular acidification mechanisms are intact, the urine can b1
acidified (pH 5.5) when there is acidosis or when given ammonium chloride.

Causes
Isolated Autosomal dominant, sporadic
Secondary Fanconi syndrome:
Primary
Secondary

219
Biochemical findings
Serum HC0 3 l, K H, Cl i
Metabolic addosis (Anion gap normal)
Urine pH may be 5.5
HC0 3 i
Renal loss of other substances in Fanconi syndrome

Clinical J~·ndjngs
• Growth failure
• Rickets, polyuria, polydipsia (in Fanconi)
• Underlying disease
• No renal calcification

Often more difficult to treat and severe than distal RTA.

• Bicarbonate supplements +++
• Potassium supplements

Type IV
In type IV there is hyperkalaemia plus acidosis secondary to failure of bicarbonate reabsorption ± aldosterone
deficiency.

Causes
• Adrenal disorders (A l , R1', renal function N) - Addiso n, CAH
• Hyporeninaemic hypoaldosteronism (A l, Rl, renal function l ): Interstitial nephritis (commonest cause)
Obstruction
Pyelonephritis
Diabetes mellitus
• Pseudohypoaldosteronism (A 1', R i) - distal tubule unresponsive
Key: A= aldosterone, R= renin .
,,. . . lj'mamgs
uwci?em7ca, ,.

Serum K i Cl i
Renin l or 1', aldosterone l or i
Metabolic acidosis (Anion gap normal)
Urine Ammonium l
pH may be <5.5

Clinical findings
Features of:
• Primary renal disease
• Adrcn<1l disease

Management
• Bicarbonate supplemenls
• Potassium reduction, e.g. diuretics

220
FANCONI SYNDROf~1E

This is a generalized defect in proximal tubular function. A hyperchloraemic hypokalaemic metabolic acidosis results
(a type II proximal RTA).

Causes

Clinical features
• Underlying disease
• Failure to thrive
• Rickets
• Polyuria, polydipsia, dehydration

Investigations
Urine There i_s excessive urine loss of: water, i.e. low specific gravity, glucose, amino acids, P0 4, HC0 3, Na, Ca, K,
urate
Plasma Cll, K.!., P0 4 .!., hypouricaemia
Metabolic acidosis with normal anion gap

Management
Diagnose and treat underlying disease:
• Rickets- large doses of vitamin 0, phosphate supplements
• Acidosis - bicarbonate supplements
• Dehydration - extra salt and water, especially in hot weather

CYSTINOSIS
Autosomal recessive condition due to cystine accumulation in lysosomes of the kidneys, bone marrow, liver, spleen,
lymp~ nodes, leucocytes, cornea and fibroblasts.

Clinical features
Infantile form Fanconi syndrome from 3 months of age
CRF by 10 years
Blonde hair, fair skin
Photophobia (eye crystals) and decreased acuity
Hypothyroidism, diabetes

221
 Growth retardation
Dementia (later)
Adolescent form Milder and later-onset renal disease
Adult type No renal disease

Diagnosis
• Fibroblast or leucocyte cystine concentration (I' x 100)
• Cystine crystals in bone marrow, rectal mucosa, lymph nodes
o Slit-lamp examination of the eyes (corneal cystine crystals)

• Genetic studies - gene analysis if family mutation known

Management
1. Phosphocysteamine (lowers intracellular cystine)
2. Phosphocysteamine eye drops
3. Fanconi treatment
4. Renal transplantation (when in ESRF)

Long-term complications
These include CNS problems, myopathy, swallowing difficulty and pancreatic dysfunction (endo- and exo-crine).

Antenatal diagnosis
• Cystine i in amniotic fluid cells
• DNA analysis (the gene is now known)

CYSTINURIA
Incidence 1:650. This is an inborn error of reabsorption at the proximal tubule of the dibasic amino acids, resulting in
increased renal excretion of them: cystine, ornithine, arginine, lysine (COAL) .
NB: There is no systemic amino acid deficiency because they are synthesized in the body.

Clinical features
• None
• Renal stones (< 3% people affected), leading to haematuria, obstruction, CRF

Diagnosis
Urine and stone analysis.

Management
• Alkalinize the urine
• High water intake
• o-penicillamine may help if the above methods are failing

BARHER SYN DR0~1 E

Autosomal recessive. This is a condition of renal potassium wasting with hypokalaemia, alkalosis, aldosterone I, but . ,
normal BP. The pathophysiology is defective chloride transport channels (NaK/( - frusemide-sensitive channels) in the i
ascending limb of the loop of Henle. There are elevated renin and aldosterone levels with juxtaglomerular apparatus · ci
(JGA) hyperplasia. :i~
/~i
222
Clinical features
• Growth failure
• Weakness
• Vomiting, constipation
• Polyuria, polydipsia, salt craving
• Dehydration
• Normal BP

Investigations
Serum K-1-, Cl J, Mg J, (Na -1- in severe cases)
Ca i
Metabolic alkalosis
Aldosterone t, renin t, prostaglandin E2 i (occasionally)
Urine Excess Kand Clloss (sometimes Na and Ca loss also)
Renal biopsy Hyperplasia of JGA

Management
• Oral Ksupplements
• NaCl supplements
• Indomethacin (reducing the GFR reduces the sodium delivery)

GITELMAN SYNDROME
A similar condition often confused with Bartter syndrome, involving hypomagnesaemia, hypokalaemia and hypo·
calciuria, with normal growth. Caused by a defect in thiazide-sensitive NaCl channels in the distal tubule. Treatmen1
includes magnesium supplements.

CONGENITAL STRUCTURAL MALFORMATIONS

DEVELOPMENT OF THE URINARY TRACT AND STRUCTURAL MALFORMATIONS

Normal development of the urogenital tract (nephrogenesis)

I

Understanding the normal development of the urogenital tract helps in understanding the mechanisms involved in
congenital urinary tract abnormalities. Three pairs of 'kidneys' arise sequentially from mesoderm lateral to the spinal
cord jn early embryogenesis: the pronephros, mesonephros and metanephros. The first two degenerate (although
mesonephric structures become incorporated into the male reproductive tract) whilst the metanephros goes on to form
the definitive kidney.

Aberrant early development

These are caused by defects in interaction between ureteric bud and metanephric mesenchyme:
• Dysplastic kidneys: mostly sporadic, 10% may have family history. When they have multiple large cysts, these are
called multicystic dysplastic kidneys -not the same as polycystic (see p. 225)
• Kidney abnormalities as part of sporadic or genetic malformation syndromes, e.g. VATER (Vertebral, Anal, Trachea-
oEsophageal, Renal or Radial anomalies) syndrome or Kallmann syndrome, respectively

223
Defects in terminal maturation
Early nephron and collecting duct development is normal, but there is later dedifferentiation, i.e. reversal of
tiated state, with cyst formation and loss of normal adjacent structures - polycystic kidney disease (AR or AD)
p. 225).

Renal dysplasia is a histological term: the kidney contains undifferentiated cells and metaplastic structures such as
smooth muscle and cartilage.
This is usually due to an early developmental problem leading to aberrant interaction between epithelial cells in the
ureteric bud and the surrounding mesenchyme cells. Later, Lower urinary tract obstruction can also cause dysplasia (but
this is usually less severe since the initial development is normal).

Dysplastic kidneys
• May be large and multicystic, normal size or small
• Initially large kidneys may become small and then disappear in utero (=false appearance of renal agenesis)
• May be unilateral or bilateral
• Associated with other renal abnormalities, often with obstruction, i.e. atretic ureters or lower urinary tract
abnormalities
• Associated with extrarenal abnormalities
If urine flow is reduced bilaterally or completely blocked, it causes the Potter sequence of severe oligohydramnios
(from any cause), resulting in:
• Pulmonary hypoplasia
• Abnormal facies - wide-spaced eyes, epicanthic folds, broad flat nose, low-set ears, small chin
• Limb abnormalities

Diagnosis
• USS (antenatal or postnatal) : Bright hyperechogenic kidneys (large and multicystic kidney disease
[MCKD), normal size or small)
Oligo- or an-hydramnios
• Abdominal mass in newborn
• Later finding (incidental scanning, family scanning, hypertension or renal failure)

224
NB: Screen siblings and parents:
• Renal USS (autosomal dominant inheritance of many conditions)
• Diabetes (maternal diabetes associated with renal agenesis, and renal cysts and diabetes syndrome)

POLYCYSTIC KIDNEYS
Polycystic kidney disease is caused by defects in terminal maturation of the renal system, with an initially normal
nephron and collecting duct, and later cystic dilatation of these and loss of adjacent normal structures.
Polycystic kidney disease may be recessive (ARPKD) or dominant (ADPKD).

Autosomal recessive polycystic kidney disease (ARPKD)

Gene: fibrocystin on 6p. Incidence 1:40 000 births.

Presentation
In utero Large hyperechogenic kidneys on USS ± oligohydramnios
At birth Massive kidneys (abdominal mass)

Clinical features
Renal Bilateral symmetrical renal enlargement with numerous microscopic corticomedullary cysts
Gradually develop BPI and slow decline in renal function
Liver Bile duct proliferation, portal fibrosis and portal hypertension
Lungs Pulmonary hypoplasia ± Potter phenotype

Prog1;1osis
Death in neonatal period (5%) or if survive, reasonable prognosis with slow decline (50% in ESRF by end of
childhood).

Autosomal dominant polycystic kidney disease (ADPKD)

Two genes found:
85% PKD1 (polycystin-1), Ch 16p
15% PKD2 (polycystin-2), Ch 4q (milder disease, later onset)
Incidence 1:600, i.e. very common indeed.

225
Presentation
Late childhood or adulthood with ESRF or hypertension or loin pain, haematuria and renal masses. (Some forms present
earlier in childhood or antenatally).

Clinical features
Renal Bilateral large kidneys with large corticomedullary cysts
Hypertension
Renal stones, renal neoplasms
Chronic renal failure
Other organs Cysts may occur in the liver, pancreas, spleen, ovary
Cardiac valve defects
Intracerebral arteries (Berry aneurysm)
NB: Prenatal diagnosis of both ARPKD and ADPKD possible with chorionic villous sampling if index case details/muta-
tion known.

Incidence 1:100 (very common).

Two ureteric buds develop on one side.

• The kidney fails to ascend from the pelvis, e.g. pelvic kidney
• Usually normal function as long as the other kidney is normal
• Increased risk of UTI
, _Obstruction
·,:- risk increased

WJRSESHOE KIDNEY
• Aberrant fusion of the two kidneys at the lower poles Figure 9.9 Ureteric
• Incidence 1:500 duplication
• May also be dysplastic
• Increased incidence of UTI, stones and PUJ obstruction

HYfHWNEPHROSIS
Hydronephrosis is dilatation of the renal pelvis. Relatively common .
May be associated with:
• Reflux (see p. 206)
• Obstruction (see p. 207)
• Renal dysplasia/hypoplasia (see page 224)
NB: Bilateral significant hydronephrosis (> 15 mm) detected antenatally must be investigated urgently since it may
indicate lower urinary tact obstruction, such as posterior urethral valves in boys which often needs rapid corrective
surgery. There is argument over the size of dilatation that needs full investigation, but> 15 mm definitely does.

Incidence 1:40 000 births. Male> female. This condition is very variable in its features and severity. Due to failure of
growth of the lower abdominal wall, and a breakdown of the urogenital membrane.

226
 Classical features
• Bladder protrudes from the abdominal wall and its mucosa is exposed
• Pubic rami and recti muscles separated
• Umbilicus displaced downwards
• Epispadias (with undescended testes in boys and clitoral duplication in girls)
• Anteriorly displaced anus, rectal prolapse
The condition results in urinary incontinence, broad-based gait, increased incidence of bladder cancer and sexual
dysfunction. Management involves complex surgery.

PRUNE BELLY SYNDROME (EAGLE-BARRETT SYNDROME)

Incidence 1:40000 births.
An association of:

-~
• Deficient abdominal wall muscles
• Undescended testes
• Urinary tract abnormalities (typically dilated ureters, large bladder, patent urachus)
The condition is thought to be due to severe urethral obstruction early in intrauterine life. Other organ abnormalities
may be present.
The infants may have severe oligohydramnios and pulmonary hypoplasia and be stillborn. Of those who survive, 50%
develop renal failure from reflux and dysplastic kidneys.

URATE METABOLISM

~p"""ereot~e~

HGPRT Purines APRT HGPRT

~·I I l )
Guanine Adenine

xo J xo J
URATE - - - - - Xanthine - + - - - - - Hypoxanthine

Key:
XO = Xanthine oxidase
HGPRT = Hypoxantheine-guanine phosphoribosyl transferase
APRT = Adenine phosphoribosyl transferase

Figure 9.10 Urate metabolism

HYPERURICAEMIA
Urates are poorly soluble and precipitate in the tissues. Joint crystallization causes classic painful gouty arthritis,
subcutaneous tissue precipitation results in gouty tophi (ears, bursae, tendons). Plasma urate is usually normal during
acute gout attacks. Kidney precipitation causes renal stones and disease.

227
Causes
Synthesist Primary gout
Turnover t Tumour lysis syndrome
Psoriasis
Starvation
Polycythaemia
Excretion J, Renal dysfunction
Thiazide diuretics
Acidosis
Low-dose salicylates
Glycogen storage disease type 1
G6PD deficiency

Management
Acute High fluid intake, then colchicine and NSAIDs if necessary
Chronic XO inhibitors, e.g. allopurinol
Uricosuric drugs, e.g. probenicid, high-dose salicylates

LESCH- NYHAN SYN DROME

X-linked recessive. This is a condition where purines cannot be recycled due to a deficiency of HGPRT, with
sequent raised uric acid levels. It results in mental deficiency, self-mutilation, gouty tophi and arthritis, athetosis and ·
spasticity.

XANTHINU RIA
Autosomal recessive, uncommon. This condition of XO deficiency results in decreased plasma urates and xanthine renal
stones because xanthine is insoluble in acid urine.

HYPERTENSION
This is persistent elevation of BP (systolic or diastolic)> 95th centile and is present in 1-3% of children .

Causes
Essential (Rare in children, v. common in adults)
Secondary Renal - parenchymal disease or renal vascular disease
Cardiovascular - coarctation, renal artery stenosis
Hormonal- Cushing syndrome, phaeochromocytoma, CAH
Drugs, e.g. steroids

Clinical features
• Usually asymptomatic
• May have headaches and blurred vision if severe
• Examine for renal masses and bruits, coarctation and eye changes (papilloedema, retinal haemorrhages)

Investigations
Renal Urinalysis, M, C &S
U&E, creatinine, Ca, P0 4, FBC
Renal USS with Doppler studies, renal function tests, e.g. DMSA

228
Cardiovascular Echocardiogram, ECG, fasting lipids
Hormonal Urine HVA and HMA, oxysteroids, 24-h cortisol
Plasma renin, aldosterone, cortisol, 21-~-hydroxylase
Ophthalmological examination

Management options
Emergency Nifedipine: Oral (not sublingual, which can cause precipitant fall)
Sodium nitroprusside: Infusion with care to avoid precipitious BP fall
Labetalol: Infusion with care
Long-term Treat underlying cause
Drug therapy, e.g. vasodilators, diuretics, ~-blockers, ACE inhibitors

RENAL FAILURE
This is a failure to maintain adequate fluid and pH balance due to renal insufficiency. Other features include impaired
erythropoietin production, impaired vitamin Dhydroxylation and hypertension.

ACUTE RENAl FAI LURE

Causes
These may be prerenal due to local or general circulatory failure, renal due to renal parenchymal damage or postrenal
due to outflow obstruction. Prerenal will convert to intrinsic renal failure if not promptly treated.

Clinical features
Acute renal failure (ARF) presents as oliguria (< 1 mljkg/h or 300 mljm 2/day) with oedema, hypertension, vomiting,
lethargy, electrolyte disturbance and metabolic acidosis. (NB. Oliguria is 0.5 mljkg/h in neonates.)

Acute tubular necrosis {ATN)

This is the most common pathophysiological finding in established ARF. It is the result of ischaemic tubular damage
secondary to hypoperfusion.

229
 Oligun·a Initially
Polyun'a During the recovery phase
The prognosis for full renal recovery is good, though it depends on the severity of the underlying cause.

Acute cortical necrosis {ACN)

Cortical necrosis is irreversible loss of renal function with glomerular damage that heals with scarring (glomerulo-
sclerosis). Any cause of ATN, if severe, can lead to ACN.

Criteria to distinguish prerenal from renal causes

(The normal response in normal kidneys is to retain sodium and water if the BP or renal perfusion falls .)

Management
Fluids In oliguric phase, restrict to insensible loss (300 mljm 2/day) +ongoing losses
In polyuric phase, maintain input and electrolytes (as above)
Twice daily weights, regular electrolytes
Hyperkalaemia An emergency if ECG changes are present (see below)
Hyperphosphataemia Give a phosphate binder, e.g. calcium carbonate
Hypocalcaemia Give calcium and 1-a calcidol
· Metabolic ao'dosis Give bicarbonate. Give dialysis if no response and pH < 7.25
Hypertension Correct for fluid overload, antihypertensives
Nutn'tion Restrict protein, K, Na and PO 4
Anaemia Transfuse as necessary (but watch Kcarefully)
Dialysis Indicated if severe hyperkalaemia, hyponatraemia, metabolic acidosis, fluid overload,
symptomatic uraemia or medical management not tolerated

Management of hyperkalaemia

230
 CHRONIC RENAL FAILURE
. This occurs with decline in renal function over months or years.

causes
• Congenital malformations
• Glomerulonephritis
• Inherited nephropathy
• Systemic illness

Clinical features
• Malaise
• Growth failure
• Polyuria, nocturia, oliguria (if late or acute on chronic), proteinuria
• Uraemia, itching, anorexia, nausea, vomiting, skin colour change, polyneuropathy (paraesthesia), restless legs
syndrome, myoclonic twitching, mental slowing, coma. Rare in children
• Symptoms of anaemia
• Oedema (peripheral and pulmonary)
• Renal bone disease (osteodystrophy - renal rickets)

Investigations
Urine Urinalysis, M, C&S, osmolality
24-h electrolytes and protein
Plasma U&E, creatinine (1}, phosphate (1}, ionized calcium (1), bicarbonate (1), PTH (1}
FBC and film (anaemia)
Radiology Left wrist X-ray (bone age and osteodystrophy), renal USS, renal function tests
GFR Estimate from creatinine or measure formally (1)

Management
Diet High energy, low protein (<1.5 gjkg/day) (controversial as children need to grow)
NG or gastrostomy feeds may be needed (nausea)
Osteodystrophy Manifest as PO 4 l,ca 1 and secondary hyperparathyroidism
Aim is for the PTH to be in the normal range
Use dietary phosphate restriction
Calcium carbonate (lowers POJ
Vitamin Dsupplements (1-a-OH-cholecalciferol)
Sodium and acidosis Sodium supplements (unless low urine output)
Bicarbonate supplements (2 mmoljkg/day)
Anaemia Erythropoietin therapy (subcutaneous)
Hormones GH if growth fails to improve with optimal nutrition
Dialysis
BPi Diuretics, nifedipine, P-blockers, etc

DIAlYSIS
This is necessary in end-stage renal failure (ESRF). There are two methods.

Peritoneal dialysis
Peritoneal membrane used as a semi-permeable membrane. The dialysate is run through a tube into the peritoneal
cavity and the fluid changed regularly to repeat the process.

231
 -~,
. I

• CAPD (continuous ambulatory peritoneal dialysis); 2-4 cycles/day done manually

• CCPD (continuous cycling peritoneal dialysis); dialysis occurs only at night with 8-12 cycles done by machine
Major complication is peritonitis.

Haemodialysis
This is technically more difficult. Access is obtained using an indwelling main venous catheter (most common in
children) or by creating an A-V fistula . Blood is directed through the dialysis machine where the semi-permeable
membrane is located. Performed on average three times per week for 3-4 h per session. Complications: line infections
and sepsis.

This is a preferred option to dialysis as lifestyle is markedly improved.

Transplant Cadaveric or live related donor kidney (HLA-matched)
In the iliac fossa (attached to the common iliac vessels)
Intra-abdominally in a small child
Immunosuppression See below
Complications Rejection (acute or chronic)
Infection (CMV, varicella)
Hypertension
Drug side-effects (see below)
Post-transplant tumours, e.g. post-transplant lymphoproliferative disease (PTLD) which is EBV
driven

Common side-effects of immunosuppressant drugs in renal transplantation

Avner ED, Harmon W, Niaudet P Pediatric Nephrology, 51h edn . Baltimore: Williams & Wilkins, 2003
Webb NJA, Posthlethwaite RJ Clinical Paediatric Nephrology, 3'd edn. Oxford: Oxford University Press, 2003

I
I

232
• Hypothalamus and pituitary • Endocrine syndromes
• Adrenal glands • Growth
• Thyroid gwnd • Puberty
• Parathyroid glands • Sexual differentiation syndromes - ambiguous
genitalia .
• Polycystic ovary syndrome
• Endocrine tests
• Glucose metabolism
• Pancreatic tumours

HYPOTHALAMUS AND PITUITARY

PHYSIOLOGY
The anterior lobe of the pituitary develops from Rathke's pouch from an inva gination of the oral endoderm. The
posterior pituitary is part of a single functional unit called the neurohypophysis which comprises the neurons of
the hypothalamus, the neuronal axons (the pituitary stalk) and the neuronal terminals in the posterior lobe of the
pituitary.

PITUITARY TUMOURS
Pituitary tumours constitute an important cause of pituitary disease, and they include the following conditions:
• Cranio-pttaryngiom·it'' -~
• Cysl:ti.n:g!-isyhdro:me ~(see p. 239)
• N.~n;fuocti6ning'fi:'ci'lhau r
• P.rola. ~i!:l.Q.IJI.q~~:,·~
• Pitl!it\H¥?'9l9~Q.f!,~,m
• Nelson.r syndrome·
----·--.. _. , . __,
'i\t.:<:~ · • · '<•"·'<'-·· ·
· ...,
':: ·!f.
-~--

Clinical features
They present with symptoms of one or both of:
1. Space-occupying lesion :
• Raised intracranial pressure symptoms and signs such as headache, papilloedema, vomiting

233
 ,
..

Hypothalamic
releasing/inhibitory
hormones

POSTERIOR PITUITARY
ANTERIOR PITUITARY

\
\
\
\
' \
I
' I
'
i - l
Pituitary LH + FSH GH Prolactin TSH ACTH
hormones

I I I I I I
T T T T T T
Organ Ovaries Many Breasts Thyroid Adrenals Renal Breasts
Testes tissues Gonads tubules

Key:
(B = Stimulation =
CRH Corticotrophin-releasing hormone
TRH = Thyrotrophin-releasing hormone
8 = Inhibition
GHRH =Growth hormone-releasing hormone
GnRH = Gonadotrophin-releasing hormone
LH = Lutenizing hormone
FSH = Follicle-stimulating hormone
GH = Growth hormone
TSH =Thyroid-stimulating hormone
ACTH =Adrenocorticotrophic hormone

Figure 10.1 Hypothalamic and pituitary hormones

• Visual field defects (bitemporal hemianopia)

• Hydrocephalus (if CSF flow is interrupted)
• Pressure on hypothalamic centres (appetite, thirst, somnolence/wakefulness, precocious puberty)
• Cavernous sinus thrombosis (III, IV, VI cranial nerve lesions)
• Diencephalic syndrome
2. Hormonal excess or deficiency

Examination and investigations

The following should be performed:
• Visual field testing
• Cranial nerve testing
• MRI or CT scan
• Hormonal investigations (showing a deficiency or an excess)
Treatment is with drugs, radiotherapy and/or surgery.

234
.l< CRANIORHARYNtifOMA
This is one of the most common supr§tent<Yii'aldumour§'iifn'':'tnitdfe'n. It arises from a remnant of the connection
between Rathke's pouch and the oral cavity. It is often large and cystic and 50% occur under the age of 20 years.
Calcification is seen in most cases on skull X-ray.

Presentation
• Headaches, visual field defects and hydrocephalus (compression of the third ventricle)
• Hormonal effects of hypopituitarism: Growth failure, pubertal delay
Diabetes insipidus
Hypothyroidism (due to TH deficiency)
Adrenocortical deficiency (due to ACTH deficiency)
Essential examination and investigations are as above for pituitary tumours.

Treatment
This is with surgical removal (transfrontat or transsphenoidal). Postoperative radiotherapy is used if resection is
incomplete or recurrence occurs. Postoperative hormonal deficiency is commqn and is treated with supplehieritati6n
as.Decessgry.

PITUITARY GIGANTISM
This is a very rare condition and usually caused by an acidophil adenoma ,.of the pituitary producing excess growth
hormone (very rarely due to excessive GHRH). The tumours are mostly microadenomas and nibs'f'$'Rt.illX~rays. are .normal\
If the epiphy:;es.are.- open;>pituitary gigantism resolts, and if they are closed, acfo'ihegaty results;;

Presel)~~.tion
• Space:: occupying effects
• Hormonal effe€ts: Rapid growth, delayed epiphyseal f~si·on and eventual tall statuce
Hypogonadism and delayed sexual maturatipn
Hypopituitarism (partial or complete of the anterior pituitary), hyperprolactinaerilia
Diaoetes mellitus

Essential examination and investigations

As for pituitary tumours. Specific hormonal tests are:
• GH levels 1(1')
• Glucosetolerance test (fail to suppress GH, 25% have a diabetic result)
• Insulin-like growth factor (IGFc 1~ levels j i
• P[qla~tin;[evels (may be raised)
• Pituitaryfunctioii tests (anterior pituitary)

Treatment
• Surgery '
• RadiOtherapy
• Octreotride (a somatostatin analogue)
• !3romHciiptihe

235
- .,.
This is the most common pituitary tumour that occurs in adolescence. They are mostly large tumours (macroadenoma)
but may be small (microadenoma, < 10 mm) producing excess prolactin. They are mostly post-pubertal and are twice
as common in girls.

Presentation
• Space-occupying effects (headache, visual field defects, nausea, vomiting)
• Hormonal effects: Galactorrhoea, amenorrhoea
Hypogonadism, impotence, delayed puberty
Hypopituitarism
Investigations are those of pituitary tumours in general, plus serum prolactin level. Prolactin levels are usually grossly
elevated (> 2000 ng/ml).

Treatment
• Medical (bromocriptine or carbagoline)
• Surgical removal of tumour

Other causes of hyperprolactinaemia

• Stress
• Primary hypothyroidism
• Hypothalamic disease (acromegaly, craniopharyngioma)
• Polycystic ovaries
• Drugs (cimetidine, metoclopramide, oestrogens, opiates)
• Pregnancy, suckling
• Liver failure, cardiac failure, renal failure

I
I

This can be a deficiency of either hypothalamic or pituitary hormones. It may also be selective or multiple, with growth
hormone being the most common hormone affected. Panhypopituitarism is the deficiency of all anterior pituitary
hormones. Vasopressin (ADH) and oxytocin will only be affected significantly if the hypothalamus is involved or there
is a very large pituitary lesion.

Causes
Congenital Septo-optic dysplasia (absence of septum pellucidum and optic nerve hypoplasia)
Kallman syndrome
Genetic deficiency of GHRH or GH (several types)
Empty sella syndrome
Holoprosencephaly, anencephaly
Destructive Neoplastic (pituitary/hypothalamic, e.g. craniopharyngioma, meningioma, glioma, secondary deposits) ~~
Infective (meningitis, encephalitis, TB, toxoplasmosis) ·J
Traumatic (post surgery or radiotherapy, NAI, traumatic delivery)
Infiltration (Langerhans' cell histiocytosis, haemochromatosis, sarcoidosis)
Functional Emotional deprivation, anorexia nervosa, starvation

236
' .... . Clinical features
These are dependent on the extent of the disease. Growth hormone deficiency is the most common, resulting in growth
failure. Secondary hypothyroidism and adrenal insufficiency (secondary to TSH and ACTH deficiency, respectively) may
be present. Hyperprolactinaemia, diabetes insipidus and deficiency of gonadotrophins may also be present.
If congenital, it may present as an emergency with apnoea, hypoglyraemla and QYanosis}~and male infants may have
a !Jlicrophallus. The child has a distinctive facies. When long-standing, there is 'alabaster skin' which is pale land hair-
le.??· Sexual maturation is delayed or absent and symptomatic hyp.ogly,§q~I1Jlq with fasting 'uccurs inz10-"15%'i

Investigations
Pituitary function tests need to be done.

Treatment
This involves treating any underlying disease and replacing hormones as necessary.

DIABETES INSIPIDUS
This is characterized by polyuria and polydipsia and is due to a deficiency of vasopressin (ADH) (cranial diabetes
insipidus) or a rerral insensitivity to it (nephrogenic diabetes insipidus).

Clinical features
• Polydipsia, polyuria, nocturia
• Anorexia, dehydration, lack of perspiration and production of large quantities of pale urine
• Rapid weight loss, constant wet nappies and collapse in infants

Investigations
These show a mismatch between urine and plasma osmolalities.
1. Osmolalities:
2. Plasma osmolality normal or high, andplasma Na high
Urine osmolality low: EMU osmolality< 280 (normal> 700)
Specific gravity 1.001- 1.005
2. Formal water deprivation test:
Deprive patient of water until either a mismatch between urine and plasma osmolality is demonstrated or> 5%
weight loss or urine osmolality> 700 mmolfkg
Obs~rve failure to concentrate urine; then give DDAVP and observe a rise in urine osmolality
3. A failure of response to exogenous ADH (DDAVP) indicates nephrogenic diabetes insipidus
4. Plasma ADH measurement is possible, and if inappropriately low for plasma osmolality indicates cranial DI
5. Cranial MRI scan

Causes

237
 Cranial . · · . . Nephrogenic . . . ·
Infection TB meningitis Drugs Demectocycli ne,
glibenclamide, lithium
Tumour ·

Ablation
DIDMOAD ~ diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Also known as Wolfram syndrome

Treatment
Cranial diabetes insipidus DDAVP (desmopressin = ADH analogue) intranasal, oral or IM
Nephrogenic diabetes insipidus Sensitize the renal tubules with thiazides, carbamazepine or chloramphenicol
NB: If initial MRI is normal, it should be repeated at 5-yearly intervals, as anatomical detection of a tumour may be
delayed by many years.

Differential diagnosis
• Psychogenic polydipsia (compulsive water drinking). Here the urine will concentrate on water deprivation testing;
however, there may be a decreased ability to concentrate urine if the condition is prolonged
• Water intoxication (fictitious or induced illness)

SYNDROME OF !NJ.\PPFH)PiUJJJE i\DH SECRETION (SIADH)

In this condition plasma levels of ADH are inappropn'ately high for the osmolality of the blood.

Clinical features
• Often vague features
• Appetite loss (early), nausea, vomiting, confusion, irritability, fits and _coma
• No evidence of dehydration, no oedema, normal blood pressure

Investigations
Plasma Electrolytes: Na l (115- 120 mmoljL), Cll
Bicarbonate (N)
Osmolality low (< 280 mmoljl)
Hypouricaemia
Un'ne Osmolality normal
Na > 30 mmoljl, i.e. sodium excretion continues

Causes
CNS Meningitis, encephalitis, brain abscess, head injury, birth asphyxia, hypoxic-ischaemic
encephalopathy, IVH, subdural haematoma, SLE vasculitis, brain tumour,
Guillain-Barre syndrome
Tumours Lymphoma, cancer of the thymus, Ewing sarcoma
Lungs Pneumonia, cystic fibrosis, IPPV, lung abscess
Metabolic Acute intermittent porphyria
Drugs Carbamazepi ne, vincristine, cyclophosphamide, ch lorpropramide, morphine
Infections Rotavirus, TB

238
.z Treatment
1. Fluid restrict
2. Daily weight, sodium and osmola lity measurements
3. Demeclocycline (dimethylchlortetracycline) therapy to desensitize the kidney
4. If severe: hypertonic saline with furosemide is given under close observation

ADRENAL GLANDS

Adrenal medulla Adrenal cortex

Zona glomerulosa
Epinephrine MINERALOCORTICOIDS (Aldosterone)
(adrenaline) and
noradrenaline
(norepinephrine) Zona fasiculata
GLUCOCORTICOIDS (Cortisol)

Zona reticulata
ANABOLIC AND SEX HORMONES

Figure 10.2 Adrenal gland

Glucocorticoid axis

CUSHING SYNDROME
This results from a state of increased circulating gtucocorticoids.

Causes
ACTH dependent Pituitary tumour (basophilic adenoma (20%) or microadenoma (80%). NB. This is Cushing
disease
Ectopic ACTH production (extremely rare)
ACTH independent Adrenal adenoma or carcinoma (most often< age 5 years)
Exogenous steroids - the commonest cause

Clinical features
• Appearance: Round face, large red cheeks - 'moon face'
Truncal obesity- 'buffalo hump', 'lemon on sticks'

239
 ..•
Striae and bruises due to protein breakdown ' 7•
.··:

Masculinization signs due to androgen production (acne, hirsuitism and clitoral hypertrophy)
• Growth impairment
• Pubertal delay
• Weakness, headache, me ntal disturbance
• Impaired glucose tolerance, diabetes (glycosuria)
• Hypertension
• Osteoporosis
• Hyperpigmentation - seen with high ACTH only

Investigations
These are divided into those investigations to establish the diagnosis and those to establish the cause of Cushing
syndrome. NB: Random cortisol is of no benefit.

Cortisol circ.adian rhythm: ·

· '"'08:oo ;and .24:00 cortisol
.-·'No~~at = lo~ at iniqni,g~t and
high in the m:()rnin.g . · . ·
· .·. ~ cushing ;,; h1gh rlliqnightJeyel5
3·:> Urine ?.4·h .frei cortisol (f)·:·:: ·,

4. · Overnightdexamethgsone .·
. suppression'test

Treatment
The options available include surgical removal of a pituitary lesion, radiotherapy to the pituitary, resection of adrenal
adenoma and reduction of exogenous steroids where possible. Medical therapy with inhibitors of adrenal steroid
biosynthesis, e.g. ketoconazole.
NB: Nelson syndrome is the occurrence of a pituitary tumour many years after bilateral adrenalectomy, causing high
ACTH levels and hyperpigmentation. It is very rare.

PRH4ARY HYPERALDOSTERONISM
This is due to an adenoma of the zona glomerulosa in 60% of cases (known as Conn syndrome) and an adrenal cortical
carcinoma in a minority. Approximately 30% are due to bilateral adrenal hyperplasia (secondary aldosteronism).
Secondary aldosteronism has several causes:
• Ascites - nephrotic syndrome, liver cirrhosis, CCF
• Hypovolaemia secondary to diuretic abuse
• Renal artery stenosis
• Wilms tumour

240
Clinical features
• Proximal muscle weakness, polyuria, polydipsia, nocturnal enuresis (a ll due to hypokalaemia)
• Hypertension with no oedema (due to hypernatraemia)

Investigations
• Plasma electrolytes- Kl Na i, metabolic alkalosis (20% have normal Kat presentation)
• Plasma renin l (NB: Secondary aldosteronism-renin i)
• Urine aldosterone metabolites
• Urine Na:Kratio l (normal= 2:1 mmoljkg/24 h)

Treatment options
• Prednisolone (suppresses the hyperaldosteronism)
• Spironolactone (aldosterone antagonist)
• Surgical resection

ADRENOCORTICAL INSUFFICIENCY
This is deficiency of all the adrenal cortical hormones, but cortisol causes the main effects.

Causes
Acute Sudden steroid withdrawal
Birth asphyxia
Severe hypotension (causing adrenal infarction)
Sepsis (e.g. Waterhouse-Freidrichson syndrome of adrenal haemorrhage secondary to
meningococcaemia)
Trauma
Chronic Primary (ACTH i):
• Congenital adrenal hyperplasia
• Destruction of adrenal cortex (Addison disease), due to autoimmune disease or TB
• leukaemia, HIV infection
• Drugs, e.g. ketoconazole
• Adrenoleukodystrophy (adrenocortical insufficiency, with demyelination in CNS)
Secondary (ACTH-1):
• Pituitary or hypothalamic disease
• Long-term steroid therapy

Clinical features
Acute 1disease Presents as an adrenal crisis: drowsiness and coma, peripheral shutdown, cyanosis, tachycardia,
tachypnoea, hypotension . Fatal if not rapidly treated
Chronic disease
Baby Apathy, drowsiness, vomiting, faltering growth, hypoglycaemia and dehydration leading to
eventual circulatory collapse and coma
Older child Weakness, fatigue, anorexia, nausea, vomiting, abdominal pain, diarrhoea and faltering
growth (except in congenital adrenal hyperplasia where height velocity is increased due to
excessive androgen production)
Postural hypotension and salt craving.
Hyperpigmentation of buccal mucosa, ski n creases and scars occur (with primary disease
secondary to ACTH i)

241
Investigations
Serum electrolytes Na t, Ki, glucose t
Serum hormones Cortisol t
ACTH I (primary disease)
Synacthen test Short and long if necessary

Treatment
Adrenal crisis IV fluids and salt replacement
Hydrocortisone IV
Antibiotics if necessary
Long-term therapy Daily hydrocortisone and fludrocortisone

PHAEOCH ROMOCYTO MA
This is a sympathetic nervous system tumour arising from chromaffin cells, secreting catecholamines. Mostly noradren-
aline is released but some adrenaline is also released . Males> females 2:1. Very rare.
• 90% adrenal medulla tumour
• 10% along the sympathetic chain
• 25% multiple
• 10% malignant
• 10% recur
Associations MEN II
Neurofibromatosis

Differential diagnosis
• Autoimmune disease
• Renal artery stenosis

Clinical features
The symptoms are frequently intermittent.
General Palpitations, sweating, tremor, headaches, panic attacks, nausea and vomiting, weight
loss
Cardiovascular instability Tachycardia, bradycardia, hypertension, orthostatic hypotension

Investigations
1. 24-h urine catecholamines increased (vanillymandelic acid [VMA] and metanephrins) . NB : Dietary vanilla inter-
feres with this test
2. MIBG scan (metaiodobenzylguanidine - a specific chromaffin tissue isotope scan)
3. Abdominal CT scan
4. Serum catecholamines

Management
Surgical resection of the tumour under a (phenoxybenzamine) and ~ (p ro pranolol) blockade.

242
:> THYROID GLAND

PHYSIOLOGY

Hypothalamus

Pituitary

T3 Triiodothyronine
j Peripheral convE!rsion
Thyroid T4 Thyroxine
j Peripheral conversion
RT3 Reverse triiodothyronine

Figure 10.3 Thyroid axis

In plasma~~j~;;_of T4 and T3 is bound to thyroid binding globulin. (Il6~)1, and thyroid binding pre-albumin (TBBM and
~~JJniin. Only the free form is active; O.i05.9/6 is in the freeralrtiY~I;fQfJll.
In acute or chronic illness, thyroid function is affected, with RT3 t TBG 1, TSH 1. This results in low:total-ano sfree
T~s?JJJt;ili:3.'fwith1ifJnorma l D't-tliJw:tTS H,
known as ·sick~.e~!JJby;rold~syn dr.Qru:e.
TbY&QJiine (T 4) and \'antitnyroidrdr:ugs~cross.~th~~~pla:~enta.

GUTHRIE TEST FOR HYPOTHYROIDISM

This is a measurement ofTSI;l;> taken as a capillary blood sample on.day 6~ An elevated level(> 5-10 mU/L) is abnormal
and indicative of hypo~hyroidiSm. False~negalive results occur with:
• Prematurity or sick euthyroid syndrome
• TBG.deficiency!(congenital or acquired)
• Secondary or tertiary hypothyroidism!!
Grossly elevated levels of TSH are most likely due to severe congenital hypothyroidism. Mildly elevated JSH levels
(5"'"2o:·mUo/L) in the presence of normatfree T4 levels require close monitoring as they may represent transient hyper-
thyrotropinaemia.
If the res~Jlti~r~peatedly equivocal (TSH 20-30 mU/L), thyroxine should·be comm·ence&and at a later date the thyroid
functi'on reassessed with'{:~ ·re'peat;-TSH me·asurenientand thyroid·imaging. '

HYPOTHYROIDISM
Causes
Primary (TbyJQi~rgtaWa;~dysru'nrtio n,,..,JSH t'):~thyroxi ne :t)';.' ~
CQuge'nitan ,
A~ro phi c <!!Jt'Oinrmun~~thyroidins (thYJ:!lt46aJ.~~r£~P~,~~,pJjllQdtes)
Ha~!lirootoi.tnytoitiiti~ (goitr.ela·nd:~ mi~:ro_~91!1~1~aJ!:11iHPdies, ass'citiate-d''with,Turner-syndrome)
Iqgj:ner£defidenty (goitrer occms:dr.l'.rnount(!jnous.'·areas).~

243
 Treatment of hyp~·rthyroid1smii:ifradiot:herapy for lymphcrmii' or leukaellJia
Drugs - amiodarone;"oiddine-cont-ainiflg -nie'dkati'Ons
Secondary or (TSH 1, thyroxine l)
tertiary Pituitary disease (secondary)
Hypothalamic disease (tertiary)

Congenital hypothyroidism
In~i.9~.nte'':r:4'060..,

Causes
Thyroid'-dysgenesis' (90%) Aplasia (!h)
Ectopic (2h) - lingual~ sublingual1o~ subhyoidthyroiq
Dysh'ormonogehesis ~ (8%) (Inborn error of thyroid hormone production), e.g. Pendred syndrome (goitre, se,n-
sori neural deafness 'and·.hypothyroidism)
Tnmsil?nt'disease Due to placental transfer of antithyroid antibodies (maternal autO'imfliUr\e~Lthyroid
disease) or an,tj},QyJ;oj,g~gll!,9S
Diagnosis usually on Guthrie test with elevated TSH, confirmed with low serum T4.

Clinical features
Physical features Macrogtos·si~r~~ wide;tsffaG~Ci~,·es, fla~:a'sa'l'il'on-age, swotle'il!i'eW~lids, lar.g_e~fqn.t_g-_geJJ_e~, dry ~skiw,
ufl)J~jJi,Gal4'neriiia, sho·ifu,;IJtlYifa?;fltig~~ ., . _
Other Hyputonia, som-rrote:nte, fee-aiffgJ\'tJ:fffl€Ulti6, hoats-el'ccy, nQ,iS:Y'M~J.g<ltbJng, ap:r:lo~e:Qs, cg,o.?JiRe;j
tion, diS,t~nde~d~-abdnr.t"ten, d ~sk:in\ cuni&irrfarn:ro:rata, ± 'lQitre (2-flPf,r):
Br-adyt'anlia, cardi~me:galy, card,iae1imntrrttm, low~\\(Q.ltgge ECG with prolttnged RR~filfe'il\lal
Prol'Of\'geal';rnroo~attr~'!<_j-atrtfdite (unconjugated)
Meotab;retardcrtiofl! I
I

Clinical features of acquired hypothyroidism

NB: Thyroid dysgenesis and ectopic thyroid can present tater, as acquired.
• Deceleration ofgrowtfi
• Delayed·ossification
• Skin and hair- dry skin, lateral third eyebrow missing, hair dry and thi·n
• Cold;:intolerante
• Low~e'r'iergy level~·
• Con~tipation ~,
• Proximal myopathy, ataxia, slow reflexes
• MentaLslowness at school often:o«turs late,
• Headaches, precocious puberty and galactorrhoea (seen in secondary and tertiary·disease)

Investigations
Thyroid function tests are performed and enable differentiation of primary from secondacy'and'tertiary disease. Other
abnormalities seen on blood testing are hypercalcaemia; hyperthblesterolaemi'a and hyperprolactinaer:ria.

Treatment
This is with thyroxine replacement, givin·g oral thyroxine 10-::15. ~.g/.kg/day.

244
HYPERTHYROIDISM

causes
Graves disease Most common childhood cause
TSH receptor antibodies (TRSAb - thyrotrophin receptor stimulating antibodies) causE
thyroid hormone production
Diffuse toxic goitre
Thyroid eye signs (see below) and pretibial myxoedema (occur only in Graves disease)
Female> male 5:1 . HLA-B8, DW3 association
Autoimmune association (vitiligo, IDDM, RhA, ITP, Addison)
Transient neonatal Secondary to transplacental antibody transfer in maternal Graves disease, lasts 6-1~
weeks
Solitary nodule/adenoma Plummer disease, toxic uninodula r goitre
de Quervain thyroiditis Acute disease with tender goitre
Viral origin (mumps, coxsackie, adenovirus)
Reidel thyroiditis ' Dense thyroid fibrosis including neck vessels and trachea
Thyrptoxicosis facticia . Ingestion of thyroxine
Tumours Ovarian teratoma, choriocarcinoma, hydatidiform mole

Clinical features
Usually of gradual onset.
fig11tfl'logfGaP Hy,p·erC'rctiVity, emotinnat~ilabiLity, shoft;attention span
6asfl:afntemn"cib lD,"~L~!!~g-~§,9 J:m1lti tei.WitiT?in<Jtwei'gh'W,g:ain
Bkiil~ S,:,m110th;i$ kin, 'lrr~reas:eds>sweati ng, tre'ffior
G.~!L~Wlfi (fgjiJiLgi;~usually), h,:,eat;rintoter:arn:e
~9J;4.i:~Mg~l~Yiw~ TaJihw~ardia, pq_t"pi't1ffi"ons, d15Pffciea, hyJYeffensi'orr;'·cardimneg'"atyptitnat;:fif5nltation (rare)
Erg_r;~9A~ \ Exopf1fli~(nfb's-;'lid ·retraction, tid lag-; impaired c6nvergence,· ophthatmopleg~a

Thyroid crisis
This is a,GJ:!.t~-~,Q!Js,e}.>ihypeYthVroidi-sm~ and presents as tachycardia, hypertension:.:,and re'stles'slt'essi, progressirig to
delirium, cama1and dea.~ h if nobrapidlytreated.

Neonatal hyperthyroidism
These babies are classically prematu r~e, have IUGRi' goitres, exophthalmos, microcephaly, They are iftitable, hyperalert
and may' have tachyc<frdia/ tachypnoea,- hyperthermia, jaundice-, hypertensioR and progress to cardiac decompensa-
tion.

Investigations
1. Fre--e'.§T'4~analiT~~te\la'tea
2. TSRYaecfe1iS~d
3. TRs?rA:os'~foun'Ciltfli"-l3Taves"OiseifS'eY ~

Treatment options
Medical Antithyroid drugs (prqpyltbiouracy~ or carbimazolf) or radioacti'iie;Xo'dine~
Symptomatic control with ~~blotl<er9 (propranolol)
Surgery SubtotaGtn_9Y51dectamy . ·
Complications - hypopilHftKyf6iBh m (transient or permanent), v.acal cord'iparalysi~

245
 ~--1
'·,,
.~}

i
I

GOITRE
Goitre is an enlargementofthe thyroid gland;
Child may be euthyroid, hypothyroid 'or hyperthyroid. ,

Causes
Congenital Dyshormonogenesis ··
Congenital(hyp,erthyroidismcl
Maternal antithyroid drugs (hypothyroid usually)
MaternaliodinecEontaining':df,ugs;-e.g. amiodarone (hypothyroid usually)
Iodinedefidenc}t ~rare)
Thyroid·teratoma
Older child Colloid;goitre (euthyroid, ~ unknown cause, p~epubertal;. gi~ls)
Autoimmune;· e.g. Hashimoto·thyroiditis ,
Graves;disease '
Infective·;thyro1d.itis v"
Iodine-,deficienGy or iodine·~containing drugs
Anti thyroid•drug$
Multioodula r:.·goitre (seen in Mc@Une."'Albr.ig.ht;:disease9
Th,yroid.:tumoun'( rare)

Investigations
1. Assess·the goitre for size, consistency; diffusejnodulN,utenderness, NB: -Tnfants may, ha_ve-respiratory difficulties
due to the large g[and
2. Check thyroid status
3. Addition a'l·inVestig ationsmay,Anclude, WSS(thyroidpt hyroidi!Sean ··arid?fhfi:!Wrieed le aspiratjon,

THYROID TUMOURS
The;set1iaf~!l(fa'f!f&i'ffi'01l1tdre n .a_od~&ar~~~§§,Q~:iat~.Q;;;W.jt8.~1 p,t~Mi,Q,I;!?BtE9Yroi d'"irr~Wia'ti0f:ltfcl'S'11afil in fa nt:;~lib~¥¥-1P!l~;~§Q,t,~~~4 solitary
thyr;o~d,modate-s<3: ceYvicat4S'hipn ~fi&de ;-metasfa5€tsG ' Fe'fnateJ>>'~mate,l 2:1 .

The investigations necessary are lymph node biopsy, thyroid 131 I scan (carcinoma usually appears as 'cold' nodules, i.e.
decreased concentration of isotope) and thyroid function tests. Treatment is with subtotal or near-total thyroidectomy
with or without radiotherapy.

246
'j,•

·y
PARATHYROID GLANDS

CALCIUM PHYSIOLOGY

Skin~
7-Dehydrocholesterol
uv light!
Diet- Cholecalciferol (vitamin D3)

Gut I Ca absorpt1on
Bone I Calcification
Kidney I Resorption
{
Parathyroid

(a)

Gut

, . ~ ~ II""
tlr'~®
j Circulation ~
PTH
Faeces

(b) Urine

Figure 10.4 Calcium physiology. (a) Vitamin 0

metabolism and actions. (b) Calcium exchange

Parathyroid hormone (PTH)

This results in I plasma calcium (increasing gut absorption and renal tubular reabsorption of calcium and increasing
1, 25(0H}2D3 synthesis,) and -1- plasma phosphate (renal P0 4 excretion and bone absorption).

Calcium
50% atbumin bound:50°/~ free ionized calcium (available). Correct plasma calcium for albumin (if albumin > 40 g/L-
corrected level is lower).

Calcitonin
32 amino acid polypeptide, secreted by the (-cells of the thyroid gland.
• Decreases serum calcium (inhibits osteoclasts, i renal calcium excretion)
• Decreases serum phosphate (I renal phosphate excretion)

247
 ~l
i
!

\ ~ Danalogues
\ 0-.'-''
Vitamin D
1'-- • = calciferol (03)
\; ~ a-Calcidol "'1-a hydroxycholecalciferol
~~ol = 1, 25-dihydroxycholecalciferol (1,25(0H) 2D)

J--'-"'p
~-1·~{pf.~CALCP~ E ~ViKJ~

Causes
PTHt (Cat, P0 4 I) Primary parathyroid aplasia or hypoplasia
(Hypoparathyroidism) DiGeorge syndrome (parathyroid and thymus hypo- or a-plasia, cardiac
abnormalities, auricle hypoplasia, T cell immune defect, abnormal facies - see p. 30)
Autoimmune (vitiligo and candidiasis associated)
Surgical (post-thyroidectomy)
Pseudohypoparathyroidism . NB: PTH t (see below)
Rickets due to:
• Intake vitamin D1
• Metabolism vitamin D1
• (Renal, liver) excretion calcium I

Clinical features
• Seizures
• Cataracts, soft teeth, horizontal lines on toe and finger nails
• Muscle cramps, paraesthesia, stiffness
• Laryngeal and carpopedal spasm, tetany
• Chovstek's sign (facial muscle twitching on tapping facial nerve)
• Trousseau's sign (tetanic spasm of hands and wrist with BP cuff> above diastolic pressure for 3 min)
• Long QT interval, papilloedema

Investigations
Serum Calcium (1)
Phosphate (t or I)
Alkaline phosphatase (1 or I)
Magnesium level (should be normal but necessary to exclude hypomagnesaemia as cause of hypocalcaemia)
PTH (1, Nor I)

Treatment
Emergency therapy 10% calcium gluconate IV stat dose, then 0.5-1 mljmin ..,
NB: Calcium gluconate = 8.9 mg/ml ,,
;i '

Calcium chloride= 27 mg/ml

Long-term Oral calcium supplements and vitamin Dsupplements (calcitriol or a -calcidol)

PSEUDOHYPOPARATHYROIDISM (PHP) . ·~

A condition of hypocalcaemia, hypophosphataemia and elevated PTH levels, usually associated with the physical fea-
tures listed below. It is due to end-organ resistance to PTH, secondary to a variety of biochemical defects subdivided ·~.
into four groups. Group 1a has decreased stimulatory G (Gs) protein activity.

248
;~ Clinical features
' Short stature, stocky with a round fac~ \
• Short 4th and 5th metacarpals , ~ -:/".
• Brachydactyly, bow legs, dimples overlying MCP joints '?
• Subcutaneous calcium deposits
• Mental retardation, calcification basal ganglia
• Cataracts, optic atrophy, dental anomalies
• Tetany, stridor, convulsions

Investigations
Serum Ca l, P0 4 i, alkaline phosphatase i, PTH i
Diagnosis on decreased response in urine cAMP and phosphate after PTH infusion.

Pseudopseudohypoparathyroidism (PPH P)
This is the clinical phenotype of PHP with as yet no demonstrable biochemical defect, possibly due to incomplete
expression of PHP.

RICKETS
This is a failure ih mineralization ofgrowing,bone. It is most commonly second~w:t~ :nuj:ritionalcaUs~s~ In fully devel-
oped bone this is called 'osteomalacia f(osteopenia is the condition otthe>'irctu~l-bolies).
Daily vitamin D requirement is 400 IU.

Causes
Vitamin Dintake inadequate Nutritional:
• Prematurity (p. 464)
• Breast-fed infants more at risk
• Poorly fed infants (malnutrition)
Malabsorption - coeliac disease, steatorrhoea, cystic fibrosis
Inadequate sunlight exposure (especially dark-skinned)
Metabolism of vitamin D Renal disease. NB: P0 4 i
Liver disease
Anticonvulsants, e.g. phenytoin (metabolizes vitamin D)
' excretion increased
Phosphate Familial hypophosphataemic rickets
Vitamin D-dependent rickets -type I, type II (receptor defect)
Fanconi syndrome

Clinical features
• Head - large fontanelles with delayed closure (:> 2 years) . Craniotabes (ping-pong ball skull), frontal bossing
• Chest - rachitic rosary (enlargement of costochondral junctions). Harrison groove or sulcus, pigeon chest
• Broad wrists and ankles
• Short stature, kyphosis, small pelvis, coxa vara, bow legs, knock knees, late dentition with enamel defects, green-
stick fractures
• Muscular weakness, pot belly
249
 ---'-,
.;.
·~

Investigations
1. Biochemical investigations. NB. Classic nutritional rickets: check alkaline phosphatase, calcium, phosphate and
P04-Ca product (low).

Vit. D-dependent type II i i N i

2. X-ray of left wrist (or left knee if< 2 years).
X-ray findings are: Widened epiphyseal plate
Cupping and fraying of the metaphysis
Increased joint space
Line of calcification seen when healing
Also: cysts, subperiosteal erosions, fractu res, Looser's zones, osteopenia if severe

Figure 10.5 X-ray changes of rickets in the

knee. Note prominent cupping and fraying

Treatment
This is with vitamin Din the necessary form.
Nutritional rickets Calciferol (D)
Renal disease a -Calcidol (1a-OHD 3) or calcitriol (1,25(0H) 2 D3)

250
Familial hypophosphataemic rickets (vitamin D-resistant rickets)
X-linked dominant.
Underlying problem
• Defective proximal tubular reabsorption of phosphate
• Reduced 1,25(0H) 2 D3 synthesis
Treatment is with 1,25(0H) 2D3 and oral phosphate supplements.

Vitamin D-dependent rickets

Autosomal recessive. Characterized by a calcium deficiency with secondary hyperparathyroidism and a renal tubular
acidosis. There are two types:
Type I Low 1,25(0H) 2D3 levels
Type II High 1,25(0H) 2 D3 (receptor defect)
Treatment is with 1,25(0H) 2D3• (Type 1 has good response.)

HYPERCALCAHHA

Causes
PTH i (Cat P04 J,) . Primary hyperparathyroidism (hyperplasia or adenoma. NB: MEN I and II)
·•Tertiary hyperparathyroidism (PTH i after Long-standing secondary hyperparathyroidism
, now treated)
Ectopic PTH (other tumours)
PTH j, (Ca t P04i) V.itamiwD :f' (ljB, Lymphoma, sarcoidosis; berylliosis, excess intake)
Malignancy (leukaemia, lymphoma., neuroblastoma) ·
Hypothyroidism (vitamin 0 metabolism decreased)
Hyperthyroidism
Williams syndrome (7q-, hypercalcaemia, supravalvular aortic stenosis, AVSD; peripheral
' '
pulmonary stenosis, stellate iris, cocktail party manner, typical facies - see p. 12)
Familial hypocalciuric hypercalcaemia (PTH inappropriately normal, autosomal dominant,
usually asymptomatic)

Clinical .features
• Stones (renal), bones (pain), abdominal moans (ulcers), psychiatric groans
• Anorexia, vomiting, constipation, peptic ulcers, pancreatitis
• CGrneal calcification, conjunctival injection
• Polyuria (nephrogenic DI from nephrocalcinosis)
• Chondrocalcinosis (30%), subperiosteal bone erosions
• Hypertension, hypokalaemia, arrhythmia
• Convulsions and cardiac arrest with high calcium levels(> 3.75)

Investigations
Serum Calcium, phosphate, alkaline phosphatase and renal function PTH levels
Hand X-ray

251
Management
Severe IV bisphosphonates (etidronate, pamidronate)
Hydration and furosemide
Mild Oral phosphates (diarrhoea) and/or calcitonin
Steroids (sarcoidosis)
Hypoparathyroidectomy if necessary (primary hyperparathyroidism).

POLYCYSTIC OVARY SYNDROME (PCOS}

This is a common condition of adolescent girls, the essential features of which are:
• Large polycystic ovaries (in arrested follicular development)
• Increased circulating androgens and high LH:FSH ratio
It is also known as the Stein-Levanthal syndrome. The onset is usually around puberty and the cause is not well
understood.

Clinical features
• Secondary amenorrhoea, irregular menstruation
• Obesity
• Hirsutism
• Mild virilization with acne
• Anovulatory infertility
• Insulin resistance
It often presents purely with menstrual irregularities or acne, with none of the classical 'fat, hairy' girl features
present.

Investigations
Pelvic USS Enlarged ovaries with multiple 3-5 mm cysts arranged circumferentially and increased stroma
Hormones Raised LH;FSH ratio (2:1)
Free circulating androgens i
Testosterone i or normal
(Plasma LH i, FSH normal or l)
Mild hyperprolactinaemia
NB: Must rule out differential diagnosis of adrenal disorders.

Treatment options
Treatment is symptomatic.
Irregular menses/virilization Ovarian suppression with the oral contraceptive pill or cyproterone (an antiandrogen),
or
Pituitary ACTH suppression with prednisolone
Infertility Ovarian wedge resection and clomiphene

GLUCOSE METABOLISM
Blood glucose is generally maintained in the non-fasted state between 3.5 and 8.0 mmoljl. Glucose may be manufac-
tured from glycogen, fat or protein by a process called gluconeogenesis.

252
;,;;_ • Glucose is consumed by the brain as a primary source of energy
• Muscle may utilize glucose for energy or store it as glycogen
·• Adipose tissue is also a store for glucose and uses glucose for triglyceride synthesis
• The liver is the principal site for glucose storage, where it is kept as glycogen
The maintenance of a constant blood glucose level is under the control of the hormone insulin.
• High insulin levels -7 blood glucose level-!-, by increasing glucose utilization and decreasing glucose production
• Low insulin levels have the converse effect
• Other hormones are involved and have the opposite effect to insulin - glucagon, adrenaline, cortisol and growth
hormone
Insulin is produced by the pancreatic P-cells as proinsulin. Proinsulin is broken down into Cpeptide (biologically inert)
and insulin during the secretory process. The insulin then travels in the portal circulation to the liver where it exerts
its main action.

DIABETES MELLITUS
Diabetes mellitus is a chronic state of hyperglycaemia due to a deficiency of insulin or of its action. It is the most
common endocrine disorder in childhood and adolescence.
Subtypes of diabetes mellitus:
Type I diabetes mellitus Insulin deficiency due to insufficient endogenous insulin. Exogenous insulin necessary
for maintenance of life
Most common form in childhood
Type 2 diabetes mellitus Mainly due to failure of insulin action (insulin resistance)
Strongly associated with obesity
Uncommon in childhood, though incidence rising, particularly in adolescents
100% concordance in identical twins
Insulin may be required to correct hyperglycaemia
Ketosis is uncommon but occurs
Other types Maturity onset of diabetes in the young (MODY)
Syndrome-associated, e.g. DIDMOAD (see Renal chapter)
Mitochondrial disease, e.g. Kearns Sayer syndrome
Pancreatic disease, e.g. cystic fibrosis
Post pancreatic surgery for persistent hyperinsulinaemia of infancy (PHHI)
Neonatal diabetes mellitus (very rare)

Type 1 diabetes mellitus

This develops as a result of destruction of the pancreatic ~-cells with consequent insufficient insulin production. It is
thoug~t that an environmental insult, e.g. viral illness, results in an antigen cross-reacting in genetically susceptible
individuals. There is evidence of both genetic, autoimmune and environmental, e.g. viral, factors contributing:
Genetic Father has type 1 OM - 1:20 risk for child
Mother has type 1 DM - 1:40 risk for child
Sibling has type 1 DM - 1:20 risk
50% identical twin concordance
Autoimmune 80% have islet cell antibodies (ICA) on presentation
Association with other autoimmune diseases and certain HLA types
Environmental Seasonal variation
Prevalence 1:300 in the UK and rising. Presentation most common in spring and autumn .

253
 -.,,"',,,,. ~
· ,~

·~
,,
,__ :;
,. .· '·

Clinical presentations j
\

• Short history (2-4 weeks) of: Polyuria (osmotic diuresis

Polydipsia (dehydration)
Weight loss (fluid depletion and muscle and fat breakdown)
• Ketoacidosis
• Asymptomatic glycosuria

Diagnosis
Symptomatic Random venous plasma glucose : : : 11.1 mmoljl or
Fasting plasma glucose::::: 7.0 mmoljl or
2 h plasma glucose::::: 11.1 mmoljl 12 h post glucose load (NB: in children need to adjust the
dose of glucose in relation to body weight) (An oral glucose tolerance test)
Asymptomatic Venous plasma sample in diabetic range and confirmation with repeat glucose test in diabetic
range on another day (fasting, random or 2 h post glucose load)
NB:
• Whole blood glucose differs from plasma glucose. The whole blood glucose measures 10% lower than plasma
glucose
• Glycosuria occurs in 1% of the population (secondary to low renal threshold)
• Impaired glucose tolerance = during a formal (75 g) oral glucose tolerance test (OGGT), fasting plasma glucose
<7.0 mmoljl and 2 h venous plasma glucose> 7.8 mmoljl but< 11.1 mmoljl

Management
Multidisciplinary approach necessary. Great deal of support necessary for child and fam ily.
Diet This should be high in unrefined carbohydrates- slow absorption profile (low glycaemic index [GI]), there-
fore fewer glucose swings
Calories ideally obtained as 55% CHD, 35% fat and 15% protein
Refined CBH (high GI) cause rapid swings in blood glucose levels
Insulin Subcutaneous insulin injections given in the thigh, arm, abdomen or buttocks
Rotated to prevent lipoatrophy or lipohypertrophy
Different regimens available to suit different lifestyles
Twice-daily regimen (used in younger children):
am before breakfast, give 2h daily dose as:
Short-acting 1h
Medium-acting 2h
pm before tea, give 1h daily dose as:
Short-acting 1h
Medium-acting 2h
Multiple-dose pen injection regimen (used in older children). Abasal background insulin is given, usually
in the evening, and a short-acting insulin is given pre-meals. This is less rigid, allowing more flexibility

254
Blood glucose monitoring
• Regular capillary blood glucose monitoring done at home to assess control
• Urine glucose unreliable due to variable renal threshold and inability to detect hypoglycaemia
• Glycosylated Hb (HbAlc) or fructosamine give an indication of blood glucose levels over the previous 12 and 6
weeks, respectively
Dawn phenomenon Increase in glucose (and insulin requirement) around 4 am due to GH surge
Somogyi phenomenon Rebound hyperglycaemia after hypoglycaemia at night due to too much insulin given to
counteract 4 am GH surge

Exercise and illness

Exercise This increases the demand for glucose and, as insulin levels are fixed, a sugar snack prior to exercise
helps provide the energy boost
Illness Insulin utilization rises during illness, though as food intake generally falls, the requirements may not
nse

Recent developments
• Increased usage of continuous subcutaneous insulin infusion (pump therapy)
• Continuous glucose monitoring
• Inhaled insulin (not licensed< 18 years age)
• Artificial pancreas
• Stem 'cell technology

Problems
'
• Hypoglycaemia - symptoms usually occur with plasma glucose levels <3 mmoljl. 'Hypos' - sweaty, dizzy and
irritable. Treat with oral glucose (drink or gel) or glucagon injection
• Weight increase
• Behavioural problems - non-compliance common in adolescence. Labelled 'brittle diabetes'
• Insulin resistance - usually due to obesity
• Skin - lipoatrophy/lipohypertrophy occur at injection sites
• Necrobiosis lipoidica diabeticorum (annular areas of waxy, atrophic skin usually on shins)

Long-term complications
These are all due to micro- and macro-vascular disease.

255
Diabetic eye disease Retinopathy (simple and proliferative), cataracts
Renal disease Initially microalbuminuria, then proteinuria, then gradual decline in renal function to ESRF
Neuropathy Peripheral neuropathy (sensory loss in extremities), mononeuropathy of a cranial or peripheral
nerve, autonomic neuropathy (orthostatic hypotension)
Feet Ulcers due to neuropathy and microvascular disease
Cardiovascular BP t, stroke, myocardial infarction, limb amputation

Diabetic ketoacidosis
This is a state of uncontrolled catabolism associated with insulin deficiency, resulting in:
• Hyperglycaemia
• Osmotic diuresis and dehydration
• Lipolysis resulting in free fatty acids broken down to ketone bodies which cause a metabolic acidosis

Causes
• New presentation of diabetes
• Intercurrent illness
• Interruption of insulin therapy

Clinical features
• Hyperventilation (Kussmaul respiration to correct metabolic acidosis)
• Dehydration
• Nausea and vomiting, abdominal pain
• Eventual drowsiness and coma

Management
1. General resuscitation if necessary
2. Bedside glucose (BM stix) and urinalysis for ketonuria
3. Blood for blood glucose, urea, electrolytes, FBC, CRP and PCV and arterial/venous blood gas
4. Blood and urine cultures, a CXR, and if clinically indicated a lumbar puncture
5. Keep child nil by mouth (due to gastric stasis and vomiting), place NG tube if impaired consciousness, and
record fluid input- output chart
6. Admit to HDU if necessary
7. Give fluid and insulin therapy under close observation of clinical state and blood parameters

256
)i Fluid Circulating volume expansion with a bolus of 10-20 mljkg 0.9% saline
Then rehydrate calculated volume deficit+ maintenance fluids over 48 h with 0.45% saline, adding K
when electrolyte results back (with careful monitoring - risk of hypokalaemia as K pushed back into the
cells)
Change fluid to 0.18% saline 4% dextrose when blood glucose < 12 mmoljl
Bicarbonate infusion in severe acidosis or if evidence of decreased myocardial contractility
Insulin Insulin infusion of soluble insulin 0.01-0.1 units/kg/h to reduce blood glucose at a rate of <5 mmolfl/h
Check blood glucose hourly, and U&Es 2 hourly
When able to eat, transfer to subcutaneous insulin regimen of 0.5-0.7 units/kg/day
NB: Although serum K initially high, this is usually due to K leaking out of the cells and total body K is greatly
depleted. There is a risk of hypokalaemia and hypophosphataemia as K and P0 4 are pushed back into the cells with
insulin treatment.

HYPOGLYCAEMIA
Hypoglycaemia is defined as a blood glucose level of< 2.6 mmoljl. As glucose levels fall, the insulin concentration
falls and lipolysis and ketogenesis are activated. With a blood glucose level of< 2.2 mmoljl, the plasma insulin should
be undetectable.

Clinical features
Neonate Apnoea, cyanosis
Hypotonia, lethargy, poor feeding and seizures
Older child Pallor, anxiety, nausea, tremor, sweatiness, headache
Tachycardia
Diplopia, decreased acuity
Dizziness, poor concentration, behavioural change
Seizures, reduced consciousness, coma

Causes

257
Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI, nesidioblastosis)
This is a developmental disorder where there are hyperplastic, abnormally dispersed ~-cells, resulting in inappropri-
ately high levels of plasma insulin. (See below for management.)

Ketotic hypoglycaemia
These children are unable to tolerate a prolonged fast. It may represent the low end of the spectrum of a child's ability
to tolerate a fast.
• Presents between 18 months and 5 yea rs and resolves spontaneously by 8-9 years _
• Occurs when a child misses an evening meal or is unwell, causing a relatively prolonged fast, and they are difficult
to arouse in the morning or may have a seizure. Hypoglyc?emia, ketonaemia, ketonuria and plasma insulin levels
are appropriately low
• These children have low alanine levels (a substrate released from muscle during fasting). so may have a defect in
this mechanism. They also have a low muscle bulk and therefore have a low supply of substrate

Investigations
Essential investigations in the event of a hypoglycaemic episode (which may be induced by fasting):
• BMStix - blood glucose, U&E
.• Plasma insulin, cortisol, growth hormone, proinsulin (and (-peptide if exogenous administration is suspected)
• ~-OH-butyrate, acetoacetate, FFAs, alanine
• Ammonia, LFTs
• First urine sample for ketones, organic and amino acids, non-glucose-reducing substances

Management
Neonates
If able to feed Oral glucose (breast milk or formula)
If unable to feed or reduced consciousness 3-5 mljkg 10% glucose bolus IV, and then infusion of 10% glucose
5 mljkg/h until blood sugars stable
Older child
Conscious Sugary drink
Reduced consciousness 3-5 mljkg 10% glucose bolus IV, and then infusion of 10% glucose
5 mljkg/h until blood sugars stable
PHHI is treated with diazoxide and a thiazide diuretic. Second-line treatment is with octeotride and/or glucagon.
Subtotal pancreatectomy is indicated if medical management fails.
NB: Normal infants produce 5- 8 mg glucose/kg body weight/min of glucose in the fasting state. This falls to 1-2 mg/
kg/min in older children. A neonate with hyperinsulinism may require up to 10-20 mg/kg/min.

258
--
i

PANCREATIC TUMOURS
These arise from APUD cells (amine precursor uptake and decarboxylation) in the pancreas. They are extremely rare in
children.

INSULINOMA
This is an islet cell adenoma that secretes insulin. It presents insidiously with recurrent fasting hypoglycaemia.

Diagnosis
• Failure to suppress insulin with fasting hypoglycaemia
• MRI scan, coeliac angiography (v. difficult in infants) to locate tumour

Treatment
Surgical excision.

GLUCAGONOMA
This is a pancreatic tu mour of the a-cells _producing glucagon. The result is diabetes mellitus. A necrotic migratory
erythematous rash is characteristic.

Diagnosis
Serum glucagon i.
NB: Enteroglucagonoma is a glucagon-secreting tumour of the right kidney and jejunal villi hypertrophy.

VIPOMA
This is a pancreatic tumour, secreting VIP (vasointestinal polypeptide).
VIP ~Intestinal secretion ~ Diarrhoea

Diagnosis
• Serum VIP I
• PHI (peptide histidine isoleucine) also raised

Treatment
. • Octreotide
• Surgical resection (if possible)

GASTRINOMA (ZOLLINGER-ELLISON SYNDROME)

Always malignant and slow growing. It is a tumour of the G-cells of the pancreas, which produce gastrin.
Gastrin ~Gastric acid ~ Peptic ulcers (stomach, duodenum, jejunum)
The symptoms are those of peptic ulcers plus diarrhoea secondary to abnormally tow intestinal pH .

Diagnosis
• Serum gastrin I
• Acid studies (high output)
• Ocreotide-labelled isotope scan
259
; ""! _
 -~~.
I
!

Treatment
• Omeprazole (proton pump inhibitor)
• Octreotide
• Surgery if possible

ENDOCRINE SYNDROMES

An autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21
involving:
• Hypoparathyroidism
• Addison disease
• Mucocutaneous candidiasis
Additional features occurring with variable frequency include:
• Hypothyroidism
• IDDM
• Pernicious anaemia
• Ovarian failure
• Alopecia areata
• Chronic active hepatitis
• Ectodermal dystrophy

POLYGLANDLH.AR AUTOIMMUNE SYNDROME TYPE 2 (SO-!MWT SYNDROMiE)

This classically involves the association of:
• Addison disease
• Hypothryoidism
• IDDM
• Ovarian failure
The sequence of glandular involvement is variable.

Autosomal dominant. The association of a number of endocrine tumours.

260
Prophylactic total thyroidectomy is performed if the child is known to carry the gene for MEN II.

GROWTH
Growth phases
Infantile phase Birth-2 years
Rapid, and rapidly decelerating growth rate
Nutrition dependent
Childhood phase 2 years-puberty
Constant growth rate (5-6 em/year)
Hormone dependent
Pubertal phase Puberty
Accelerated rateto a peak, then slowing to stop
GH and sex hormone dependent
Linear growth complete when epiphyses fused

Assessing growth
Essential growth measurements:
• Single height, weight (and head circumference< 2 years) are measured and plotted to assess:
Growth is within normal range for parents and age-appropriate general population
Any discrepancies between height, weight and head circumference
• Growth pattern plotted over 6-12 month period assessing:
Rate of growth
Deviations across centiles
Other measurements may be taken for specific reasons, e.g. sitting height, skinfold thickness.

Growth charts
Charts for height, weight and head circumference from extreme prematurity (23 weeks) to 20 years. There are nine
equidistant centile lines 2h of a standard deviation apart (0.41h centile to 99.6 1h centile- equivalent to± 2.67 standard
deviations from the mean).
Children falling outside the expected range for their parents (target centile range) or below the 0.4 1h centile or above
the 99.61h centile should be formally assessed (4 in 1000 normal children though will be below the 0.41h centile).

Predicte~ eventual adult height

Predicted eventual adult height is an estimate made on the basis of the child's height and bone maturation (bone
age).
The mid-parental height centile (median expected height for any child) and the target centile range (range of
normal height for a particular child) are calculated from parental heights. They give a rough guide to the expected
adult height of the child.

261
Bone age (skeletal maturity)
This shows how far the skeleton has matured and can give an idea of potential height, and clues as to the cause of
short stature.
Delayed bone age in absence of pathology = slow maturation = more potential growth.
Bone age is assessed by rating a number of epiphyseal centres (and hence the rate of ossification) in a wrist X-ray (left
wrist or left knee if< 2 years). This is then compared to chronological age.

: ·. •:
- ~ ;·,-. .

GH,qeficiency ··

Catch-up growth
This is rapid growth in babies who had IUGR and after an illness.
Chronological age= age since birth
Post-conceptional age= age since conceived
NB: Most low birthweight and premature babies should have their growth charts adjusted for their post-conceptional
age until the age 2 years, as they will have 'caught up' by then. --~

. -,_~

Growth velocity
._:;,
_

• This is a sensitive indicator of growth problems, and is the 'gold standard' for assessing whether growth is : ·
progressing normally. It is age-dependent
• Two measurements are needed 4 months apart (though measurements over 12 months are desirable before clinical '-.
decisions are made). The difference between the two height measurements is divided by the time interval between .;
them to give the growth velocity in em/year and is plotted on a growth velocity chart at the mid-point in time
• Growth velocity should remain between the 25 1h-75 1h velocity centiles for height to remain normal

SHORT STATURE
Short stature is height< 2"d centile (approximately 2standard deviations below the mean). Height velocity< 25th:{~
centile is abnormal. >.

Causes
Familial Most common cause
Expected height calculated from parental heights
Constitutional delay 'Slow grower: Delayed bone age, usually delayed puberty and family history of this _.. ·.
--~

pattern. Final height falls within predicted centile range ·

Psychosocial deprivation Small child (may also be underweight)
May have biochemical picture of GH deficiency
:· ,;,
Chronic illness Any chronic illness, also inadequate nutrition
·';....1f~:;
";_~~

262
}~
Endocrine (rare) Growth hormone deficiency: Isolated GH synthesis or release defects
Pituitary deticiencyjhypopituitarism/hypothalamic defect
Post-cranial irradiation or chemotherapy
Laron dwarfism (GH insensitivity)
Hypothyroidism
PHP and PPfW (seep. 249}
Cushing syndrome (usually iatrogenic)
Chromosomal/gene Turner syndrome, Down syndrome, Prader-Willi syndrome, Noonan syndrome, Bloom
abnormality syndrome
IUGR Russell-Silver dwarfism
Skeletal dysplasias Achondroplasia and hypochondroplasia
Investigations
These are determined by the history and clinical findings.
General Bone age
TFTs
FBC, ESR, bone profile
Urinalysis
Specific Karyotype
Coeliac screen
Insulin-tike growth factor 1 (IGF-1} and IGF-binding protein 3 (IGFBP3)'
USS uterus and ovaries
CT or MRI brain
Skeletal survey
Pituitary provocation tests
·rGF-1 levels correlate well with GH status and this together with IGFBP3 are the initial screening tests for suspected
growth hormone deficiency. Random GH levels are unhelpful because GH is secreted in a pulsatile manner and is Likely
to be low in normal children during the daytime.
Treatment
Dependent on underlying cause. Children with GH deficiency, Turner syndrome, Prader-Willi syndrome and those who
have suffered from IUGR can be treated with daily recombinant GH injections.

TALL STATURE
Tall stature is height> 98th centile. It is much less common as a clinical problem than short stature, mainly because
of perceived social acceptability.
Causes
'
Familial Most common cause. Tall expected height (from parental height)
Hormonal Precocious puberty }In these two conditions the final height is short although child taller than
CAH their peers while growing because the growth spurts are reached earlier
Pituitary gigantism (GH secreting tumour- rare)
Hyperthyroidism
Syndrome Klinefelter syndrome (XXV)
Marfan syndrome
Homocystinuria
Soto's syndrome ('cerebral gigantism' - learning difficulties, clumsiness, big hands and feet, large ears,
prominent forehead)
Beckwith-Wiedemann syndrome (see p. 17)

263
Investigations
These are determined by the history and clinical findings .
General Bone age
Karyotype
TFTs
Specific IGF-1 and IGFBP3'
USS uterus and ovaries
MRI brain scan
Homocystine
17 -OH -progesterone and urine steroid profile

Treatment
Depends on the underlying cause. It is possible to treat/limit final height in those with familial tall stature by inducing
puberty early (using oestrogen therapy in gi rls and testosterone therapy in boys), which limits the childhood growth
phase and causes premature fus ion of the epiphyses.

PUBERTY

Pubertal staging
Pubertal stage is assessed using the sexual maturity rating devised by Tanner in 1962.
Boys G (1-5) , P (1-5), A (1-3), testicular volume (2-25 ml)
Girls B (1-5), P (1-5), A (1-3), menarche

264
puberty onset (timing variable)
Girls (8- 13 years) Breast stage 2 (First sign - breast development)
Boys (9-14 years) Testes 4 ml (First sign - testicular enlargement)

Pubertal growth spurts

Girls At breast stage 3
Boys At testicular volume 10-12 ml

Definitions
Menarche Commencement of menstruation. Occurs at breast stage 4. Average = 12.2 years
Thelarche Breast development
Adrenarche Pubic and axillary hair development

PRECOCIOUS PUBERTY
Gonadotrophin-dependent precocious puberty Dext:l9.H!!.l~,QtQfseEQOd9.ry.,gJS!'9.t.£he.JR£.;~~Jj~~~ at a young age in
a normal progression accompanied by a growth spurt, leading to
full sexual maturity from activation of the central axis
Gonadotrophin-independent precocious puberty Gonadotrophin-independent development, and there may be an
unll~Y.a:l.fprlfgless1<fflliof~:sexoaLtmatgJity. Is"Btwtra~pfe'mafureRhe£i';
~;tar@lie~ adre~n'arclle and menar;~hel can occur as s~llarat~;;,~1i.ttlG.9J
eo.tities::·~
Girls Development of secondary sexual characteristics < 8 years is abnormal
Menarche < 10 years warrants investigation
Mostly familial cases
Boys Development of secondary sexual characteristics < 9 years is abnormal
Mostly pathological causes, e.g. CAH, intracranial tumours, dysgerminomas

Causes
Tr!Je (Gonadotrophin dependent, hypothalamic-pituitary-gonadal axis activated), LH l FSH i•
F~j~i~k~
ae'nffalt~
•;;iG'on-g·enitat e.g. ~~~A9~~-'i~~~y"'9£?E,~B~,~JJ!~~
• 1\'tquir_eq}.fe~g;; i;P.OStoSepsis, SU[g~, on ~- ,
· ~st~i ,;;;~~~:t[i 'ic;..J;;;;c':,;,n,.>,;',Oi!;~~~!i<:H~;c:;,~}g,;.~iiolifl
.
9
.,- H~~_l~ -,
Fals_e ;; (Gonadotro-phin-independent,c excesscsex steroids not driven centrally) LHt FSH-1
•Kdrenat:r~;:.\
•
-~;'3-~~...._.::,._,.0'....- c.-·

• GJlf19~Jlitia.~~-gJ;gnal!lliY:Pe tpl~sla
' -- ~

• ''bNi!f.fan~trnnofif.!
• Te_ililJ.~!zititutQ!lJ (Leydig cell)
M€Eon~~Atlin§lit:rsyndfo'fue (see below)
H@otfiYY'OiaiSfiil
Ei9genous;;sex~-st~rojgs"

265
Examination and investigations
Always check:
• Clinical pubertal staging
• Bone age
• Pelvic USS (girls) or orchidometer (boys)
• Features of intracranial mass- visual fields and optic discs
NB: In boys, have a low threshold for cranial imaging (?tumour) and a-FP and hCG measurement(? testicular tumour)
due to high incidence of pathological causes.

Treatment
This depends on the underlying condition. True pre.cociows -puberty can be treated with GnRH analogues, and false
precocious:pub:erty with:·androgen inhibitors (ooys) or oestrogen inhibitors (girls).

McCune-Albright syndrome (polyostotic fibrous dysplasia)

This is a syndrome of endocrine dysfunction with hyperpigmentation and skeletal fibrous dysplasia. I tis due to a
defect in the G-proteimcontrotlitrgt:tAM p,:·;n;:eelJsT';,~h,1 th~~~~Iilfffil' activatio'n':of'r~ce'p-to-r~' witW~tft:r.,;fp:'~'eth~nism and
aut6n'o'motis~'gtanCJUlar,ifiypeffuffE'tio'r[-~'flre::syh'tfr~m~!:ti'iv"'6lv~s:
Endacn·ne Precocious :puber.ty
Mult:iple hormonal hyperactivity may be seen <(e.g. ovary, thyroid, adrenal glands, pituitary)
Bone Polyost9tic fibrous dysplasia (visible as radiolucent areas on X-ray)
Skin Patchy hyperpigmentation and cafe-au-laitpatches (of very irregular outline)

DELAYED PUBERTY
Girls Failure of onset of any signs of puberty by 13 years
Boys Failure of onset of any signs of puberty by 14 years
Mainly boys are affected, and the cause is usually constitutional delay (short child with delayed bone age and family .
history).

Causes

Investigations
1. Pubertal staging and bone age
2. Routine FBC, biochemistry, ESR and coeliac screen

266
. ~·

3. TFTs
4. Gonadotrophin and sex steroid hormone levels
5. Karyotype
6. Occasionally LHRH test and hCG test to check testicular responsiveness in terms of testosterone production
7. MRI brain and hypothalamic-pituitary area

Treatment
This depends on the cause. In males with constitutional delay, low-dose testosterone can be given to induce puberty.
In females, ethinyl oestradiol can be used for the same purpose.

Kallman syndrome
Syndrome of isolated hypogonadotrophism, causing secondary hypogonadism. Other features are anosmia, cleft palate,
colour blindness, ichthyosis and renal abnormalities. Inheritance usually X-linked.

·;; SEXUAL DIFFERENTIATION DISORDERS- AMBIGUOUS GENITALIA

Disorders of sexual differentiation can be due to:
• Virilizatjon of a female {female pseudohermaphrodite, 46, XX)
• Undervirilization of a male (me,le , p_~eudohermaphrodite, 46, XY)
• True, hermaphrodite (botb,.ovari(ll1.andJesticular tissue present)
Affected patients have a discrepancy between the morphology of the gonads and the morphology of the external
genitalia.

CAUSES

Female pseudohermaphrodite (virilized) ( 46, XX + ovaries)

Fetal CAH 21 -hydroxylase deficiency
11~-hydroxylase deficiency
Maternal Virilizing tumours (adrenat ovarian)
Virilizing drugs

Male pseudohermaphrodite (undervirilized) {46, XV+ testes)

Defect in testes differentiation Gonadal dysgenesis/agenesis
Defect in' testicular hormones CAH-3~ - hydroxysteroid dehydrogenase deficiency
pefed in androgen activity 5a-reductase deficiency
Androgen insensitivity syndrome (complete or partial)
'
True hermaphrodite (ovarian + testicular tissue)
• 46, XX
• 46, XY
• Mosaic karyotypes, e.g. 46, XX/XY (chiniera), <XO/XY

INVESTIGATIONS
• Karyotype
• Pelvic and abdominal USS (to assess internal genitalia and adrenal glands)
• Adrenal steroid profile

267
 • Testosterone and dihydrotestosterone (DHT)
• Other tests such as LH RH test, hCG test, Synacthen test
• Occasionally need to perform EUA or laparoscopy to determine external and internal genitourinary structures
NB: The basic pattern in development is female. The presence of testosterone causes the external male sexual charac-
teristics to develop. The sex of rearing of a child should be determined in infancy to allow for the appropriate medical
and social management before the child has a clear sexual identity; late changes may be very traumatic.

CONGENITAL ADRENA L HYPERPLASIA

Incidence 1:10 000. Agroup of autosomal recessive conditions resulting from various defects in the enzymes involved
in the adrenal steroid synthetic pathways. The enzyme defect causes the steroid pathway to be deflected from cortisol
synthesis down alternative mineralocorticoid and androgenic pathways, with resultant excess or deficiency of other
steroids.

Mineralocorticoids G lucocorticoids Sex hormones

ACTH {I)
:·-- - :
'

'
Cholesterol

~ DHEA

__ t_~]l~~d~o_:<y_s~':.Oi9~~':_y~r9~e~a_s~
Pregnenolone
t___________ _
17-0H- pregnenolone ___._ Dehydroepiandrosterone
______ __ _______

Progesterone 17-0H-progesterone Androstenedione ( 1)

__ } _ ?~·~Y9f_9XJI~~e _ ______t_ '
' '

Deoxycorticosterone
1 11-~-hydroxylase
Deoxycortisol (I)
1
'
Testosterone ( 1)
'
'
- -.f - - - - - - - - - - - - - - - f -
~ '
Co~isol {I) '
Oestradiol
'
'
Aldosterone (I)

Figure 10.6 Effects of congenital adrenal hyperplasia on steroid biosynthesis

._,
· .'

21-hydroxylase deficiency
The··mostcommon cause. (jehetic defect on chromosome 6.

Clinical features
• Virilization of a female baby (cliteromegaly, etc.) ; ;;' ;

• Adrenal crisis may occur in first 1-2 weeks of life (NB: They lose salt)
• May present late with precocious puberty, advanced bone age, tall stature in childhood (eventual short stature), f
hypertension, hirsutism and skin pigmentation

hormones ·.;~

..~-)
• ACTH (1)
• Aldosterone l

268
- ;j
J; • Testosterone i
• Cortisoll
· • Androstenedione I

Investigations
• Plasma P.~P~ -progesterbne (1)
• Urine steroi'(fprofile- urine pregnanetriol (1}
• Serum electrolytes: Na l, KI, glucose l
• Karyotype
• Pelvic uss·: (looking forfemale organs in a virilized female)
NB: Boys with CAH are more likely to be diagnosed late because the androgen excess does not cause a clearly abnormal
appearance in the newborn.

Treatment
Drugs Hydrocortisone and fludrocortisone daily
Surgery If necessary to improve female anatomy
Monitor Monitor growth and skeletal maturity
NB: Antenatal diagnosis is possible. Dexamethasone is given to the mother in order to decrease fetal ACTH and hence
reduce the chance of having a virilized female infant.

Other variants
11{3-hydroxylase deficiency (5-8%) Non salt-losing, Na I, Kl, BPI
Virilization
Diagnosis: 11-deoxycortisol I
3{3-hydroxysteroid dehydrogenase deficiency (<5%) Salt-losing, Na l, KI
Virilization of girls, incomplete virilization of boys
Diagnosis: elevated pregnenolone, DHEA, U-GH-pregnenolone

ENDOCRINE TESTS
NB: These are outlined for exam reference only. Tests performed in expert centres.

GH STIMULATION TEST
GH secretion is stimulated in a variety of ways, e.g. exercise, glucagon, clonidine or arginine. Hypoglycaemia with a
qlood glucose< 2.2 mmoljl is produced and samples collected as described below. ·

269
COMBINED PITUITARY PROVOCATION TEST
Growth hormone stimulation test+ TRH + LHRH stimulation tests.

TRH STIMULATION TEST

Give TRH and sample:

Prolactin * * *

tHRI·l STIMULATION TEST

Give LHRH and sample:

DEXAMETHASONE SUPPRESSION TESTS

Overnight suppression test
• Used to confirm normal suppression of adrenal cortex
• Dexamethasone 0.3 mg/m 2 given orally at 22:00 hours
• Plasma cortisol measured at 08:00 on the following day
• Normally plasma cortisol is suppressed to < 100 nmoljl
• .In Cushing syndrome there is failure to suppress

low-dose suppression 48-h test

• Confirmation of Cushing syndrome, where there is failure of suppression
• Dexamethasone given 0.5 mg/kg orally 6 hourly for 48 h

High-dose suppression
• Used to differentiate pituitary-dependent Cushing syndrome (which will suppress in 90%) from ACTH-ind~pendent
disease which will still not suppress. NB: This test can be hard to interpret
• Dexamethasone 2 mg given 6 hourly for eight doses from 09:00 on day 1
• Plasma cortisol and 24 h urine steroids measured at 09:00 on days 0 and 2
• Normally plasma cortisol is suppressed on day 2 to < 50% of the value on day 0

270
SYNACTHEN STIMUlATION TESTS

·Short Synacthen test (AOH analogue)

. • Purpose - used to detect primary adrenal failure, where the cortisol levels are below expected
• Dose of 0.25 mg (250 ~g) Synacthen (tetracosactrin) given IM or IV and cortisol levels measured as follows

long .Synacthen test

• Purpose - differentiates primary from secondary adrenal failure (in secondary adrenal failure, cortisol production
will be stimulated)
• Six 12-hourly tetracosactrin 0.5 ~g/m 2 SA IM. Measure:

GlUCOSE TOLERANCE TEST

Astandard dose of glucose is given after an overnight fast. Blood glucose levels are taken at time 0 and 2 h, though
usually serial measurements at 30 min intervals are also taken, i.e. 0, 30, 60, 90, 120.

FURTHER READING
Brook CG, Clayton P, Brown R, eds Brook's Pediatric Clinical Endocrinology, 51h edn. Oxford: Blackwell Publishing, 2005
Brook,CGD A Guide to the Practice of Paediatn·c Endocrinology. Cambridge University Press, Cambridge, 1993

271
• Basic mechanism underlying metabolic disorders • Group 4: Defects in the metabolism of large complex
molecules
• Classification
• Group 5: Mitochondrial diseases
• Group 1: Rapid toxic accumulation of a small molecule
• Hyperlipidaemias
• Group 2: Lack of energy
• Pofphyrias
• Group 3: Defects in the synthesis of large molecules
resulting in a dysmorphic child

Inborn errors of metabolism are inherited biochemical disorders and are generally autosomal recessive caused by
single gene disorders. They are individually rare yet collectively not uncommon .

BASIC MECHANISM UNDERLYING METABOLIC DISORDERS

• The molecular anomaly leads to a defect in an enzyme (or cofactor), or less commonly a structural protein such
as a transmembrane transporter
• Decreased enzyme activity results in an accumulation of the biochemical substrate or a deficiency of a product.
This can be particularly harmful if the former is toxic or the latter is essential for cellular function
• The enzyme may require a particular cofactor such as a vitamin to function and deficiencies of this cofactor can
lead to symptoms similar to those caused by deficiency of the enzyme ·

Metabolic diseases usually affect children although

increasingly adult phenotypes are being described . Due
to the rarity of the individual conditions, the multitude
of possible presentations and the perceived complexity
c B A
of the investigations required, metabolic diseases are .j
likely to be frequently undiagnosed. This is unfortunate .j
as once suspected they are, in general, relatively easy I B A · ..
· ,_
· ·l
to ding nose and subsequent treatment is often inexpen-
sive yet effective.
Figure 11.1 Decreased enzyme Cfunction leading to an
j
accumulation of Aand/or a deficiency of B

272
.;·,~
~~
: CLASSIFICATION

FEATURES SUGGESTIVE OF A ~1ETABOLIC DISORDER

The following are features to look for when considering a metabolic diagnosis.

Parental history
• Consanguinous parents
• Previous unexplained neonatal deaths
• Particular ethnic group (certain diseases only)

Clinical features
Neonatal presentation Poor feeding
Vomiting
Lethargy
Seizures
Coma
Unusual odour
Metabolic imbalance- hypoglycaemia, acidosis, alkalosis (with some defects)
May appear normal at birth (some conditions associated with dysmorphism)
Post-neonatal presentation Developmental regression, encephalopathy, seizures
Intermittent episodes of vomiting, acidosis, hypoglycaemia and/or coma triggered by
stress, e.g . infections, surgery

Examfnation findings
• Neurological abnormalities, developmental delay
• Unusual odour
• Skin manifestations
• Ocular involvement, e.g. cherry red spot
• Cardiac disease, Liver disease, renal disease
• Organomegaly, e.g. hepatomegaly
• Dysmorphism

273
 ·. . .
Investigations that may be used in a metabolic screen ·_ . . : .
Serum Ammonia t Urea cycle defects, organic acidaeinias
Glucose t FAODs and mitochondrial defects
Ketones I Organicacidaemias
Inappropriately low in FAODs
Lactate I Mitochondrial disorders
U&Es May be deranged; features of dehydration
LFTs May be abnormal (tyrosinaemia, urea cycle defects, FAODs,
mitochondrial defects and galactosaemia)
Plasma amino acids Ami noacidopathies
Urea cycle defects
Acylcarnitine profile Organicacidaemias, FAODs
VLFCAs Peroxisomal biosynthesis disorders
Blood gas pH Acidosis (organic acidaemias, mitochondrial defects)
Respiratory alkalosis (urea cycle defects)
Urine Organic acids Organic acidaemias, FAODs
Orotic acid Urea cycle defeCts
Amino acids Aminoacidopathies
GAGs Mucopolysaccharidoses
Ketones I Organic acidaeinias
Inappropriately low in FAODs
I Mitochondrial disorders

Enzyme assays (lymphocytes, liver biopsy,

fi bra blasts)
Molecular diagnosis (gene analysis) Most conditions
Transferrin isoelectric analysis COG
CSF Amino acids (NKH), glucose (GLUT1 transporter)
Muscle biopsy Mitochondrial disease

GROUP 1: RAPID TOXIC ACCUMULATION OF A SMALL MOLECULE

This group includes:
• Organic acidaemias
• Urea cycle defects
• Aminoacidopathies

ORGANIC ACIDAEMJ.AS
Organic acids are produced though the removal of the amino group (nitrogen) from amino acids. They are metabolized
in the cell to produce energy. Enzyme defects in these pathways lead to an accumulation of the preceding organic
acids. This occurs particularly during periods of increased protein turnover from:
• Dietary sources, or
• Intercurrent illness (endogenous catabolism i)
• Early neonatal period (a natural physiological catabolism occurs making this a particularly vulnerable time)

274
Presentation
Neonate Lethargy, poor feeding and vomiting, and severe ketoacidosis
Infancy Intermittent acute attacks of above symptoms during illness or certain diets
Episodes are often initially mistaken for sepsis
Long-term (If untreated) Mental retardation, movement disorders, faltering growth, renal impairment

Investigations
Initial Blood gas - acidosis
Plasma ketones i, ammonia i, glucose J,
Diagnosis Urine organic acids, or
Plasma or blood spot acylcarnitine profile (carnitine derivatives of organic acids)
Confirmation of diagnosis is with enzyme or molecular analysis.

Biotinadase deficiency
Classically presents in infantile period with a combination of seizures, lactic acidosis, developmental delay, an eczema-
type rash, angular stomatitis, alopecia, hearing loss and ataxia. There is a characteristic urinary organic acid picture
with confirmation of the diagnosis by measuring biotinadase activity.

UREA
,, CYCLE DISORDERS
Similar acute episodes can occur in the urea cycle disorders, a group of conditions caused by enzymological defects
in the conversion of ammonia and nitrogen waste into urea.
The urea cycle converts ammonia to non-toxic urea:
Urea cycle
Protein feed (amino acids) ~ Ammonia ~ Urea
Toxic Non-toxic

The five enzymes involved in urea synthesis are:

• Carbamylphosphate synthetase (CPS)
• Ornithine transcarbamylase (OTC)
• Arginosuccinate synthetase (AS) (citrullinaemia)

275
 ---,,_··.
- ~-1

l
I
i

• Arginosuccinate lyase (AL) (arginosuccinic acidaemia)

• Arginase (argininaemia)
N-acetylglutamate synthetase is required for the activation of the cycle. Deficiencies of all these enzymes occur, result-
ing in urea cycle defects.

Citrullinaemia

Citrulline
Arginosuccinic
acid
NH 3 OTC deficiency

C;

+
2
__ --hf
1 L.._~..~ Carbamyl
CPS
deficiency
phosphate
_/ Arginosuccinic
addoem;a J~
ATP

Ornithine Arginine
~gininaemia

Urea

Figure 11.2 Urea cycle

Presentation
Neonate (common) Severe hyperammonaemia and subsequent encephalopathy (lethargy, poor feeding,
seizures and coma)
Childhood Faltering growth, cyclical vomiting and encephalopathy
Developmental delay (some types)

Investigations
Initial Plasma ammonia ii (> 200 jlmoljl) (key investigation)
(urea cycle disorder or an organic acidaemia should be suspected)
Blo'od gas (respiratory alkalosis - may be present)
Diagnosis Plasma amino acids (particular profile will usually indicate type of urea cycle disorder)
Urine orotic acid
Confirmation with enzyme or molecular analysis

Management
Acute Urgent haemofiltration to lower the toxic ammonia and related compounds
Long-term Low protein diet
Ammonia lowering medication, e.g. sodium phenylbutyrate, arginine

Episodes of metabolic decompensation

Despite treatment, children with organic acidaemias and urea cycle diseases may have frequent episodes
of metabolic decompensation. These often occur during periods of intercurrent viral infections. Prompt

276
 ..... ... ...... . . - ... ... - -· .. . . ... __ .. ..
_,

~:

instigation of a high carbohydrate- low protein diet (the emergency regimen) can prevent or at least curtail
these, although hospital admission for IV glucose and medications is often required.

AMINOACIDOPATHIES
Maple syrup urine disease (MSUD)
This is an inability to break down the branched chain amino acids isoleucine, Leucine and valine. Usually present in
the neonatal period with encephalopathy.
Defects in the metabolism of the other amino acids (aminoacidopathies) do not tend to present as suddenly or acutely
as MSU Dor the organic acidaemias.

Phenylketonuria (PKU)
Incidence 1:15 000 (the most common metabolic disorder)
Adefect in the breakdown of phenylalanine:
Phenylalanine
hydroxylase
Pathway: Phenylalanine--X.- - --7Tyrosine
Enzyme deficiency Phenylalanine hydroxylase (low or absent)
Biochemical result Phenylalanine and its alternative pathway metabolites accumulate in the tissues

Clinical features
'
NB: These only develop if condition is untreated.
,,
• Slowly progressive mental retardation
• Mw;ty odour (classic, though in reality simply smells unusual)
• Spastic cerebral palsy, athetosis, hyperactivity, acquired microcephaly
• Fair hair, fair skin and blue eyes (if not treated)
Neonatal screening is well established for PKU (Guthrie test - phenylalanine Levels t) and the classical phenotype is
now rarely seen.

Tyrosinaemia (Type 1)
Enzyme dejidency Fumarylacetoacetase
Biochemical result Tyrosinaemia and succinylacetonuria

277
Clinical features
Liver Acute or chronic liver disease
Renal Renal Fanconi syndrome, renal rickets
Odour Cabbage/sweet
Other Faltering growth, developmental delay

Homocystinuria
Prevalence 1:200 000, autosomal recessive.
Enzyme deficiency Cystathionine synthase
Biochemical result Homocysteine and methionine accumulation

Clinical features
General Marfanoid habitus, fair hair, fair skin, blue eyes, malar flush
CNS Learning difficulties (common), seizures (20%)
Skeletal Osteoporosis, platyspondyly
cvs Cerebral vascular events, arterial and venous thromboembolism
Eye Lens subluxation

Diagnosis of the aminoacidopathies

• Amino acid profile (plasma or urine), e.g. PKU - phenylalanine I
• Enzyme or molecular test confirmation if necessary

Treatment of the aminoacidopathies

• Very low protein diet
• Specialized medications (BH4 for some forms of PKU, NTBC for tyrosinaemia, and pyridoxine or betaine for
homocystinuria)
• Supplementary specialized formula (contains all the vitamins, minerals, carbohydrates and essential amino acids
minus the one(s) the patient cannot metabolize, to make a complete diet). E.g. PKU -low-phenylalanine diet for
life. Some phenylalanine must be given as it is not synthesized in the body. During pregnancy woman with PKU
must strictly adhere to the diet because high phenylalanine levels result in fetal abnormalities, e.g. CHD, and
mental retardation

Non-ketotic hyperglycinaemia
Autosomal recessive.
Enzyme defect Defect in the glycine cleavage system involved in glycine degradation

Clinical features
• Neonatal illness with vomiting, lethargy, seizures, coma and death within hours if untreated
• If survival occurs, severe mental retardation, myoclonic seizures and spasticity are seen
• A late-onset mild form with developmental delay, ataxia and seizures is also described

Investigations
• Glycine levels - i in plasma, urine and CSF. High CSF:plasma glycine ratio
• No demonstrable organic acidaemia

278
;7> Management
Sodium benzoate lowers glycine levels but in typical severe cases there is no effective long-term treatment and man-
agement is palliative.

GROUP 2: LACK OF ENERGY

The small molecule diseases leading to a lack of energy include:
• Disorders of carbohydrate metabolism
• Fatty acid oxidation defects

DISORDERS OF CARBOHYDRATE METABOLISM

Glycogen storage diseases (GSDs)

To maintain blood glucose normal children, when fasted, rely initially on the breakdown of hepatic glycogen and
~ later on the oxidation of fat. Children with GSDs can make glycogen but cannot effectively catabolize it. Glycogen
is thus stored in huge quantities in the liver. During periods of starvation, e.g. during an intercurrent viral illness,
the children become hypoglycaemic and lethargic. There are several different types of GSD involving different enzyme
deficiencies.

Presentation
GSD I and III Hypoglycaemia and massive hepatomegaly in first few months of life
GSD VI and IX Milder disease. Hypoglycaemia if significantly stressed, often only have mild moderate
hepatomegaly and an otherwise excellent prognosis
Long-term complications Short stature, developmental delay, seizures (from hypoglycaemia), hepatoma, osteoporosis
and cardiac disease if untreated

Diagnosis
• Enzyme activity (blood or liver) and/or
• Molecular analysis of appropriate gene

Management
• Regular high carbohydrate meals during the day
• Continuous feeds during the night (or uncooked cornstarch, a slow release form of glucose, every 4-6 h)

Prognosis
Depends on the degree of metabolic control. It is hoped that with modern management the previously seen long-term
complications can be mostly avoided.

279
 ~1
·,,.,
.,
-~

I
!i
i
Galactosaemia
Incidence 1:60000. Autosomal recessive. Gene locus 9p13. Common mutation 0188R accounts for majority of cases
although many mutations described.
Enzyme deficiency Galactose-1-phosphate uridyl transferase (mnemonic= GAL-I-PUT) . This results in inability to
metabolize galactose or lactose (glucose+ galactose)
Pathogenesis unclear but probably related to accumulation of metabo lites

Newborn/infant Vomiting, hypoglycaemia, feeding difficulties

Seizures, irritability, developmental delay
Jaundice, hepatomegaly, liver failure, DIC
Cataracts, splenomegaly, E. coli sepsis (typical)

Diagnostic investigations
Diagnosis Enzyme assay in red blood cells
Urine Non-glucose reducing substances present whe n milk fed, i.e. Clinitest positive, Clinistix
negative (specific for glucose)

Monagement
Lactose and galactose-free diet. Speech an·d language problems (es pecially dysarthria), mild progressive cognitive
problems and ovarian failure almost inevitable even with therapy.

Hereditary fructose intolerance

Incidence 1:40000, autosomal recessive.
Enzyme deficiency Aldolase B. This results in inability to metabolize fructose or sucrose (glucose+ fructose)
Biochemical result Fructose-1-phosphate accumulates in hepatocytes
Breast milk and most formulae do not contain fructose; thus symptoms occur upon introduction of fruits and
vegetables.

Clinical features
• Abdominal pain, vomiting (often soon after ingesting fructose)
• Proteinuria
• Liver disease results from chronicfructose ingestion

Diagnostic investigations
• Urine-reducing substance that is not glucose
• Enzyme analysis (liver)
• Genetic marker

Managernent
Elimination of fructose from the diet.

280
FATTY ACID OXIDATION DEFECTS (FAODs)
During fasting fats or fatty acids are metabolized to ketones. These are used as an alternative energy source to
glucose and are the main source of energy during starvation. FAODs are defects in this pathway and are more variable
than the GSDs in their presentation.
Some children may not be exposed to significant catabolic stress during early life and therefore FAODs may not present
until mid-childhood or even adulthood.

Clinical features
Typical presentation Hypoglycaemia and encephalopathy during fasting
Other initial symptoms Rhabdomyolysis/ cardiomyopathy and arrhythmia (as skeletal and cardiac muscle is particu-
larly reliant on fatty acids for cellular metabolism)
Dun·ng metabolic stress Hypoglycaemia with inappropriately low ketones (hypoketotic hypoglycaemia)
Diagnosis
Relies on a strong clinical suspicion and specialized tests:
Measurement of fatty acids Urine organic adds
Fatty acid carnitine derivatives Blood acylcarnitine profile (can be done on Guthrie test)
Confirmation is by fibroblast FAOD enzyme studies and/or molecular analysis.

Treatment
Relatively easy/ cheap and effective:
• Regular oral feeds
• Regular intake of a carbohydrate solution/ either orally or N during periods of catabolic stress is essential
NB: Many of the small molecule metabolic diseases can now be screened for on Guthrie test with tandem mass
spectrometry. Hopefully this will result in the classical presentations described above becoming much less
common.,
,,
GROUP 3: DEFECTS IN THE SYNTHESIS OF LARGE MOLECULES RESULTING IN A DYSMORPHIC CHILD
This is a relatively new yet rapidly expanding group of metabolic disorders, including:
Enzyme defects in the synthesis of cholesterol/ e.g. Smith-Lemni-Opitz syndrome
Peroxisomal biogenesis disorders. There is a defect in the transport of enzymes into the peroxisome and thus normal
peroxisomal anabolic function is not possible. (Peroxisomes are intracellular organelles and are important in cell mem -
brane formation/ synthesis of bile acids and breakdown of very long chain fatty acids [VLCFAs]). Diagnosis is usually
made by measurement of VLCFAs
Congenital disorders of glycosylation (CDG disorders/ alternatively carbohydrate deficient glycoprotein disorders).
Prior to a protein being exported from a cell carbohydrate moieties are attached by the endoplasmic reticulum and
golgi apparatus in a process known as glycosylation. This requires a huge variety of enzymes and defects in any one

281
of these lead to a CDG disorder. Preliminary diagnosis is made by studying the glycosylation pattern of transferrin
glycoprotein)
These children tend to be abnormal at birth although recognition of this may not be until Later. Treatment of all these
conditions is generally disappointing .

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GROUP 4: DEFECTS IN THE METABOLISM OF LARGE COMPLEX MOLECULES

LYSOSOMAL STORAGE DISEASES (LSDS)

lysosomes are cell organelles important in lhe recycling of sphingolipids, mucopolysaccharides and oligosaccharides.
These large complex molecules are made up of fatty acid chains, carbohydrate moieties and amino groups and are

282
 important as structural components of cells and organelles. They are catabolized in a stepwise fashion by a series of
enzyme reactions in the lysosome. Adefect in any one of these enzymes leads to a slow accumulation of the preced-
ing compound and a corresponding slowly progressive clinical phenotype.
These lysosomal diseases can show considerable locus and allelic heterogeneity. Different enzyme defects can result
in a similar phenotype; alternatively, various lesions in the same gene can result in a severe infantile disease or a
relatively mild adult onset depending on the degree of residual enzyme activity. There are over 40 known LSDs.

Clinical features
CNS Neurological regression (most affect the CNS and thus they need to be strongly considered in
children and young adults with neurological regression)
Other organs All organ systems can be affected by the accumulation of these compounds:
Hepatosplenomegaly _
Cardiomyopathy, valvular lesions
h
Bone disease
r' All frequently seen
Infiltrative lung disease
Renal impairment
Progressive dysmorphic facial features

Diagnosis
Blood white cell enzymes Measurement of individual enzyme activity in leucocytes

Management
• Traditionally treatment has been supportive only
• Organ transplantation (BMT) is successful in some conditions
• Recombinant enzyme replacement therapy is becoming increasingly available (expensive yet effective)

283
*Skelet<il deformity involving: gibbus deformity, oval-shaped vertebrae, oar-shaped ribs, thickened skull, coax valga, cortical thinning of
long bones, tapered phalanges.

·Mucopolysaccharidoses

Typ.e j , ~G_;ter :
TyPe z··;
-.: .•.. ;:·.
Type)(
..
TyfJe4

GROUP 5: MITOCHONDRIAL DISEASES

Mitochondrial disease usually refers to defects in the respiratory chain. This electron transport chain is responsible
for the production of ATP via the transport of electrons from NADH and FADH obtained primarily from the Krebs cycle.
Defects in this pathway lead to a failure of ATP production and/or an accumulation of oxidative stress and thus cell
death.
Tissues that have high-energy demands appear to be particularly vulnerable to mitochondrial cytopathies. The CNS,
especially the brainstem and basal ganglia, is often affected. The eye, heart, liver and renal tubules are also vulner-
able, and multiorgan involvement is common.

284
·~ Inheritance
The respiratory chain involves five enzyme complexes each composed of a number of subunits. These subunits can
be encoded for by the nuclear DNA in the traditional manner or alternatively by the 16 kb circular DNA present in
each mitochondria. As mitochondria are inherited from the mother, this leads to the possibility of the unique concept
of inheritance of disease through maternal lines. Without a molecular diagnosis genetic counselling can thus be
difficult.

Clinical features
Features suggestive of mitochondrial dysfunction include (especially when in combination):
Muscle Abnormal tone, weakness, exercise intolerance
Eyes Ophthalmoplegia, optic atrophy, cataract, retinitis pigmentosa, cortical blindness
CNS D~velopmental del~y, seizures, movement disorders, coma, .stroke
Cardiac Cardiomyopathy, conduction defects
Hepatobiliary Liver failure, pancreatic dysfunction
Haematological Anaemia (sideroblastic in Pearson), pancytopenia
Renal Tubulopathy
Gastrointestinal Dysfunction
Other Growth retardation

Examples of mitochondrial diseases

Diagnosis
Plasma lactate i (and especially an elevated CSF lactate) is strongly suggestive of mitochondrial disease (if
characteristic signs and symptoms)
M~scle biopsy The next investigation in most childhood cases. Should be sent to a recognized laborato ry fo r
specific histochemistry and enzymology
Molecular diagnosis May then be sought based on the results of the muscle biopsy. Recent rapid advances in mito-
chondrial genomics and DNA technology suggest that a molecular approach may be more reward-
ing and could be rega rded as the first-line investigation in the near future

Management
Current treatment is unfortunately generally disappointing. A var:iety of vitamins, antioxidants and special diets
are used and while there is theoretical, laboratory and anecdotal support for these treatments there is, as yet, little
objective evidence of clinical benefit.

285
HYPERLIPIDAEMIAS
These are a range of inherited disorders that result in raised serum lipoproteins. Investigation is with a fasting blood
lipid profile.

Classification

PORPHYRIAS
These are disorders of the enzymes involved in haem biosynthesis. They may cause cutaneous symptoms, acute symp-
toms or a mixture of both. The excess porphyrins may be stored in the liver (hepatic) or the bone marrow (erythro-
poietic). Certain porphyrins react on exposure to sunlight to produce oxygen free radicals and cause photodamage.

286
 Clinical classification

-·Haem biosynthesis pathway

Clinical features
Cutaneous porphyrias Mostly present in childhood (not sporadic PCT)
Acute photosensitivity (severe sunburn, bullae, scarring) (EPP, CEP, HEP)
Subacute symptoms (skin fragility, vesicobullous lesions with minor trauma) (PCT, CEP,
HEP)

287
 Hypertrichosis (PCT, CEP)
Red teeth, nail dystrophy, photophobia, corneal scarring, blindness and splenomegaly
(CEP)
Chronic liver disease (EPP and PCT)
Acute porphyn"as Present after puberty
Acute attacks (abdominal and neurological symptoms induced by metabolic stress, e.g.
illness, and certain drugs)
Mixed porphyn"as Usually present after puberty, may develop earlier
Acute attacks and subacute skin symptoms (PV and HCP)

Diagnosis
• Measurement of porphyrin metabolites in urine, stool and RBCs (during attack in acute porphyrias)
• Enzyme assay (tissues/RBCs)

Management
• Photoprotection -avoid sun exposure, sunscreen, ~-carotene (EEP) (a scavenger of singlet oxygen)
• Chloroquine - PCT
• Acute attacks - emergency porphyrin removal. Avoidance of future attacks
• Stem cell transplant may be indicated, e.g. CEP

fURTl-lER READING
Fernandes J, Saudubray JM, Van den Berg he G, eds. Inborn Errors of Metabolism, 3'd edn. Berlin: Springer-Verlag,
2000
Nyhan WL, Ozand PT Atlas of Metabolic Disease. London: Chapman and Hall Medical, 1998
Scriver CR, Beaudet AL, Valle D, Sly WS, ed. Metabolic and Molecular Basis of Inherited Disease, sth edn . New York:
McGraw-Hill, 2001

288
....
r:. • Dermatological examination • Vascular birthmarks
• Terminology of common lesions • Naevi
• Neonatal conditions • Alopecia
• Nappy rash • Disorders of pigmentation
• Atopic eczema (atopic dermatitis) • Congenital ichthyoses
• Acne vulgaris • Vesiculobullous disorders
• Psoriasis • DNA fragility syndromes
• Keratosis pilaris • Ectodermal dysplasias
• Pityriasis rosea • Ehlers-Danlos syndromes
• Infections • Cu"tis taxa
• Cutaneous reactions

DERMATOLOGICAL EXAMINATION
Includes:
• Examination of all the skin (do not miss bits)
''• Hair
• Nails
• '
Mucous membranes
• Teeth

Describing/illustrating rashes
Include:
Individual lesions Type (see below), shape, colour, margination, consistency
Arrangement Linear, annular, localized, diffuse, confluent, symmetrical
Distribution Areas affected, mucous membrane involvement

289
 ·-, .... \~....
~

II
TERMINOLOGY OF COMMON LESIONS I

NEONATAL CONDITIONS

ERYTHEMA lOXICUivt NEONATORUM

Benign condition occurring in first few days of life in half of term infants. Eruptions .of red papules ± pustules (con-
taining eosinophils) with surrounding erythematous flare. Affects whole body except palms and soles. Self-limiting
condition (2-4 days).

MILIA AND SEBACEOUS GlAND HYPERPLASIA

Milia are epidermal follicular keratin-filled cysts, seen in around half of neonates. Small white papules common on the
face, gingiva (Epstein's pearls), labia minora, arolae +scrotum. Resolve within a few weeks.
Sebaceous gland hyperplasia (secondary to maternal androgens) . Seen in most neonates. Similar appearance to milia
- small white papules over the nose, forehead, cheeks and upper lip.

SUCKING PAD
Area of hyperkeratosis on the central lower± upper lip.
NB: Sucking blister is a bulla on the finger, lips or forearm caused by in utero sucking of the affected area.

M!JNGOUJ\N BLUE SPOT

Blue macule(s) on trunk± limbs. Common in dark-skinned races. Due to melanocytes arrested in the dermis on their
way to the basal layer of the epidermis. <:ienerally fade during first few years (though they may persist) .

290
SEBACEOUS NAEVUS
Yellow oval plaque with no hair, on the head or neck. Composed of sebaceous glands and may become malignant (basal
cell carcinoma) around adolescence, therefore should be removed before adolescence.

APLASIA CUTIS CONGENITA

Developmental absence of skin, usually solitary or multiple small ulcers on the scalp. May be associated with malfor-
mation syndromes, embryological defects or intrauterine infection .

NAPPY RASH
The main causes of nappy rash are:

ATOPIC ECZEMA (ATOPIC DERMATITIS)

An itchy recurrent or chronic inflammatory skin disease, often associated with other atopic diseases.
Incidenc~ 10- 20% of children.
Associations
,, Fami ly/personal history of atopy, i.e. asthma, hayfever, eczema, raised total IgE (80%)
Generally begins from 3 months-2 years and improves with age.
T

Features
• Pruritis (itchiness)
• Dry skin, lichenification post-inflammatory pigmentation changes (chronic eczema)
• Hyperlinearity palms and soles
• Dry irritated swollen eyelids, Denni-Morgan fold (fold under eyes, not specific to eczema)
• Lymphadenopathy in widespread disease · .
• Acute and subacute eczema -erythema, vesicles, ' weeping and crusting of excoriated areas
• Chronic eczema·- lichenification (thickening) and post-inflammatory hyper- and hypo-pigmentation
• Other forms include discoid (annular lesions) and pompholyx (tiny vesicles, very pruritic, palms and soles)

291
 .

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Distribution varies with age:
Infants Face and extensor surfaces
Older children Elbow and knee flexures, wrists, ankles, neck± lichenification

Complications
Secondary bacterial infection With Staphylococcus aureus or Streptococcus pyogenes usually
Viral infection Several viral infections are more widespread and severe in children with eczema:
• Eczema herpeticum- HSV infection in a child with atopic eczema. Can be widespread,
potentially serious infection. Must be treated with antivirals (aciclovir given IV if
concern)
• Molluscum contagiosum
• Viral warts
• Varicella
Growth impairment An intrinsic feature of atopic children. More common in severe eczema. Can also be sec-
ondary to overzealous dietary restrictions, associated enteropathy with malabsorption,
prolonged course of systemic steroids or, rarely, if too much potent topical steroids are
gJVen

Management
Several therapies are available. In order of increasing disease severity:
General advice Detailed advice about eczema, environmental factors and how to use topical steroids.
Keep nails short
Avoid triggers Allergens: House dust mite reduction (regular hoovering, no carpets, mattress, duvet
and pillow covers)
Pets (cats, dogs and horses)
Irritants: Soap and biological detergents
Hot and cold conditions
Wool (only loose cotton clothing)
Emollients In the bath and instead of soap, e.g. emulsifying ointment BP
After baths on skin, e.g. white soft paraffi n BP
Topical corticosteroids Use minimum strength effective to minimize side-effects

Antihistamines Regular oral antihistamines reduce eczema severity

Antibiotics If infected
Topical immunomodulators E.g. tacrolimus
Food allergy management In some children certain foods worsen their eczema. Atrial avoiding them may be under-
taken with the dietician's help
Wet wraps and bandages Wet wraps are double layer cotton wraps, the inner layer is applied wet and under this
topical emollients ± steroids are applied. They are changed 12-24 hourly. They pro-

292
 . . . . . --· ··· ···- ···· · ........ . . . . . . . . . .. . . .. .... .... - ··· ·· ..

vide (1) physical protection, (2) prolong the effect of emollients and (3) increase the
penetration of steroids. NB: These increase the steroid potency by 10 times
Paste bandages with icthamol impregnated into them help reduce lichenification
Ora/steroids May be given as short oral beclomethasone course
Phototherapy A 6- 8-week course of narrow-band ultraviolet-B phototherapy
Chinese herbs E.g. tea (NB: renal and liver toxicity reported)
Immunosuppressives For severe eczema courses of these drugs may be needed, e.g. cyclosporin

ACNE VULGARIS
Acommon inflammatory disorder of the pilosebaceous unit. Incidence high during puberty and generally improves by
early- mid 20s. Primarily due to androgen-induced sebum production. Lipophilic bacteria (especially Propionibacterium
acnes) colonize the hair follicles.
Androgen levels are high directly after birth (due to maternal androgens) and can cause infantile acne.

Clinical features
Face, chest and upper back (sebaceous glands most numerous) most commonly affected.
Lesions of acne Comedo (plug of sebaceous material within the hair follicle)
(Open comedo = blackhead; closed comedo = whitehead)
Papules, pustules, cysts, nodules, scars

Treatment
Topical therapy Antibacterial and keratolytic agents, e.g. benzoyl peroxide
Antibiotics, e.g. erythromycin, clindamycin
Retinoic acid lotion or gel (prevents comedones by reducing follicular hyperkeratosis)
Systemic therapy Antibiotics, e.g. erythromycin for 6-12 months
Antiandrogens, e.g. oral contraceptive pill containing cyproterone acetate
Isotreti no in (oral therapi 1·mg/kg i::lose over 4-6 months) :
• Actions - decreases size of sebaceous glands, reduces sebum production and reduces follicular
hyperkeratosis
• Side-effects - dry skin and lips, muscular aches, depression, elevated serum lipids, hepatitis,
teratogenicity

PSORIASISI

An inflammatory disease of rapid epidermal proliferation (increased skin turnover) causing patches of red thickened
skin.
UnusGal in childhood (affects 2% population, but< 10% present in childhood). Childhood onset most commonly 7-8
years. Often positive fami ly history.

Clinical features
Two common forms in childhood:
Chronic plaque psoriasis Well-demarcated silvery-scaled red plaques
In children the face and scalp are often first affected
Classically over extensor surfaces (elbows, knees)
May present as intractable nappy rash in infancy
Nail pitting and onycholysis rare in children

293
 Guttate psoriasis Many scattered small plaques on trunk
Often precipitated by streptococcal sore throat (therefore perform throat swab and
ASOT titre)

Treatment
Emollients (In baths, as soap and after baths)
Topical treatments applied once or twice daily:
• Mild or moderate topical steroids
• Steroid and tar mixtures (ointments, shampoo, soap)
• Vitamin D3 analogue, e.g. calcipitriol
• Dithranol (a tree bark extract applied in day treatment centre)
Phototherapy Often used in guttate psoriasis as plaques too small to apply topical therapies
A 6-8-week course of narrow-band ultraviolet-B phototherapy
Systemic treatment In severe refractory cases, e.g. acitretin, methotrexate

KERATOSIS PILARIS
• Common autosomal dominant condition
• Small rough keratin plugs develop in the hair follicles
• Affects outer arms, thighs and cheeks
• Associated with atopic dermatitis and Down syndrome
• Treatments limited (emollients containing keratolytics give temporary improvement)

PITYRIASIS ROSEA
Common rash in children and adolescents.

Clinical features
Prodrome (unusual) Mild fever, malaise, arthralgia
Skin Herald patch - a large (1- 10 em) pink annular lesion with raised.border
5- 10 days later many smaller pink lesions with a peripheral cellarette of scale. Sometimes
pruritic
Rash follows cutaneous cleavage lines and hence makes a 'Christmas tree' pattern on the back.
Resolves spontaneously in 2-12 weeks

Management
Emollients only. Mild topical steroids if necessary to speed resolution.

INFECTIONS

IMPETIGO
Common contagious bacterial epidermal infection seen in two forms:
Impetigo contagiosa Honey-coloured crusts usually around the mouth and nose, may be widespread. Highly
contagious
Bullous impetigo Fragile vesicles and bullae, i.e. localized SSSS

294
- --- - - .. .. . - ... . - . .. .. . . .. . . .. . . . .. . . . . . .. . .. .. --- - -- - .. ·-- - - -. ·- ·-

Causes
• Staphylococcus aureus (bullous impetigo usually due to phage group II)
• Group A ~-haemolytic streptococcus (Streptococcus pyogenes)

Treatment
• Topical antibiotics if minor
• Systemic antibiotics if widespread

STAPHYLOCOCCAL SCALDED SKIN SYNDROfvtE (SSSS}

Rare exfoliative dermatitis caused by epidermolytic toxin (ET) producing strains of Staphylococcus au reus (usually
phage group II types 3A, 3(, 55 and 71).
Generally affects children < 5 years.

Clinical features
Skin Brightly erythematous skin, fissuring and crusting around eyes, nose and lips, blistering and skin
tenderness
Superficial desquamation (peeling sheets of epidermis) 2-3 days later
Nikolsky sign positive, i.e. epidermis separates with gentle pressure
Systemic Severe malaise, fever, dehydration, irritability, sepsis, electrolyte imbalance
Other Pharyngitis, conjunctivitis

Investigations
Cultures Skin swabs of potential causative sites, e.g. nose, umbilicus, and blood cultures
Blood FBC (features of sepsis), electrolytes (features of dehydration)
Skin biopsy Intraepidermal splitting (between granular and spinous Layers)
(If diagnostic doubt) Frozen section of peeled skin can give a rapid diagnosis if necessary

Management
Antibiotics Systemic antistaphylococcal antibiotic therapy
Skin Emollient application, non-adherent dressings, low pressure mattress
General Care of systemic state. Monitor closely vital signs and fluid balance
(Problems - fluid and electrolyte balance, protein loss, temperature control)
Keep in warm side-room. IV fluids may be necessary

MOLLUSCUM CONTAGIOSUM
Comrnpn infection in school children with DNA pox virus. Spread by contact and scratching lesions. Widespread
infection in immnuosuppression and atopic dermatitis.

Clinical features
Pearly papules with a central umbilicus. If squeezed, the central cheesy core of cells infected with viruses is
extruded.
Clinical diagnosis, though central plug material may be identified on microscopy.

Management
Spontaneous resolution within 6-9 months (can last years) . Advise to use separate towel and baths. No treatment is
usually necessary. If necessary can be treated with cryotherapy.

295
VIRAL WARTS
Extremely common in childhood; spread by contact with people or objects. The various wart viruses (human
papillomaviruses [HPV]) are associated with different forms of wart:
Common warts Papules typically on fingers, hands, face, knees and elbows. HPV type Z
Plantar warts Flat painful warts on soles. 'Verrucas'. HPV type 1
Filiform warts Protruberant warts, around lips and nostrils. Refractory to topical therapy
Plane warts Small flat warts on face and dorsum of hands. Resistant to treatment. Koebnerize. HPV type 3
Anogenital warts Condylomata accuminata (occur on mucous membranes)
Papillomatous in perianal area, labia, vaginal introitus and penis
Also occur on the lips, tongue and conjunctivae
NB: May indicate sexual abuse
If< 3 years, may be transferred from the birth canal

Management
Warts eventually disappear spontaneously (months-years). Treatments to speed up resolution:
• Wart paints (keratolytics) together with paring of the wart (common, plantar)
• Cryotherapy (freezing) . NB: This is painful, therefore best avoided
• Imiquimod 5% cream (anogenital warts)

lUNGWORM (TINEA) ·
Ringworm is caused by superficial fungal infection with dermatophytes which invade the keratin layer. The three
species of superficial dermatophyte are: trichophyton, epidermophyton and microsporum .
'Tinea' means moth-eaten.
The areas affected are:
• Tinea capitis =scalp } . .
• Tinea corporis = body (trunk and limbs) Common m chlldren
• Tinea pedis =feet (mainly soles and toe webs)
• Tinea ungium = nails- rare in children

Cli nical features

A ringworm lesion is typically red, scaly and annular with an active raised border and central clearing.
In tinea capitis hairs may be broken just above the scalp, producing a black dot appearance. A kerion is an inflamed,
pustular scalp lesion.

Investigations
Fungal identification (Skin scrapings, nail clippings, hair) Fungal hyphae may be seen on microscopy but fungal
culture is essential for confirmation and identification of the fungus

Treatment
Tinea corpon's Topical antifungal for 2-4 weeks
Tinea capitis, T. ungium Systemic antifungal course for at least 6 weeks
and widespread T. corpan·s
NB: Check if siblings/parents are affected.

296
 PITYRIASIS VERSICOLOR
Common superficial yeast infection of adolescence with Pityrosporum orale (Malassezia furfur) (a skin commensal).
Presents as pink-brown (hypopigmented if sun-tanned) macules, usually on the neck, upper chest, upper arms and
back.

Investigations
Woods light view Lesions become more apparent
Skin scrapings Microscopy and cu lture

Management
Topical anti-yeast cream, e.g. ketoconazole.

HEAD LICE
~ Very common infestation usually confined to the scalp. Pediculus humanus capitis (head louse).

Clinical features
• Itchy scalp
• Eggs stuck to hair shaft
• Lice crawling around scalp

Treatment
• Comb hair with lice comb to remove both eggs and lice
• Chemical applications, e.g. malathion, superior to shampoos (resistance is a problem)

SCABIES
An irritative skin reaction to the female mite Sarcoptes scabiei.
Transmission by direct contact.

Clinical features
Scabies burrows Curved red tracts with the mite in a vesicle at one end. Usually very few (< 10) mites
Most likely to be found:
• Infants: palms, soles and side of feet. Often widespread papules
• Older children: finger webs, wrists, elbows, ankles, axillae, scrotum and penis
Rqsh Widespread intensely itchy allergic reaction to mites, their eggs and excretia after 4- 6 weeks -
erythematous papules, pustules and excoriations

Investigations
• Clinical diagnosis
• Removal of the mite or its eggs by applying KOH solution over a burrow, scraping with a needle and identification
under the microscope

Treatment
• Treat patient and all close contacts
• Topical scabicide, e.g. permethrin cream, after a bath to whole body (and head in infants< 2 years)
• All bed linen and immediate clothes hot washed

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NB: The itching usually improves rapidly but may take a few weeks to resolve completely.

CUTANEOUS REACTIONS

ERYTHEMA NODOSUM
Females > males. Usually >age 6 years.

CLinicaL features
• Painful, shiny, hot, red elevated oval nodules (1-3 em) over the shins (sometimes thighs and upper limbs)
• Become purple and then fade over 2-4 weeks
• Systemic symptoms: fever, malaise, arthralgia and hilar lymphadenopathy

Causes
Infections Bacterial - streptococcus, mycoplasma, TB
Enteric infections - salmonella, yersinia
Viral- EBV, HBV, chlamydia
Fungal - histoplasma, coccidiomycosis
Inflammatory bowel disease Crohn disease, ulcerative colitis
Autoimmune disease Sarcoidosis, SLE, Beh~et disease
Drugs Sulphonamides, oral contraceptive pill

Management
Bed rest and NSAIDs. Treat the cause.

ERYTHEMA MUlTIFORME
A cutaneous reaction pattern of variable appearance.

Clinical features
• Target lesions -erythematous border, dusky centre and middle paler ring . May become bullous. Anywhere on the
body (classically hands and feet initially)
• Typical target lesions not always seen
No treatment is required. Spontaneous resolution in 2- 3 weeks.

Causes
• Herpes simplex virus infection (most common cause)
• Post-infection
• Drugs, e.g. sulphonamides

Stevens-Johnson syndrome
A severe form of EM (considered on a spectrum with TEN) involving:
• Cutaneous erythema multiforme rash
• Systemic upset with fever
• Profound mucous membrane involvement: Conjunctivitis, uveitis, corneal ulceration, corneal scarring may occur
Oral and genital ulcers

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 causes
Infections Bacterial - Group A streptococcus, mycoplasma
Viral- HSV, EBV
Fungal - histoplasmosis
Drugs Penicillin, sulphonamides, aspirin, anticonvulsants, barbiturates
Connective tissue disease SLE, sarcoidosis
Malignancy Leukaemia, lymphoma
Other Vaccinations, radiotherapy

Treatment
• Supportive, e.g. IV fluids and intensive therapy, as needed
• Steroids controversial
• Ophthalmological consultation essential

,,;..,
)'
TOXIC EPIDERMAL NECROLYSIS (TEN)
Amore severe disease (usually a drug reaction) causing damage to the basal cell layer of the epidermis with generalized
bullae and loss of sheets of epidermis. Extensive mucous membrane involvement and systemic upset. More common
in adults.

Management
• Remove cause
• Intensive care with attention to fluid and electrolyte balance, analgesia, secondary infection, specialist skin and
eye care, nutrition, ventilation if necessary and monitoring of other systems (renal, liver, gut, cardiovascular,
respiratory)
Most cases survive but there is significant mortality.
NB: Toxic shock syndrome (TSS) is a condition seen most commonly in menstruating women, involving erythema and
desquamation, but there are no bullae and no skin tenderness (see p. 58).

MASTOCYTOSIS
Disorder involving proliferation of mast cells, mostly in the skin. The clinical picture is variable with urticaria pigmen-
tosa most commonly seen in children.

Clinical features
Urticaria pigmentosa Small red-brown macules and papules containing the mast cells widely dispersed
on the skin; may blister
Develops during first 2 years of life
Darier's sign = if lesions rubbed, wheal and flare occurs due to local histamine
release
Solitary mastocytoma Solitary skin lesion 1-2 em diameter. Involutes spontaneously
Diffuse cutaneous mastocytosis Rare. Diffuse skin involvement causing yellow thickened cracked skin, intense
pruritis ±systemic involvement
Systemic features of histamine release (tachycardia, hypotension, syncope, wheezing) may rarely occur.

Prognosis
Spontaneous resolution over a number of years.

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VASCULAR BIRTHMARKS

Permanent vascular malformation due to ectasia of superficial dermal capillaries. Always present at birth. Appear as a
macular erythema that gradually darkens with age.

Treatments
• Pulsed dye laser therapy (destroys the ecstatic capillaries)
• Cosmetic camouflage

Associations
Glaucoma PWS of the face with eyelid involvement may be associated with glaucoma of the affected
eye
Sturge-Weber syndrome 1. PWS of the face roughly in the distribution of Vl and V2 branch of the trigeminal
nerve, almost always involving the forehead and upper eyelid, and
2. Ipsilateral leptomeningeal vascular abnormality with neurological symptoms:
• Focal seizures, and/or
• Hemiparesis (slowly progressive)
• Mental retardation
Glaucoma of the ipsilateral eye may be present (30-60%)

Investigations
(Necessary if glaucoma or Sturge-Weber syndrome suspected)
Skull X-ray Intracranial calcification, 'railroad track' appearance
CT brain scan Intracranial calcification, cortical atrophy
MRI brain scan Vascular anomaly outlined (with gadolinium enhancement)
Ophthalmology Intraocular pressure measurement

Management
Seizures Anticonvulsants
Surgery (hemispherectomy or lobectomy) may be considered
Glaucoma Regular intraocular pressure checks and any necessary treatment
Port-wine stain Laser therapy and camouflage, as above

KUPPEL-TRHJA.UNAY SYNDROME
A syndrome involving:
• Port-wine stain on a limb
• Soft tissue and bony hypertrophy
There may also be:
• Venous varicosities, thromboses, ulceration
• A-V fistulae (described by Weber, i.e. Klippel Trenaunay Weber syndrome)

Complications
Cardiac failure, OVT, pain, haernaturia (bladder lesions), rectal bleeding (bowel lesions).

300
 Investigations
• Angiograms, if needed
• MRI scan, if needed

Management
• Port-wine treatment, as above
• Cardiac failure treatment
• Orthopaedic procedures (leg length discrepancies)
• Surgical treatment if necessary

SALMON PATCH

Acommon pale pink vascular malformation (dueto dilated superficial dermal capillaries) present at birth on the face
(eyelids, glabella, forehead). They tend to fade during first few months of life.
Those on the nape of the neck are known as 'stork bites' and usually remain for life.

- INfANTILE HAEMANGIOfVlAS
Incidence 1:20 infants.
Assodation Premature birth
• Benign vascular tumours
• Rarely present at birth, but appear during the first few weeks
• Enlarge over 6- 12 months, then slowly regress. Most have involuted by 5 years. Residual cosmetic defect in a
few
• May be superfidal (bright red, strawberry haemangiomas), deep (bluish, cavernous haemangiomas) or mixed
No treatment necessary unless:
• Large disfiguring lesion
• Complications.

Complications
• Ulceration/infection
• Haemorrhage
• Intert'ering with vision
,,• Interfering with breathing
• Interfering with feeding
• Platelet consumption coagulopathy (Kasabach-Merritt)
• Heart failure (multiple haemangiomas with internal lesions)

Treatment
• Systemic steroid course
• Intralesional steroid injection
• Laser therapy (early, ulcerated lesions)
• Surgical excision '

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 · ~:

KASABACH-iViERRITI SYNDROME
A syndrome of:
• Rapidly enlarging haemangioma
• Consumption coagulopathy (acute or chronic) -thrombocytopenia , consumption of clotting factors, petechiae,
haemorrhage, anaemia
High-output cardiac failure may result from A-Vshunting in large lesions.

Management
• Platelet, blood and FFP transfusions
• Cardiac failure treatment
• Haemangioma therapy (as above); embolization may be necessa ry

NEONATAl ~IAEIVJANGIOMATOSIS

• Multiple small haemangiomas of the skin, with internal haemangiomas of two or more organs, e.g. liver, CNS,
gastrointestinal tract and lung
• USS and CT/MRI scans needed to detect extent of disease
• High-output cardiac failure may occur from A-V shunting, particu larly if liver haemangiomas are present

NAEVI
Naevi are skin lesions with a collection of particular cells that are normally fou nd in the skin. Melanocytic naevi
(moles) are benign tumours of melanocytes. They may be congenita l or acquired.

CONGENITAl MELANOCYTIC NAEVI (CMN)

• Present at birth. May be small or very extensive ·(giant)
• Incidence approximately 1% of infants
• Giant CMNs (> 20 em diameter) incidence 1:10 000. Generally on the trunk or lower limbs, e.g. 'bathing trunk
naevus'
• Associated with intracranial and intraspinal melanosis (diagnosed on MRI scan)
• Small increased risk of malignant transformation (melanoma) with larger CM Ns
• Treatment to improve cosmetic appearance is possible but case-specifi c. Treatment options include de rmabrasion,
laser therapy and full depth excision. Often left untreated

ACQUIRED ~~I ELANOCYTIC NAEVI (MOLES)

• These develop during childhood and new moles continue to appear well into ad ult life. Average number is 25-50
per adult
• Classified as junctional (within the epidermis - flat and pigmented), compound (junctional and dermal compo-
nents - raised and pigmented), intradermal (within the dermis- raised and flesh-coloured) or blue naevus (deep
dermal- dark bluish colour) according to their depth
• Increased melanoma risk related to number of naevi, family history, sun exposure and sunburn during childhood,
and immunosuppression

SPITZ N?\fV US
Rapidly growing reddish naevus of childhood, most commonly on the face. It is benig n, however histological features
can resemble a melanoma and therefore it is removed if there is diagnostic doubt.

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INFlAfv1MATORY LINEAR VERRUCOUS EPIDERMAL NAEVUS (ILVEN)
An uncommon condition usually appearing in the first 6 months of life. A linear epidermal naevus that has a warty
appearance and may be pruritic. It is generally refractory to treatments. Treatment options include steroids, cryo-
therapy, surgical excision and laser therapy. ILVEN may improve spontaneously.

ALOPECIA
This is hair loss to the extent that the scalp becomes abnormally visible.

DIFFUSE HAIR LOSS

Telogen effluvium Hair loss in the telogen (resting) phase
Seen 3-4 months after an event or illness, e.g. severe illness, pregnancy, stress, sudden weight
loss, recovers 6 months later
Anagen effluvium Hair loss in the anagen (growing) phase, e.g. chemotherapy

PATCHY HAIR LOSS

Alopeda areata Gradual patches of hair loss develop
Lower occipital hairline may be lost
Cause unknown
Scalp is normal, and short broken }exclamation mark' hairs seen (short new hairs the shape of
exclamation marks under the microscope)
Eyebrows, eyelashes and body hair may be affected
Nail pitting is common
Alopecia totalis - total scalp hair loss
Alopecia universalis- total scalp and body hair loss
Associations: autoimmune disease, atopy, Down syndrome
Variable prognosis. Usually hair re-grows spontaneously within weeks/months. 90% recovery if
only one patch, worse prognosis if extensive
Trichotillomania Hair loss (usually patchy) due to child pulling hairs
Common in a mild form in young children, in whom it may reflect anxiety. Extensive disease
(generally seen in adolescents) can be a sign of severe emotional disturbance, and associated
with other psychopathology

DISORDERS OF PIGMENTATION
I

AtBINISM
This i3 due to a partial or complete failure of melanin synthesis of which there are many types, mostly autosomal
recessive.
The degree of hypopigmentation varies depending on whether there is reduced or absent melanin synthesis.
Ocular albinism Affects only the eyes. Four types. Sensorineural deafness may be associated
Oculocutaneous albinism Affects eyes and skin . Nine types
Melanin production:
Phenylalanine --7 Tyrosine --7 Melanin
Tyrosinase catalyses three steps in this process.

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Clinical features
Skin Depigmentation of skin (white or pale) and hair (white or blonde)
Eyes Blue-grey iris, nystagmus, photophobia, decreased acuity, prominent red reflex
Depigmentation of retina
Complications Blindness, skin cancers

Oculocutaneous albinism
There are nine types of oculocutaneous albinism, including:
Type IA (tyrosinase negative) Pale skin, white hair, red iris. Tyrosinase gene mutations
Type II (tyrosinase positive) Most common, some pigmentation. Gene defect on chromosome
15q11-13 (p gene, catalyses steps in melanin synthesis)
Seen in 1% of Prader-Willi and Angelman syndrome
Hermansky-Pudlack syndrome Atyrosinase-positive albinism associated with:
• Platelet storage pool deficiency and coagulation problem
• ± Pulmonary fibrosis, granulomatous colitis
Chediak-Higashi syndrome Tyrosinase-positive oculocutaneous albinism with abnormal leucocyte
granules and increased infections (seep. 34)

Management
There is no specific management. Complete sun protection and regular ophthalmology follow-up are important.

INCONTINHlTIA PIGIV!ENTI
X-linked dominant (mostly lethal in males, functional mosaic in females). Gene locus has been demonstrated on Xq28
and Xp11.2.

Clinical features
There are three stages but the sequence is irregular and stages may. overlap.
Skin Stage 1 Vesicles in linear patterns on limbs, occur in crops (first weeks of life)
Stage 2 Red plaques, papular, warty lesions in linear patterns (from 4 months)
Stage 3 Classic picture, from 1-16 years. Hyperpigmentation in linear
streaks and whorls (following lines of Blashko) in a 'splashed' or
'Chinese figure' distribution. This may be the only stage seen.
These slowly fade to become hypo pigmented, atrophic lesions
Teeth Conical teeth, hypodontia
Hair (25%) Cicatricial alopecia
Eye (30%) Microphthalmos, optic atrophy, strabismus, cataracts, blindness
CNS (25%) Seizures, microcephaly, mental retardation, spasticity, paralysis
Nails Usually normal, may be dystrophic and small

HYPOMElANOSIS OF ITO
A clinical picture of hypo pigmented lines and whorls following lines of Blashko, usually present from birth, resembling
(though unrelated to) the late stages of incontinentia pigmentii.

Clinical features
CNS Mental retardation, seizures, microcephaly, hypotonia
Musculoskeletal ·Scoliosis, limb deformities

304
Eyes Strabismus, nystagmus
cvs CHD

PIEBALDISM (WHITE SPOTIING)

Autosomal dominant. Localized patches of depigmentation due to absence of melanocytes, mostly on the upper chest,
abdomen and limbs, and a white forelock. Bilateral involvement, though not symmetrical. The patches are present from
birth and remain unchanged throughout life.

WAAROENBURG SYNDROME
Autosomal dominant, variable penetrance. Type I caused by mutations in PAX3 gene (Ch2q), type II by mutations in
Ch3p.
Asyndrome of:
• Lateral displacement of inner canthi (type I only), inner third of the eyebrow is hyperplastic, brows may be
confluent, broad nasal bridge
• White forelock, premature greying in the third decade
• Deafness (25% type I, 50% type II)
• Heterochromic iris (25%), hypopigmented fundus
• Cutaneous depigmentation lesions resembling piebaldism

VITILIGO
A common acquired condition in which the melanocytes are destroyed, resulting in depigmented patches, which may
be extensive.
Thought to be autoimmune. Associations with other autoimmune disorders:
• Thyroid disease, hypoparathyroidism
• IDDM, pernicious anaemia, Addison disease
• Myaesthenia gravis, alopecia areata, morphoea
• Halo naevus
• Raised autoantibodies
• Positive family history (40%)

Clinical features
• Usuatly symmetrical completely depigmented macules, especially around the eyes and mouth, nipples, genitalia,
. knees and elbows (areas that are usually hyperpigmented), and trauma sites
,, • Premature greying of hair associated
• Pfesentation < 20 years in half of cases
• Segmental childhood form (in which only one area is affected) has a good prognosis

Management
May repigment spontaneously (10-20%) but usually progresses. Treatment is disappointing and includes:
• Drug treatments: Topical steroids to affected areas for a few weeks, topical immunomodulators
Oral psoralens with UV light
• Camouflage make-up
• Sun protection for affected areas

305
 ..,~
.­
··.~

''

CONGENITAL ICHTHYOSES
These are a heterogeneous group of conditions with rough, dry skin and scaling.

KHnlVOSIS VUlGARIS
• Autosomal dominant. Incidence 1:300
• Mild dry rough skin and hyperlinear palms
o Increased incidence of atopic eczema. Treated with regular emollients

COU.OirHAN BABY
A distinct appearance at birth of a tight, glistening membrane (like a sausage skin), which slowly sheds to reveal the
skin beneath. Everted lips and eyes may be present. These features result in limited chest expansion, temperature
instability, potential dehydration and electrolyte imbalance, feeding difficulties and susceptibility to infections.

Initial management
• Intensive care in a warm humidified incubator
• Regular application of paraffin oil
• High fluid intake (may need NG or IV) with careful electrolyte monitoring
• Early recognition and treatment of sepsis
Usually due to rare forms of ichthyosis (lamellar or ichthyosiform erythroderma), and occasionally to a mild
ichthyosis.

i~ARLEQUIN ICHTHYOSIS
A severe type of ichthyosis with a distinct appearance at birth. Features include the following:
• Prematurity (occasionally stillborn)
• A rigid, hyperkeratotic covering of thick, yellow plaques at birth
• Cracks occur soon after birth leaving deep red fissures (like a harlequin)
• Ears are tethered, hands anc_l feet encased, mouth open
• Severe ectropion (everted eyes) and eclabion (everted lips)
Treatment is as for colloidian baby, and in addition oral retinoid therapy may be used. With good general care and early
retinoid therapy these babies now survive. They have a distinct severe ichthyosis however.

X-LINKED RECESSIVE IC HTHYOSIS (XlRI)

• X-linked, female carriers may have some features
• A mild ichthyosis with dark skin scaling, corneal opacities
• There is an underlying lipid defect of steroid sulphatase deficiency
• Prolonged labour in carrier mothers (due to placental steroid sulphatase deficiency)

Kallman syndrome
XLRI associated with anosmia, hypogonadotrophic hypogonadism and neurological defects.

• Autosomal recessive, very rare condition

• Brown, scaly skin ('lizard skin'), with thick soles and palms

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NON-BUllOUS ICHTHYOSIFORM ERYTHRODERMA (NBIE)
Autosomal recessive, rare condition. Fine white scales and erythroderma.

Management of Ichthyoses
• Emollients (bath oils, frequent application of paraffin oil)
• Oral retinoid therapy in severe types

VESICULOBULLOUS DISORDERS

EPIDERMOLYSIS BULLOSA
Agroup of inherited skin disorders characterized by skin fragility and blister formation.
The three main types (of which various subtypes exist):

Epidermolysis bullosa simplex

The most common form. Autosomal dominant. Non-scarring intraepidermal blisters of the arms, legs, hands, _feet and
scalp. Palms and soles mainly affected in some types. Limits walking. Improves with age. Mutations in keratin genes.

Junctional epidermolysis bullosa

A more severe form involving blisters within the lamina lucida of the epidermis. All areas of skin affected, nails are
shed. Internal blistering of the respiratory and gastrointestinal tracts, mid-facial erosions, hoarse voice, stridor.

Dystrophic epidermolysis bullosa

A variably severe form involving blisters below the lamina densa of the epidermis. The blisters leave atrophic scars
and milia. Two types, both caused by mutations in the COL7 Al gene that encodes for the anchoring fibril protein, type
VII collagen .
Autosomal dominant form Scarring blisters mostly of the hands, feet and sacrum
Nail loss. Generally less severe than recessive form
Autosomal recessive form Severe disease with widespread atrophic scarring blisters with milia formation, mitten
hand deformity (digital fusion)
Oesophageal strictures affect nutrition. Sparse hair, dystrophic nails, corneal ulceration

CHRONIC' BULLOUS DERMATOSIS OF CHILDHOOD (UN EAR IgA DERMATOSIS)

Us-ually occurs < 10 years.
Associations HLA-B8, DR3

Clinical features
Bullae Multiple tense bullae on buttocks, genitals, trunk, perioral area, face and limbs
Urticated plaques with blisters around the edge (string of pearls sign)
Mucosal involvement. Blisters may form rosettes
Pruritis sometimes present
Usually of 3-4 years' duration

Investigations
Skin biopsy Subepidermal blister, linear lgA BMZ antibodies

307
Management
Dapsone (steroids if no response).

DNA FRAGILITY SYNDROMES

Autosomal recessive. Disorder of defective DNA repair. Light in the wavelengths 280-340 nm results in DNA damage.
Seven complementation groups (on different chromosomes) known .

Clinical features
Skin Freckling, erythema, scaling, crusting and telangiectasia in sun-exposed areas (premature ageing)
Skin cancers develop (BCC, sec, malignant melanoma)
Eyes Cornea l opacities, blepharitis, photophobia, eventual blindness
CNS {20%) Mental retardation, deafness

Management
• Total sun protection (glasses, clothes, total sunblock)
• Antenatal diagnosis possible with amniocentesis

Prognosis
Early death from developing cancers and neurological problems.

ECTODERMAL DYSPLASIA$
A group of many disorders involving a defect of teeth, hair, nails and skin. There are many subtypes.

HC SYNDRm~E {ECTFWDACTVLY-ECTODERMA.l DYSPLASIA CUFTING SYNDROME)

Autosomal dominant.
• Ectodermal dysplasia (dry skin, wispy hair, no eyelashes)
• Cleft lip palate
• Lacrimal duct stenosis
• Ectrodactyly (split hands and feet, 'lobster claw' deformity)
• Peg-shaped teeth

HYPmm:monc ECTODERMAL DYSPLASIA

X-linked recessive. A syndrome of:
• Decreased/absent sweat glands - discomfort in hot tempe ratures, unexplained fevers
• Hypotrichosis
• Hypodontia, conical teeth
Other features include:
Facial dysmorphism Large ears, flat nasal bridge, frontal bossing, thic k everted lips
Hair Sparse, dry, short scalp hair
Skin Dry, hypopigmented, prematurely aged, brittle nails
CNS . Learning difficulties in approximately 30%

308
 Investigations
sweat pores Absent or decreased in palmar ridges
Sweat test Reduced or absent (pilocarpine iontophoresis)
Skin biopsy (palm) Eccrine gland hypo/aplasia

HIDROTIC ECTODERMAL DYSPLASIA

Autosomal dominant.
• Smalljabsent dystrophic nails
• Hyperkeratosis of palms and soles
• Thin, pale, brittle hair
NB: Normal sweating and teeth.

~ EHLERS-DANLOS SYNDROMES
A group of connective tissue disorders of different genetic origin, involving deficiencies of collagen.

Clinical features
Normal at birth
Skin Hyperelasticity, fragility, easy bruising, atrophic 'cigarette paper scars'
Joints Hypermobile, tendency to dislocate
There are several different types (10 at present), each possessing specific clinical features which include:
• Premature birth (with PROM)
• Mitral valve prolapse, dissecting aortic aneurysm
• Bowel rupture, uterine rupture
Mutations_ have been found in collagen III and other genes.

CUTIS LAXA
Autosomal recessive, autosomal dominant or acquired. Pathogenesis is due to defect(s) in elastin (exact mechanism
unknown). Acquired cutis Laxa appears during childhood and may follow a febrile illness; connective tissue disease,
e.g. SLE, amyloidosis; inflammatory skin condition, e.g. erythema multiforme; or occur in babies from women on
penicillam,ine.

Clinical features
Skin r Folds of lax skin from birth or later in childhood. Premature ageing, 'bloodhound' facial
appearance
Other features (Seen in recessive types) Hernias, rectal prolapse, diverticular disease, pneumothoraces,
emphysema, peripheral pulmonary stenosis, aortic dilatation, skeletal abnormalities,
dental caries and growth retardation

FURTHER READING
Harper J, Oranje A, Prose N Textbook of Paediatric Dermatology. Oxford: Blackwell Science, 2000
Higgins E, duVivier ASkin Disease in Childhood and Adolescence. Oxford: Blackwell Science, 1996

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 ----,
I

• Autoantibodies • Vasculitis
• Juvenile idiopathic arthritis • Amyloidosis
• Systemic lupus erythematosus • Osteogenesis imperfecta
• Antiphospholipid syndrome • Osteopetrosis (marble bone disease)
• Idiopathic inflammatory myopathies • Osteochondrodysplasias
• Scleroderma disorders • Non-inflammatory pain syndromes
• Mixed connective tissue disease • Syndromes involving absent radii
• Sjogren syndrome

AUTOANTIBODIES
Non-organ specific autoantibodies associated with rheumatic disease are outlined. None is absolutely diagnostic but
many are quite sensitive and specific.

Rheumatoid factor (RhF)

Antibody to the Fe portion of IgG (usually IgM detected, also IgG, IgA and IgE).
Positive in JIA (some types)
Adult RA (commonest group)
Connective tissue disease, e.g. SLE, Sjogren syndrome
Chronic infections, e.g. HIV, hepatitis, TB, endocarditis
Leukaemia, lymphoid malignancies
Pulmonary fibrosis
General population (:S: 4%)

Antinuclear antibodies {ANA)

These arc antibodies to nuclear components and include:
Anti-ds DNA SLE (80%, specific)
Anti-ss DNA SLE (90%, non-specific), drug-induced lupus, other connective tiss ue disease

310
 Anticentromere Limited cutaneous systemic sclerosis (formerly CREST syndrome)
Antihistone SLE, drug-induced lupus particularly

Antiextractable nuclear antigens (ENAs)

. Anti-Sm (Smith) SLE (20%, quite specific), normal population
; Anti-nRNP MCTD (100%), SLE
Anti-SSA (Ro) SLE, neonatal lupus, Sjogren syndrome, rarely normal population
Anti-558 (La) SLE, neonatal lupus, Sjogren syndrome, rarely normal population
Anti Jo-1 JDM some forms, rarely juvenile

Antineutrophil cytoplasmic antibodies (ANCAs)

Antibodies to antigens within the cytoplasm of neutrophils.
c-ANCA (cytoplasmic) Wegener granulomatosis (specific usually to proteinase 3 antigen), microscopic polyangiitis
(renal)
p-ANCA (perinuclear) Non-specific usually to myeloperoxidase (infection, many autoimmune diseases, e.g. Churg-
Strauss, Kawasaki disease)

Antiphospholipid antibodies
Antibodies to phospholipid antigens. Associated with thrombosis in vivo but coagulation prolongation in vitro (lupus
anticoagulant test positive) .
Seen in SLE and antiphospholipid syndrome, e.g. anti-~ 2 -glycoprotein and anticardiolipin antibodies.

JUVENILE IDIOPATHIC ARTHRITIS (JIA)

Agroup of disorders defined as:
• Chronic synovitis (~ 6 weeks) ±extra-articular features
• Occurring before 16 years of age
Some are reclassified at 6 months due to evolution.
Cause unknown, though autoimmune genetic and environmental factors probably interact.

Features of involved joints

• Early morning stiffness
I
• Swelling, warm (not hot), occasionally red and tender
.,•
•
•
Limited painful movement
Contractures may develop rapidly
Bony deformity may develop rapidly
Naccow;og of
the joint
i,i!
space~ Osteoporos;s
E .
Cystsw roSIOOS
X-ray changes
Early Soft tissue swelling, osteopenia, periosteal new bone formation
Late Bony overgrowth, osteoporosis, subchondral bone erosions, joint
space narrowing, collapse, deformity, fusion, subluxation
Figure 13.1 X-ray changes in JIA

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OUGOARTICUlAR JlA
Involvement of::::; 4 usually large lower limb joints in the first 6 months of disease.
• Female > male, onset 2-4 years of age
• Knees, ankles, elbows - bony overgrowth, leg length discrepancy and valgus deformity are important features
• lfs will go on to have> 4 joints affected beyond 6 months (extended oligoarticu lar JIA)
• Chronic iridocyclitis (uveitis) eh)
No early symptoms, detectable with slit-lamp only. Untreated ca uses synechiae, glaucoma, cataracts and blind-
ness
Slit-lamp examination imperative 3 monthly
Treatment with topical steroids and mydriatics
• ANA positive {90%) -increased risk of eye disease
• HLA-DR5, 8, DP0201 positive
• RhF and HLA-B27 negative
• ESR (i or N)

POlYARTICUlAR JIA
Involvement of> 4 joints by 6 months of onset (usually many more) . Female > male.
Two sub-types:
RhF negative (30% of JIA) Moderate to severe disease,< 8 years, HLA-DRl
Asymmetrical, small and large joints, especially the TMJ and cervical spine
Occasional iridocyclitis (5%)
RhF positive (10% of JIA) Equivalent to adult RA
More severe, ~ 8 years, HLA-DR4
Symmetrical, hands and feet and hips
Rheumatoid nodules, tenosynovitis and vasculitis may develop
Particular joint problems seen due to distorted growth :
Cervical spine Fusion or subluxation, anaesthetic difficu lties
Temporomandibular joint (TMJ) Micrognathia, dental hygiene and anaesthetic difficulties
Hips Destruction, limb shortening
Knee Overgrowth causing valgus deformity

Investigations
• ESR often marked i
• ANA may be positive in 30-40%

312
 SYSTEMIC-ONSET JIA (SOJIA)
All ages, but peak 3-6 years. Females = males.
Aclinical diagnosis of exclusion. Differential diagnoses:
• Infection
• Malignancy, e.g. leukaemia, neuroblastoma
• Vasculitis, other connective tissue disease

Clinical features
Defined by:

• Arthritis and characteristic fever - quotidian fever (39-40°( x 1-2 per day returning to baseline); usually
appears very unwell while febrile
• Plus one of: Evanescent rash - classically heat/fever-induced salmon pink macular but may be
urticarial and red in some
lymphadenopathy
Hepatosplenomegaly
Serositis (typically pericarditis)
• Also: myalgia, arthralgia, abdominal pain, pleuritis
• Joints - polyarthritis may be delayed some months in onset and is severely destructive in 50%. The other half
have relatively remittive or mild disease
• late features- short stature, micrognathia, amyloidosis (now rare)

Investigations
FBC Anaemia of chronic disease, wee i (neutrophilia), platelets i
Acute phase proteins ESR usually very marked/, CRP i
Autoantibodies ANA and RhF negative

ENTHESITIS-RELATEO ARTHOPATHY (ERA)

These children typically have an enthesitis (swelling at tendon and ligament insertions, including Achilles tendon and
plantar fascia). ERA is part of a general group called spondyloarthropathies. Predominantly males, : : : 8 years.
• Arthritis and enthesitis, or
• Arthritis or enthesitis plus at least two of: Sacroiliac or inflammatory spina l pain
Acute anterior uveitis (10%)
HLA-B27 positive
-, Positive family history of 827 positive disease
• Typically
7
lower limb, great toe, tarsus, hip and enthesitis (especially heel), sacroiliac and axial arthritis in only
s; 20% over time
• May progress to ankylosis
• HLA-827 (90%)
• RhF and ANA negative, ESR (i or N), anaemia of chronic disease
X-ray changes
As for oligo/polyarthritis, and with spinal disease:
• Erosion of sacroiliac joints
• Loss of lumbar lordosis
• Tram line appearance (due to calcification of interspinous ligaments)
• Bamboo spine

313
REACTIVE ARTHRITIS
Reactive arthritis is viral and post-infectious arthritides, includin~J acute rheumatic fever and arthritis following
respiratory, genitourinary tract and gastrointestinal tract infections. ·
(Reiter syndrome is a special subtype with a classical triad - arthritis, conjunctivitis, urethritis/cervicitis - usually
coexisting. Very rare in childhood.)

Clinical features
• Predominantly lower limb, asymmetric, oligoarthritis
• Clear history of infection during preceding 4 weeks (esp. diarrhoea) _
• No clear clinical infection of the joint and no other known cause of arthritis present
• Yersinia, shigella, salmonella, campylobacter (adolescent - venereal infection)
• Mycoplasma and streptococcal infections may precipitate
• May last weeks-months with recurrences over several years

Investigations
• Throat and stool culture
• Serology and PCR
• ANA and RhF negative. Sometimes HLA-B27 positive (if arthritis ERA-like)
• Synovial and urethral tests where appropriate

MANAGEMENT Of JIA
• Early intervention improves prognosis and may delay/prevent irreversible bony changes and loss of function
• Physiotherapy, occupational therapy, podiatry - for stretching, increasing strength, improving function, joint
splinting, foot orthoses
• NSAIDs for initial symptom control
•. Intra-articular crystalline steroid injections are mainstay of all mild to moderate disease
• Disease-modifying drugs (DMARDs) if polyarticular or uncontrolled oligoarticular or systemic, e.g. methotrexate,
leflunomide, cyclosporine
• Biological anticytokine therapies for severe resistant disease - etanercept or infliximab (anti-TNF therapy), or
anakinra (anti-IL-1)
314
 • Sulphasalazine for ERA
• Steroids - oral prednisolone or IV pulsed methylprednisolone if rapid control required, but aim to withdraw as
soon as possible

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

A multisystem autoimmune disease associated with serum antibodies against nuclear components. Females > males,
usually > 10 years at onset.
Associations HLA-88, -DR2, -DR3
African/oriental> Caucasians

Clinical features
General (v. common) Faltering growth, malaise, weight loss, fever
Skin (v. common) Butterfly rash (80%) - over nose and cheeks
Photosensitivity (33%)
Discoid Lupus: plaques causing scarring and scarring alopecia. Skin only involved in
some
Also papular, vesicular, purpuric, vasculitic lesions or periungual erythema
Raynaud phenomena, alopecia, mucosal ulcers
Kidneys (common) Proteinuria, glomerulonephritis, BP t, renal failure (see p. 229)
Musculoskeletal (common) Arthralgia (80%), arthritis, aseptic necrosis hip and knee, myalgia, myositis
Blood (common) Platelets t, haemolytic anaemia, neutrophils j,
CNS Headache, behavioural change, depression, epilepsy, blurred vision
Eyes Iritis, episcleritis, retinitis, Sjogren syndrome
Lungs Effusions, pleurisy, interstitial fibrosis, haemorrhage
Heart Pericarditis, myocarditis, Libman-Sachs endocarditis, cardiomyopathy
Gastrointestinal Hepatosplenomegaly, mesenteric arteritis, IBD

Investigations -
FBC Anaemia (chronic disease or haemolytic), platelets J,, lymphopaenia characteristic
Acute phase proteins ESR i (with disease activity), CRP typically low or normal
Autoantibodies dsDNA (50%), anti-Sm (20%) specific for SLE
ANA (usually strongly positive)
Anticardiolipin (antiphospholipid), RhF (50%)
Immunology Complement (C3 J, in active disease), IgG and IgM (i)
Histology' Haematoxylin bodies (amorphous extracellular material staining with h<Jematoxylin), vasculitis,
granulomas. Immune complex, immunoglobulin and complement deposition

Man~gement

• NSAIDs for mild joint disease

• Hydroxychloroquine (for skin, arthralgia and lethargy, and prevention of dyslipidaemia)
• Systemic steroids (oral or pulsed IV)
• Immunosuppressants, e.g. cyclophosphamide, azathioprine, mycophenolate mofetiL BioloQics for severe resistant
disease.
• For skin disease: topical steroids and hydroxychloroquine

NEONATAL LUPUS
Usually occurs in infants of mothers with SSA(Ro) ± SSB(La) antibodies (SLE or Sjogren syndrome), and is acquired
transplacentally. ·

315
Clinical features
This presents with different combinations of clinical features.
1. Congenital heart block (permanent), or
2. Neonatal lupus rash, often with )
3. Haematological abnormalities (Hb t, platelets l,WCC 1) Self-limiting
4. Hepatic involvement- mild

Investigations
Autoantibodies ANA, anti-SSA (Ro ), anti-platelet, Coombs' positive
FBC Platelets l Hb t,wcc t
ECG Complete heart block, may be partial and progress

Management
Pacing for cardiac disease.

ANTIPHOSPHOLIPID SYNDROME
Asyndrome characterized by antiphospholipid antibodies which are involved in thrombosis. May-be associated with SLE.
The lupus anticoagulant is a specific laboratory test which usually correlates with the presence of APL antibodies.

Clinical features
Thrombosis Arterial and venous, strokes, Budd- Chiari syndrome
CNS disease Epilepsy, migraine, strokes
Skin Livedo reticularis, thrombophlebitis, splinter haemorrhages, fingertip ulcers
Other Valvular heart disease, recurrent spontaneous abortions

Investigations
Serum -antibodies Antiphospholipid antibodies
Lupus anticoagulant
Coagulation APTI prolonged and does not correct with added serum in vitro

Management
• Anticoagulation -aspirin if antibody strongly positive, warfarin if serious thrombotic event
• Treatment of SLE

IDIOPATHIC INFLAMMATORY MYOPATHIES

These include:
• Dermatomyositis (commonest)
• Polymyositis (no skin involvement)
• Other myositis: Infectious, e.g. cryptococcus
Postinfectious, e.g. influenza A, streptococcus
Inclusion body
Focal

.JUVENIU:~ONSH !JERM!HOMYOSHIS
A multisystem disease involving inflammation of striated muscle and skin.

316
Assodations HLA-B8, -DR3, DQA1 *0501
Female > male

Clinical features
Muscle Symmetrical proximal muscle weakness and pain (Gower sign and waddling gait)
Respiratory muscle weakness
Dysphagia, dysphonia, palatal regurgitation
Skin Classic heliotrope violaceous rash over upper eyelids
Gottron's papules- red rash overlying DIP, PIP joints and knees
Nail fold capillaritis
Photosensitive rash, butterfly rash
Subcutaneous calcium deposits (20-50%) which may extrude
Joints Arthralgia and arthritis with contractures
Gastrointestinal Vasculopathy (ulcerations, bleeding), hepatosplenomegaly
Cardiac Myocarditis (arrhythmias)
Other Nephritis, interstitial lung disease, pulmonary haemorrhage, retinitis, CNS involvement
Investigations
Diagnosis based on clinical picture plus:
MRI Confirms typical inflammation of thigh muscles
Muscle enzymes LDH i, CK i, AST i, ALT i (may be deceptively normal)
EMG Myopathic. Rarely required
Muscle biopsy (Vasculopathy, inflammatory infiltrate and consequent muscle fibre necrosis) in equivocal cases.
Autoantibodies ANA may be positive, RhF usually negative, anti-Jo-1 when overlap with other CTD
Management
• Early active physiotherapy and splinting
• Systemic steroids (oral or pulsed IV)
• Immunosuppressives - methotrexate or cyclosporin. Cyclophosphamide in severe disease. Biologics in resistant disease.
• Other treatments, e.g. IV immunoglobulins, plasmapheresis, autolog.ous stem cell transplantation in rare cases
Prognosis
Untreated, the mortality is up to 40%, otherwise 2-5%. 30-40% will remain disabled

SCLERODERMA DISORDERS

L'OCAL!ZED SCLERODERMA (MORPHOEA)

Clinical features
Skin Discrete firm plaques (morphoea) or linear lesions following Blashko's lines (linear scleroderma). The lesions
are initially erythematous, becoming atrophic and shiny with raised violaceous borders. They are hyper- or
hypo-pigmented
Scarring and fibrosis beneath affected skin may lead to severe contractures and limb shortening
en Coup de Sabre (Lesion involving half of upper face, forehead and scalp, and may involve underlying
vasculitis in the brain and uveitis)
Other Tendon nodules, joint stiffness, arthritis
The natural history is usually for the disease to 'burn out' after a number of years. Methotrexate and biologics are used
to limit damage during the active phase.

317
SYSTEMIC SCLEROSIS
This is a multisystem disease characterized by occlusive vasculitis and fibrosis. Two forms are recognized:
• Diffuse cutaneous
• Limited cutaneous (formerly CREST syndrome)
Females> males. Rare in children, systemic manifestations cause significant morbidity and mortality.

Clinical features
Hands Raynaud phenomenon, digital ulcers, sclerodactyly (sausage fingers)
Skin Diffuse thickening and tightening, beak nose, small mouth, telangiectasia
Musculoskeletal Synovitis, tenosynovitis, myopathy
Gastrointestinal Dysphagia (oesophageal involvement), malabsorption
Lungs Fibrosis, pulmonary hypertension
Cardiac Pericarditis, cardiac failure
Renal Obliterative endarteritis, hypertension, chronic renal failure

Investigations
ESR Normal
Autoantibodies ANA (positive), RhF (may be positive), Scl70 (positive in some in systemic forms)
Skin biopsy Typical features of morphoea
Muscle biopsy Perivascular infiltration and fibre necrosis may be present

Management
• Physiotherapy
• Systemic steroids, immunosuppressants
• Antiprostacyclin agents for gangrene
• Bosentan (endothelin receptor blocker) or sidenafil for pulmonary hypertension
• Autolog_ous stem cell transplantation

MIXED CONNECTIVE TISSUE DISEASE (MCTD)

One of the overlap syndromes. This may not be a distinct entity and includes features of SLE, rheumatoid arthritis,
dermatomyositis and scleroderma. Mostly girls >6 years are affected. High titres of anti-RNP (ribonucleoprotein)
autoantibodies and speckled ANA. Predominantly a moderate polyarthritis and features of peripheral scleroderma
(sclerodactyly).
Prognosis is variable; renal involvement may occur and it may prog ress to classic SLE or scleroderma.

SJOGREN SYNDROME
Very rare in children, this disease typically involves:
• Dry eyes (keratoconjunctivitis sicca)
• Dry mouth (xerostomia)
• Parotitis
• Other vasculitis complications
• Dryness of the vagina and skin may also occur
Mothers who are anti-Ro positive may have infants with congenital heart block.

318
Assodations HLA-88, -DR3
Other connective tissue disease, e.g. SLE, vasculitis, Raynaud phenomenon
Autoimmune disease, e.g. thyroid disease, chronic active hepatitis
Renal tubule defects, e.g. nephrogenic DI, renal tubular acidosis
Clinical features
Eyes Photophobia, burning eyes
Glands Parotid and salivary gland enlargement
Mouth Decreased taste, dysphagia, angular cheilitis, fissured tongue
Nose Decreased sense of smell, epistaxis
Respiratory Bronchitis, otitis, hoarseness
Malignancy Lymphoma risk
Investigations
Autoantibodies Anti-Ro (SSA) (70%), anti-La (SSB)
ANA (positive 70%)
Schirmer test Filter paper placed inside eyelid. Wetting of< 10 mm in 5 min indicates decreased tear production
Biopsy Lip or salivary gland (focal lymphocytic infiltration)

Management
• Symptomatic (artificial tears and lozenges)
• Systemic steroids or immunosuppression may be needed

VASCUliTIS
Vasculitis is inflammation of the blood vessel wall. It may be a primary or secondary phenomenon.
Suggestive features
General Weight loss, fever, fatigue of unknown origin
Skin Levido reticularis, palpable purpura, vasculitis urticaria, nodules, ulcers
CNS Focal CNS lesions, mononeuritis multiplex
Musculoskeletal Intense arthralgia ± myalgia, arthritis, myositis
Vascular BP i, pulmonary haemorrhage ·
Laboratory ESR i, CRP i, eosinophilia, anaemia, ANCA, factor VIII related AG (VWF), haematuria, cryoglo-
bulinaemia

MJ Dillon, 5:11:8, p. 1402. Oxford Textbook of Rheumatology, Second edition, Maddison PJ, Isenberg D, Woo P, Glass DN. Oxford Medical
Publications 1998.

319
KAWASAKI DISEASE
A predominantly infanti le polyarteritis postulated to be secondary to an as yet unidentified infectious agent in an
immunologically or geneti,cally susceptible individual.

Diagnostic criteria
Fever 38.5 oc for > 5 days and four of:
Conjunctivitis - bilateral non-purulent
Cervical lymphadenopathy - with one node > 1.5 em
Rash - polymorphous, no vesicles or crusts
Changes of lips or oral mucosa - red cracked lips; 'strawberry tongue'; or diffuse erythema of
oropharynx
Extremities (feet and hands) - initially erythema and oedema of palms and soles. In convalescent
stage peeling skin from fingertips
(May be diagnosed with fewer than four of the above if coronary artery aneurysms are detected)
Other features Extreme irritability (almost universal)
Arthritis, asceptic meningitis, pneumonitis, uveitis, gastroenteritis, meatitis, dysuria and otitis

Cardiac complications
• 20-40% of untreated children will develop coronary artery aneurysms, a major cause of morbidity
• Cardiac tamponade
• Cardiac failure
• Myocarditis, myocardial infarction
• Pericarditis

Investigations
Bloods Neutrophils i
Marked thrombocythaemia (2"d-3rd week)
ESR, CRP i
LFTs (may be deranged)
Urine Sterile pyuria
Cardiac ECG and 20 echocardiogram. Consider CXR

Management
• High dose IVIG (2 gjkg) over 10 h, within 10 days of disease
• Aspirin for 6 weeks or until coronary aneurysms gone
• Steroids may be used in resistant disease
• 20 echocardiogram at presentation, regularly during acute disease and at follow-up
Early treatment with aspirin and IVIG reduces the occurrence of co ronary artery aneurysms.

POLYARTERITIS NODOSA (PAN)

A necrotizing vasculitis of medium and small arteries. Males> females, uncommon in children.

Clinical features
General Malaise, fever, weight loss, myalgia
Joints Migratory arthralgia, arthritis .
Renal Haematuria, proteinuria, chronic renal failure (major cause of death), hypertension
Neurological Mononeuritis multiplex, symmetrical peripheral neuropathy, seizures, stroke

320
 Cardiac Aneurysms, myocardial infarction, cardiac failure
Lungs Cough, wheeze, pleuritis
Abdominal GI bleeding, infarction, abdominal pain, liver pain (splenic and coeliac vessels)
Gonads Orchitis, epididymitis
Skin Nodules, ulcers, erythematous rashes, purpura

Investigations
FBC Anaemia, wee i
ESR Marked i
Autoantibodies p-ANeA (may be positive)
Biopsy Muscle, nerve or skin may show characteristic features
Angiography Mesenteric or renal microaneurysms

Management
~ Steroids and imunosuppressants or biological agents.

TAKAYASAU DISEASE
An arteritis of the aorta and major branches ('pulseless disease'), autoimmune inflammatory disease. Most common in
young wom_en. Poor prognosis in children.
Associations Orientals, blacks

Clinical features
cvs Claudication in arms and legs, absent peripheral pulses, BPi
General Fever, malaise, myalgia
Other Arthritis, pericarditis, rashes, eNS disturbance

Investigations
ESR i
FBC Anaemia, neutrophilia
Doppler and angiography (Occlusion, stenosis and aneurysms)

Management
• Systemic steroids and cytotoxic agents may be considered
• Surgery as necessary

WEGENER GRANULOMATOSIS
r
Asystemic necrotizing vasculitis most prominent in the lungs and kidneys, and destructive granulomas of the respiratory
tract. Rare in childhood.

Clinical features
Upper respiratory tract Rhinorrhoea, nasal ulceration, granulomas, progressive destruction of nasal septum,
pharynx, Larynx and trachea
Lungs Cough, haemoptysis, pleurisy, granulomas
Kidneys Proliferative glomerulonephritis, renal failure
Other Malaise, fever, weight loss, arthritis, arthralgia, splenomegaly, rash

321
Investigations
Autoantibodies c-ANCA, good correlation (90%)
CXR Pulmonary infiltrates
Sinus X-ray Bony destruction nose and sinuses
Renal junction Microhaematuria, red cell casts
Biopsy Granulomatous inflammation respiratory tract, and nephritis

Management
Steroids and cyclophosphamide or biological agents.

BE~l~H SYNDROfvlE
Rare in children.
Associations Turkish, Arabic, Japanese, HLA-B51
A vasculitis of small and medium-sized arteries involving:
• Oral ulcers
• Genital ulcers
• Eye inflammation (anterior or posterior uveitis, retinal vasculitis may lead to blindness)
The course is variable with recurrent exacerbations and disease-free intervals. Additional features include:
Skin Mucous membrane ulcers, erythema multiforme, erythema nodosum
Joints Arthritis (asymmetrical, recurrent, knees, wrists, ankles)
Vascular Thrombophlebitis, arterial aneurysms, pericarditis
CNS Cranial nerve palsies, psychosis, meningo-encephalitis
Other Fevers, colitis

Diagryosis
• Clinical diagnosis
• Skin pathergy may be present (pustule developing at site of skin needle prick after 24-48 h)

Management
Systemic steroids, colchicine, thalidomide and other immunosuppressive therapy have been effective in some
patients.

AMYLOIDOSIS
This is characterized by deposition of amyloid in the extracellular matrix around blood vessels and in parenchymal
organs. It may be primary or secondary.

322
Diagnosis
Biopsy Staining with Congo red dye, green under polarizing light.

Treatment
Treat underlying disorder; alkylating agents, e.g. chlorambucil, may be used in secondary amyloid.

OSTEOGENESIS IMPERFECTA
Agroup of disorders of fragile bones due to defective and/or reduced type 1 collagen. They are most commonly due to
mutations in the genes COL1A1 and COL1A2. The severity of the clinical features depends on the type.

Clinical features of type I

Skeletal Multiple fractures pre-puberty
Kyphoscoliosis, barrel-shaped chest, soft skull
Short bowed legs and arms, joint hypermobility
Triangular face, small nose
Soft brittle discoloured teeth (dentinogenesis imperfecta)

323
 Short stature
Skin Loose, thin and smooth, easy bruising
Eyes Blue-grey sclera
ENT Deafness in 50% from age 20 years (most commonly conductive)
Other Compromised cardiovascular and respiratory function secondary to skeletal deformity

.. -,._.

.• · •Marfan.. synB[gi11€,:;:;r::;J
• ·.· Ehters~Dant6s iyridfdme
• Pseudoxanthoma .ela~d(l:{~·H
• · Osteogehesis .~mperf~ct~ . ·:.·<

Investigations
Blood Alkaline phosphatase (Nor i), acid phosphatase (i)
Urine 24-h hydroxyproline (i)
X-rays Wormian bones (skull), fractures, osteopenia, deformity

Management
Supportive Physiotherapy, splints, physical aids, psychological support
Drug therapy Bisphosphonates (increase bony density), growth hormone
Surgical Fracture management. Corrective surgery (scoliosis, bowing of bones)

OSTEOPETROSIS (MARBLE BONE DISEASE)

A disease of increased skeletal density and brittle bones. There are several forms; the type presenting in the new-
born period with early death, osteopetrosis with precocious manifestations, an autosomal recessive condition, is
described.

Clinical features
General Faltering growth
Marrow failure Anaemia, thrombocytopenia, infections, hepatosplenomegaly
Hyperostosis Optic atrophy, blindness, deafness, cranial nerve palsies, hydrocephalus

Investigations
Blood Ca -1, P04 .l-, alkaline phosphatase i
Hb l platelets -!-,wee .t
X-rays Bone density i
'Bone in bone' appearance of vertebral bodies
Clubbed metaphyses, 'rugby jersey' pattern of spine
Osteosclerosis

Management
• Low-calcium diet, phosphate supplements
• Drugs - oral steroids, interferon-a
• Stem cell transplant
• Neurosurgery to the orbital roof

324
, -'.'-)
,;;

OSTEOCHONDRODYSPLASIAS

ACHONDROPLASIA
Apure skeletal dysplasia. Incidence: 1:15 000-27 000. New mutations (mostly), autosomal dominant.

Clinical features
Proportions Short limbs and trunk, large head
Other skeletal Exaggerated lumbar lordosis, genu varum, 'trident' hands and brachydactyly
Mid-facial hypoplasia, relative prognathism, narrow nasal airways
Neurological Hydrocephalus (1- 2%)
Obstructive sleep apnoea
Spinal canal stenosis
Intelligence normal
Hypotonia in infancy and delayed motor milestones
ENT Serous otitis media
NB: Specific growth charts have been desig~ed for these children. Lifespan is normal.

THANATOPHORIC DWARFISM
A'lethal' dwarfism, though a few survive > 1 year.

Clinical features
• Similar proportions to achondroplasia (large head, small body)
• Severe thoracic dysplasia with respiratory distress
• Bow limbs, flat nasal bridge, brachydactyly
• X-rays -thin vertebral bodies, femoral head banana-shaped, metaphyseal flaring and cupping

ELLIS-VAN CREVELD SYNDROME

Autosomal recessive syndrome featuring:
• Skeletal dysplasia including mild thoracic involvement
• Four limb postaxial polydactyly
• Conical teeth, oligodontia, dysplastic nails
• CHD (tO%)

STICKLER DYSPLASIA
A group of autosomal dominant disorders with a defect in the COL2A1 gene for type II collagen on chromosome 12q.

Clinical features
• Marfanoid habitus, hyperextensible joints, enlargement of large joints
• Retinal detachment, myopia, deafness, cleft palate
• X-ray- 'dumbbell'-shaped long bones
• Early severe degenerative OA of hips and knees

325
SPONDYLOEP!PHYSEAL DYSPLASIAS
These diseases are characterized by disproportionate short stature (short trunk) . They include three main forms .

MULTIPLE EPIPHYSEAl DYSPLASIA$

These are similar to spondyloepiphyseal dysplasias, with mild spinal disease, short phalanges and fragmentation of the
epiphyses of hips, knees and other joints.

NON-I NFLAMMATORY PAIN SYNDROMES

These pains have characteristic patterns, are often distressing and may lead to significant loss of function. Aetiologies
are not well understood. Diagnoses are best made through a full history and examination, which will exclude other
pathologies and may identify the features below. May be acute soft tissue rheumatism diso rders such as 'anterior knee
pain syndromes', 'bursitis' or 'housemaid's knee', all of which are rare in children.

CHRONIC IDIOPATHIC PAIN SYNDROiliiE

Includes reflex sympathetic dystrophy, fibromyalgia, chronic widespread pain disorders synd rome.
• Onset often associated with minor trauma and immobilization
• If diffuse pain, onset is vague with gradual deterioration
• Pain generated by normally non-painful stimuli (allodynia)
• Generally heightened sensation (hyperaesthesia)
• Skin changes - colour (blue, pallor), hair loss, shiny
• Symptoms and loss of function in excess of clinical signs
• Possible pseudoparalysis if limb involved
• Psychosocial features may have precipitated and maintain pai n

Management
Two goals:
Restore fundi on Multidisciplinary team approach focusing on rehabilitation
Intense physiotherapy
Psychological support
Relief of pain Acknowledgement of pain and explanation of management
Simple analgesia
Teaching skills to cope with pain

326
 -. -- -· ·· · - .. . · ··· ··· . . .. . . · · ··· ·· . .. · ···· · -

r GROWING PAINS
• Typically shin pain in evening and may wake from sleep
• Mostly affect young children
• Settlewith gentle rubbing of the area

BENIGN HYPERt40BILITY SYNDROME

• Pain associated with hypermobility of joints
• A probable mild form fruste of Ehlers-Danlos syndrome
• Typic.ally pain in evening or after increased activity
• Usually minimal functional loss unless unfit or unwell for long periods

Management
• Education
• Supportive footwear
• Physiotherapy- correct imbalance and improve muscle support

FURTHER READING
Cassidy JT, Petty RE Textbook of Paediatric Rheumatology, 5th edn. Philadelphia: WB Saunders, 2003
Maddison PJ, Sen berg DA, Woo P, Glass DN, eds The Oxford Textbook of Rheumatology, 3'd edn. Oxford : Oxford University
Press, 2004

327
- - -- - - - - - - - - - - - - -- -- - - -- - -- - - -- - - -- - -- - - -- - - - -

. . _·:.. -=.-· .-.

• Physiology and anatomy • Ataxia

• Investigations • Cerebral palsy
• Development • Neurodegenerative disorders
• Structural brain anomalies • Stroke
• Seizures • Spinal cord disorders
• Headaches • Neuromuscular disorders
• Neuroectodermal syndromes • Psychiatric disorders

PHYSIOLOGY AND ANATOMY

The nervous system can be divided into:
1. Central nervous system (CNS) - brain and spinal cord
2. Peri pheral nervous system (PNS) - somatic and auto nomic nervous systems conveying information into
(afferent, sensory) and away from (efferent, moto r) the CNS
For a detailed review, anatomy and physiology texts must be consulted.

Somatic motor area

Some major areas of function within the cerebral cortex Somatic sensory area

are shown in Figure 14.1 and the ventricular system is Frontal lobe Parietal lobe
outlined in Figure 14.2.
The internal carotids and the basilar artery supply the Occipital lobe

circle of Willis, from which the three cerebral arteries

(anterior, middle and posterior) branch. The vertebra-
basilar system supplies the cerebellum and brainstem Broca's motor
speech area
and the cerebral arteries supply the cerebrum (see Figure Visual area

14.3). Auditory area

Temporal lobe

Figure 14.1 Major fu nctio nal areas of the cortex

32 8
 Lateral ventricle

Figure 14.2 The ventricular system

Other important Main arteries Anterior cerebral artery

arteries

1 0 1 - - - - - - Anterior cerebral
Anterior
communicating

Middle cerebral
Internal carotid
Medial striate
m------'- Posterior
communicating
Medial view
Frontal Occipital
Posterior cerebral pole pole

_____ Basilar

Anterior inferior ____/&,

cerebellar ____ Vertebral

Posterior inferior------,~
,· cerebellar Anterior spinal
Speech area
Posterior cerebral
Middle cerebral
artery artery

Lateral view

Figure 14.3 Blood supply to the brain

329
CRANIAL NERVES
For a detailed outline see an anatomy text.

330
,~ MOTOR AND SENSORY SYSTEMS

Motor system

Corticospinal tracts (pyramidal system)

These originate in the cortex (layer V) and terminate on the motor nuclei (cranial nerves) or anterior horn cells (spinal
cord).
The nerve fibres decussate (cross over) in the medulla.
Disease of the pyramidal system causes an upper motor neuron (UMN) lesion and disease of the anterior horn cells and
peripheral nervous system results in a lower motor neuron (LMN) lesion.

Extrapyramidal system
Basal ganglia, involved in movement. Lesions result in a reduction m movement, involuntary movements and
rigidity.

Cerebellum
Involved in posture and balance, lesions producing classic cerebellar signs.
Peripheral.nerves run from the anterior horn cell via a motor nerve fibres to the motor endplate (the LMN pathway) ..

Clinical signs of cerebellar disease

1

Gait Ataxic, broad based. Patient falls to the side of the lesion
Movements Dysmetria (imprecise movements in force and distance)
Dysdiadokinesis, past-pointing on finger-nose testing
Tremor Intention tremor
Titubation (head tremor)
Nystagmus Towards the affected side
Coarse, horizontal
Speech Dysarthria, 'scanning' speech
Reflexes ·Pendular
Lesions within a lateral lobe produce symptoms in the same side of the body. Midline lesions produce truncal ataxia .

331
 , ·~,
'

Sensory system
Peripheral nerves run from free or specialized nerve endings to the dorsal root ganglia and along the spinal cord (see
Figure 14.4) via:
• Posterior columns (vibration, proprioception, light touch). Decussate in the medulla
• Spinothalamic tracts (crude touch, temperature, pain). Cross in the cord at entry

Ascending (sensory) Descending (motor)

Fasciculus gracilis - - - - - - - - - - . . .

Fasciculus cuneatus -----T"'----'i

Spino- { Posterior , ~---T- Pyramidal (lateral

cerebellar and cerebrospinal)
tracts anterior

Lateral spino-
thalamic
r-c-....-;,,, '---J.___---r--- Vestibulospinal
\'+-~~--7"'---- Anterior cerebrospinal

Figure 14.4 Motor and sensory tracts

This may be an acute emergency or a chronic disorder.

Causes
Infection Meningitis, encephalitis
Trauma Intracranial haemorrhage, stroke
Intracranial mass Brain tumour, haematoma, cyst, abscess
Cerebral oedema Stroke, hepatic encephalopathy, infection
CSF disorder Hydrocephalus, blocked VP or VA shunt
Benign intracranial hypertension (BIH)

Acute I ICP

Clinical j2·atures
Vita/signs BP i and pulse t (Cushing reflex) - due to medullary ischaemia
Pupillary dilatation
False localizing signs III and VI cranial nerve palsies (these nerves become squashed as they have a long
pathway in the CSF)
Coning (i .e. herniation of brain contents) Bradycardia, hypertension, respiratory
depression, bilateral pupillary dilatation, decerebrate posturing and then death

Lrnergency rnonoge.~nent

1. Mannitol 0.25 gjkg over 30 min on 2-3 occasions

2. Hyperventilation Aim for PC0 2 25-35 mmHg (low end of normal range causes cerebral
vasoconstriction)

332
 3. Minimize cerebral metabolism Sedation, analgesia, muscle paralysis, low:normal temperature
4. Treat cause E.g. steroids for cerebral oedema, surgery for blocked shunt or acute bleed

Chronic I ICP
Clinical features
• Headache (early morning, worse on lying down and with coughing and crying)
• Drowsiness, diplopia, vomiting
• Papilloedema (seep. 378)
• Infant- bulging fontanelle, macrocephaly, faltering growth

Management
Drugs Acetazolamide
Steroids (may make BIH worse)
~ Surgery Shunt in-sertion
Treat underlying cause.

Benign intracranial hypertension (BIH)

This is a condition of raised intracranial pressure in the absence of an obstruction to CSF flow. It may be seen in:
• Idiopathic in adolescent girls
• Steroid withdrawal, oral contraceptive pill, isotretinoin, tetracycline
• Head injury

Clinical features
Those of chronic 1' ICP, in particular:
• Diplopia
• Marked papilloedema
• Infarction of the optic nerve may occur with subsequent blindness

Investigations
• Lumbar puncture- diagnostic (very high CSF pressures)
• CT brain - normal (normal ventricles)

Managen1ent
'• Lumbar puncture (CSF drainage) and thiazide diuretics
• Dexamethasone if prolonged (ICP 1')
• Surgical shunting may be necessary

INVESTIGATIONS

ELECTROMYOGRAPHY (EMG) AND PERIPHERAL NERVE CONDUCTION

EMG
A needle electrode is inserted into voluntary muscle and an amplified recording is made.
Changes seen Myopathic, myotonic, myaesthaenic, denervation, reinnervation

333
Peripheral nerve conduction
Measurements are taken of conduction velocity, distal motor latency, sensory and muscle action potentials.

Notes on EEG interpretation

1. Obvious pattern present, e.g. hypsarrythmia, 3/s spike and wave
2. No obvious pattern, check: Scale (amplitude)
Montage (map)
Time marker
• Nature of the feature, e.g. spikes, slow waves
• Whether it is generalized (in all channels)
• Or focal (in certain channels only)

Some basic EEG patterns

1. Absence seizures. 3 per second spike and wave activity

Figure 14.5 (a) Absence

seizures

2. Myoclonic epilepsy. Bursts of generalized spikes and slow waves

Figure 14.5 (b) Myoclonic epilepsy

334
3. Focal activity left temporal area, e.g. caused by a left temporal infarct. High-amplitude slow activity over the left
temporal and posterior temporal areas

Figure 14.5 (c) Focal activity in left

temporal area

4. Hypsarrhythmia. A mixture of high-amplitude irregular slow activity and some discharges, following no pattern

Figure 14.5 (d) Hypsarrhythmia

5, Acute encephalopathy. Typical pattern of irregular slow activity caused by encephalopathy of any cause

Figure 14.5 (e) Acute encephalopathy

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 ·.·.

6. Burst suppression pattern. Isoelectric EEG with bursts of spikes and other activity. These findings indicate a
hopeless prognosis for recovery in a child.

Figure 14.5 (f) Burst suppression

pattern

DEVELOPMENT

AREAS OF CHilD DEVELOPMEN'T

• Gross motor (includes primitive reflexes and postural responses)
• Fine motor (and vision)
• Communication (speech and language, non-verbal communication and hearing)
• Social, emotional and behavioural

KEY DEVELOPMENTAL MILESTON ES

336
NB: The above ages are the latest that these skills should be acquired by.

REFLEXES

Primitive reflexes
These are all present from birth and asymmetry or persistence for longer suggests neurological deficit.

337
 ... _,
'

Postural responses

The Babinsky reflex is upgoing initially and downgoing from around 1 year.

STRUCTURAL BRAIN ANOMALIES

ABNORMAL HEAD SHAPE AND S!Zt

Large (macrocephaly) Familial, i.e. nor_!llal
Neurofibromatosis
i ICP, e.g. hydrocephalus, subdural haematoma
Sotos syndrome
Metabolic storage disorder, e.g. Hunter syndrome
Small (microcephaly) Familial, i.e. normal
AR
Craniosynostosis (see below)
Prenatal/delivery cerebral insult, e.g. cerebral palsy, congenital infection
Postnatal cerebral insult, e.g. meningitis
Abnormal shape Positional moulding, e.g. premature infants lying head side_a lot (dolicocephaly)
(symmetrical or Floppy babies head remains stationary for prolonged time
asymmetrical) Normal infants always put on back (brachycephaly)
Premature suture closure
Differential growth rate at the sutures

Abnormal head shapes

Brachycephaly Flat occiput, e.g. Down syndrome
Scaphocephaly (dolichocephaly) Long, narrow, e.g. premature babies, Hurler syndrome
Turricephaly Tall head
Trigonocephaly Keel-shaped forehead, hypotelorism
Kleeblattschadel deformity Cloverleaf shape
Plagiocephaly Asymmetrical, parallelogram (as if skull pushed one side and pulled the other)

338
 Coronal suture
brachycephaly
frontal plagiocephaly ~·
Sagittal suture
scaphocephaly

Lambdoid sutures
occipital plagiocephaly
Normal skull Brachycephaly

Metopic
Key:
suture
- -= prematurely closed sutures
~= normal sutures .
.
- = main direction of skull growth

Plagiocephaly Trigonocephaly

Figure 14.6 Cranial sutures and abnormal head sha pes

CRANIOSYNOSTOSES
This is premature closure of the cranial suture, with resultant cranial defo rmities dependent on the suture(s) involved.
It can be only one suture, some or all sutures (causing microcephaly) . It may be associated with a syndrome (see
below) .
Children with craniosynostosis may develop:
• Hydrocephalus, I ICP, optic atrophy
• Deviated nasal septum, choanal atresia, speech disorde rs and deafness
Craniofacial surgery may be necessary
Some craniosynostoses have been found to have mutations in the FGFR2 (fibrob last growth facto r receptor 2) g~ne,
e.g. Apert, Crouzon.

339
 Pfieffer

Normally the anterior fontanelle (2- 3 em at birth) closes between 9 and 18 months, and the posterior (< 1 em at
birth) at 6- 8 weeks.

NEURAl TUBE DEfECTS (NTDS)

These result from failure of the neural tube to close on day 21-26 of intrauterine life and may involve spinal cord and/
or brain. If compatible with survival, may be closed surgically soon after birth.
Associations Folate deficiency, sodium valproate, previous NTD
Antenatal detection Direct view on USS, raised amniotic fluid a-FP
Recurrence risk 1 previous NTD 4%
2 previous NTD 10%

340
 Normal spine Spina bifida
occuha

Meningocoele Meningomyelocoele

Figure 14.7 Neural tube defects

Spina bifida occulta

• Failure of vertebral arch fusion (L5, 51}. Up to 5% population affected. (NB: This is normal< 10 years) .
• Overlying skin lesion (hair tuft, sinus, lipoma, pigmented lesion)
• Mostly asymptomatic
.• Neural tethering may cause bladder & lower limb problems (cauda equina syndrome)
Meningocoele
1

• Protrusion of meninges only through vertebral defect

• May be normal with surgical repair

Meningomyelocoele
• Protrusion of meninges and spinal cord/nerves
• Incidence 1:1000 live births
• Paralysis (UMN) and sensory loss in legs
• Neuropathic bladder and bowel (involvement< 51)
• Talipes, hip dislocation, scoliosis
• ±Hydrocephalus {Arnold-Chiari malformation)

341
Raschisis
• Open meningomyelocoele
• Failure of fusion of the neural tube with CSF leakage
• Incompatible with postnatal survival

Encephalocoele
• Midline defect of the skull with brain protrusion. Usually occipital, may be frontal or nasofrontal
o Developmental delay, visual defects, hydrocephalus, seizures, microcephaly
• Operative excision and repair of defect may be possible

,.A1 euel-(;ruoer
I ' - '
syn drome
• Autosomal recessive
• Occipital encephalocoele
• Cleft palate
• Microphthalmus, microcephaly
• Abnormal genitalia, polycystic kidneys
• Polydactyly

Anencephaly
• Failure of closure of the rostral neuropore results in rudimentary brain and large defect of the meninges and
skull
• Incidence 1:1000 live births
• Other anomalies in 10- 20%
• Incompatible with survival

HYDROCEPHALUS
This is dilatation of the CSF spaces.

Causes

Obstruction to CSF
Intraventricular block Meningitis
Congenital aqueductal stenosis (aqueduct of Sylvius)
Dandy-Walker syndrome:
• Occlusion of the exit of the fourth ventricle
• Large 4th ventricle and cerebellar hypoplasia
Arnold-Chiari malformation:
• Downward displacement of cerebellar tonsils and brainstem
• ± Spina bifida
Neoplasm or vascular malformation
Extraventn·cular block Posthaemorrhagic, e.g. SAH in premature infant
Infection, e.g. TB meningitis
Leukaemic infiltrates

Decreased CSF reabsorption

Venous hypertension from dural venous sinus thrombosis (severe dehydration) .

342
Increased CSF production
Choroid plexus papilloma (very rare).

Clinical manifestations
These are variable depending on the duration and rate of increase of the CSF pressure/ and age of the child.
Infant Head circumference crossing centiles
Bulging fontanelle/ distended scalp veins
'Setting-sun/ eye sign
Developmental delay
Ataxia
Older child Signs of raised intracranial pressure (see p. 332)

Investigations
Neuroimaging (USS/CT/MRI) Dilated ventricles/ structural malformations

Management
• Treat the underlying cause if possible
• Surgical shunt is inserted to drain the excess CSF either to the peritoneum (V-P shunt) or less commonly the right
atrium (A-P shunt). Shunt complications: blockage/ infection

NEURONAL MIGRATION DISORDERS

These occur during fetal development and may be very minor or have major sequelae. They are diagnosed on MRI brain
scans. Important types include the following.

lissencephaly (smooth brain)

• Absent cerebral convolutions and rudimentary Sylvian fissure
• Large lateral ventricles/ microcephaly/ microphthalmia
• Manifest as severe developmental delay/ failure to thrive and seizures

Miller-Deiker syndrome
• Lissencephaly/ characteristic facial dysmorphism
• Chromosome deletions of 17p 13.3

Schizencephaly
,,

• Clefts in the cerebral hemispheres from the cortex to the ventricles, the entire cleft being coated with cortex
• Presents with epilepsy and/or focal neurology

Porencephaly
• Cysts within the brain
• Presents with focal neurology

AGENESIS OF THE CORPUS CALLOSUM

X-linked recessive/ autosomal dominant sporadic. This may be completely asymptomatic (if isolated) or produce
severe intellectual impairment when associated with other defects.
Associations Cell migration defects/ e.g. pachygyria/ microgyria; trisomy 18

343
 --~~. ·>

'.1

Aicardi syndrome I
• Agenesis of the corpus callosum
• Retinal abnormalities, e.g. coloboma, pits
• Seizures refractive to treatment
• Severe mental retardation
• Vertebral abnormalities

SEIZURES
A seizure (convulsion) is an abnormal burst of electrical activity in the brain, which may manifest in various ways.
Epilepsy is recurrent seizures unrelated to fever or acute cerebral insult.
Generalized seizures Whole cortex involved diffusely, always impaired consciousness
Partial seizures One area of the cortex involved; may become generalized

INTERNAUONAl Clft.SSIHCATWN OF EPILEPTIC SEIZURES

INVESTIGATING EPilEPSY
It is always necessary to do a full history and clinical examination, including developmental check. For first convul-
sion, investigate only if <1 year of age or unwell child, or abnormal findings on examination.
EEG Demonstrate baseline activity and seizure if occurs during recordi ng
Blood Glucose (peri-ictal)
Electrolytes, metabolic screen, congenital infection screen
Neuroimaging USS (infants with patent fontanelle)
Skull X-ray (intracranial calcification, tra uma)
CT scan (urgent if unwell)
MRI scan

344
· ~· Lumbar puncture In an unwell child. Low threshold in febrile convulsion if child < 18 months. NB: Not if raised ICP
signs

COMMON SEIZURE n'PES

Absence seizures
Typical Sudden loss of awareness with eyelid fluttering, no motor activity
No postictal phase
Last< 30 s
Complex Motor component (myotonic movements, loss of body tone)
EEG Typical 3/s generalized spike and wave
Treatment Ethosuximide
Sodium valproate (NB:. Potential for precipitating fulminant liver failure)
Lamotrigine

~ Generalized tonic-clonic seizures

These may follow a partial seizure. May be idiopathic or induced by infection, stress or drugs. An 'aura' suggests a
focal origin.

Features
Tonic phase Sudden loss of consciousness with a tonic contraction, apnoea, cyanosis, eyes roll backwards
Clonic phase Rhythmic contractions of all muscle groups
Tongue-biting, sphincter control lost
Postictal phase Semiconscious for 30 min-2 h

Treatment
• Sodium valproate, carbamazepine
• Lamotrigine
• Clobazam

Simple partial seizures

These are usually motor, involving asynchronous tonic or clonic movements and the child is conscious. Aura may occur.
May be confused with tics (which can be suppressed temporarily) .

Complex partial seizures

These involve altered consciousness and may follow on from a simple partial seizure. Temporal lobe epilepsy (a form
of complex partial seizure) may produce outbursts of emotions. Automatisms are a common feature (lip smacking,
chewing, drooling).
EEG Focal spikes or sharp waves
Brought on by sleep deprivation
MRI scan Looking for structural brain abnormalities

EPILEPSY SYNDR0~1ES

Childhood absence epilepsy

Usually age 3-10 years, girls> boys, family history in 40%.

345
Seizure types Typical or atypical absence seizures
Induced by Hyperventilation, emotion, hunger
Treatment As for absence seizures

Juvenile myoclonic epilepsy

5% of all epilepsy. Onset 12- 16 years.
Associations 25% family history
90% develop generalized tonic-clonic seizures
25% develop absences
Features Myoclonic jerks, worse in the morning (cannot brush their teeth, spill their tea)
No impairment of consciousness
EEG Normal background, 4- 6/s irregular polyspike and wave discharge pattern
Photosensitivity
Treatment Sodium valproate
Lamotrigine

Infantile spasms
Incidence 1:3000. Onset age 4- 6 months, boys> girls. Associated with arrested development.
Features Symmetrical contractions of whole body, occur in bursts
May be extensor, flexor (Salaam spasms, jack-knife) or mixed
EEG Hypsarrhythmia (chaotic EEG with high-amplitude activity)

Cause
Aetiology not identified {20%} Normal prior development, examination and CT scan
Aetiology identified (80%) Structural, e.g. tuberous sclerosis, lissencephaly
Metabolic disease
Birth injury, e.g. hypoxic-ischaemic encephalopathy, IVH
Postnatal injury, e.g. trauma, meningitis

Investigations of cause
o MRI brain
o Metabolic screen
• Chromosome analysis
o If tuberous sclerosis (TS) is suspected, do renal US and echocardiogram

Treatment options
o Vigabatrin
• ACTH (second line)

West syndrome
A triad of:
1. Infantile spasms
2. Hypsarrhythmia
3. Mental retardation

346
 Temporal lobe epilepsy
Complex partial seizures originating in the temporal lobe area.
Features Aura, e.g. dysphoria, fear or gastrointestinal symptoms
May manifest as outbursts of emotions
EEG Anterior temporal lobe focal spikes or sharp waves
MRI To look for temporal lobe abnormalities

Benign Rolandic epilepsy {benign partial epilepsy with centrotemporal spikes)

Common partial ·epilepsy with good prognosis. Onset 2-14 years (peak 9- 10 years).
Features Drooling, abnormal sensations in mouth
Secondary generalization
. 75% occur in sleep, 25% occur on waking
EEG Repetitive spike focus in the Rolandic area (centrotemporal)
Treatment Carbamazapine
Spontaneous resolution usually occurs by mid-teenage years

landau-Kleffner syndrome (LKS)

• Onset 5 years, male >female
• Loss of language skills associated with seizures of several types in 70%
• EEG abnormalities more common during sleep

Rasmussen encephalitis
• Subacute inflammatory encephalitis with frequent focal seizures
• Associated with progressive hemiplegia

Pyridoxine deficiency
• Neonatal, infancy or adult onset generalized tonic-clonic seizures
• Autosomal recessive
• Treat with pyridoxine supplements

Lennox-Gastaut syndrome
This is an electroclinical syndrome comprising:

• Multiple seizure types (myoclonic, atypical absences, atonic 'drop' attacks, tonic nocturnal seizures, generalized
tonic-clonic seizures)
• EEG shows slow spike and wave (2-3/s)

Onset mostly 4-5 years. Pre-existing severe seizures in 60%. Mental handicap initially 75% and regression. Epilepsy
often intractable.

FEBRILE CONVULSIONS
These are convulsions secondary to a fever (often during a rapid temperature rise) caused by an infection (not directly
involving the CNS). Often due to an URTI. Incidence 2-4% children under 5 years. Males >females. Family history in
30%.

347
Investigations
These depend on the clinical examination, searching for a source of infection, and age of the child. Urine specimen
for infection should be done. Further investigations depend on clinical evaluation (FBC CRP, blood cultures, CXR and
LP if< 1 year or unwell and not contraindicated).

Management
• Admit if first fit, complex or child unwell
• Management of ABC and seizure control if still fitting
• Fever control with paracetamol or ibuprofen and tepid sponging
• If infectious bacterial focus or septicaemia or meningitis suspected give appropriate antibiotics
• If herpetic lesions or contact give aciclovir
• Parental advice on fever control and management of a fit

Risk of later development of epilepsy

General population 0.5%
Febrile convulsions 1% if typical
5-10% if risk factors (complex, family history epilepsy, febrile seizure< age 9 months, delayed
milestones)

NON-!EP!lEPHC 'fUNNY TURNS'

Syncope
Due to cerebral hypoperfusion and hypoxia causing bradycardia, pallor and then collapse. Different forms:
Vasovagal syncope Precipitated by stress, emotions and confined spaces
Reflex anoxicseizures Due to sensitive-vago-cardiac reflex. Seen in toddlers after trauma
Orthostatic hypotension Seen in adolescents on standing a long time
Cardiac syncope Secondary to arrhythmias, e.g. prolonged QT syndrome. Rare in children

Breath-holding attacks
Age 6 months-3 years. Precipitated by fear, anger and pain. The child holds their breath in expiration causing
cyanosis, then limpness, unconsciousness, and then tonic stiffening if severe. Rapid recovery.

Benign paroxysmal vertigo .

1-5 years. Sudden onset of unsteadiness, pallor, horizontal nystagmus and vomiting. Consciousness maintained. Ear
infections and migraine associated.

348
Night terrors
18 months- 7 years. Partially wake from sleep during REM stage IV. Screaming, thrashing, tachycardia, does not recog·
nize parents. Normal sleep afterwards.

Narcolepsy
Usually commences in adolescence. Attacks of REM sleep during the day, cataplexy (sudden inhibition of tone of a
muscle group), frightening visual hallucinations, daytime sleepness and sleep paralysis (paralysis of voluntary muscles
while falling asleep).

EMERGENCY MANAGEMENT OF STATUS EPILEPTICUS

NB: Status epilepticus is said to occur when a seizure lasts for 30 min.
• Stabilize the child (airway, breathing, circulation) and give high flow oxygen
• Establish IV access. Give IV fluids if signs of shock. Give antibiotics if sepsis or meningitis suspected.
• Bloods: BMStix (give IV glucose if hypoglycaemia)
Glucose, U&E, Ca, Mg, FBC, cultures, ABG, drug screen
• Drug therapy (protocols vary, see latest APLS guidelines):
IV lorazepam if IV access quickly established. If no IV access give rectal diazepam
If convulsion continues after 10 min repeat lorazepam. Rectal paraldehyde in olive oil if no IV access
If seizure continues get senior help (and liaise with anaesthetist/ITU). Give rectal paraldehyde if not already
given
IV phenytoin infusion over 20 min with ECG attached (phenobarbitone if already on phenytoin)
If fitting continues: Re-check ABC
Have anaesthetist present
Take blood, correct any metabolic abnormality and treat pyrexia. Consider mannitol
Rapid sequence induction of anaesthesia with thiopentone and short-acting paralysing agent

ANTIEPILEPTIC DRUGS

349
HEADACHES
These are a common problem and are rarely due to a severe underlying organic disorder. A full history and examina-
tion (including neurological) should be performed and further investigations only if worrying findings on history, e.g.
increase in frequency or severity of headaches, developmental deterioration, behavioural change, features of i ICP, or
abnormal examination.
Examination should include:
• Full neurological, especially visual fields (intracranial mass), squint and pupil examination and cranial bruit
examination (A-V malformation)
• Fundoscopy (BP i) and visual acuity
• Head size (crossing centiles)
• Blood pressure
• Teeth (dental caries)
• Face (sinus pain)

350
 TENSION HEADACHE
Clinical features
• Common
• Dull ache or sharp pain at the vertex or unclear location
• May occur daily for weeks or be continuous
• Medication often ineffective
• No aura, no precipitants, no neurological signs
• Associated with difficulty sleeping, dizziness, family or school problems

MIGRAINE
These are recurrent headaches of uncertain pathology thought to involve both neurogenic and cerebrovascular mecha-
nisms.

~ Clinical features
• Throbbing, bifrontal, unilateral, photophobia, phonophobia
• May wake child from sleep
• Transient hemiplegia or ataxia
• Lasts 1- 72 h
Must be accompanied by at least two of: nausea, vomiting, abdominal pain, visual aura, family history.

Management
General measures Regular mealtimes, regular bedtime, sufficient sleep, relaxation after a stressful situation
Avoid stimuli E.g. stress, insufficient food, certain foods (chocolate, cheese, colourings), sun, lack of or excess
sleep, dehydration
Acute episode Bed restjsleep in a dark quiet room
Drugs: analgesics (paracetamol), antiemetic if nausea
Selective 5-HT agonist if severe and > 12 years old ·
Prophylaxis Pizotifen (histamine [H1] and serotonin receptor antagonist) is licensed in children> 2 years old

HEADACHES OF OTHER UNDERLYING PATHOlOGY

Features
• Those of underlying local pathology, e.g. sinusitis, toothache, fever
.• • Those of i ICP - diffuse, frontal, worse on coughing, sneezing or lying down and in the mornings

Causes
Neurological Postictal, post-concussion, meningitis, encephalitis, hydrocephalus (V-P shunt blockage), intracranial
haemorrhage, BIH, brain tumour
Other Infective illness (commonly URTI or viral illness), dental malocclusion, dental caries, myopia,
hypermetropia, sinusitis, lead poisoning

NEUROECTODERMAL SYNDROME
These involve a defect in the differentiation of the primitive ectoderm and include:
• Neurofibromatosis

351
 • Tuberous sclerosis
• Sturge- Weber syndrome (seep. 385)
• Von Hippel-Lindau disease
• Ataxia telangiectasia (see p. 32)
• Incontinentia pigmenti (see p. 304)

Autosomal dominant, 50% new mutation rate. Incidence 1:4000. Extremely variable in severity.

NF1 {90%)
Gene on chromosome 17q. Diagnosis if two or more of the following occur:
1. ~ 6 Cafe-au-lait patches (prepubertal> 5 mm, postpubertal> 15 mm)
2. Axillary freckles
3. ~ 2 neurofibromas or one plexiform neurofibroma
4. ~ 2 Lisch nodules (hamartomas) in iris
5. Bone lesion- sphenoid dysplasia (pulsating exophthalmos), or dysplasia of cortex of a long bone
6. Optic glioma
7. First-degree relative with NF

Other features
CNS Macrocephaly, seizures, learning difficulties, speech defects, attention deficit disorder, aqueduct
stenosis
Endocrine Precocious puberty
Tumours CNS tumours, Wilms tumour, phaeochromocytoma, leukaemia, sarcomas
Other Renal artery stenosis, cardiomyopathy, lung fibrosis, kyphoscoliosis

NF2 (10%)
Gene on chromosome 22q . Diagnosis if one of the following present:
1. Bilateral VIII nerve acoustic neuromas
2. Unilateral VIII nerve mass in association with any two of: meningioma, neurofibroma, schwannoma, juvenile
posterior subcapsular cataracts, glioma
3. Unilateral VIII nerve acoustic neuroma or other brain or spinal tumour as above and first-degree relative with
NF2
Clinical features include: cerebellar ataxia, hearing loss, facial nerve palsy, headache. Skin lesions are less common
than in NF1.

Management
• Investigations (led by examination) - MRI brain and optic nerves, ophthalmological assessment, skeletal survey,
EEG, audiogram, brainstem auditory and visual evoked potentials, psychometric testing
• Genetic counselling
• Yearly assessment, including neurological examination, auditory and visual screening, and BP

Autosomal dominant, 80% new mutations. Gene on chromosome 9q and 16p. Wide variation in severity.

352
 Clinical features
Skin Adenoma sebaceum (angiofibromas) 85%, over cheeks and nose (> 3 years age)
Hypomelanotic macules (Ash leaf macules) (80%, > 3)
Shagreen patches (connective tissue naevi -'orange peel skin' over lumbar spine)
Ungual or periungual fibromas (>teenage)
Fibrous plaque on forehead or scalp
Gingival fibroma
CNS Epilepsy (infantile spasms, partial)
Autism
Cortical tuber (hard nodules with bizarre giant cells), may calcify
Subependymal glial nodules, project into ventricles, calcify, 'candle-dripping' appearance on CT scan
(> 3 years age)
Subependymal giant cell astrocytoma
Gliomas
White matter radial migration lines
"
;ox
Eye Multiple retinal nodular hamartomas (phakoma) (optic nerve astrocytoma), Mulberry tumour
Retinal achromic patch
cvs Cardiac rhabdomyoma (s) (40-50%)
Renal Multiple angiomyolipomas, hamartomas, polycystic kidneys
Lung lymphangiol~iomyomatosis
Dental Multiple pits in dental enamel
GIT Hamartomatous rectal polyps
Bone Cysts
Those in bold are major features . Two major features are required for diagnosis.

Management
This includes baseline investigations to look for associated features, seizure control, genotype, genetic counselling
and regular follow-up (general and skin examination, neurodevelopmental assessments, renal USS, BP, echocardio-
gram, MRI brain scan, CXR and eye examination).

VON HIPPEL-LINDAU DISEASE

Autosomal dominant. Gene locus on chromosome 3p25.

Features I

.• Retinal angiomata
• Cerebellar haemangioblastomas
• Cystic lesions - renal, pancreas, liver, epididymis, spinal cord
• Tumours- phaeochromocytoma, renal carcinoma (most common cause of death)

ATAXIA
This may be due to cerebellar disease (most common cause in children) or to sensory loss.

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Causes

lATE XNFANTRE 8ATIEN DISlEASE (CEROID UPOfUSCINOSIS)

Autosomal recessive.

Clinical features
• Normal early development then developmental regression from 2-5 years
• Ataxia, choreoathetosis
• Seizures
• Retinitis pigmentosa

Diagnosis
• Eye examination
• EEG
• Rectal biopsy (typical neurological features)

FR!EDREIOi ATAXIA
Autosomal recessive. Gene on chromosome 9q13-21.1, encoding fraxatin. A progressive degeneration of cerebellar
tracts and dorsal columns. Presentation usually around 10-12 years (always< 20 years) with difficulty walking, with
progression of disease and death around 40 years.

Clinical features
• Progressive ataxia and dysarthria
• Lower limb weakness and amyotrophy

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 • Loss of position and vibration sense
• Pes cavus, scoliosis
• Loss of deep tendon reflexes with upgoing plantars
• Optic atrophy, nystagmus
• Dilated or restrictive cardiomyopathy, diabetes mellitus

Investigations
• Sensory (± motor) conduction velocities slightly decreased
• Sensory evoked potential absent or reduced
• Visual evoked potential diminished

CEREBRAL PALSY
Cerebral palsy is a disorder of movement and posture due to a non-progressive lesion in the developing brain. It is a
static encephalopathy. Pr-evalence 2:1000 population .

Additional impairments
• Learning impairment
• Visual impairment and strabismus
• Hearing loss
• Speech and language difficulties
• Behavioural problems
• Epilepsy

Causes
Antenatal {80%) Cerebral dysgenesis, cerebral malformation, congenital infection
Intrapartum {10%) Hypoxic-ischaemic encephalopathy
Postnatal {10%) Cerebral ischaemia, IVH, hydrocephalus, head trauma, non-accidental injury (NAI), severe neo-
natal hyperbilirubinaemia

Types
Spastic Initial hypotonia progressing to spasticity with UMN signs. It may be:
• Hemiplegia - unilateral involvement (arm >leg usually), e.g. IVH , meningitis
• Diplegia- legs > arms (arms may be normal), e.g. PVL
• Quadriplegia- all limbs involved (arms> legs), e.g. birth asphyxia
Ataxic hypotonic Hypotonia, poor balance, tremor, incoordinate movements, e.g. hydrocephalus
Dyskinetic Involuntary movements (athetosis, dystonia), fluctuating muscle tone (dyskinesia) and poor
postural tone, e.g. hyperbilirubinaemia

Presentations
• Delayed motor milestones
• Abnormal tone in infancy
• Abnormal gait, e.g. toe walking, wide based
• Feeding difficulties
• Other developmental delay, e.g. language, social
• Persistence of primitive reflexes

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Investigations
• Bra1n 1mag1ng - USS 1n neonates, CT or MRI scan
• Metabolic screen

Management
Cerebral palsy may be mild, requiring little input, or severe, necessitating an inte rdisciplinary approach to optimize
the development of the child. Specialities involved include occupatio nal therapist, physiotherapist, speech therapist, ,
social worker, teacher and developmental psychologist. Physicians involved include t he paediatrician, orthopaedic
surgeon, neurologist, ophthalmologist and audiologist.

NEURODEGENERATIVE DISORDERS
Neurodegenerative disorders are diseases with a progressive deterioration in neurological function, with loss of
speech, vision, hearing or locomotion. Often associated seizures, fee ding difficulties and intellectual impairment.
• These diseases are usually rare neurometabolic, autosomal recessive diso rders due to a specific enzyme defect,
but may be due to chronic viral infection, e.g. SSPE, prion infectio n, e.g. Creutfeldt-Jakob disease (CJD) or other
unknown cause
• In the metabolic conditions the neuronal degeneration occurs as a result of a build-up of the product preceding
the missing enzyme, which is toxic to the nervous system, or lack of an essential metabolite. The excess product ,
will also cause other effects and result in the characteristic disease fi ndings. Some of these diseases are termed
'storage disorders', referring to the storage of the accumu lated substance
o Can be subdivided into predominantly grey matter or white matter disorders:
White matter disease UMN signs early on
Grey matter disease Convulsions, intellectual impairme nt and vis ual impai rment
o May present congenitally or in early or late childhood, adolesce nce or ad ulthood
• Generally progress relentlessly until death occurs months or yea rs from onset

INVESTIGATIONS
These should be led by the clinical features,- especially MRI find ings. Often the re will be strongly suggestive features
suggesting a certain group of diagnoses.

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TYPES OF NEURODEGENERATIVE DISORDERS

RETI SYNDROME
A rare neurodegenerative disease. The gene is McCP2 on chromosome Xq28. Only females are affected.

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Presentation is generally after 1 year of age with:
• Developmental regression (language and motor milestones)
• Characteristic 'hand wringing' repetitious movements and loss of hand function
• Ataxic gait
• Acquired microcephaly
• Autistic features
• Apnoeas, sighing respirations
• Seizures (generalized tonic-clonic)
• Death between 10 and 30 years (often from cardiac arrhythmias)

SUBACUTE SCLEROSING PANENCEPf1AUTIS (SSl'E}

A neurodegenerative disease secondary to an altered host response to the measles virus.
• Incidence 1:100 000
• Usually develops 5-7 years after measles infection
• Insidious onset of intellectual deterioration, abnormal behaviour
• Rapid progression with intractable myoclonus, choreoathetosis, dementia and death
• E~G shows characteristic periodic complexes (normal background with high -voltage slow wave bursts)
• CSF may contain intrathecal anti-measles antibody
• MRI brain scan may be normal early on, then white matter abno rmalities, cortical atrophy and ventricular dilata-
tion develop
• No effective treatment

MENKE KINKY HAIR DISEASE

X-linked recessive, gene on chromosome Xq13 . Underlying defect in copper transport.

Clinical features
Presentation in early months of life with:
• Progressive neurodegeneration, severe mental retardation
• Seizures, hypotonia, feeding difficulties, optic atrophy
• Hair colourless, kinky and fragile
• Chubby red cheeks
• Death < 3 years

Investigations
Hair shaft Trichorrhexis nodosa (fractures along hair shaft)
Pili torti (twisted hair)
Monilethrix (brittle hair)
Serum Copper (t ), caeruloplasmin (.L)

Management
Copper-histidine subcutaneously slows deterioration in some patients.

MUL1'1PLE SCLEROSIS
Adisease of multiple central demyelinating lesions with plaque formation, separated by space and time. Characteristic
remissions and relapses occur. It is mostly slowly progressive, though may have a rapid course.

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 ... .. ... . .. .. . · · ·- · .. . . · · ··· ·- ····· ·· ·· ..

Usual onset 20- 35 years, though can occur in children (0.2-2% of cases).
Assodations Female> male, lower incidence closer to the equator
First-degree relative with multiple sclerosis, HLA-A3, B7 and DR2

Clinical features
Neurological symptoms depending on where the demyelination occurs. Some common symptoms are:
• Ataxia, weakness, headache, paresthaesias
• Optic neuropathy (blurred vision), optic neuritis (swelling of optic disc), optic atrophy
Unusual features include epilepsy, trigeminal neuralgia.

Investigations
MRI brain . Plaques
CSF Cells i (5-60/mm 3, mononuclear)
Protein i (0.4-1 g/L) (in 60%)
lgG i (in 60%)
Oligoclonal bands (in 80%)
VER Delay (if optic nerve involvement)

Management
• Mostly supportive
• Steroids may help in acute attacks

STROKE
A focal neurological deficit with an underlying vascular pathology is defined as:

• Stroke - lasting > 24 h

• Transient ischaemic attack (TIA) - lasting < 24 h
• Reversible ischaemic neurological deficit (RIND) - lasting > 24 h but with full recovery
'Stroke-like episode'- focal neurological deficit lasting> 24 h with no obvious vascular pathology, e.g. brain tumour,
brain abscess.

Causes
\
Stroke may be due to haemorrhage or ischaemia. Ischaemia may be caused by vessel spasm, stenosis or dissection or
vessel occlusion (by thrombosis or embolism).

Ischaemia
Thrombosis Sickle cell disease
Severe dehydration (venous sinus thrombosis)
Meningitis
Clotting disorder, e.g. protein S or C deficiency, antithrombin III deficiency, lupus
antibodies, factor V Leiden
Thrombocytosis
Homocystinuria
Leukaemia
Embolism Cyanotic CHD, endocarditis
Vessel spasm Meningitis

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Large vessel stenosis Sickle cell disease
Varicella, AIDS, homocystinuria
Vessel dissection Trauma, e.g. fall on a pencil in child's mo ut h
Congenital heart disease
Maya maya disease Moya moya (basal artery occlusion with tela ngiectasia)
Also seen in Williams syndrome, Down synd rome

Haemorrhage
Low platelets ITP
Bleeding disorder Haemophilia
Vessel disorder A-V malformation, cerebral aneurysm
Trauma

Clinical features
• Deterioration in level of consciousness (seen in progression of bleed)
• Seizures (common in neonates)
• Hemiparesis, hemisensory signs, visual field defects

Investigations
These will be led by any underlying disease, and history and examination are essential to help elucidate the cause.
MRI brain scan Outline area affected (thrombosis, bleed, abscess, tumour, etc. )
CTscan If MRI unavailable (to exclude haemorrhage)
Magnetic resonance Vascular outline
angiography (MRA scan)
Transcranial Doppler USS Large vessel disease
Cerebral angiogram For more detailed outline. If MRA normal in ischaemia
Later, after haemorrhage for, e.g. A-V malfo rmation, aneurysm
ECG and echocardiogram Cardiac anomaly or arrhythmia
Infection screen
Haematological screen Including sickle screen, FBC and clotting defects
Metabolic screen If metabolic disease suspected

Management
This is dependent on the cause, e.g. exchange transfusion acutely in sickle cell disease, anticoagulants may be required
in prothrombotic coagulopathy and surgery in A-V malformation and cerebral aneurysm . Extensive rehabilitation,
depending on stroke severity, from multidisciplinary team.

SPINAL CORD DISORDERS

SPINAL CORD COMPRESSION

Causes
• Tumour- spinal cord intradural or extradural tumour, secondary deposit
• Trauma
• Infection - epidural abscess, TB
• Disc protrusion
• Vascular malformation

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Clinical features
These depend on whether the transection is partial or involves the whole cord. Basic features are:
• Pain- back pain and pain at the level of compression (radicular pain)
• Paralysis - spastic para- or tetra-paresis from the level of compression
• Sensory loss - loss to the level of compression

Complete transection
Paralysis Initial flaccid muscle paralysis (spinal shock), then spastic paralysis from the level of compression
Loss of voluntary sphincter control (reflex emptying returns)
Sensory loss Total loss of sensation in the regions supplied below the level of injury
NB: Fatal if above 41h cervical cord segment due to paralysis of the diaphragm.

Hemisection (Brown-Sequard syndrome)

Paralysis Paralysis of muscles on the same side as injury below the level of transection
Sensory loss Same side (paralysed limb) - loss of position sense, proprioception and tactile discrimination in
the same side (dorsal columns)
Opposite, unparalysed limb - loss of pain and temperature sensation (spinothalamic)

Investigations
X-ray spine (Bony destruction?)
MRI spine Outline of lesion
Myelogram (May be considered)

SYRINGOMYELIA AND SYRINGOBULBIA

A cystic degeneration of the centre of the cord (myelia) or brainstem (bulbia).

-Clinical features
Destruction of spinothalamic tracts Bilateral loss of temperature and pain in a bizarre distribution
Destruction of corticospinal tracts Spastic paraparesis, absent tendon reflexes upper limbs, wasting of the small
muscles of the hand
Brainstem (syringobulbia) Nystagmus, hearing loss, Horner syndrome, loss of facial sensation, tongue
atrophy and fasciculation

Investigations
'• MRI
• Myelogram

Management
Surgical aspiration may be attempted.

TRANSVERSE MYELITIS
This is acute inflammation of the cord and paraplegia.

Causes
• Viral infection - EBV, HSV, mumps, ru bella, influenza
• Multiple sclerosis, radiotherapy, anterior spinal artery occlusion

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:; . ·>· ~.
I, ' .

Clinical features
Abrupt onset of:
• Weakness - initially flaccid, becoming spastic, legs
• Sensory loss - pain, temperature and light touch, legs
• Back pain
• Sphincter disturbance
• Fever and nuchal rigidity

Investigations
LP CSF shows lymphocytes I, (protein l N)
MRI spine Lesion outlined

Management
Supportive, complete spontaneous recovery may occur.

Differential diagnosis
• Guillain-Barre syndrome
• Acute poliomyelitis
• Cord compression

NEUROMUSCULAR DISORDERS
The neuromuscular disorders are diseases in which the main pathology is peripheral:
Anterior horn cells Spinal muscular atrophies
Peripheral nerve Peripheral neuropathies
Neuromuscular junction Myaesthenic syndromes
Muscles Myopathies and muscular dystrophies
They can be remembered and clas- Anterior horn cell:
sified according to where along Werdnig·Hofmann disease
the motor pathway the pathol- poliomyelitis
ogy exists. They result in muscular Peripheral nerves:
weakness, often progressive. HMSN
Guillain-Barre syndrome
Botulism
Bells palsy

Neuromuscular transmission:
Myaesthenia gravis

Muscular:
Muscular dystrophy
Duchenne, Becker
Myotonias
Dystrophia myotonica
Myotonia congenita
Metabolic myopathies
Congenital myopathies
Inflammatory myopathies e.g.
Dermatomyositis

Figure 14.8 Neuromuscular disorders

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CLINICAL FEATURES

SPECIFIC INVESTIGATIONS
(These are tailored depending on the clinical features)
EMG Specific features may be seen, e.g. muscular dystrophy, myotonic dystrophy
Muscle imaging (USS, MRI) Myopathies, muscular dystrophies
Muscle biopsy SMA, Duchenne muscular dystrophy, myotonic dystrophy, congenital myopathies
Nerve stimulation test Myaesthenia gravis
Nerve conduction studies HMSN, SMA, Guillain-Barre disease
Sural nerve biopsy HMSN
Creatinine phosphokinase 1' In myotonic dystrophy and Duchenne muscular dystrophy
DNA analysis Specific disorders, e.g. muscular dystrophy, myotonic dystrophy
Tensilon test Myaesthenia gravis.
Acetylcholine receptor antibodies Myaesthenia gravis

THE FLOPPY BABY

The congenital neuromuscular disorders present as a neonatal hypotonia ('floppy baby'). There are many causes of
floppy babies, which can be divided into central and peripheral (neuromuscular) causes. The latter are identified by
the presence of weakness (limb movement absent or decreased) in addition, although in practice they can be difficult
to differ~ntiate:
Central causes (brain and spinal cord) Floppy only (limb antigravity movement present)
Neurqmuscular causes Floppy and weak (no/reduced limb antigravity movement)

Causes (neonatal hypotonia)

Central causes Neonatal sepsis
Drugs, e.g. maternal pethidine during delivery
Hypoxic-ischaemic encephalopathy
Metabolic disea_se, e.g. hypothyroidism, peroxisomal disorders, MSUD
Syndromic, e.g. Down syndrome, fetal alcohol syndrome, Prader-Willi ' syndrome
Neuromuscular causes Anterior horn cell disorder, e.g. spinal muscular atrophy
Neuromuscular junction disorder, e.g. transient neonatal myasthenia
Skeletal muscle disorder, e.g. congenital myopathy, congenital myotonic dystrophy

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 , .
~1

SPINAL MUSCULAR ATROPHY TYPE 1 (SMA, WERDNIG-HOHMAN DISEASE)

Autosomal recessive, severe disease. Deletion in SMN1 gene 5q11- 13. Incidence 4:100 000 approximately.
Due to progressive degeneration of the anterior horn cells as a result of failure of arrest of apoptosis.

Clinical features
o Severely affected - floppy and weak
• In utero: decreased fetal movements, arthrogryphosis
o Respiratory distress
• Tongue and other muscle fasciculation
• Extraocular muscles not affected
• Absent reflexes
• Progressive weakness
Death in infancy (from respiratory failure).

Investigations
Muscle biopsy Characteristic perinatal denervation pattern
EMG Few definitive changes
DNA testing Possible to confirm diagnosis
NB: CK normal.

Management
Supportive only (physiotherapy, orthopaedic, occupational therapy) .

POUOf\iiYHJTIS
Due to infection with poliovirus type 1, 2 or 3. Transmission faecal-ora l route.

Clinical features
Incubation 7-14 days. Subclinical infection (95%) .
Abortive poliomyelitis {5%) Fever, sore throat, myalgia
Non-paralytic poliomyelitis (2%) Above plus meningeal irritation
Paralytic poliomyelitis (0.1%) Initial fever, sore throat, myalgia, then meningeal irritation, muscle pain (neck
and lumbar region) . Then asymmetrical paralysis:
• Spinal poliomyelitis - limbs, thorax, diaphragm, trunk
• Bulbar poliomyelitis (5-30%) motor cranial nerve paralysis
NB: No sensory involvement

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 Predisposing factors:
• Exercise early in illness
• Male
• Trauma, surgery, IM injection
• Tonsillitis (bulbar polio)

Investigations
• Clinical diagnosis
• Viral PCR and culture

Management
Supportive therapy, early bed rest.

Prevention
• Intramuscular inactivated polio vaccine

HEREDITARY MOTOR-SENSORY NEUROPATHIES (HMSN, CHARCOT-~·MRIE-TOOTH, CMT)

This is a group of many disorders in which there is progressive disease of the peripheral nerves involving demyelination
and/or axonal degeneration. Treatment is supportive only.

HMSN Type 1 (CMT 1)

Autosomal dominant. Different genes found underlying different subtypes. Peripheral myelin protein 22 (PMP-22) gene
mutations in CMT1A. Prevalence 15:100 000.

Clinical features
• Presentation in Late childhood
• Progressive distal weakness: Weakness of dorsiflexion (foot drop), pes cavus
Gait disturbance
Inverted champagne bottle-shaped Legs
• Absent tendon reflexes
• Milder involvement of hands
• Distal sensory loss - paraethesias, loss of proprioception and vibration

InvestigFJtions
DNA testing
Nerve conduction studies Reduced motor and sensory velocities; differentiate demyelinating from axonal
Sural nerve biopsy 'Onion bulb' formations of Schwann cell cytoplasm (due to de- and re-myeliniation. Not
necessary for diagnosis)

Management
Supportive only- foot splints, ankle fusio n, pillows under legs at night.

GUILLAIN-BARRE DISEASE
This is a post-infectious demyelinating neuropathy, developing 1-3 weeks after an often trivial viral infection.

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 Clinical features
Trivial viral infection, then 1- 3 weeks later:
• Distal limb weakness, ascending and symmetrical
• Areflexic
• Muscle pain and paraesthesia
• Respiratory muscle and facial weakness (20%)
• Urinary retention or incontinence
• Autonomic features rare (BP and heart rate lability)

Investigations
Clinical diagnosis.
Nerve conduction Delay in motor and sensory conduction
LP CSF Protein i (x2 normal)
Oligoclonal bands
wee normal, glucose normal
Respiratory function tests Spirometry

Management
Supportive therapy with ventilation in severe cases. Spont?neous recovery usual in 2-3 weeks/ though there may be
some residual weakness.
Gamma-globulin (IV) reduces duration and severity. Plasmapheresis occasionally used.

Miller-Fischer syndrome
A rare/ severe form involving:
• Ataxia
• Proximal muscle weakness
• External ophthalmoplegia

MYASTHENIA GRAVIS
A disease of immunological neurom uscular blockade in which there are IgG antibodies to acetylcholine receptors
(AchR).
Mostly acquired/ may be hereditary. Incidence approximately 15:100 000. Female:male = 2:1. Average age of onset 30
years.
Associations Drugs (o-penicillamine/ lithium/ propranolol)
HLA-88, DR3
Hashimoto thyroiditis
Collagen vascular disease

. Clinical features
Eyes External ocular muscle weakness/ diplopia and ptosis
Bulbar Dysphagia (bulbar muscle involvement)
Face Sad facial expression (facial muscle weakness)
Limbs Proximal weakness
Reflexes fatiguable
Fatiguability Muscle fatiguability/ i.e. progressive weakness with use - a cardinal feature

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Diagnosis
Tensilon test An anticholinesterase, e.g. edrophonium, given IV, brings transient relief. NB: Cannot use
edrophonium in neonates (causes arrhythmias)
Serum AChR antibodies (90%)
Nerve stimulation Fibrillation and decreased muscle response with repetition

Management
Anticholinesterase drugs 4-6 hourly, e.g. pyridostigmine, neostigmine
Antibody removal Using thymectomy, steroids or plasmapharesis can be done
Care during anaesthetics.

Transient neonatal myaesthenia gravis

In a pregnant mother suffering from myaesthenia gravis, AChR antibodies will cross the placenta because they are IgG
antibodies, and cause a transient neonatal disease, generally lasting 2-3 weeks.

Congenital myaesthenia gravis

This is a condition of different aetiologi (due to congenital abnormality of AChR channels and not autoimmune
disease) which has similar features to myasthenia gravis but is non-progressive.

MUSCULAR DYSTROPHIES
These are genetic myopathies involving progressive disease and death of muscle fibres.

Duchenne muscular dystrophy

X-linked recessive, ' incidence 1:3600 live male infants. Due to absence of dystrophin (a muscle protein), caused by a
mutation in the dystrophin gene on chromosome Xp21.3.

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 -"!

Clinical features
Normal early motor development
Proximal limb weakness Evident from 3 years of age
Gower's sign evident at 3- 6 years: A manoeuvre to stand from lying down
involving rolling over, then using hands to 'climb up' the knees
Waddling (Trendelenburg) gait
Calf muscle pseudohypertrophy As a toddler
Progressive deterioration Eventually wheelchair bound (usually by teenage years) with scoliosis
Pharyngeal weakness and respiratory failure develop
Cardiac Dilated cardiomyopathy, Q waves in left chest leads
Learning disability (33%)

Creatinine phosphokinase (CK) Extremely elevated (i 10 x normal)

Muscle biopsy Fibre necrosis, fat infiltration, no dystrophin on staining
EMG Myopathic pattern
Cardiac ECG, CXR
Genetic testing Dystrophin gene mutation looke_d for

Management
Supportive only at the present time, with physiotherapy, nutritional support, orthopaedic involvement and occupa-
tional therapy. The prognosis is poor with eventual death from respiratory complications.

Detection
• Female carriers- CK i in 70%
• Antenatal detection is possible on CVS sampling using DNA probes

~4VOTONIC DYSTROPHY
A progressive distal muscle weakness in which the cardinal feature is a failure of muscle relaxation (myotonia).
Autosomal dominant. Chromosome 19q13 expansion with numerous trinucleotide CTG repeats. Anticipation occurs,
i.e. more severe with each generation (see p. 16). Worse if inherited from the mother.

Clinical features
May present in the neonatal period or later.
Face Fish mouth (inverted 'V' shaped upper lip)
Facial muscle weakness, decreased muscle mass in temporal fossa, high-arched palate
Eyes Ptosis, cataracts
Other muscles Weakness of distal limbs and respiratory muscles
Cardiac Cardiomyopathy, conduction defects
Mental Learning disability (50%)
Hair Frontal baldness in males
Endocrine Hypogonadism, small pituitary fossa, glucose intolerance
Immunity IgG 1
Gastrointestinal Constipation

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Investigations
Diagnosis is clinical. Shake hands with the child (if old enough) and the parent and they cannot quickly let go.
Muscle biopsy Prognostic value in neonates
EMG Classic findings seen after infancy
Other Endocrine, immunoglobulin and cardiac assessment is necessary

Management
• Phenytoin or carbamazepine may help with myotonia (increase depolarization threshold)
• Care must be taken during anaesthesia

MYOTONIA CONGENITA (THOMSEN DISEASE}

• Autosomal dominant (chromosome 7q35) or recessive
• Myotonia with generalized muscle hypertrophy - appearance of a body builder

CONGENITAL MYOPATHIES
The term congenital myopathies encompasses many unrelated congenital diseases of the muscles, which may be mild,
causing little problem throughout life, or severe; they may also be either static or progressive.
Some are due to ultrastructural deformities of the muscles, and some to abnormalities within the mitochondrial DNA
and involve metabolic defects and features in other organs. Muscle biopsy is usually involved in diagnosis.

General features
• Those of neuromuscular causes of floppy baby (see p. 363), i.e. neonatal hypotonia with weakness. They have a
distinctive appearance with a thin muscle mass at birth and undescended testicles
• Features may be mild at birth but are often progressive

Myotubular myopathy
Usually X-linked recessive (also autosomal dominant and recessive forms).
Disorder of muscle ultrastructure, possibly due to developmental arrest.

Clinical features
In utero Decreased fetal movements, polyhydramnios
Neonatal Severe myopathy at birth. Ptosis prominent. Most die within few weeks of birth

Diag,'tfosis
Muscle biopsy is diagnostic.

Congenital muscle fibre-type disproportion (CMFTD)

Sporadic, autosomal recessive. Features as in myotubular myopathy but less severe, with a high degree of clinical
variability. Diagnosis on muscle biopsy.

Nemaline rod myopathy

Abnormal rod-shaped inclusions within muscle fibres (mostly a-actinin). Autosomal dominant or recessive. Variable
penetrance of dominant form, with mildly affected individuals having poorly developed muscles only.

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Asevere neonatal form exists, with early death in most infants, and a milder form with motor delay, feeding difficulties
and recurrent respiratory infections, dolicocephaly and high arched palate.
Diagnosis on muscle biopsy (nemaline rods are abnormal structures within the muscle fibres) .

POTASSWI\1-RELATED PERIODIC PARi~LYSES

Autosomal dominant. Involves periodic attacks of paralysis with transient alterations in serum potassium:
Kl Hypokalaemic periodic paralysis
Ki Hyperkalaemic periodic paralysis
Normal between attacks in chi ldhood.
Episodes of paralysis, e.g. on awakening, lasting minutes or hours. Liquorice may precipitate attacks. Progressive
disease with weakness in adulthood. Diaphragmatic muscles unaffected, ECG changes occur during attacks.
Care must be taken during anaesthesia.

HEREDITARY SENSO RY NEUROPATHY, FAMILIAl IY1SAU"WNOMIA (R!lEY~DAY SYNDROME)

Autosomal recessive. Gene at chromosome 9q31-33. Disease of peripheral nervous system involving reduced numbers
of small nerve fibres (pain, temperature, taste, autonomic functions).
Associations Eastern European Jews

Clinical features
Autonomic features Excessive sweating, blotchy erythema, abnormal tearing
'Crises' (labile BP, heart rate, vomiting, irritability, sweating, poor temperature control)
Peripheral neuropathy Insensitivity to pain, feeding difficulties and aspirations, clumsy gait, scoliosis,
_corneal ulcers, slurred speech
CNS Breath-holding seizures, mental retardation

Investigations
Diagnosis Intradermal histamine produces no flare.
Metacholine infusion causes exaggerated hypotensive response
Metacholi ne eye drops produce miosis (no reaction normally)
Plasma Dopamine-~-hydroxylase enzyme t
Urine VMA t, HVAt
Sural nerve biopsy Decreased unmyelinated fibres
CXR Chronic changes from aspirations
ECG Prolonged QT

Management
• Eye drops, protection from injury
• Autonomic crises - anxiolytics, antiemetics, electrolyte control

Prognosis
Death in childhood from chronic pulmonary failure.

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 .. . .. · -- -·· - - - ··· .. ······· · . .... . .. .. .. ··- ---·- -· - .

PSYCHIATRIC DISORDERS

ATTENTION DEFICIT HYPERACTIVITY DISORDER {ADHD}

Diagnostic criteria
• Inattention
• Hyperactivity
• Impulsivity
Lasting > 6 months and commencing < 7 years, and inconsistent with the child's developmental level. These features
should be present in more than one setting, and cause significant social or school impairment.

Risk factors:
• Male >female 4:1
• Learning difficulties
• CNS disorder, e.g. epilepsy, cerebral palsy
• Specific developmental delay
• First-degree relative with ADHD
• Family member with depression, learning disability, antisocial personality or substance abuse
These children also have an increased risk of:
• Conduct disorder
• Anxiety disorder
• Aggression
Asignificant proportion of children with ADHD will become adults with antisocial personality and there is an increased
incidence of criminal behaviour and substance abuse.

Management
Psychotherapy Behavioural therapies
Family therapy
Drugs If behavioural therapy alone insufficient:
Stimulants, e.g. methylphenidate (Ritalin), amphetamines (dexamphetamine)
Side effects: insomnia, appetite suppression, headaches, abdominal pain, growth retardation
(reversible on stopping drug)
Diet Some children benefit noticeably from exclusion of certain foods from their diet, e.g . red food
colouring, cow's milk
This is not universal though, and any changes should be made with the assistance of a dietician
r
AUTISM (CLASSICAL OR REGRESSIVE)
Prevalence 5-6:1D 000 (currently rising).
A developmental behavioural disorder of social interaction and understanding, which is the end-point of several
organic aetiologies, e.g. prenatal insults, metabolic disorders, localized CNS lesions, postnatal infections (e.g.
encephalitis). The specific organic cause is rarely found (< 10%). Features and severity very variable and thought to
be part of a spectrum.
Genetic factors Siblings have a 2- 3% prevalence, i.e. 50-100 x greater than average incidence
Monozygotic twin concordance 60%
Increased risk of epilepsy in teenage years.

371
Clinical features
• Diagnosis made at 2-3 years. Features noticeable from 1 year
• Severity varies greatly between individuals and over time in a single child
• Impairment of social interactions Limited eye contact
Child relates to parts of a person not the whole person
Plays alone
• Narrow range of interests and repetitive behaviour Repetitive play, fascination with movement
Interest in detail
Poor concentration span
Early development of numbers
• Rigidity of thought and behaviour - difficulty in changing from one activity to the next or in stopping an
activity
• Abnormal speech and language development- delay in speech, echolalia
• Developmental stasis or regression- seen in 25-30% at 15-18 months of age
• Most have low IQ
·,I
Management
1. Assessment Detailed medical and developmental history (focusing on development and core behaviours)
Medical examination and play observation
Hearing and vision testing
Other investigations if indicated, e.g. lead, FBC and iron studies, chromosomes and fragile X,
Rett gene, thyroid function, PKUtest
Neuroimaging only if specific neurological signs. EEG if epilepsy
2. Written report Produced for parents and all relevant professionals and an action plan is made for the family
3. Interventions Behavioural therapies and educational programmes (several approaches may be used, none of
which has been shown to be more effective than others)

ASPERGER SYNDROME
These children have a severe impairment in reciprocal social interaction, but are otherwise relatively normal.
• No delay in language, but have unusual language development, e.g. interpret literally, have one-sided
conversations
• Variable fine and gross motor delay (clumsy, walk later than they speak)
• Difficulty in understanding non-verbal communication
• Generally high level of intelligence
• Develop all-absorbing special interests
• May be able to memorize large amounts of information, though not necessarily fu lly comprehend it

FURTHER READING
Aicardi J Diseases of the Nervous System in Childhood, 2"d edn . London: MacKeith Press with Blackwell Science Publica-
tions, 1998

372
• Visual development • Orbital abnormalities
• Visual impairment • Refractive error and strabismus (squint)
• Eye lid aonormalities • Infections and allergies
• Lacrimal system abnormalities • Retinopathy of prematurity
• Anterior segment, iris and lens malformations • Non-accidental injury
• Optic nerve abnormalities • Phakomatoses
• Disc abnormalities

VISUAL DEVELOPMENT
• Eye grows rapidly during the first 2 years of life
• Neonates have poor visual acuity (approx 6/200)
• By 6 months of age electrodiagnostic tests show that vision improves to 6/6
• Any untreated obstruction or interference with focusing on objects during the first 7 years of life prevents
normal development of visual acuity (amblyopia)
• Binoc1,1lar vision develops in the first 3-6 months of age
• Depth perception begins at 6-8 months, is accurate at 6-7 years and improves during adolescence

VISUJ\LACUITY
• Top number is the distance the subject is away from the chart in metres
• Bottom number is the number written by the side of the letter on the chart. This number indicates the maximum
distance (in metres) that a normal sighted person can see that letter
• In the UK normal vision is 6/6 since meters are used (20/20 in USA as feet are used)

373
Visual acuity testing

VISUAL IMPAIRMENT
Causes
• Congenital - anophthalmos, optic nerve hypoplasia, cataracts
• Prematurity - retinopathy of prematurity
• Hypoxic-ischaemic encephalopathy
• Refractive error- amblyopia, myopia, hypermetropia
• Strabismus
• Optic atrophy
• Tumour, e.g. retinoblastoma .
• Systemic condition, e.g. juvenile idiopathic arthritis (uveitis)
• Infection - orbital cellulitis, trachoma
• Delayed visual maturation (normal children with learning difficulties; they develop normal vision later)
• Cortical blindness, i.e. cortical defect, no eye abnormality

Clinical presentation
• Lack of eye contact
• Failure to smile by 6 weeks of age
• Visual inattention, failure to track objects or fix on face by 3 months
• Nystagmus
• Squint
• Photophobia
• White pupillary reflex (leucocoria) (see below)

374
r~ Management
Initial assessment by a paediatrician, an ophthalmologist and a neurologist is necessary.
• Ophthalmological assessment: general eye examination and visual acuity
• Full neurological assessment

Investigations
These are led by the individual case history and examination, but may include:
Electrophysiological tests Electro-retinogram (ERG) (abnormal in retinal defects)
Visual evoked response (VER) (abnormal in both eye and cortical defects)
Bloods Serology for congenital infection
Pituitary function tests
Inborn error of metabolism, e.g. galactosaemia
Brain CT/MRI

Treatment
• Treat any treatable cause
• Specialized regular developmental assessment with help from teachers from the Royal National Institute for the
Blind (RNIB)
• Maximize non-visual stimulation
• Education: Mainstream school or school for the blind
Braille (if blind)
Low vision aids (if impaired vision, e.g. high-power magnifiers, telescopic devices)
• Genetic counselling if appropriate

EYE LID ABNORMALITIES

Ptosis Droopy lids, can cause am_blyopia if obstructing the vision
Lid coloboma Varying from a small notch to absence of lid (usually upper lid)
Epiblepharon Horizontal fold of skin in upper or lower lid turning eye lashes in; usually resolves spontaneously
by 2 years old
Dystichiasis Extra row of eyelashes
Autosomal dominant inheritance
Associated with lymphoedema
Ectropion Eversion of usually lower lid
Entropion' Inversion of usually the lower lid
Epicanthus Vertical crescentic fold of skin between upper and lower lids
May mimic strabismus
Especially prominent in Asian children
Telecanthus Wide interpupillary distance
Blepharophimosis Shortening of palpebral fissures horizontally and vertically

LACRIMAL SYSTEM ABNORMALITIES

Nasolacrimal duct obstruction

• A persistent membrane across the lower end of the nasolacrimal duct is very common at birth, leading to a
watery eye (about 5% of newborns)
• Normally disappears after the first year

375
 • If the problem persists beyond 12 months the nasolacrimal ducts are probed under general anaesthetic. This
usually gives immediate resolution and, if not, the procedure is repeated

Dacrocystocele
• Uncommon, cystic swelling of the nasolacrimal duct due to obstruction
• Can mimic a dermoid cyst, haemangioma or encephalocele
• Treatment is topical antibiotics and digital massage
• It may lead to dacrocystis if it becomes infected, and will need systemic antibiotics± surgical decompression

ANTERIOR SEGMENT, IRIS AND LENS MALFORMATIONS

Keratoconus is thinning of central cornea leading to cone formation and astigmatism. Usually presents and progresses
through adolescence.

Differential diagnosis of corneal opacities

• Sclerocornea - cornea indistinct from white scleral tissue with no apparent limbus. Rare
• Forceps injury causing a tear in Descemet's membrane in the cornea leading to corneal oedema
• Mucopolysaccharidosis and mucolipidosis (see p. 284)
• Posterior corneal defects - iris undifferentiated from cornea
• Congenital hereditary endothelial dystrophy- uncommon, hereditary dystrophy, onset at birth. Corneal oedema
and clouding
• Dermoid - usually straddle the corneo-sclerallimbus. Associated with Goldenhar syndrome
• Infantile glaucoma (see p. 377)
• Congenital hereditary stromal dystrophy- very rare, autosomal dominant corneal clouding
• Other causes - cystinosis, Wilson disease, congenital syphilis, Riley-Day syndrome

KRIS ABNORMtidJTIES
Aniridia Iris hypoplasia. Sporadic or autosomal domi-nant
Sporadic form: 1h develop Wilms tumours, therefore yearly abdominal USS and
clinical evaluation for Wilms tumour needed
Iris coloboma Notching of iris. May involve retina and optic nerve
Associations: trisomy 13, triploidy, trisomy 18, Klinefelter, Turner syndrome,
CHARGE, Walker-Warburg, Aicardi~ Rubensten-Tayabi, Goldenhar syndrome
Brushfie/d's spots Iris stromal hyperplasia surrounded by hypoplasia .
Seen in 90% of Down syndrome
Heterochromia Variation in colour between the two irises
Occasionally associated with Wilms tumour
Hypochromic Reduced iris pigmentation compared to other eye.
E.g. congenital Horner, Fuchs heterocromia, Waardenburg-Klein syndrome, tumours
Hyperchromic Increased iris pigmentation
E.g. pigmented tumours, siderosis, ectropion uvea, oculodermal melanosis
Persistent pupillary membrane Most common developmental abnormality of iris
If especially prominent can lead to ant~rior polar cataracts

376
:; PUPil ABNORMALITIES (ANISOCORIA)
Small pupil May be associated with other eye abnormalities, e.g. congenital rubella syndrome, Lowe
oculocerebrorenal syndrome
Drugs, e.g. morphine
Large pupil Iris trauma
Drugs, e.g. ecstasy
Parasympathetic neurological disorder:
• Holmes-Adie pupil
• Unilateral VI nerve palsy (seen in i ICP)

Causes of Leucocoria (white pupil)

• Retinoblastoma
• Cataract
• Colobomas
• Infection - toxocaria, toxoplasma
• Retinopathy of prematurity
• Uveitis
• Coats disease
• Vitreous haemorrhage
• Retinal detachment
• Persistent hyperplastic primary vitreous

CAUSES OF CATARACT IN CHILDREN

CONGENITAl GLAUCOMA
• Primary congenital glaucoma incidence 1:10000 births
• Mainly sporadic, may be autosomal recessive. Males >females .,
• Intraocular pressure rises due to maldevelopment of the drainage angle in the anterior chamber
• May present at birth or develop later (usually< 3 years old)

377
 • May be secondary to Sturge-Weber syndrome, dysgenesis syndromes, Lowe syndrome, rubella, aniridia,
neurofibromatosis, microcornea, ROP and retinoblastoma

Clinical features
!
• Buphthalmos (excessive corneal diameter [> 13 mm] due to stretching of the eye from the constant elevated
intraocular pressure). Cornea becomes white and hazy due to corneal oedema
• Photophobia, lacrimation and eye rubbing
• Both eyes are usually affected but asymmetrically
• Eyes have a tendency to become myopic with disc cupping

Management
Involves topical antiglaucoma medication +/- drainage angle surgery, with regular follow-up and refraction.

OPTIC NERVE ABNORMALITIES

Morning glory disc Very rare, usually unilateral, mostly sporadic inheritance
Enlarged optic disc, with central area of white tissue
Associated with high myopia and other developmental abnormalities, and poor
visual development
Coloboma Unilateral or bilateral, vision depends on area of retinal or optic nerve involvement
Myelinated nerve fibres Bilateral in 20%. White flame-shaped area at disc, causing visual field defects
Tilted discs Usually bilateral, associated with reduced vision and visual field defects
Persistent hyaloid membrane Remnants of hyaloid arte ry which normally disappears before birth. Usually
asymptomatic.
Optic nerve hypoplasia Uni - or bi-lateral. Small, pale optic disc with crowded vessels at disc
Causing visual field defects, nystagmus and amblyopia
Assodations: fetal alcohol syndrome, endocrine abnormalities, e.g. hypothalamic
and pituitary dysfunction, CNS anomalies

DISC ABNORMALITIES

DISC SWHJJ NG
Causes
Raised ICP (Think of this first). Papilloedema is optic disc (papilla) swelling secondary to raised ICP
Optic (local) Infiltration, e.g. leukaemia
Retinal vein occlusion
Ischaemic optic neuropathy
Disc drusen (Whitish hyaline/calcific deposits at the disc, present in 0.3% of the norma l population. Usually
bilateral and may be present in other family members. Us ua lly cause no ocu lar complications
apart from very rarely a minor loss of visual field)
Hypermetropia

Clinical features
Symptoms Blurred vision
Enlarged blind spot (later in disease)
Signs Disc: blurring, erythema, heaping up of the disc margins, obliteration of the physiological cup, disc
haemorrhages
Retina: retinal vein dilatation and loss of venous pulsation, retinal haemorrhages

378
OPTIC ATROPHY
This is visible as disc pallor.

Causes
• Optic nerve compression, e.g. tumour, aneurysm
• Ischaemia, e.g. severe anaemia, arteritis
• Optic and retrobulbar neuritis, e.g. multiple sclerosis
• Deficiency, e.g. vitamin B12
• DIDMOAD
• Hereditary optic neuropathy
• Infection, e.g. orbital cellulitis, syphilis
• Toxic neuropathy, e.g. methyl alcohol, quinine, tobacco
• Causes of papilloedema

ORBITAL ABNORMALITIES
Differential diagnosis of proptosis in children
Malignant E.g. rhabdomyosarcoma, neuroblastoma
Benign Inflammatory, e.g. orbital cellulitis, mucocele
Traumatic, e.g. haematoma
Metabolic, e.g. Graves disease
Infiltrative, e.g. glioma
Developmental, e.g. dermoid cyst

CRANIOFACIAL MALFORMATIONS AFFECTING OCULAR DEVELOPMENT

Craniosynostosis Proptosis, corneal exposure, strabismus, papilloedema, optic atropy
Hypertelorism Increased distance ·between the orbits. Associated with d2ft lip and palate, and
strabismus
Waardenburg syndrome AD. Iris heterochromia, white hair, retinal hypopigmentation, confluent eyebrows±
deafness
Goldenhar syndrome Facial asymmetry, small low set ears often with ear tags, wide mouth with jaw
abnormalities, vertebral dysgenesis, strabismus, microphthalmos (small globe)
Treacher-Collins syndrome Jaw and maxillary hypoplasia, ear abnormalities, lid defects
Pierre-Robin syndrome Retinal detachment, cataracts, myopia, microphthalmia (see p. 125)
Fetal alcohol syndrome Short horizontal palpebral apertures

REFRACTIVE ERROR AND STRABISMUS (SQUINT)

REFRACTIVE ERROR

Hypermetropia
• Long-sightedness
• Most common childhood refra·ctive error
• Early correction (with glasses) necessary to prevent amblyopia

379
Myopia
• Short-sightedness
• Uncommon in childhood, often hereditary

Amblyopia
Amblyopia is permanent impairment of visual acuity in an eye that did not receive a clear image while vision was
developing . Usually only one eye affected, known as a 'lazy eye.'

causes
It results from any interference with visual development:

• Refractive errors
• Squint
• Obstruction of vision, e.g. strawberry haemangioma occluding vision, ptosis

Treatment
• Patching the good eye for periods of time during the day to force the affected eye to work and therefore develop, and
• Treat underlying cause,_ e.g. correct any refractive error with glasses, treat squint
• Treatment while young is very important. After age 7 years, improvement is unlikely

SQUANT (STRABISMUS)
Squint is a common condition and is due to misalignment of the visual axes.
,_'--.··..,
,:;:.:,;··. ;·_: -:--··;:·. ::.~ _.:·,__:~ :;:·.

• ; co.Ui~ant (allgte ofdeviati9l1 )s, tg,nsta~t}9F{~~coiTJita_!lt ' (angle ,_ofdeviatiori changes _on 'direction of gaze)
- • Nori~paralyticorparalytic · · · · ·· - ' · ·· ·- · - - ·

Convergent squint
The most common childhood squint. Usually related to accommodation and caused by an imbalance between accom-
modation and convergence. (Eyes accommodate and converge when looking at near objects. Accommodation is the
process of altering the shape of the natural lens to focus the incoming light onto the retina).
Convergent squints are usually constant in childhood.
Accommodative convergent squint Refractive (due to child being long-sighted/hypermetropic):
Difficulty on focusing on near objects. The stimulation for convergence
is increased by the eyes trying to accommodate to focus on a near
object, causing a squint
Non-refractive:
No hypermetropia is present. The stimulation for convergence is
disproportionately high for the stimulation of accommodation
Mixed accommodative convergent squint Hypermetropia and an abnormal stimulation of accommodation and
convergence is present. Squint is most noticeable when focusing on near
objects

380
Essential infantile convergent squjnt Idiopathic squint which presents in the first 6 months. The child
alternates fixation between the two eyes. Usually corrected surgically
by the age 2 years

Divergent squint
Intermittent divergent squint Usually presents around the age of 2 years as an intermittent squint
With tiredness or inattention this may become constant
Constant divergent squint May be congenital, due to underlying visual impairment in older children or after
surgical over-correction of a convergent squint

Paralytic squints
Rare.
• Divergent, e.g. III'd nerve palsy
• Convergent. e.g. VIth nerve palsy
• Vertical, e.g. IVth nerve palsy (head tilt occurs)
NB: Young babies often have a squint at times (particularly on convergence looking at a close object) as_ they have not
yet developed binocular vision. There should be no squint by age 4 months. Any squint present after 2-3 months of
age should be referred to the ophthalmologist as binocular vision should have developed by this time.

Tests for squint

Visual acuity must be assessed first.
1. Cornea/light reflection test Pen torch is shone to produce reflections in both corneas.
If reflection is in different places in each cornea, a squint is present
2. Eye movements Child is asked to look at an object/toy which is moved in a horizontal, vertical and
diagonal direction at 1j3 of a meter. Detects a paralytic squint
3. Cover test Eyes covered individually with a card using a toy for visual fixation
If the fixing eye is then covered, the squint eye moves to take up fixation
On removal of the cover the eyes move again as the normal fixing eye takes up
fixation (manifest squint)
Used to detect a latent squint where the eye squints when covered
An alternating squint is where each eye moves in turn when covered

Squint eye Fixing eye

Cover applied

Manifest squint

Figure 15.1 Cover test in a manifest squint of the right eye

381
Children should have fundoscopy and a refraction test for glasses if there is any history of squint. This should be ·
repeated yearly as their refraction may change.

INFECTIONS AND ALLERGIES

CONJU NCTIV.IHS
Clinical features
• Conjunctival injection · ~·

o Pus in the eye

• 'Gritty' or irritating eye
• Otitis media commonly associated with bacterial conjunctivitis, and should be examined for

Causes

NB: Chlamydia, Neisseria gonorrhoea, streptococcus, chemical and herpes simplex can be acquired during delivery from
the genital tract. Neissen·a gonorrhoea is particularly dangerous as it can penetrate the cornea within 24 h.

Management
• Eye swab - microscopy (Gram stain) and culture. (Chlamydia and gonorrhoea require special media.) PCR for
rapid detection
• Frequent eye and lid hygiene
• Neonate: Chloramphenicol or neomycin eye drops hourly or 2 hourly
Chlamydia: oral erythromycin (2 weeks) plus tetracycline eye ointment
Gonococcus: eye irrigation with crystalline penicillin hourly. IV penicillin 10 days
• Infant/child: Fusidic acid, chloramphenicol or neomycin eye drops
• Pseudomonas and Haemophilus influenzae type b - oral antibiotics needed

ORBITAL AND PRE-SEPTAl H U..lH.ITIS

Preseptal cellulitis Infection in the tissues anterior to the eyelid septum, with white conjunctiva,
no diplopia, proptosis or loss of vision
Orbital (post-septal) cellulitis Infection posterior to orbital septum, much more serious and can lead to loss
of vision, cavernous sinus thrombosis, meningitis and septicaemia

382
.. - ··· · ..... . .. .. - .. . ..... . . . . .... ..... _ . ··-

Distinguishing clinical features

NB: These features of orbital cellulitis are danger signs indicating possible need for surgery:
• An ophthalmologist should be contacted to help make the differentiation between pre- and post-septal-cellulitis
• Orbital cellulitis may result from severe sinusitis, and therefore an ENT specialist should also be involved to assess
the need for any urgent intervention
• Complications of orbital cellulitis include cavernous sinus thrombosis, meningitis, subdural and periosteal
abscesses, and amblyopia/blindness if visual axis is interrupted.

Investigations
• Eye swab
• Blood cultures
• FBC
• Orbital and sinus CT scan (to show any If orbital cellulitis suspected
involvement of the sinuses and intraorbital
complications necessitating surgical
drainage)

Treatment
Presepta/ cellulitis Oral antibiotics
Orbital cel(ultis Broad spectrum IV antibiotics± surgical intervention

ATOPIC CONJUNCTIVITIS
• Common, especially in boys aged 5-15
• Recurrent inflammation of the conjunctiva in spring and summer months, associated with severe itching and a
milky white discharge
• Giant papillae form under the upper and lower lids which appear as large nodules
• Treatment involves topical antihistamines and occasionally low dose topical steroids

STEV-ENS-JOHNSON SYNDROME
A rare acute inflammatory reaction affecting the skin and mucous membranes, which is life threatening (seep. 298).

383
Ocular signs
• Conjunctivitis
• Scarring of the conjunctiva (corneal scarring may develop)
• Dry eye 1

Management of eye features

Lubricants and artificial tears.

RETINOPATHY OF PREMATURITY {ROP)

Thought to be due to proliferation of the retinal vasculature due to high oxygen saturation in the blood of premature
babies. Normally retinal vasculature begins to develop from the optic disc in the 16th week in utero. The vessels reach
the nasal peripheral edge of the retina by the 8th month of gestation. The temporal edge of the retina is vascularized
by birth.
May result in:

• Decreased visual acuity

• Retinal detachment
• Blindness

-Management
• Screening all premature infants at risk (< 1500 g at birth or< 32 weeks gestation) from 32 weeks by ophthal-
mologist
• Prevention by minimizing oxygen therapy to lowest necessary level
• Laser photocoagulation or cryotherapy if necessary

International classification of ROP

Std~~5
Plu~ di;~a;e
Thepresence of dilated veins :and tortuous arterioles with vitreous clouding and poor pupil dilatation

384
t~ NON-ACCIDENTAL INJURY
Child abuse presents with eye signs in approximately 5% of total NAI presentations. A reliable clinical history is often
difficult to obtain and often the clinical signs do not match the timing or mechanism of the injury.

Clinical features
• Retinal haemorrhages (most common), usually as a consequence of shaking. Usually< 1 year old
• Subconjunctival haemorrhage, hyphaema and periorbital bruising
• Cataract, lens dislocation and retinal detachment are signs of long-term abuse
Acommon feature of shaken baby syndrome is that there is often no external evidence of trauma around the eyes but
there may be bruising on the child's limbs or trunk from where they have been held. Intracranial haemorrhage is
often co-existent.
Other causes of retinal haemorrhages:
• Birth trauma (normally resolved by 1 month)
• Leukaemia
• Coagulation disorders
• Tussive injury, e.g. whooping cough

PHAKOMATOSES
Group of disorders with neurological abnormalities and congenital abnormalities of the skin, retina and other organs.
Neurofibromatosis Autosomal dominant, cutaneous neurofibromas, cafe au lait spots, axillary freckling, tumours of
the CNS, iris nodules, glaucoma, choroidal naevi, optic nerve and orbital tumours (see p. 352)
Von Hippei-Lindau Autosomal dominant, haemangioblastoma, phaeochromocytoma, hypernephroma, retinal angi-
oma, hypertensive retinopathy (see p. 353)
Tuberous sclerosis Autosomal dominant, 50% sporadic mutations, mental handicap, epilepsy, adenoma sebaceum,
shagreen patches, ash leaf patches, subungual fibromas, retinal tumours, iris hypopigmentation
(see p. 352)
Sturge-Weber Cutaneous angioma over trigeminal nerve l't and 2"d divisions, leptomeningeal angiomas with
epilepsy and/or seizures, glaucoma, choroidal haemangiomas (see p. 300)

385
• Physiology • Polycythaemia and thrombocythaemia
• Anaemia • Haemostasis
• Haemoglobinopathies • The spleen

PHYSIOLOGY

HAEMOGUJBIN
A red blood cell contains about 640 million molecules of haemoglobin (Hb ). Haemoglobin is composed of four
polypeptide chains (normal adult Hb has two a and two pchains/ a 2 P 2 )~ each with a haem group.

Haem

Oxyhaemoglobin Deoxyhaemoglobin
Figure 16.1 Oxyhaemoglobin and deoxyhaemoglobin

Haemoglobin carries oxygen from the lungs to the tissues. Each Hb molecule combines with four 02 molecules to form
oxyhaemoglobin . Deoxyhaemoglobin contains no oxygen molecules and has the metabolite 2)-DPG in the centre~ .
which acts to decrease its affinity to oxygen.

386
HAEI\o\ SYNTHESIS
This occurs in the mitochondria via a series of biochemical reactions:

Glycine+ succinyl coenzyme A

ALA (rate-limiting enzyme)
Protoporphyrin
+
l··,
~
Haem
2
Vitamin B6 (coenzyme) Iron (Fe •, ferrous)

CONTROL OF ERYTHROPOIESIS
Substances necessary for erythropoeisis include:
• Hormones- erythropoietin, IL-3, stem cell factor, thyroxine and androgens
• Metals -iron, manganese, cobalt
• Vitamins - B11 , folate, C, E, B6 (pyridoxine), thiamine, riboflavin, pantothenic acid
• Amino acids

ERYTHROPOIETIN
This is a hormone that regulates Hb synthesis. It is a glycosylated polypeptide made mostly in the peritubular complex
of the kidney. A low 02 tension in the kidneys stimulates erythropoietin synthesis.

Recombinant erythropoietin
Shift to left -
This is given subcutaneously (or intra-
(increased affinity)
venously) three times per week. Indi- Acute alkalosis
cations include endstage renal failure, Decreased temperature
inherited haemoglobinopathies, e.g. pC02 1
thalassaemia, and anaemia of chronic 2,3 DPG I
Carboxyhaemoglobin
disease. Side-effects include hyperten- Methaemoglobin
sion, high blood viscosity and, rarely, Abnormal haemoglobin (e.g. fetal
encep_halopathy. haemoglobin)
Cyanotic congenital heart disease

OXYHAEMOGLOBIN
100%
DISSOCIATION CURVE
90%
The oxyhaemoglobin dissociation curve
describes the relationship between the 75% .,....-.--Mixed venous
blood
affinity
,, of Hb for oxygen and the sur- c
0
rounding partial pressure of oxygen. ~:J 50% Shift to right-
a; {decreased affinity)
(f)
Acute acidosis
METHAEMOGLOBINAEMIA Fever
pC02 I
This is a clinical state where Hb contains 2,3 DPG t
iron in the oxidized form (Fe 3•, ferric). Abnormal Hb (eg.SS)
This can be an inherited condition or 27 40 60 100
result from a drug toxicity reaction Pa0 2 (mmHg)
oxidizing the iron (see p. 96).
Figure 16.2 Oxyhaemoglobin dissociation curve

387
RED CELL fu1 HABOUSivi
Red blood cells generate:
• Energy as ATP via the anaerobic Embden- Meyerhof pathway
• Reducing power as NADH via this pathway, or NADPH via the hexose-monophosphate pathway

Embden-Meyerhof (EM) pathway

Glucose <• ATP (helps RBC keep their shape)

lactate
NADH (reduces MetHb to Hb)

Hexose monophosphate (HM) pathway

G6PD
Glucose-6-phosphate ~ ~ 6-Phosphogluconate~Ribulose-5-phosphate

NADPH (maintains Fe in ferrous state)

388
REO BLOOD CELLS

Target· cells e Ring sideroblasts

Pencil cells ~~ Howell-Jolly bodies

.; Acanthocytes V Prickle cells

Burr cells Bite cells

Heinz bodies Blister cells

Basophilic stippling Sickle cells

Figure 16.3 Red blood cells

389
ANAEMIA
Anaemia is an inadequate level of haemoglobin.

Clinical features
Symptoms Headaches, fatigue, fainting
Breathlessness, palpitations
General signs Pallor, faltering growth
Tachycardia, tachpnoea, flow murmur, cardiac failure, retinal haemorrhages (if severe)
Hydrops fetalis (in utero)
Specific signs E.g. koilonychia (iron deficiency), jaundice (haemolysis) (see individual causes below)

Investigations
Full blood count To assess degr~e of anaemia
Red cell indices Size (mean corpuscular volume [MCV)) - normocytic, microcytic, macrocytic
Haemoglobin content (mean corpuscular haemoglobin [MCH] and mean corpuscular
haemoglobin concentration [MCHC]) - normochromic or hypochromic
Reticulocyte count Rises within 2- 3 days of a bleed. High in haemolysis
Low count suggests marrow failure. Normal = 1.5-2%
Platelet and WCC Low in pancytopenia
Rise in haemolysis, haemorrhage or infection
Blood film Red cell morphology
Dimorphic blood film is when features of both microcytosis and macrocytosis are present
Haematinics Iron studies, 812 , folate
Hb electrophoresis If haemoglobinopathy suspected
Red cell enzymes G6PD deficiency, pyruvate kinase deficiency
Coombs' test or DAT Haemolytic anaemia
Membrane studies Hereditary spherocytosis
Bone marrow Aspiration - smear of bone marrow to view developing cells
Trephine :... core of bone and marrow, useful to view overall marrow architecture,
cellularity and abnormal infiltrates

390
MICROCYTIC HYPOCHROMIC ANAEMIA

Causes
• Iron deficiency
• Thalassaemia
• Sideroblastic anaemia (congenital)
• Anaemia of chronic disease

Iron-deficiency anaemia
Iron-deficiency anaemia is very common among infants due to insufficient dietary iron. Infants have high iron require-
ments for their rapid growth and because they have small stores. Premature infants are particularly susceptible as they
have lower iron stores and more to grow, and therefore oral iron supplements are recommended for these infants until
the age of 2 years. Many formula milks contain added iron.

Iron metabolism
Iron absorption (Maximum 3-4 mgjday) occurs in the duodenum and jejunum (as ferrous Fe 2•) mainly derived
from cereals
Absorbed iron is transported as transferrin (a ~-globulin, with Fe 2•) in the plasma
Body iron 2h incorporated into Hb molecule
1h in stores as ferritin 2h or haemosiderin 113 or other iron proteins. Stores are found in the RE

cells of the liver, spleen and bone marrow, and in parenchymal liver cells
Small fraction of ferritin circulates in the serum. The amount of serum ferritin is related to tissue
iron stores.
Iron loss/use Mainly in the stool (in iron-laden macrophages)
Nail, hair and skin cell turnover
Rapid growth periods and in pregnancy (high requirements)
Menstruation accounts for significant losses in females
As iron can only be absorbed in the ferrous soluble form, much iron in the diet is unavailable and, as there is no physi-
ological mechanism for excretion of iron, the control of iron balance is through absorption. Thus iron deficiency is the
commonest cause of anaemia worldwide and iron overload may occur in certain situations. In iron overload, excess
iron is transferred to parenchymal celts, e.g. those in the heart, pancreas, liver and endocrine organs.

Causes
• Inadequate intake - most common cause of anaemia in infants
,, • Malabsorption - coeliac disease
• Excess loss (bleeding) - gastrointestinal loss, e.g. hookworm, menstrual loss
Infants most at risk of inadequate iron intake:
• Premature infants (lower iron stores and more to grow)
• Inadequate solid food after 6 months of age (solid foods rich in iron provide more iron than milk), i.e. given too
much milk. Seen especially in the developing world in predominantly breast-fed infants after 9-12 months of
age
• Formula-fed infants (iron poorly absorbed)
• Those fed cow's milk under 1 year (iron from cow's milk is very poorly absorbed)
Factors which increase iron intake and absorption:
• Encourage breast feeding during first 6 months (iron absorbed better than from formula milk)
• If fed formula milk, use those fortified with iron

391
 • Baby cereals contain extra iron
• Standard cow's milk not recommended below 1 year of age
• Fresh fruit and vegetables (vitamin C) enhance iron abso rption by changing ferrous (predominant in vegetables)
to the better absorbed ferric iron (predominant in meat)
• Food rich in iron (red meat, oily fish, dark green vegetables, beans and pulses, dried fruit and nuts)
• Avoid high -fibre foods and tannins (tea) as they decrease iron abso rptio n

Clinical
• Usually asymptomatic. Discovered on incidental blood test
• General features of anaemia (see p. 390)
• Nails - brittle, ridged, spoon shaped (koilonychia)
• Mouth - angular stomatitis, painful smooth glossitis
• Gastrointestinal tract - pica (todd lers with iron deficiency), atrophic gastritis, if severe- oesophageal web
• Subtle neurological impairment in toddlers (low motor and cognitive scores and increased behaviou ral problems)

Spec(fic investi_
r;;otions
RBC indices and film Hypochromic, microcytic,
Anisocytosis, target cells, pencil cells, mode rately raised platelets
Serum iron l
Serum femtin l
Total iron-binding capacity (TIBC) t
Free erythrocyte porphyn'n (FEP) t
Bone marrow No iron stores in macrophages, no siderotic granules in erythroblasts
Small erythroblasts

ft1anagernent
Investigate and treat Take full dietary and absorption history, do baseli ne investigations
underlying cause Coeliac screen if necessary
Search for blood loss· if necessary (endoscopy, colonoscopy, Meckel scan, check fo r hook-
worm, haematuria and menorrhagia)
Oral iron supplements (Elixir or tablets) :
Ferrous sulphate (67 mg iron in 200 mg ta blet)
Ferrous gluconate (37 mg iron per 300 mg tab let)
Dietary management if necessary
Parenteral iron Rarely needed. It can be given IMor IV. Anaphylactic reactions can occur

Sideroblastic anaemia
This is an anaemia with hypochromic peripheral cells and increased ma rrow iron and ring sideroblasts. There is dis-
ordered haem synthesis. ·

Causes
Inhen'ted X-linked disease, mitochondrial (Pearson syndrome)
Acquired Primary - myelodysplasia (RARS- refractory anaemia with ri ng sideroblasts)
Seconda ry:
• Malignant disease of marrow
• Drugs, e.g. isoniazid, alcohol
• Lead poisoning. NB: Basophilic stippling occurs
• Other conditions, e.g. malabsorption, haemolytic anaemia

39 2
t' Investigations
1. Blood film . Microcytic, hypochromic, often dimorphic
z. Bone marrow. Erythroblasts with a ring of iron granules on staining with Perls' reaction

Management
• Withdraw cause
• Pyridoxine therapy (especially inherited disease) and folate therapy if deficient
• Repeated blood transfusions

MCHC I (Acq uired)

Serum iron j_ j_ t N

Serum ferritin 1 Nor I t N or I

TIBC t 1 N N.
Marrow iron stores Absent Present I in nucleated . Present
RBCs (ring ..
sideroblasts)

MACROCYTIC ANAEr-UA
This is divided into macrocytic and megaloblastic.

Causes

. Megaloblastic anaemia
In megaloblastic anaemia there are erythroblasts with delayed maturation of the n11rleus pre~ent in the bone marrow
due to defective DNA synthesis. There may also be platelet and wee deficiencies. In children it is most commonly due
to folate deficiency, and more rarely B12 deficiency.

393
Folate
Found in green vegetables, liver and kidney. Stores of 3-4 months present. Absorbed in the small intestine.
Causes of folate deficiency:
Inadequate intake Special diets, coeliac disease, Crohn disease
Increased utilization Physiological - prematurity, pregnancy
Pathological:
• Haemolysis
• Malignant disease
• Inflammatory disease
Increased urine loss Acute liver disease
Antifolate drugs Phenytoin, methotrexate, trimethoprim

Vitamin 812 metabolism

Found in animal produce only (liver, fish, dairy produce). Body stores of 2-3 years present.
Diet--7IF-B 12 complex--7Absorbed in--7Plasma bound to--7Bone marrow
(stomach) terminal ileum [TC I and TC II) (TC II necessary)
IF= intrinsic factor (made by parietal cells); TC = transcobalamin (I and II).

Causes of 812 deficiency:

Low intake Vegans
Impaired absorption Ileal resection
Bacterial overgrowth
Crohn disease (impaired ileal mucosa), ileal TB
Congenital intrinsic factor impairment (pernicious anaemia)
Abnormal metabolism Nitrous oxide, transcobalamin II deficiency

Specific clinical features of megaloblastic anaemia

Mouth Red, sore glossitis, angular stomatitis
Skin Pale yellow (mild jaundice), purpura, melanin pigmentation (unknown mechanism)
Neuropathy NB: This is in B12 deficiency only
Polyneuropathy and subacute combined degeneration of the cord

Subacute combined degeneration of the cord:

• Progressive neuropathy of posterior and lateral columns (vibration, proprioception) of the spinal cord
• Difficulty walking, ataxia, tingling hands and feet
• Absent ankle jerks (peripheral), increased knee jerks (cord)
• Optic atrophy, retinal haemorrhage, dementia may also occur

Investigations
Blood film Macrocytosis
Neutrophils have hypersegmented nuclei (five or more lobes)
wee and platelets may be low
Bone marrow Hypercellular marrow with megaloblastic changes
Chemistry Unconjugated bilirubin i, hydroxybutyrate i, LDH i (due to marrow cell breakdown from
ineffective erythropoiesis)
Iron and fern"tin N or i

394
;: B12 and folate tests

Schilling test
This is used to differentiate inadequate intake from malabsorption and pernicious anaemia. Oral radioactive-labelled
~yanocobalamin i? given. Absorption is measured , by detecting the amount in a 24-h urine after 'flushing' it into the_
urine by giving a large unlabelled IM dose simultaneously, or by whole-body counting of labelled cyanocobalamin. The
test is repeated with an IF preparation to see if this allows absorption to occur.

Management
• Treat underlying cause.
• Give supplements: Folate- oral supplements daily (1-5 mg)
B12 (hydroxycobalamin) regular int~amuscular injections

HAEMOLYTIC ANAEMIAS
These result from an increased rate of red cell destruction. Clinical features due to the anaemia, increased requirements
and increased red cell breakdown products (causing jaundice). Intravascular haemolysis causes specific features (see
below). Normal RBC lifespan is 120 days.

Causes
Herecjitary Membrane - spherocytosis, elliptocytosis
Metabolism - G6PD deficiency,* PK deficiency
Haemoglobin - HbS, HbC, thalassaemias
Acquired Immune:
• Autoimmune:* Warm Ab, e.g. SLE, dermatomyositis
Cold Ab, e.g. CMV, mycoplasma
• Alloimmune: Transfusion reactions*
Haemolytic disease of the newborn
Transplant, e.g. BMT, cardiac transplant
• Drug-induced antibodies,* e.g. quinine
Red cell fragmentation syndromes:*
• ECMO
• Prostheses, e.g. cardiac valves
• Microangiopathic: HUS,TIP, DIC
Meningococcal septicaemia
Kassabach-Merritt syndrome
Systemic disease, e.g. renaL liver
Infections,* e.g. malaria
Toxins, e.g. burns, drugs (diapsone, sulphasalazine)
Membrane defect, e.g. paroxysmal nocturnal haemoglobinuria (PNH) *
*Denotes that intravascular haemolysis may occur.

395
Clinical features
• Features of anaemia (pallor, breathlessness, etc.)
• Fluctuating mild jaundice (acholuric, urobilinogen in the urine)
• Folate deficiency (due to rapid Hb turnover)
• Splenomegaly
• Pigment gallstones
• Aplastic crises precipitated by parvovirus, e.g. SS disease

Investigations
Increased RBC production Reticulocytosis
Erythroid hyperplasia of bone marrow
Increased RBC breakdown Unconjugated hyperbilirubinaemia (albumin bound)
Urine urobilinogen I
Faecal stercobilinogen 1'
No serum haptoglobins (become saturated with Hb and removed)
Damaged RBCs Microspherocytes, elliptocytes, fragments
Osmotic fragility I
Autohaemolysis
Shortened RBC survival (using chromium labelling)
Autoimmune tests Coombs' test, other Abs
Red cell enzymes G6PD deficiency, PK deficiency
Membrane studies Hereditary spherocytosis and elliptocytosis

Intravascular haemolysis
This is destruction of the RBC within the circulation. The particular features are:
• Haemoglobinaemia, haemoglobinuria
• Haemosiderinuria (from breakdown of Hb in renal tubules)
• Methaemoglobinaemia
• Red cell fragments

Hereditary spherocytosis (HS)

Autosomal dominant, variable expression. Spherical RBCs, i.e. not biconcave discs, due to a defect in a membrane
protein (spectrin, ankyrin or band 3). Their shape results in the cells being unable to pass through the splenic micro-
circulation, so they die prematurely.
Associations Northern Europeans (incidence 1:3000)

C!inicol manifestations (very variable even within families)

• Neonatal jaundice
• Symptoms of mild haemolytic anaemia as above, particularly: Splenomegaly
Pigment gallstones, leg ulcers
Aplastic or anaemic crises especially with
parvovirus
• May be asymptomatic
..... J.." ''
}t7i/2SLl90L70nS

Blood Anaemia (may be mild)

Film Reticulocyte counts of 5-20%
Microspherocytes

396
Membrane studies Defect in membrane protein
Others Autohaemolysis i

Management
Splenectomy after childhood if severe anaemia requiring transfusion or impaired growth. Folic acid supplements. No
treatment if mild.

Hereditary elliptocytosis
Autosomal dominant.
Similar to spherocytosis. Cells are elliptical and the clinical features milder.

Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency)

X-linked recessive. Females may be mildly affected. NB: Carrier state protects against Falciparum malariae. Millions
affected worldwide.
G6PD is an enzyme involved in the hexose- monophosphate pathway (see p. 388), and is the only source of NADPH for
a red blood cell, which prevents oxidant damage to the cell. Defective activity of-the enzyme results in a susceptibility
of the RBC to acute haemolysis with oxidant stress.
There are several types, the commonest being:
• Type A, African type - milder, young RBCs have normal enzyme activity
• Type B, Mediterranean type- severe, all RBCs affected

Clinical features
• Neonataljaundice
• Haemolytic crises (rapidly developing intravascular haemolysis) induced by oxidant stress, including:
Sepsis
Drugs, e.g. antimalarials (primaquine, chloroquine, fansidar, maloprim), sulphonamides (co-trimoxazote),
chloramphenicol, naphthalene (moth balls)
Fava beans (type B only).

Investigations
Diagnosis G6PD levels in RBC. NB: These may be normal during a crisis
During a cnsis Intravascular haemolysis, bite cells, blister cells, Heinz bodies, reticulocytes
NB: No spherocytes
(Hb normal between attacks)

Management of a cn"sis
• Treat the cause (sepsis, stop suspected drug)
• High fluid input (IV)
• Transfusions as required

Pyruvate kinase deficiency (PKD)

Autosomal recessive. Prevalence: thousands worldwide
Pyruvate kinase is an enzyme involved in the Embden- Meyerhof pathway. Deficiency results in .a reduction in ATP
formation and rigid RBCs.

397
Clinical features
• Anaemia (Hb 4-10 g/dl) with relatively mild symptoms due to compensatory increased 2,3 -DPG levels
• Splenomegaly, jaundice, gallstones, frontal bossing

Investigations
Diagnosis Direct assay of PK levels
Blood film Prickle cells, poikilocytes, reticulocytes
Blood Features of autohaemolysis

Management
• Repeated transfusions
• Splenectomy if necessary

Autoimmune haemolytic anaemias {AIHA}

These occur as a result of autoantibody production . They are divided into 'warm' and 'cold' types, depending on the
temperature at which the antibody reacts better with the red cells. They all have a positive direct antiglobulin test
(OAT, Coombs' test).

398
~- Red cell fragmentation syndromes
These result from physical damage to red cells from:
• Abnormal surfaces, e.g. artificial heart valves or grafts
• Microangiopathic anaemia when red cells pass through:
Fibrin strands in small vessels during DIC
Damaged vessels in HUS, TIP or meningococcal sepsis
Investigations as listed above (for intravascular haemolysis).

Paroxysmal nocturnal haemoglobinaemia (PNH)

Acquired defect of red cells making them susceptible to destruction by complement. Platelets and WBCs may also be
affected.

Clinical features
• Haemolysis
• Dark urine (haemosiderinuria, haemoglobinuria)
• Thrombosis

Specific investigations
Ham's test- red cell lysis occurs at low pH (due to complement activation at low pH) .

Management
• Supportive only
• Consider anticoagulation
• Development into leukaemia or aplastic anaemia may occur

APLASTIC ANAEMIAS
Aplastic anaemia is due to bone marrow aplasia, causing a pancytopenia (anaemia, leucopenia and thrombocytopenia) .

Causes
Primary Congenital: Fanconi anaemia
Dyskeratosis congenita
Idiopathic (most cases)
Secondary' Drugs: Regular effect, e.g. cytotoxics
Sporadic effect, e.g. chloramphenicol, azathioprine, penicillamine
Infection - viral hepatitis, measles, EBV, parvovirus;TB
Radiation
Pregnancy

Clinical features
Those of bone marrow suppression.

Investigations
Blood film Anaemia (normocytic, normochromic or macrocytic, low reticulocytes)
Leucopenia (particularly neutrophils)
Thrombocytopenia
Bone marrow Trephine biopsy (hypoplasia with replacement with fat cells)

399
 · · · ····'r
. , '. .,

Management
• Remove any cause
• Initial supportive therapy (blood and platelet transfusions, antibiotics for infections)
• Specific therapy options: Stem cell transplant can offer acure
Drugs, e.g. haemopoietic growth factors, methylprednisolone, immunosuppressants
(e.g. antilymphocyte globulin and cyclosporin)

Fanconi anaemia
Autosomal recessive. Presentation at 5-10 years.

Clinical features
• Aplastic anaemia (developing during childhood)
• Growth retardation
• Absent radii or thumbs, microcephaly
• Pelvic or horseshoe kidney
• Mental retardation (25%)
• Cafe-au-lait patches, hypopigmented macules
• Increased chromosomal breakages, with AML often developing

Management
Stem cell transplant is the only chance of cure (androgen therapy delays progression of disease) .

Prognosis
Without SCT, most die from bone marrow failure or AML at< 30 years.

RED CEll APl ASIA

This is an isolated anaemia due to reduced or absent erythroblasts in the bone marrow. It may be an acute, transient
disease lasting 2-3 months, or a chronic problem .

Causes

Chronic disease
Congenital Diamond-Blackfan syndrome
Acquired Idiopathic
Thymoma, SLE, leukaemia

Acute disease
Infections Parvovirus infection in patients with shortened red cell survival, e.g. SS, spherocytosis
Infants following viral infection (transient erythroblastopenia of infancy)
Drugs E.g. azathioprine, co-trimoxazole

Management
• Supportive therapy with regular transfusions and iron chelation
• Specific treatments include steroid therapy and growth factors
• BMT rarely needed

400
 ··- - -- - - - -- ----- -------- ---

Diamond-Blackfan syndrome
• A pure red cell aplasia, presenting with profound anaemia by Z-6 months of age. Other congenitat anomaties, e.g.
dysmorphic facies, triphalangeal thumbs, in 30%. Autosomal recessive
• Blood film shows a macrocytic anaemia, young red cell population and reduced reticulocytes. Thrombocytosis and
neutropenia may be present initially. Bone marrow shows reduced erythrocyte precursors
• Treatment is with steroids and transfusions as necessary. If steroid unresponsive, immunosuppression, androgens
and stem cell transplant may be tried

HAEMOGLOBINOPATHIES

SICKLE CELL HAEMOGLOBINOPAHIIES

These involve synthesis of an abnormal haemoglobin. Sickle haemoglobin (HbS) = Hb a 2 ~ 2 (in
5
the~ chain, valine is
substituted for glutamic acid on codon 6).
HbS is insoluble at low 02 tensions and polymerizes as long fibres, resu lting in the red cells becoming sickle shaped.
The sickle cells block areas of the microcirculation and result in microinfarcts. HbS also releases 02 in the tissues more
readily than HbA, i.e. the oxyhaemoglobin dissociation curve shifted to the right.
Sickle cell anaemia HbSS (homozygous disease) 85-95% HbS, 5-15% HbF, no HbA
Sickle cell trait HbSA (heterozygous disease) 40% HbS, 60% HbA

Sickle cell anaemia

HbSS disease, seen in Africans, Mediterraneans and Indians.

Clinical features
Clinical features vary depending on any co-existing haemoglobinopathies, e.g. HbSS + ~-thalassaemia is mild.
The clinical features are due to:
• Anaemia - severe haemolytic, and
• Intermittent crises

Sickle cri.ses
P,~inful (vascular-occlusive) crises Vascular-occlusive episodes precipitated by cold, hypoxia, infection br
dehydration . They occur in:
• Bone (commonest)
• Chest (sickle chest syndrome)
• Dactylitis (hand-foot syndrome) (digital infarcts, usually in small children,
resulting in fingers and toes of differing lengths)
• Cerebral (strokes)
• Spleen (results in autosplenectomy usually by age 5 years)
• Also kidney, liver, heart
Haemolytic crises Haemolysis, usually accompanying a painful crisis
Acute sequestration Sickling within organs with blood pooling
Occur in the spleen, chest and liver
Aplastic crises Sudden fall in Hb and reticulocytes
Occur with parvovirus 819 infection

401
Injection
Increased risk of infection with encapsulated bacteria, especially Streptococcus pneumoniae, Haemophilus influenzae
B, meningococcus and salmonella. At risk of overwhelming infection (meningitis, pneumonia, septicaemia), particu-
larly < 3 years of age.

Long-term problems
• Faltering growth (due to chronic disease)
o Pigment gallstones (due to haemolysis)
• Salmonella osteomyelitis
• Asceptic necrosis of the hip
• Priapism (pooling of blood within the corpora cavernosa)
• Renal fai lure
• Congestive heart failure
• Proliferative retinopathy
• Leg ulcers
o Splenomegaly in infancy with autosplenectomy (due to splenic crises) later

Investigations
Blood film Hb 6- 8 g/dl
Sickle cells, target cells, Howell-Jolly bodies
Sickledex test HbS blood sickles when deoxygenated with dithionate and Na 2HP0 4
Hb electrophoresis To detect relative quantities of HbS, HbF and HbA

Management
General Folic acid 5 mg daily
Oral penicillin daily (because of autosplenectomy)
Triple vaccination (pneumococcal, Hib and meningovax) essential (splenic protection)
Regular inftuenzae· vaccination
Avoid crisis precipitants
Crises Admit to hospital
Check FBC, film, reticulocytes, group and save, U&Es, LFTs
CXR if respiratory symptoms/signs, ECG if chest pain
MSU and blood cultures if infection suspected
Ana lgesia (strong, usually IV opiates)
Fluids (IV, 50% above usual formula)
Bed rest and keep warm
Monitor closely (saturations, pulse, BP, respiratory rate, pain and nausea)
IV antibiotics if infection present or suspected
Transfusion if necessary (multiple may be needed)
Exchange transfusion if indicated (severe painful crises, neurological damage, sequestration,
sickle chest syndrome, priapism)
Surgery Transfusions are performed preoperatively for major surgery to reduce HbS fraction to < 30%
Anaesthetic care is taken to keep patient warm, well oxygenated and hydrated, and avoid
acidosis, and pain free
New therapies · Stem cell transplant (if unaffected HLA-identical sibling and severe disease)
Hydroxyurea (may increase HbF and decrease frequency of crises)

402
Sickle trait
Heterozygous expression of the sickle Hb gene (HbSA). HbS makes up 30-40% of the haemoglobin. This blood type
appears to protect against Faldparum malan·ae, and is thus genetically selected for.
Clinical course is usually benign with no anaemia. In severe hypoxia, sickling can occur, with resulting ischaemic con-
sequences. Haematuria is the commonest symptom. Care is needed with general anaesthetics and pregnancy.
Diagnosis by Sickledex test and Hb electrophoresis.

HAEMOGLOBIN C
In HbC, lysine replaces glutamic acid on codon 6 on the ~ chain.
Heterozygous state (HbAC) No anaemia, target cells
Homozygous state (HbCC)' Haemolytic anaemia, splenomegaly, target cells
HbSC disease (HbS and HbC genes) Hb 9- 10 gjdl, target cells
Less severe than HbSS
Thrombosis, pulmonary embolism and retinal vascular changes
Large spleen

THALASSAEMIAS
These are a heterogeneous group of disorders in which there is a partial or complete deletion of globin chain genes,
resulting in a reduced rate of synthesis of normal a- or ~-chains and precipitation of the other excess chains in the red
cells which causes haemolysis. Other Hb types, e.g. HbA2, are also made with increased frequency.
Thalassaemia comes from the Greek 'thalassa' meaning 'sea', as the disease was found in people on the shores of the
Mediterranean. It is found in tropical and subtropical areas (Asia, N. Africa and the Mediterranean).
~-thalassaemia Due to reduced or absent ~-globin chains (excess a-chains precipitate)
a-thalassaemia Due to reduced or absent a-globin chains (excess ~-chains precipitate)
Chromosome 16 codes for a-globin. Chromosome 11 codes for~, 8 and y-globins.
In a-thalassaemias whole a-globin genes are deleted, whereas in ~-thalassaemia mainly point mutations within the
~-globin genes occur (> 100 mutations have been identified)

Diagnosis
Suspicion Of thalassaemia may be made clinically and is confirmed by the blood film. Specific identification of the type
ofJhalassaemia is made from Hb electrophoresis and DNA analysis:

,
• a-Thalassaemias
• ~-Thalassaemia major
• Thalassaemia intermedia
• Thalassaemia minor

403
~-Thalassaemia major
Homozygous disease. Affected children have either no (~ 0 ) or very small amounts (W) of ~-chains .
Haemoglobin electrophoresis HbF 70-90%
HbA2 2%
± HbA 0-20%
,.._, , • 1 :" '

LtuncaL _rea rures

The clinical features are a result of:
• Haemolytic anaemia
• Attempt by the body to make more Hb (medullary and extramedullary haemopoesis) and the effects of multiple
transfusions (iron overload, infections)
Severe anaemia from 3-6 months When switch from y to P-chain production normally occurs
Hepatosplenomegaly Due to haemolysis and haemopoiesis
Extramedullary and Thalassaemic facies (frontal bossing, maxillary hyperplasia)
medullary haemopoiesis 'Hair on end' skull X-ray appearance
Cortical thinning with fractures
Iron overload See below. Due to multiple transfusions
Infections Hepatitis B and C (multiple blood transfusions)
Yersinia enterocolytica (seen with desferrioxamine therapy)
Encapsulated organisms (autosplenectomy) ·
Faltering growth
Investigations
Blood film Microcytic hypochromic anaemia
Target cells, basophilic stippling, nucleated red cells
Hb electrophoresis As above
· DNA analysis May be used to identify the mutation
\J .
fvwnagemenr
Transfusions 4- 6 weekly (transfuse when Hb ::: 10 g/dl; this is 'hypertransfusion')
Folic acid 5 mg daily
Iron chelation Subcutaneous desferrioxamine for 8-12 h, overnight, 5 days per week. Chelated iron is
excreted in the urine and stools
NB: Auditory and ophthalmological assessments needed while on desferrioxamine
Vitamin C 200 mgjday. Increases iron excretion
Splenectomy May be needed to decrease blood requirements (usually done only if> 6 years old)
Endocrine therapy As necessary (insulin, thyroid, parathyroid and pituitary hormones)
Stem cell transplant Recommended in childhood if unaffected HLA-identical sibling is present

404
~-Thalassaemia minor (trait)
Heterozygous disease with reduced ~-chains.

Clinical features Asymptomatic, picked up as incidental find ing

Blood film Mild or no anaemia (Hb 10- 15 g/dl)
Microcytic, hypochromic picture, target cells
Hb electrophoresis HbA
HbA2 > 3.5%
HbF 1- 3%
NB: It is important to check iron status to exclude iron defi ciency.

Thalassaemia intermedia
This is a clinical syndrome, resulting from several different gene defects:
• Homozygous ~-thalassaemia with persisting HbF
• Homozygous ~ - thalassaemia with coexisting o:-thalassaemia
• Heterozygous ~-thalassaemia (trait) with coexisting extra ex-ch ains

Clinical features
Variable.
• Symptomatic anaemia (Hb 7-10 mg/dl)
• Splenomegaly, hepatomegaly, extramedullary haemopoiesis, infections, leg ulcers, gallstones

Management
• Transfusions may be required
• Hydroxyurea
• Splenectomy if necessary

a -Thalassaemias
These all involve decreased synthesis of a-chains. There are four genes for a-globin because the gene is duplicated on chro-
mosome 16. Deletion of one a-globin gene results in a silent carrier wit.h only a mild microcytosis (a -thalassaemia trait).

a-Thalassaemia trait
One or two a-globin genes are deleted. Asymptomatic.
Hb electrophoresis Normal± HbH

405
 .,

Blood film No/mild anaemia, hypochromic, microcytic cells

Globin chain synthesis studies a:p-chain synthesis ratio is reduced
DNA studies

HbH disease
Three a -globin genes are deleted.
Hb electrophoresis HbH, HbA, Hb Barts (in fetus)
Blood film Microcytic, hypochromic anaemia (Hb 7- 10 g/dl)
'Golf ball' cells (aggregates of ~-glo bin chains)
Splenomegaly Thalassaemia intermedia syndrome
No treatment required.

1-/ydrops fetalis (Hb Barts)

No a-chains (four genes deleted) .
Hb electrophoresis Hb Barts (y4)
No HbF
Death occurs in utero due to lack of HbF, unless there is early prenatal diagnosis and intrauterine transfusions.

ANTENATAL AND NEONATAl DIAGNOSIS OF SICKLE CELL AND THALASSAEMIA

Antenatal diagnosis Chorionic villous sampling (first trimester) (8-10 weeks) } Fetal DNA analysis
Amniotic fluid (second trimester)
Fetal blood sampling - umbilical cord blood in second trimester (18-20 weeks) to check
normal chain manufacture (electrophoresis)
Neonatal diagnosis Hb electrophoresis can be done at birth but the switch from y-chains (HbF) to ~-chains
occurs at 3-6 months, making testing at 6 months accurate. DNA analysis can be used to
identify the defect on each allele

POLYCYTHAEMIA AND THROMBOCYTHAEMIA

POLYCYTHAEMIA
Polycythaemia is an increased Hb lev~l to above the upper limit of -.normal and increased haematocrit. It may be
'relative', due to decreased circulating volume.

Causes
Secondary Appropriate: Cyanotic heart disease
Lung disease
Central hypoventilation
High altitude
Inappropriate: Renal disease, e.g. hydronephrosis, cysts, tumour
Adrenal disease, e.g. CAH, Cushing syndrome
Tumour, e.g. cerebellar haemangioblastoma
Neonatal, e.g. infant of diabetic mother, IUGR, twin-twin transfusion
Relative Dehydration, e.g. gastrointestinal losses, burns
Stress polycythaemia
Primary Polycythaemia rubra vera (PV) (very rare in children)

406
 Clinical features
• Haemorrhage or thrombosis
• Headaches

Management
• Treat cause
• Venesection if necessary

THROMBOCYTHAEMIA
Thrombocythaemia is increased platelet levels to above upper limit of normal.

Causes
Reactive Haemorrhage
Postoperative
Kawasaki disease
Acute infection, e.g. URTI
Chronic infections, e.g. TB
Postsplenectomy .
Iron-deficiency and haemolytic anaemia
Connective tissue disease
Chronic renal disease
Drugs, e.g. steroids
Malignancies
Endogenous CML (very rare in childhood)

Clinical features
Usually asymptomatic; risk of thrombosis is low.

Management

Often no treatment is required. To reduce the risk of thrombosis, platelet pheresis, low-dose aspirin or anagrelide
(antiplatelet drug) may be used.

HAEMOSTASIS
'I

Haemostasis involves:
1
• Normal vasculature
• Platelets
• Coagulation factors

PlATELETS
Produced from megakaryocytes in the bone marrow, lifespan 7-10 days.

Functions

Mechanical plug formation in vascular trauma. This involves adhesion (vWF involved), secretion of granule contents
(including arachidonic acid), aggregation and procoagulant activity (involving PF3 and coagulation factors).

407
 -,

BlOOD COAGUlATION CASCADE

This involves activation of the blood coagulation factors, resulting in production of thrombin and a fibrin clot. Fibrin
stabilizes the initial platelet plug.

Extrinsic pathway Intrinsic pathway

XII a
kallikrein
VII HMWK
IX

~ --~f -
I

(PT) -XI a ___!__ XI

(Warfarin) VIla----- --- - (APTI)
(Liver damage) ' IXa (Heparin)
'
' I

I
''
X ' ' Xa
I
I v
Prothrombin _____!_..Thrombin
II 1 lla
I
I

Fibrinogen
I
' Fibrin

!'a
XIII a

Cross-linked
fibrin

Figure 16.4 Blood coagulation cascade: HMWK = High molecular weight kininogen

INVESTIGATIONS OF ClOTTING DISORDERS

408
DISORDERS OF THE VASCULATURE
These involve abnormalities in the vessels or the perivascular connective tissues.

Causes
Inherited Connective tissue disorders, e.g. Ehlers-::_Danlos syndrome
Hereditary haemorrhagic telangiectasia
Acquired Easy bruising syndrome
Henoch-Schonlein purpura (HSP)
Infections, e.g. meningitis
Scurvy
Drugs, e.g. steroids

Clinical features
Features generally mild. Skin and mucous membrane bleeding (easy bruising, petechiae, ecchymoses).

Investigations
Screening tests all normal (including the bleeding time) .

Hereditary haemorrhagic telangiectasia

Autosomal dominant. Telangiectasia in the skin, mucous membranes and internal organs, becoming more numerous
throughout life. Recurrent GI bleeding occurs.
'

'I

PLATElET DISORDERS
r
These include thrombocytopenia and platelet function disorders.

Thrombocytopenia
Causes
Decreased production Isolated megakaryocyte depression : Infections
Drugs
Thrombocytopenia and absent radii (TAR)
syndrome
Abnormal megakaryocytes - Wiskott-Aldrich syndrome
Bone marrow failure - aplastic anaemias

409
Increased consumption Immune disease: ITP
Drug induced, e.g. trimethoprim, quinine, heparin
Post-infectious, e.g. malaria
Neonatal isoimmune ITP (maternal antiplatelet antibodies)
Post-transfusional (PlA' antibodies)
SLE
Die
HUS, TIP
Abnormal distn"bution Splenomegaly

Immune thrombocytopenia (ITP, idiopathic thrornbocytopenic purpura)

Common in children. Thought to be due to immune complex platelet destruction.

Clinical features
1-4 weeks post-infection, e.g. chicken pox, measles, EBV, or vaccination : bleeding, bruising, petechiae, mucosal
bleeding (if platelets< 20 xl0 9/L). Intracranial bleeds (very rare) .

Investigations
Blood film Platelets t (< 10- 20 x 109/L)
Hb and wee normal
Bone marrow Megakaryocytes I or N
Antibodies Antiplatelet IgG, antiplatelet IgM

Management options
• Monitoring only (clinically and platelet count)
• Oral steroids for 2-3 weeks
• Intravenous immunoglobulin (IVIG)
• Platelet transfusions (in emergency, as they are quickly destroyed)
• Immunosuppression and/or splenectomy only if no response to above treatments and chronic disease
• Avoid aspirin and contact sports.

Prognosis
Spontaneous remission Most cases
Chronic disease 5-10% in childhood (commoner in adults)

Thrombotic thrombocytopenic purpura (TTP)

This is a serious disease involving thrombocytopenia with arteriolar thrombi. Features are similar to HUS, with more
widespread involvement.

Clinical features
A classic pentad of:
1. Fevers
2. Haemolytic anaemia
3. Thrombocytopenia - purpura
4. CNS - fluctuating neurological signs
5. Renal - ischaemic damage

410
CLOTTING FACTOR DISORDERS
Haemophilia A
• Incidence 30-100:1 000 000
• X-linked recessive, 30% spontaneous mutation rate
• Gene located at Xq2.8
• Disease due to absent or low factor VIII

Clinical features
Spontaneous bleeding Joints (haemarthroses), painful and swollen, resulting in deformity (arthritis)
unless rapidly treated
Muscle haematomas
'Pseudotumours' in bones (due to subperiosteal bleeds)
Haematuria
Intracereb ral bleeds (rare)
Excessive traumatic bleeding Surgery, e.g. post-circumcision, dental extractions
Infection (transfusion related) Hepatitis B and C (subclinical liver disease), HIV (now all screened for)
Severity varies dependent on the level of factor VIII (% of normal) present:
< 1% of normal Severe disease. Frequent spontaneous bleeds
1-5% of normal Moderate disease. Severe bleeds with injury, occasional spontaneous bleeds
> 5% of normal Mild disease. Bleed a lot after surgery

Investigations
• Factor VIlle activity (1 or absent)
• APTT t

Management
• Prophylactic recombinant factor VIII infusions - aim to keep> 2% of normal, usually given· 2-3 times per week
• Recombinant factor VIII infusions after injury or prior to surgery:

• Desmopressin (DDAVP) infusion - used in mild disease. Causes a rise in the patient's own factor VIII levels
• Fibrinolytic inhibitor, e.g. tranexamic acid. May be given with DDAVP
• Advice - avoid contact sports, maintain good oral hygiene

Factor VIII antibodies

These develop in 10% of haemophitiacs as a result of frequent factor VIII transfusions. They inhibit future factor VIII
treatment. Management options include:
• Give very large doses of factor VIII
• Immunosuppression
• Give factor IX concentrate, which bypasses the factor VIII, recombinant factor VIII or porcine factor VIII

412
 ----------- -----. - --· · .
---------·-· ---- ------- -- . -- -- - --- ~
- - ~- - - - · - - - --· ---· ··
---· -

Antenatal and carrier detection

Carrier female detection Analyse plasma factor VIII activity (usually ha lf normal in carrier female)
DNA analysis (more accurate)
Antenatal screening Chorionic villous sampling (8-10 weeks)
Fetal blood sampling for factor VIII activity {18-20 weeks)

Haemophilia B (Christmas disease)

• Incidence 1:30 000 males
• X-linked recessive, gene at Xq2 .6
• Due to deficiency of facto r IX
• Clinical features identical to haemophilia A
• Management is with infusions of factor IX concentrate

von Willebrand disease

Incidence 3-10:100 000. Autosomal dominant, variable expression, worse in females .
Disorder of:
• Low vWF (causing low factor VIII activity)
• Platelet adhesion abnormalities
von Willebrand factor (vWF) is the carrier protein for factor VIII and promotes platelet adhesion .

Clinical features
These are variable.
Excessive traumatic bleeding From cuts, operative, mucous membra nes (epistaxis, gums, menorrhagia)
Spontaneous bleeds Haemarthroses and muscle bleeds (both rare except in homozygotes)

Investigations
Bleeding time Prolonged
Factor VIIIc activity t
vWF levels t
Platelet aggregation with ristocetin t
Management
Acute ble~ds treated with factor VIII concentrate containing vW Fin severe disease, and DDAVP or fibrinolytic inhibitors
in milder disease.

Vitamin Kdeficiency
Vitamin K is a fat-soluble vitamin, present in ·green vegetables and synthesized in the gut. Deficiency affects the
vitamin K-dependent clotting factors II, VII, IX and X.

Causes of vitamin K-dependent clotting factor deficiency

Low vitamin Kstores Haemorrhagic dtsease of the newborn (see p. 455)
Inadequate diet
Malabsorption of fat-soluble vitamins Cystic fibrosis
Small bowel disease, e.g. coeliac disease
Hepatic obstruction
Vitamin K antagonists Phenytoin, rifampicin, wa rfarin

413
.....................................
Investigations
PT 1i
APTT i or N
Management
Vitamin K IV (takes 6 h to work)
IM or oral (as prophylaxis)
Fresh frozen plasma (FFP) Immediate effect
Prothrombin concentrates Immediate effect

Disseminated intravascular coagulation (DIC)

This is a state of consumption of platelets and clotting factors with widespread intravascular fibrin deposition due to
uncontrolled activation of the clotting cascade. It may be acute or more rarely chronic.

Causes
Sepsis Meningococcal, Gram-negative, viral (purpura fulminans)
Widespread tissue damage Trauma, burns, surgery
Hypersensitivity reactions Anaphylaxis
Malignancy Acute promyelocytic leukaemia
Other Hypoxia, hypothermia, snake venom, Kasabach-Merritt syndrome

Clinical features
Severely unwell patient with generalized bleeding (acute disease).

Investigations
Blood count and film Platelets (1), microangiopathic anaemia
TT i
APTT 1'
PT 1'
FDPs 1', fibrinogen 1
Factors V and VIII (1)
NB: Chronic disease may have normal screening results, due to production of new factors.

Management
1. Treat the underlying cause
2. Supportive therapy (blood, FFP, fibrinogen, platelets)

Haemophilia_B _
vW disease l -
liver disease N, i

414
 -
--~,......-----·-· ·· --·- -~--~ ... ··-

THROMBOSIS
Pathogenesis of thrombosis is related to Virchow's triad of:
1. Hypercoagulability
2. Intravascular stasis
3. Vessel wall damage: Arterial thrombosis occurs mainly as a result of vessel wall damage, e.g. arteriosclerosis
Venous thrombosis occurs mainly as a result of hypercoagulability and venous stasis

Causes of venous thrombosis

Hypercoagulability Congenital: Antithrombin III deficiency (involved in inhibition of thrombin and
factor X)
Protein C deficiency (protein C inactivates factors V and VIII and
stimulate,s fibrinolysis)
Protein S deficiency (a co-factor for protein C)
Factor V Leiden (abnormal factor V protein)
Increased fibrinogen or factor VIII levels
Abnormal plasminogen or fibrinogen
Acquired: Thrombocytosis
Trauma
Lupus anticoagulant
Pregnancy and OCP
Malignancy
Intravascular stasis Dehydration
Immobilization
Venous obstruction
Pump failure

Investigations
These may include:
Blood count and film Platelets (1}, haematocrit (1}, malignancy
PT, APTT May be shortened. NB: If prolonged and does not correct with normal plasma, suggests lupus
anticoagulant
TT, reptilase time Prolonged if fibrinogen abnormal
Fibn"nogen assay
Protein 5 .and Cassay
Antithrombin III assay
Factor V Leiden (PCR)

THE SPLEEN

SPLENECTOMY
This may occur naturally (autosplenectomy, e.g. sickle cell anaemia) or as a result of therapeutic surgical therapy, e.g.
ITP, or secondary to trauma.
The consequences are:
Immediate Marked thrombocytosis (platelets> 1000 x 109/L), usually for 2-3 weeks, then moderate increase
Long-term Susceptibility to encapsulated organisms, e.g. pneumococcus, and malaria infection. Young infants at par-
ticular risk of infection with Streptococcus pneumoniae, Haemophilus influenzae and Niessen"a meningitides

415
......................______________
Blood count and film findings in hyposplenism
• Platelets may be high
• Monocytosis, lymphocytosis
• Howell-Jolly bodies, Pappenheimer granules, target cells, irregular contracted red cells

Management
• Try to avoid splenectomy in children < 6 years (increased susceptibility to infections)
• Prophylactic penicillin for life
• Triple vaccination> 2 weeks prior to splenectomy (pneumococcal, Haemophilus influenzae and me ningococcal C)
• Malaria prophylaxis when travelling to endemic areas

SPLENOtv1EGAlY
This can result in abdominal discomfort and a pancytopenia (hypersplenism), as the spleen sequesters and destroys
cells.

Causes
Infections Acute: EBV, SBE, septicaemia
Chronic: TB, brucellosis, schistosomiasis
Extra-medullary haemopoeisis Haemolytic anaemias, haemoglobinopathies, osteopetrosis
Neoplasm Leukaemia, lymphoma, haemangioma
Storage diseases Gaucher disease, Niemann-Pick, Langerhans' cell histiocytosis, mucopolysaccharoidoses
Portal hypertension
Systemic disease JIA, SLE, amyloidosis
Massive splenomegaly Malaria, Kalar-Azar, CML, myelofibrosis

FURTHER READING
Hann IM, Lake BD, Lilleyman J, Pritchard J, Weatherall DJ Colour Atlas of Paediatn"c Haematology. Oxford: Oxford
University Press, 1996
Lilleyman JS, Hann IM, Blanchette VS Paediatric Haematology, 2nd edn. Edinburgh: Churchill Livingstone, 1999
Nathan DG, Orkin SH, Look T, Ginsburg D (eds) Nathan & Oski's Hematology of Infancy and Childhood, 6th edn, Voll
and 2. Philadephia: WB Saunders, 2003

416
...
• Mechanisms of carcinogenesis • Retinoblastoma
• Incidence of childhood cancer • Gonadal and germ cell tumours
• Cancer treatment • Liver tumours
• Neuroblastoma • Brain tumours
• Nephroblastoma (Wilms tumour) • Leukaemias
• Soft tissue sarcomas • Lymphoma
• Bone tumours • Childhood histiocytosis syndromes

MECHANISMS OF CARCINOGENESIS
• Cancer develops when there is genetic alteration of the normal cell regulatory system (growth and development)
via mutation(s)
• Cancer-causing genes fall into three types (see below)
• Mutations activating the cancer genes can be germline (familial/inherited), somatic (most) or both
• The environment can increase the frequency of genetic mutations (see below)
External growth factors (steroid hormones and proteins e.g. PDGF)
~ transmit signals from other cells

r;'?'· Growth factor receptor

'(~'1li'
Signal transduction pathways (e.g. protein kinases)
Cell wall
\\
0 Nuclear transcription factors (e.g. myc)
Alter DNA transcription
of specific genes whose
protein products affect ce ll
growth and differentiation

Mutations anywhere along the pathway of cell regulation can result in cancer. Mutations in the regulatory genes are rare. The multi-hit
concept of carcinogenesis~ several mutations are needed to produce a malignant neoplasm.

Figure 17.1 Normal cell regulation of growth and differentiation

417
CANCER GENES

Types
There are three major categories of cancer genes:
Tumour suppressor genes Involved in restricting cell proliferation
Inactivation can result in tumours
E.g. RBl gene (ch 13q14) -retinoblastoma, osteosarcoma
WT1 gene (ch 11p13) -Wilms tumour
Oncogenes Genes whose product can lead to unregulated cell growth
Most arise from mutations in proto-oncogenes
E.g. Bcr-abl gene - ALL, CLL
MYCN amplification -neuroblastoma
DNA repair genes DNA repair and replication continually occur throughout life
Some inherited disorders involve defective DNA repair mechanisms, and thus the
chances of cancers developing secondary to somatic mutations is increased, e.g. ataxia
telangiectasia, xeroderma pigmentosum

Mechanism of activation
The above genes may be altered by:
• Single gene germline mutations - sporadic or inherited, e.g. retinoblastoma, or
• Somatic mutations, or
• Both
Two-hit theory of carcinogenesis is that a tumour will develop only when both copies of a gene are damaged. In
many inherited cancers, the first allele is a germline mutation and the second a somatic mutation. This would explain
why not all children who inherit the retinoblastoma mutation develop the tumour, and that they develop it at differ-
ent ages.

Environmental factors
Environmental factors can increase the risk of mutations. Carcinogens are environmental cancer causing agents, i.e.
increase the frequency of genetic cancer-causing events:
• Ionizing radiation, e.g. leukaemia, thyroid carcinoma, breast cancer
• Ultraviolet radiation, e.g. skin cancers
• Viruses, e.g. EB virus (Hodgkin disease, Burkitt lymphoma and nasopharyngeal carcinoma)
• Drugs, e.g. immunosuppressive drugs (nori-Hodgkin lymphoma), diethylstilboestrol in pregnancy- vaginal adeno-
carcinoma in the daughter

418
INCIDENCE OF CHILDHOOD CANCER
1:650 children develop cancer by age 16 years.

CANCER TREATMENT
Cancer management is multifactorial involving many specialists and therapists, and includes:
• Chemotherapy
• Radiotherapy
• ,Surgery
• Stem cell transplantation (which acts by either high-dose therapy or immunological means)
• Immunotherapy

CHEMOTHERAPY
Many different drugs and regimens are used, and new developments are continually being made in this area, so that
many children are treated as part of continually evolving drug trials. These drugs preferentially target rapidly dividing
ceHs, e.g. cancer cells, but also affect normal cells that rapidly divide, e.g. bone marrow progenitors, gut epithelium.

r
Chemotherapeutic agents

419
Drug group Examples Action Toxicity
Alkylating agents Cyclophosphamide Inhibits DNA synthesis •· ·····Myelosuppression
. Haemgrrhagic cystitis (give Mesna)
S~con·darymalighancy ·· ·
··: ste~Lity : ':·:c:- · .·.· ··..
. Lung .fibrosis
SIADI} · ·

Nephr?toxic
Neurotoxic, ototoxic
Myelosuppression
Etoposide ·Topoisomerase inhibitor Myelosuppression
Secondary AML

Side-effects common to most agents

• Bone marrow suppression: Anaemia
Thrombocytopenia
Immunosuppression (neutropenia, most marked 10 days after chemotherapy
commenced. Infections treated with broad-spectrum antibiotics)
• Nausea and vomiting
• Mouth ulcers
• Tumour lysis syndrome
• Hair loss
• Secondary malignancy - many agents, especially alkylating agents

420
Tumour lysis syndrome
The high rate of cellular breakdown in fast-growing tumours (especially with high WCC ALL and bulky NHL) after
chemotherapy can cause this potentially life-threatening syndrome of:
1. Rise in urate
2. Then P0 4 iwith simultaneous Cal (within 1-2 days)
3. Then rapid development of hyperkalaemia

Prevention
Prevention with hyperhydration and the use of allopurinol and rasburicase are essential. If the syndrome develops,
then treatment with dialysis may be necessary. Haemofiltration removes less solute than dialysis and is reserved for
milder cases.
• Intravenous fluids (with no added K) and some units feel that alkalinization prior to chemotherapy is beneficial
• Regular monitoring of biochemistry
• Allopurinoljrasburicase
• Dialysis or haemofiltration (used prophylactically in bulky tumours)

Nausea and vomiting

These are common side-effects of chemotherapy.
Centres involved:
• Visceral afferents
• Chemoreceptor trigger zone (CTZ)
• Vomiting centre (in the medulla)
• Higher centres (emotional)
• Vestibular apparatus

Common antiemetics

RADIOTHERAPY
.,
This is often used as an adjunct to chemotherapy, e.g. cranial irradiation in ALL. Side-effects include:
1

Early Nausea and fatigue, inflammation of skin, gut and bladder

Late Organ damage dependent on location of treatment:
• Brain - cognitive impairment
• Skin - radiation damage, skin malignancies
• Gonads - infertility
• Other organs - secondary malignancy

SURGERY
Direct initial surgical excision may be done, or the tumour may be 'pre-shrunk' using chemo- or radio-therapy, and then
excised. Regional lymph nodes are generally also excised if affected or for staging of the disease.

421
S~1ALL MOLECULE INHIBITORS
A new class of drugs called small molecule inhibitors, e.g. Glivec, that target signal transduction pathways are being
used in CML.

IMr4UNOTHERAPY
Immunotherapy is being developed with both non-specific mediators of immune defence, e.g. interfer.on-a, and
cancer-targeted therapies using monoclonal antibodies and T-cell based tumour vaccines.

STEM CELL TRANSPLANTATION (SCT)

Haemopoietic stem cells replace the diseased marrow with normal marrow cells. The child's diseased marrow is ablated
with high-dose chemotherapy+ radiotherapy and then the child is rescued with the SCT. Used for therapy after relapse
of leukaemia and also in initial consolidation therapy.

Autologous SCT
The child acts as their own donor. Their own marrow is harvested before ablation, purged of malignant cells,
cryopreserved and then re-infused into the child after marrow ablation. Alternatively, peripheral blood stem cells may
be harvested with granulocyte colony-stimulating factor (G-CSF) .

Complications
• Residual cancer cells may cause relapse
• Conditioning toxicity (including infertility and secondary malignancy)
• Infections in cytopaenic phase (2 weeks for peripheral blood stem cell transplant, 4 weeks for BMT)

Allogeneic SCT
Marrow from a matched donor (HLA screened, preferably an HLA-identical sibling) is used. The conditioning with
chemotherapy and radiotherapy here is also used to destroy the patient's immune system to prevent rejection.

Complications
• Marrow rejection
• GvH D (acute or chronic)
• Infections
• Acute regimen-related toxicity (initial ablative therapy causes vena-occlusive disease, pneumonitis, haemorrhagic
cystitis)

Graft~versus~host disease (GvHD)

This is due to the donor T cells mounting an immune response to the host major histocompatibility complex (MHC)
antigens. It may be acute or chronic, though the former can transform into the latter:
Acute GvHD < 100 days of SCT (usually 10-14 days post SCT)
Fever
Rash - fine pruritic maculopapular may progress to bullae or exfoliation of ears, palms, soles,
then trunk
Enteritis - bloody diarrhoea, protein-losing enteropathy
Cholestatic hepatitis
Predisposing factors: HLA differences between donor and host, sex mismatch, active malignancy
at time of BMT
422
 Prevention: T-cell depletion of donor marrow
Chronic GvHD > 10q days post-SCT
Rash - hyperpigmented nodules, lichenoid, erythema, hypopigmented, then scleroderma-like
Arthritis
Malabsorption
Obstructive jaundice
Autoimmune features - SLE, scleroderma, Sjogren syndrome, primary biliary cirrhosis
Predisposing factors: acute GvHD, increasing age, buffy coat transfusions
A beneficial graft-versus-leukaemia effect occurs in the process and helps eliminate any remaining cancer cells.

Management
Further immunosuppression, e.g. cyclosporin A, steroids.

NEUROBLASTOMA
Atumour arising from neural crest cells of the sympathetic nervous system developing in:
• Adrenal medulla - 50%
• Sympathetic chain - 50% (anywhere from the posterior cranial fossa to the coccyx)
Tumours of neural crest cells may be benign ganglioneuromas, ganglioneuroblastomas or malignant neuroblastomas,
and may spontaneously regress in infants.

Clinical features
Usually < 5 years
Abdominal mass
Metastatic disease (70%) Bone pain, limp
Proptosis, periorbital bruising
Massive hepatosplenomegaly
Skin nodules, lymphadenopathy
Weight loss, pallor, malaise·
Cord compression (paraplegia) - usually direct extension not metastasis
Horner syndrome - again direct pressure from thoracic primary

Diagnostic investigations
Un"ne catecholamine metabolites i Homovanillic acid (HVA) and vanillylmandelic acid (VMA)
CT or MRI scan
Meta-iodobenzylguanidine (MIBG) scan (A catecholamine precursor; will also outline metastases)
Tissue piopsy or positive bone marrow Necessary to confirm diagnosis and define molecular features that
determine prognosis and therapy
Staging is complex. Stage 4S refers to neonates with small adrenal tumour and metastases in skin, liver or bone marrow
only (can undergo spontaneous remission).

Cytogenetic abnormalities
A poor prognosis if these are present.
• Chromosome 1p partial deletion
• Chromosome 17q gain
• Amplification of N-myc (MYCN) oncogene

423
Management
Treatment is dependent on the child's age, tumour stage and biology (presence or absence of the MYCN oncogene).
Low-risk disease Surgical resection ± chemotherapy
Subtype (stage 4S) resolves with no therapy
High-risk disease More aggressive chemotherapy, surgery, high dose chemotherapy with stem cell rescue,
local radiotherapy and differentiation treatment
Differentiation therapy Use of retinoic acid derivatives to force cells to differentiate past a point of
development so that they lose the capacity to grow quickly and spread
New therapies using targeted radiation therapy with mr-MIBG monoclonal antibodies are being trialed . (High-dose
therapy with stem cell rescue is standard treatment.)

Prognosis
Low-risk tumours > 90% cure rate
High-risk tumours 10- 40% cure rate

NEPHROBlASTOMA (WilMS TUMOUR)

Nephroblastoma is tumour of embryonic renal precursor cells. Incidence 7.8:million.
Assodations Genitourinary anomalies
Overgrowth disorders (hemihypertrophy, Beckwith-Wiedemann syndrome)
Aniridia
Chromosome 11 short arm deletions involving one of two Wilms genes, e.g. WIT gene (11p13)

Clinical features
• Mean age 3 years
• Abdominal mass (the most common presentation)
• Abdominal pain and vomiting
• Hypertension
• Haematuria
5% have bilateral disease at presentation.

Investigations
Imaging Abdominal USS, CT or MRI scan abdomen and CXR (lung metastases)
Urine Haematuria (micro- or macro-scopic)

Staging {determined after tumour resection)

I Completely resected disease of kidney only
II Disease beyond the kidney but completely resected
III Residual disease post-surgery or nodal involvement
IV Metastatic disease (bilateral used to be called stage V but now just called bilateral)

Management
Dependent on the stage.
• Initial chemotherapy then nephrectomy is riow standard in the UK and rest of Europe
• Primary nephrectomy then chemotherapy is still used in the USA

424
 • Radiotherapy is used as part of a combined strategy for local residual disease post-surgery and for pulmonary
metastatic disease

Prognosis
This is related to both histology and disease stage, tumour size and child's age.
Favourable histology 89- 98% 2-year survival
Poor histology 17-70% 4-year survival (variation due predominantly to precise histology of tumour)

SOFT TISSUE SARCOMAS

Incidence 1.4:million per year.
These comprise:
• Rhabdomyosarcoma (50%)
• Non-rhabdomyosarcoma soft tissue tumours (NRSTs), e.g. liposarcoma, angiosarcoma, leiomyosarcoma, neuro-
fibrosarcoma and fibrosarcoma

RHABDOMYOSARCOMA
Rhabdomysarcoma is a tumour of primitive mesenchymal tissue (which striated skeletal muscle arises from) .
Associations Neurofibromatosis type 1
Beckwith-Wiedemann syndrome
These tumours may occur anywhere, but the most common sites are:
• Head and neck
• Genitourinary tract
• Extremities

Clinical features
Head and neck tumour Proptosis
Facial swelling
Nasal obstruction, blood-stained nasal discharge
Cranial nerve palsies
GU tract tumour Urinary tract obstruction
Dysuria
Blood-stained vaginal discharge

Investigations
'
Imaging of relevant area CT, USS, MRI scan
Metastases search Bone scan, CXR and CT, bone marrow
Tumour tissue Histology

Staging
I Completely resected
II Microscopic residual tumour
III Macroscopic residual tumour
IV Metastatic disease

425
Management
This depends on the resectability, stage, location, histology and presence of metastases.
• Initial surgical resection then chemotherapy
• If unresectable initially, chemotherapy, second-Look surgery± radiotherapy

Prognosis
Localized standard-risk histology disease has a 70% 5-year survival.

BONE TUMOURS
The two most common bone tumours are osteosarcoma (the most common) and Ewing sarcoma. Rarer tumours
include chondrosarcoma and fibrosarcoma.
Incidence 5.6:million (whites> blacks). Commonly present in adolescence. Male> female.

RETINOBLASTOMA
Retinoblastoma is a tumour arising in the retina. Usually develops in the posterior portion of the retina. Incidence
approximately 4:million children.
Both hereditary and sporadic forms exist.
Hereditary tumour (40%) All the bilateral tumours
May be unilateral (75%)
Sporadic tumour (60%) Unilateral tumours

426
Hereditary tumours
• Retinoblastoma (RB1) gene on chromosome 13q (tumour suppressor gene)
• Autosomal dominant, incomplete penetrance
• Increased incidence of secondary malignancies (osteosarcoma, soft tissue sarcoma and melanoma)

Clinical features
• Leucocoria (white pupillary reflex)
• Squint (any new squint in a child should be investigated, though retinoblastoma will be an unusual finding in
these children. Ophthalmological problems and brain tumours will be more common pathologies)
• Decreased vision
• If advanced disease- proptosis, raised ICP, orbital pain

Investigations
• Fundoscopy
• Orbital imaging - CT or MRI of orbits, USS orbits

Management
• Local therapy (radiotherapy, photocoagulation or cryotherapy)
• Enucleation of the eye if unavoidable '
• Chemotherapy to reduce tumour volume prior to local therapy or if residual or metastatic disease
Treatment that minimizes radiotherapy to improve visual sparing and reduce the incidence of future secondary tumours
is being optimized.

Prognosis
• Overall survival> 90%
• Poor survival if extensive or metastatic disease

GONADAL AND GERM CELL TUMOURS

These are tumours arising from primitive pluripotent germ cells, which migrate from the fetal yolk sac to form the
gonads. Extragonadal tumours occur due to abherrant germ cell migration. They are mostly benign .
Associations Cryptorchidism, gonadal dysgenesis
Classification is based on the differentiation pathway:
·i
Embryonic differentiation Teratoma (usually benign), e.g. sacrococcygeal teratoma
Embryonal carcinoma
Extraembryonic differentiation Choriocarcinoma Highly malignant
Gonadal or extragonadal
~-hCG I
Yolk sac carcinoma AFP I
Suppressed differentiation Germinoma
Seminoma
Dysgerminoma (ovarian tumours)

427
..........................................
SACROCOCCYGEAl T£RAT0~1A
Most common neonatal tumour. Rectum and urinary tract may be involved and 90% have an external component.
10% are malignant at birth, but if benign teratomas are left unresected malignant transformation can occur.
Malignancy is defined by a tumour that secretes AFP or ~-hCG or has particular histological appearance (yolk sac
tumour).

Investigations
Imaging CT or MRI scan of affected area, bone scan, chest CT
Biological markers AFP I and ~-hCG
Histology of lesion (Biopsy or resected specimen)

Management
This involves surgical resection wherever possible for benign tumours. Malignant tumours should be treated with
chemotherapy before surgery to minimize morbidity.

Prognosis
Excellent if benign, and 60- 90% 5-year survival if malignant.

TESTICULAR GERf'i1 CELL TW;lOURS

Present as Testicular swelling (painless or painful)
Gynaecomastia (if secretes hCG)
Metastases (retroperitoneal, LN, lung)
Seminoma (1/3) Dysgerminoma is the ovarian counterpart
Teratoma_ (2/3)

OVARIAN GERM CElL TUMOURS

Present as Abdominal pain (acute or chronic) and swelling
Abdominal mass

LIVER TUMOURS
Liver tumours may be:
Primary Benign (50%) Haemangioma, liver cell adenoma
Haemangioendothelioma
Hamartoma, focal nodular hyperplasia
Malignant (50%) Hepatoblastoma (65%)
Hepatocellular carcinoma (35%)
Metastatic Neuroblastoma, Wilms tumour

428
 Investigations
Include CT or MRI scans to search for extent of tumour and metastases. It can be difficult to differentiate between
the two tumours.

Management
• Hepatoblastoma is chemosensitive and primary chemotherapy followed by surgery should be used
• Pril}lary surgical excision (possible in 50% of hepatoblastomas and 33% of HCC)
• Chemotherapy (preoperatively if initially unresectable or for metastases)
• Liver transplantation is indicated in a minority
/

BRAIN TUMOURS
Brain tumours are almost always primary in children. They can be divided into
I

• Supratentorial
''• Infratentorial (posterior fossa)
<2 yeafs Equal frequencies of posterior fossa and supratentorial tumours
2-12 years 2
13 are infratentorial (posterior fossa)

Clinical features
Signs of raised ICP Morning headache, drowsiness, vomiting
Diplopia, strabismus, papilloedema (a late sign in young children)
Nystagmus: Horizontal in unilateral cerebellar tumours, worse on looking to the side
of the lesion
All directions in cerebellar vermis or fourth ventricle tumours
Horizontal, vertical and rotatory in brainstem tumours

429
 Head tilting and nuchal rigidity
Bulging fontanelle with loss of pulsation, macrocephaly
Cranial nerve palsies (IV and VI)
Focal neurological signs Long-tract signs: hemiparesis
Seizures: complex partial seizures
Ataxia: Truncal (cerebellar vermis)
Ipsilateral (cerebellar hemisphere)
Other features Endocrinopathies, e.g. diabetes insipidus
Behavioural change

Astrocytoma

Craniopharyngioma
Brain stem gl
Ependymoma ·

Figure 17.2 Location of brain tumours

INFRATENTORIAL TUMOURS

Medulloblastoma. {20%)
• Usually midline
• Present with truncal ataxia and ICP i
• 20% have spinal metastases at diagnosis
• Treatment is surgical resection followed by chemotherapy and radiotherapy
• Standard risk tumours have 80% long-term disease control; poor risk have 20% long-term disease control
• Neurocognitive sequelae problematic secondary to tumour, raised ICP, radiotherapy and probably chemotherapy

Brainstem glioma (10%)

• May be: 1. Diffusely infiltrating the pons (most cases; very poor outlook)
2. Low-grade focal midbrain or cervicomedullary tumours (good outlook if resectable)
• Present with ataxia, cranial nerve palsies and long-tract signs
• Treatment is mostly radiotherapy, unless low-grade focal tumour is resectable

Astrocytoma (20%)
• Usually cystic, slow growing
• May be in a cerebellar hemisphere or midline
• Present with ICP i by blocking the fourth ventricle or aqueduct of Sylvius
• Treatment is surgical resection ± chemotherapy and radiotherapy .
• 5-year survival 90- 95%

430
t Ependymoma (10%)
• Locally invasive
• Presents with ICP i and cranial nerve signs
• Treatment is surgery and radiotherapy, though chemotherapy has a role in younger children
• 5-year survival 50%

SUPRATENTORIAL TUMOURS
Craniopharyngioma (see p. 235)
• Develops from a squamous remnant of Rathke's pouch in the sella turcica
• Solid and cystic areas; 90% show calcification on skull X-ray
• Presents with endocrine abnormalities, ICP i, bitemporal hemianopia
• Treatment is surgical resection ± radiotherapy

Optic nerve glioma

• 1h associated with neurofibromatosis
• Presents with: Decreased acuity and disc pallor
Diencephalic syndrome - anorexia, or increased appetite, emaciation, hyperalert, euphoric
(occurs if hypothalamus invaded)
• Treatment is dependent on site, age and presence of neuro~bromatosis . In isolated optic nerve tumours in a blind
eye, surgical resection may be indicated. In other tumours, chemotherapy or radiotherapy are the major modali-
ties. No treatment until progression is observed as the natural history is variable with spontaneous stabilization
or even regression of tumour occurring in patients with NFl

Astrocytoma
Prognosis is dependent on age, site and histology of the tumour. Supratentorial low-grade astrocytomas amenable to
surgical resection do well, whereas high-grade tumours of the thalamus do badly.

Choroid plexus papiLLoma

• Predominantly tumours of very young children
• Secrete CSF and cause slowly progressive hydrocephalus
·• Prognosis is excellent after resection
• Choroid plexus carcinoma carries a much worse prognosis

Pineal tumours
• Variety of tumour types can occur in the pineal gland in children
1
'• Therapy and prognosis are dependent on the histology and the age of the patient
T

LEUKAEMIAS
The leukaemias are the most common form of childhood cancer. They include:
• Acute lymphoblastic leukaemia (ALL) (75%)- peak incidence 4 years
• Acute myeloid leukaemia (AML) (20%) - stable incidence < 10 years, higher incidence during adolescence and
older
• Chronic myeloid leukaemia (CML) (3%)
• Juvenile CML and the myelodysplastic syndromes (2- 3%)
The leukaemias are classified according to morphology and cytochemistry, immunophenotyping, chromosome analysis
and gene rearrangements.

431
ACUTE LY~1PHOBLASTIC LEUKAEMIA (ALL)
The most common form of childhood cancer. Arises from early cells in the lymphoid series.
Genetic associations Down syndrome
Hyperdiploidy (good prognosis)
Hypodiploidy (poor prognosis)
Translocations, e.g. t (9:22) Philadelphia chromosome } Poor risk leukaemias,
t (4:11) infant ALL SCT indicated in first remission

Classification

Fre:~ch-A111eri~~n--Bri~sh
>' ' -' ;.. ' ' .,_ ,' . ' -.·
.>:_f;''·:·,.·;: _.,,;~-
(FAB)
. . -_
system (morp~o
. -- ., ,·- ' . '- ; ,;. _ .. .

L1 .Small lymphoblasts, little cytopl~slll (good.pr~g~osis )-·_

L2 · . Larg~talld
\•.:.;;,;:; ..
pl~omorphi~ tyfuphoblasts,'
··-.'--~ · --- •.
;bre
~1'. . : ··
- ::-·
Cytoplasm
.. ·,. _-c-~·,,··:,;: .

L3 '.,;/ ·/·cytoplasmic va~~oles,firtelystipptednucle~r th~omatin

. . . . -• .· ·. . ·. .. . .. , ' >- .' . . .. ,. , .. '· ·. .. . ~

Clinical features
Bone marrow failure Hb (J,) Pallor, lethargy
WCC (1 or N) Infections, fever
Platelets (1) Bruising, bleeding gums, menorrhagia
Infiltration Hepatosplenomegaly
Lymphadenopathy
Testicular swelling
Limp (bone pain)
Acute renal failure
Meningeal syndrome (ICP 1', papilloedema, retinal haemorrhage)
Anterior !'flediastinal mass (on CT scan, in T-ALL)

Investigations
Pen'pheral FBC and film Anaemia (normochromic, normocytic)
Blasts present
wee 1, N or i
Platelets 1
Bone marrow (aspirate or biopsy) ;;. 30% leukaemic blast cells
CXR Mediastinal mass (in T-ALL)
CSF Blasts seen in cytospin if CNS involvement
Renal function + un'c acid Impaired renal function with i uric acid if renal infiltration or tumour Lysis
syndrome
Special classification tests Chromosomal analysis, immunocytochemistry, immunophenotyping,
Immunoglobulin and T-cell receptor (TCR) gene rearrangement studies

432
- _.
l Treatment
1. Induction of remission Multiagent chemotherapy: vincristine, daunorubicin, asparagine, steroid
2. Consolidation of remission
Intensive multiagent chemotherapy: ara-c, cyclophosphamide, etoposide
CNS prophylaxis (treatment that crosses the blood-brain barrier), e.g. high dose
IV methotrexate, intrathecal chemotherapy, CNS radiotherapy
3. Intensification
2- 3 blocks of intensive, multiagent chemotherapy
Aim to clear submicroscopic or minimal residual disease
4. Maintenance chemotherapy
2 years chemotherapy. An outpatient treatment usually with oral 6-MP, vincristine
and prednisolone or dexamethasone
Consider allogeneic SCT if very poor features such as initial WCC > 100, Philadelphia positive or t (4:11).

Relapse
• Common sites are the bone marrow, CNS and testes
• Treated with intensive chemotherapy (and cranial irradiation in CNS relapse)
• Stem cell transplant may offer the best chance of cure

Prognosis
• Dependent on type and other factors (see below)
• Overall 5-year survival is 70-80%

Prognostic indicators

,,

ACUTE MYELOID LEUKAEMIA (AMl)

The predominant form of congenital leukaemia that probably arises from a pluripotent cell or myeloid progenitor
committed to erythroid, granulocytic- monocytic or megakaryocytic lines.
Associations Down syndrome
Aplastic anaemia
Fanconi anaemia
Bloom syndrome
Previous chemotherapy (secondary AML)

433
C\assiflcation

Clinical features
Bone marrow failure As in ALL (WCC may be -1-, N or 1)
Other Gum hypertrophy (M4 and M5 especially)
ore (M3)
Chloroma (a Localized mass of Leukaemoid cells; common sites are retro-orbital, skin and
epidural)
Bone pain less common than in ALL

Investigations
As for ALL. Bone marrow must contain at least 30% blast cells (blasts may contain Auer rods).

Management .
1. Induction of remission Chemotherapy, e.g. daunorubicin, cytosine arabinoside, thioguanine or etoposide
> 80% achieve remission (if not achieved SCT is necessary)
2. Consolidation E.g. daunorubicin, cytosine arabinoside, thioguanine or etoposide
Intrathecal chemotherapy(± cranial irradiation) if CNS leukaemia at diagnosis or
CNS relapse
3. Further consolidation Total of 4-5 courses of multiagent chemotherapy, e.g. etoposide, ara-c,
m-amascrine
SCT is usually only considered after relapse of AML in children
Other treatments All-trans-retinoic acid (ATRA) given in M3

Prognosis
Overall cure rate 60-70%. Cure rates depend on type (highest for M3 AML), and decreases with increasing age.

MYELODYSPLASTIC SYNDROMES

Juvenile myelomonocytic leukaemia (JMML)

This is unlike adult CML, generally occurring at a young age and having features of AML. Philadelphia chromosome is
not present.

434
.-
 .. -···-··· · · .... .. . . .. ... ... .. . . .. ... .. . .. ·- .. · ·· ·· ·· ·· . .... . · ··· -··· - - ····-

Predominant findings Abnormal monocytes on the blood film

HbF elevated
Platelets 1
Leucocytosis
Hepatosplenomegaly, lymphadenopathy, bleeding tendency, eczema
Chronic desquamative maculopapular rash
Due to resistance to treatment, allogeneic SCT is recommended.

Myelodysplasia (including monosomy 7)

Children initially develop only anaemia, thrombocytopenia or leucopenia. The bone marrow has characteristic dysplastic
features and blast cells.
Associated chromosomal changes Trisomy 8
Complete or partial deletion of chromosome 5 or 7
Monosomy 7 (the most common abnormality in infants with myelodysplasia
and AML)
The condition usually evolves into AML and so patients are treated as for AML. BMT is considered more often as this
condition is more resistant to chemotherapy.

CHRONIC MYELOGENOUS LEUKAEMIA (CML, ADULT TYPE)

This is a malignancy of a haematopoietic stem cell capable of entering both myeloid and lymphoid lineages and con-
taining the Philadelphia (Ph) chromosome. The Ph chromosome has the translocation: t (9:22). This produces a fusion
gene (bcr-abl) which encodes the bcr-abl protein, i.e. activates the abl oncogene.

Phases in CMl
Chronic phase 3-4 years. Cell counts easily controlled with chemotherapy
Accelerated phase More difficult to control
Blast crisis ALL or AML

Clinical features
• Hypermetabolism - fever, weight loss, anorexia, night sweats
• Massive splenomegaly
• Anaemia, bleeding, bruising
• Leuc?stasis- visual disturbance, priapism
, •
1
Renal failure and gout

Investigations
Peripheral blood film Hb N or 1, platelets i, Nor l,WCC it, immature myeloid cells but few blasts on film
Bone marrow Hypercellular, myeloid hyperplasia
Others Neutrophil alkaline phosphatase score -1, uric acid I, B12 i
Cytogenetic studies Philadelphia chromosome ( ~ 95%)

Management
Chemotherapy E.g. busulphan, hydroxyurea,
a-Interferon (suppresses the Ph chromosome); signal transduction inhibitors (STI) are in
trial with encouraging results
SCT in chronic phase · Only known cure

435
Prognosis
• If BMT during chronic phase, survival is 80% (matched sibling), 50-60% (partiaLly matched or unrelated)
• If BMTduring accelerated phase, survival is 20-30%
• If BMT during blast crisis, survival is 0-10%

LYMPHOMA
These malignancies of lymphoid tissue are classified into:
• Hodgkin disease
• Non-Hodgkin lymphoma
Incidence 13:million children per year.

HODGKIN DISEASE
A malignancy of lymphoid tissue with Reed-Sternberg (RS) cells and Hodgkin cells seen on histology. It is a B-cell
malignancy, but the exact origin of the malignant cells is unclear.
Bimodal age distribution: peak in mid-20s and > 50 years. Male> female, 2:1.

Histological classification

Clinical features
Lymphadenopathy Painless, firm Lymph nodes
Cervical, supraclavicular, axillary, inguinal
Mediastinal (cough, airway compression)
Retroperitoneal
'8' symptoms Fever (Pel-Epstein)
Night sweats
Weight Loss
Other constitutional symptoms Fatigue, pruritis, anorexia
Extranodal involvement Hepatosplenomegaly, bone pain, skin deposits, SVC obstruction, bone marrow
failure (rare)

Investigations
Careful clinical examination essential.
Bloods FBC: Normocytic normochromic anaemia
NeutrophiLs i, eosinophiLs i
Platelets (initially high, low in advanced disease)
ESR i (used to monitor disease progress)
LDH i (poor prognosis)
LFTs i (poor prognosis)

436
Lymph node biopsy For diagnosis and histological classification
CT chestjabdomenjpelvis For staging
Other (if necessary) Bone marrow aspirate
Bone scan
Liver biopsy
MRI scan
Laparotomy

Stages

Management
Stages IA and IIA Radiotherapy only or chemotherapy (ABVD)
Advanced disease Chemotherapy, e.g. adriamycin (doxorubici n), bleomycin, vinblastine, dacarbazine (ABVD)
± Radiotherapy
Relapse Alternative combination chemotherapy, e.g. MOPP, and autologous stem cell transplant

Prognosis
Stage I and II >90% 5-year survival
Stage lilA >80% 5-year survival
Stage IIIB, IV >70% 5-year survival

NON-HODGKIN LYMPHOfV\A
Arises from abnormal Tor B lymphocytes.
Associations Autoimmune disorders
Congenital immunodeficiency disorders, HIV
C)lildren have high-grade, diffuse disease.

Classifi cation
There are several classifications.

437
Clinical features
These are dependent on the site of the primary.
Systemic symptoms Fever, night sweats, weight loss
Abdomen (31%) Abdominal distension, nausea, vomiting, acute abdomen, hepatosplenomegaly
Mediastinum (26%) Dyspnoea, pleural effusions, SVC obstruction
Oropharyngeal Sore throat, stridor
Lymph nodes Painless hard lymph nodes. Cervical LN most commonly affected
Bone marrow Bone marrow failure symptoms and signs
CNS Headache, raised ICP, cranial nerve palsies
Other organ Skin deposits, testes mass

Investigations
Excision biopsy or Of lymph node or other mass
fine-needle aspirate
Bloods FBC (anaemia, neutropenia, lymphoma cells platelets J,)
Urea and creatinine I, uric acid I, bone profile
LDH i (prognostic marker)
Bone ·marrow aspirate (Involvement in around 20%)
or trephine
CSF CNS involvement
Imaging CT scan chestjabdomenjpelvis and bone scan
Spedal tests Chromosome analysis, immunological markers

Staging
This is as for Hodgkin disease, though it is less clearly related to prognosis than is the histological type.

Management
This depends on the grade of malignancy. High-grade malignancy in children is usually treated with multiagent chemo-
therapy, like ALL protocols.
Relapses are treated with intensive chemotherapy, radiotherapy and SCT.

Prognosis
Limited-stage disease > 90% cure
Stage III and IV 70% cure

Burkitt lymphoma
An unusual B-celllymphoma, related to EBVinfection. Endemic in Africa Uaw involvement seen). Sporadic in developed
countries (abdominal involvement seen).

CUnical features
• Massive jaw lesions
• Abdominal extranodal involvement
• Ovarian involvement

Specific investigations
Lymph node biopsy 'Starry sky' appearance (a few histiocytes amongst masses of lymphocytes)

438
Cell culture For EBV
Chromosome analysis t (8:14) usually present

Management
Intensive sequential chemotherapy (four cycles), with SCT in relapse. Recently very good results have been obtained
(70% cure).

CHILDHOOD HISTIOCYTOSIS SYNDROMES

The histiocytoses are a group of disorders involving proliferation of histiocytic cells in the bone marrow of the
dendritic cell or monocyte-macrophage systems. Many are benign proliferations, though some are malignant. They
are classified on the basis of histology.

ClASS I HISTIOCYTOSES: DENDRITIC CELl DISORDERS

Langerhans' cell histiocytosis (LCH)
Langerhans' cells are skin histiocytes with antigen-presenting function (part of the antigen-specific immune response).
They are COla positive. Identified on EM with the cytoplasmic organelles Birbeck granules, which look like tennis
rackets.
The cause of LCH is unknown.
2-5 cases:million children annually, peak incidence age 1-3 years, males> females.

Clinical features
Features are a result of infiltration with Langerhans' cells and the subsequent immunological reaction to these cells.
Presentation and extent of involvement vary widely: it may be single system or disseminated.
Bone pain and swelling Due to isolated or multiple lytic lesions:
• Punched-out skull lesions, mastoid necrosis with middle ear involvement
• Jaw (floating teeth), orbit (proptosis), vertebral fractures, long bone lesions
Bone marrow infiltration seen
Skeletal survey should be performed at diagnosis
Skin rash Pink or brown papules becoming eczematous, scaly and pruritic
Involving face, scalp, behind ears, axillary and inguinal folds, back and nappy area
Ear dischqrge
Lymphadenopathy
Hepatosplenomegaly
Other Lung- infiltration causing cough, tachypnoea, chest pain (CXR: diffuse micronodules,
later reticulonodular pattern)
Endocrine - e.g. hypothalamic-pituitary infiltration causing endocrine abnormalities,
especially diabetes insipidus
GIT- infiltration causing abdominal pain, vomiting, diarrhoea, protein-losing
enteropathy
CNS - involvement, e.g. ataxia, pyramidal signs, tremor, encephalopathy (all rare)

Treatment

Single system disease Observation alone

Topical treatment (rash), analgesia, steroids and chemotherapy if necessary
Multisystem disease Chemotherapy then SCT if necessary, i.e. non-responders with bone marrow disease

439
Prognosis
May regress spontaneously or progress to life-threatening disease. The prognosis is worse if multisystem, < 1 year old
and with active disease.

ClASS II HISTIOCYTOSES: MACROPHAGE DISORDERS

These are proliferations involving macrophages and the many different types are divided into systemic and cutaneous
forms.

Systemic

Haemophagocytic lymphohistiocytosis (HLH)

This may be:
• Primary (familial or sporadic). Mutations in the perforin gene found (10q21-22) in some cases (with absent
perforin granules in cytotoxic lymphocytes), or
• Secondary (to infections, immunosuppression, metabolic disorders, fat infusions or malignancy)
It is a disorder involving immune dysregulation. Cytotoxic lymphocyte defects have been found:
• CD8 and CD56 T cells in perforin gene defects
• NK cells in EB virus associated disease
Diagnostic criteria are:
• Fevers
• Splenomegaly
• Pancytopenia
• High triglyceride or low fibrinogen
• Typical histology (with haemophagocytosis)
Other features include lymphadenopathy, skin rash, LFT i, ferritin i.
Treatment is:
Primary disease Chemotherapy then BMT if needed (persistent or familial disease)
Secondary disease May resolve with treatment of the precipitating factor
Primary HLH is generally fatal without BMT.
Future pregnancy risk is 1:4 for familial disease and there are no predictive tests currently available . .

Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy)

This is usually a benign disorder with spontaneous regression involving massive cervical lymphadenopathy, fever,
weight loss and skin papules, nodules or plaques.

Cutaneous

Juvenile xanthogranuloma (JXG)

• Single or multlple yellow-orange papules
• Lipid-laden macrophages seen on histology
• Usually regresses over a few years
• Systemic involvement (most commonly ocular) is rare

440
CLASS III HISTIOCYTOSES
These are the malignant histiocytoses of monocytic/myeloid origin.
Examples Acute monocytic leukaemia (M5)
Acute myelomonocytic leukaemia (M4)
Treatment is with chemotherapy or SCT.

FURTHER READING
Pizzo PA, Poplack DG Principles and Practice of Pediatric Oncology, 5th edn. New York, Lippincott Raven, 2005

441
• Neonatal definitions qnd statistics • Intrauterine growth retardation
• Antenatal screening and diagnosis • Large for gestational age
• Pregnancy food and drug advice • Prematurity
• fetal medicine • Raspiratory disordors
• Congenital infections • Cardiac disorders
• Delivery • Neurological disorders
• Normal newborn • Neonatal convulsions and jitteriness
• Infant feeding • Gastrointestinal disorders
• Birth injuries • Osteopenia of prematurity
• Intrapartum and postnatal infections • Haematological disorders
• Neonatal intensive care • Hypoglycaemia

NEONATAL DEFINITIONS AND STATISTICS

Deft nitions

442
 ····- . ····-··· ·-··- .. ..... .. ...... .- . ... .... ... _
.... _,........ .._......... ........... .. ... ..... _........... - ... ......... ... . -- _......... .... .. ..... . .. ... ...... . .. .. .. .. ..... . . . ................ ..... _ -· ·· ... ..... .

Birth statistics

Predicted survival percentage for infants admitted for neonatal care (adapted from Draper Eet al
Tables for predicting survival for preterm births are updated. BMJ 2003;327:872)
By gestation

By birthw~ight

443
ANTENATAL SCREENING AND DIAGNOSIS

Disorders diagnosable by ultrasound at 20 week anomaly scan

444
 NB: If nuchal scanning is not available, at 14-22 weeks maternal serum screening for Down and other trisomies is
done (the triple test):
Maternal serum Free ~-hCG i }
Unconjugated oestradiol (uE3) 7 in Down's
a -Fetoprotein (AFP) _.,
Provides data to calculate an individual risk in a woman with known gestational dates with a 62% sensitivity for
identifying as high risk of Down fetus for a 5% false-positive rate.

INVASIVE TESTS

Future screening methods

Non-invasive techniques are being developed. These include:
• Diagnostic techniques using fetal DNA obtained from fetal cells in the maternal circulation or free fetal DNA in
maternal plasma
• 3D uss
• Fetal MRI scanning } Looking for structural anomalies

'
PREGNANCY FOOD AND DRUG ADVICE
Things to take
1
Supplements Folic acid:
• Pre-conceptually and for the first trimester
• Reduces incidence of neural tube defects
• (Low dose all women [400 11g daily], high dose [5 mg daily] if previous neural tube defect)
Foods Oily fish:
• Important for neonatal brain development.
• Omega-3 oils reduce incidence of preterm labour
• (Avoid excess salmon or tuna due to high mercury content)

445
Things to avoid
Foods Non-pasteurized products, soft cheeses
Pate, chicken, raw vegetables
} Listeria manacytagenes (see p. 452)
Over the counter warm pre-cooked meats
Blue vein cheeses
Uncooked and smoked meats (lamb or pork) }
Raw eggs, e.g. mayonnaise Toxoplasmosis
Unwashed fruits and vegetables
Liver - keep to minimum as the high levels of vitamin A it contains are potentially teratogenic
Drugs Avoid all drugs if possible due to possible teratogenic effects (see below)
No routine iron
Drug abuse - teratogenic effects (not opiates), fetal ischaemia with cocaine, IUGR, placental
abruption, prematurity, neonatal addiction
Alcohol (limit quantity) -fetal alcohol syndrome if excessive alcohol (> 6 units/day)
Smoking Avoid - IUGR, increased risk of miscarriage, stillbirth and SIDS (including passive smoking from
partner/work/social)
Cats and cat Litter Avoid - toxoplasmosis risk from cat faeces

FETAL MEDICINE
Fetal medicine is concerned with antenatal detection, pregnancy management and treatment (where applicable)
of fetal disorders. This includes:
• Antenatal screening (see above) and additional diagnostic tests where indicated, including interventional tests,
e.g. CVS, and counselling of options should they be abnormal
• Genetic counselling
• Treatment during pregnancy (see below) and termination of pregnancy where appropriate

446
HIGH-RISI< PREGNANCIES
Pregnancies are classified as high-risk due to:
Pre-existing maternal disease Chronic disease, e.g. diabetes mellitus, heart disease, renal disease, asthma
Nutritional disorders resulting in excessively low or high BMI and deficient
dietary intake
Maternal alloimmune disease (see below)
Antenatally detected fetal disorder Identified genetic abnormality, e.g . Down syndrome, cystic fibrosis
Fetal structural abnormality diagnosed via antenatal USS, e.g. spina bifida,
renal abnormality
Fetal arrhythmia
Pregnancy complication/indication Multiple pregnancy
Oligo- or poly-hydramnios
Antepartum haemorrhage
Pregnancy induced hypertension and pre-eclampsia (toxaemia of pregnancy)

MULTIPLE PREGNANCY
• Twin, triplet and higher multiple pregnancies are associated with specific increased risks to both the mother and
the fetuses
• Establishing chorionicity (indirect aids zygosity testing) in the first trimester gives best results
• Growth discordance affects all twins after 32 weeks (monochorionic more so). Triplets> 30 weeks
• Regular scanning in pregnancy required - dichorionic: 4 weekly; monochorionic: 2 weekly

Monozygotic (identical)
• Single fertilized egg, incidence 3.5:1000 pregnancies
• These may be: Single chorio11 and amnion
Mixed (separate amnion, but monochorionic), or
Separate chorion and amnion
• Risk: twin-twin transfusion syndrome. A monoamniotic pregnancy may also lead to fatal cord entanglement and
locked twins at delivery

Dizygoti~ (non-identical)
• Familial, variable rate. 1:66 spontaneous rate
''• Two separately fertilized eggs
• Di~horionic placenta

Risks associated with multiple pregnancy

• Prematurity
• IUGR, discordant growth
• Asphyxia

447
 -,
;

• Second twin at particularly increased risk of asphyxia, trauma and respiratory distress syndrome
• Monozygotic twins: Increased congenital anomalies
If single chorion and amnion: twin-twin transfusion syndrome, cord entanglement,
discordant growth
• Increased fetal and maternal mortality

Twin-twin transfusion syndrome -

This can occur in utero between monochorionic twins, i.e. share the same placenta, and is defined as a difference in
Hb of> 5 g between the twins. If untreated, death of both twins occurs in > 90%; if treated, both twins survive in
66%. Essentially one twin has the majority of the placental blood flow (and nutrients), and hence grows larger and
is plethoric, while the other twin is anaemic and smaller. It is the large plethoric twin who is at higher risk because
diminished blood flow through smaller vessels (secondary to high haematocrit) can cause multiorgan damage.

Antenatal treatments include amnioreduction (repeated removal of amniotic fluid) and laser septostomy, or selective
fetal reduction .

MATERNAL DISEASES ASSOCIATED WITH MALFORiviATIONS AND NEONATAL DISORDERS

• Maternal illness has a general impact on fetal growth and wellbeing , e.g. pre-eclampsia, chronic renal disease
• They can cause fetal malformations, e.g. diabetes, feta l damage, premature delivery or result in temporary
neonatal disease due to a maternal transfer of IgG antibodies (IgG will cross the placenta), e.g. autoimmune
thrombocytopenia. Sometimes, a transient transfer of antibodies can result in permanent consequences for the
infant, e.g. congenital heart block in maternal lupus

448
Examples

CONGENITAL INFECTIONS

Vertical transmission may be:

• Transp'lacental
,,. Intrapartum (cervical secretions, haematogenous) or
• Postnatal (breast milk, saliva, urine)
f

Features that would arouse suspicion of a congenital infection:

• IUGR
• Petechial rash
• Hepatosplenomegaly
• Brain - fits, microcephaly, developmental delay, calcification
• Eye - cataracts, chorioretinitis, microphthalmia
• Deafness

449
 • Cardiac defects
• Pneumonitis
Congenital infection may also result in miscarriage or stillbirth.

CYTOMEGALOVIRUS (CMV)
• Most common congenital infection. Approximate incidence: 2000/year in the UK live births
• 50% fetal infections are asymptomatic, around 5% will have clinical infection at birth, others presenting later. Up
to 10% develop neurological sequelae (mainly deafness)
• Primary maternal CMV infection during pregnancy is associated with a worse prognosis than reactivation. It can
be postnatally acquired

Clinical features
Brain Cerebral periventricular calcifications
Sensorineural deafness (can be progressive)
Developmental delay (mild or severe)
Microcephaly, encephalitis
IUGR
Skin Petechial rash
Liver Hepatosplenomegaly, jaundice
Lungs Pneumonitis (usually with postnatally acquired)
Eyes Chorioretinitis, optic atrophy
Teeth Dental defects

Diagnosis
Urine PCR, blood PCR.

TOXOPLASMOSIS
Intracellular parasite, acquired from raw meat, unwashed vegetables and fruit, and cat faeces (kittens with primary
infection can be high excreters).
Incidence of primary maternal infection during pregnancy is 1:1000. The risk of infant infection is inversely related to
gestational age at the time of primary maternal infection:
First trimester maternal infection 15% risk
Second trimester infection 45% risk
Third trimester infection 65% risk
The severity of disease in the infant is dependent on the gestation. Highest risk at 24-30 weeks. Overall 10% have
clinical features.
The recent BPSU study, however, found 12 cases per year in the UK, highlighting an inconsistency between the above
figures.

Clinical features
Infection particularly affects the developing brai~. Most have no apparent symptoms, but intracranial calcification is
often present with neurological consequences.
Brain Cerebral calcifications diffusely scattered dense, round lesions, basal ganglia curvilinear streaks
Seizures, hydrocephalus, microcephaly, encephalitis, developmental delay (mild or severe)

450
Eyes Chorioretinitis, cataract
Liver Hepatosplenomegaly, jaundice
Blood Anaemia
Lungs Pneumonitis

CONGENITAL RUBELLA
This is now very rare (only 6 cases reported in the UK in the last 5 years).
Risk arid severity are dependent on gestation at maternal infection:
Very high risk < 8 weeks gestation
High risk < 18 weeks
Low risk > 18 weeks

Clinical features
Eyes Cataracts, corneal opacities, glaucoma, microphthalmia
Brain Sensorineural deafness, psychomotor delay (mild to severe), behavioural problems, autism, progres-
sive degenerative brain disorder
Liver Hepatosplenomegaly, hepatitis
Skinjhaem Petechial rash, thrombocytopenia
Cardiac PDA, pulmonary artery stenosis, aortic stenosis, VSDs
Lung Pneumonitis
Bone Radiolucent bone lesions
IUGR
Endocn"ne Juvenile diabetes, thyroid disorders, precocious puberty
Diagnosis
Urine and blood rubella-specific IgM I.

VARICELLA
Congenital varicella infection
Pri mary maternal infection during pregnancy may rarely (< 2% of cases of maternal infection) produce congenital
varicella syndrome:
Skin Cicatrix (zigzag scarring), skin loss
Limbs M?lformation and shortening, paresis
Ey~s Cataracts, chorioretinitis, microphthalmia
CNS Microcephaly, hydrocephaly, brain aplasia
It is th6ught to result from viral reactivation in utero rather than the initial fetal infection.

Maternal chicken pox around delivery (< 5 days pre-2 days after)
May cause severe chicken pox illness in the infant (high titres of virus, with no maternal antibodies yet made to protect
the infant). These infants are given :
• Anti-varicella zoster IgG (VZIG) IM (post-exposure prophylaxis)
• If any vesicles develop, commence IV aciclovir

451
Indications to give VZIG to baby
• Maternal infection < 5 days pre- 2 days after delivery
• < 28 weeks' gestation or < 1000 g, regardless of maternal history (little antibody crosses placenta < third
trimester)
• Other babies on the ward who may have been exposed if< 28 weeks' gestation or mother non-immune

LISTERIA MONOCYTOGENES
This may be acquired transplacentally or by ascending infection and may present in different ways.
Source Unpasturized cheeses and milk products, soft cheeses, chicken, raw vegetables
Uncooked meats, over-the-counter reheated foods

Clinical features
• Premature delivery, abortion or stillbirth, maternal flu-like illness
• Meconium passed in utero (in premature delivery)
• Pneumonia, meningitis, septicaemia
• Disseminated infection (fits, rash and hepatosplenomegaly)
• Hydrocephalus is a common sequelae

Treatment
Ampicillin IV and gentamicin IV.

CONGENITAL SYPHILIS
High transmission rate, 40% morta lity untreated.

Clinical features
Infancy Snuffles, congenital nephrotic syndrome, glaucoma, chori0retinitis
Hepatosplenomegaly, lymphadenopathy, osteochondritis, periostitis
Rash (desquamation hands and feet maculopapular, bullous, condylomata)
Childhood Hutchinson teeth (peg-shaped incisors with central notch)
(>2 years) Sabre tibia, saddle nose deformity, frontal bossing
Meningovascular involvement
Optic atrophy, corneal calcification (blindness), photophobia
Vertigo arid deafness (VIII nerve involvement)
Paroxysmal nocturnal haemoglobinuria

OTHER CONGENITAL INFECTIONS

• Hepatitis B (see p. 192)
• HIV (see p. 36)
• Parvovirus B19 (seep. 53)

452
DELIVERY

RESUSCITATION
A minority of infants do not establish respiration rapidly after birth (they are 'flat'), and they need immediate assess-
ment and intervention. Apgar scores are performed on all babies directly after birth (at 1, 5 and 10 min after birth, and
longer if necessary) in order to assess their condition. These are a poo rly predictive indicator of later adverse outcome.
Five parameters are assessed, each scoring 0- 2, and the total (out of 10) give the Apgar at that time.

Apgar scores

Basic resuscitation Start the clock

Dry and stimulate baby, and keep it wa rm
Bag and mask ventilation
External cardiac massage
Advanced resuscitation Endotracheal intubation and ventilation
Drug therapy
Blood/fluid therapy via umbilical venous catheter
Transfer to NICU
NB: Infants of 3 kg lose l"C per min in ambient theatre temperature.

Drug therapy
Adrenaline IV orETT 0.1-0.3 mljkg of 1:10 000 (10 ~g/kg ) repeated as needed every 3-5 min
0.1 mljkg of 1:1000 (100 ~g/kg) if required after two doses as above
Glucose 10% IV 2 mljkg
Blood/4.5°/p albumin 10-20 mljkg
Sodium bicarbonate (4.2% soln) IV 1 mmoljkg

453
 . ····- .. -- - ······ ·--· -··.. . ----·- -·- ----· .. ..... ..... - .... ....... -· ...... . . ......... .... .. .... .. -- ·- --·-·· ··· ·· ·-·-···.. ·---·--·-···---- --···- .. -····----....···-·-··---- --. .

HIGH-RISK DELIVERIES

NORMAL NEWBORN

NEONATAL EXAMINATION
All infants should be given a general examination within 24 h of birth.
Measurements Gestational age, weight (length), head circumference
General Appearance (dysmorphic), posture, movements
Skin Colour (cyanosis, jaundice, anaemic, plethoric), birthmarks
Head Fontanelles (normal size, pressure, fused sutures), head shape
Face Features of dysmorphism
Ears Size, formation, position
Mouth Size, other abnormality (cleft lip/palate), neonatal teeth
Palate Inspect and palpate (cleft palate), sucking reflex checked
Eyes Red reflex, discharge, colobomas, size
Neck Any swellings (cystic hygroma, sternomastoid 'tumour')
Respiratory Respiratory movements, rate, auscultation
Cardiovascular Auscultation, femoral pulses
Abdominal Palpation (masses)
Genitalia Inspection (malformations, ambiguous genitalia), testes (both fully descended)
Anus Patent. NB: Meconium normally passes within 48 h of birth (and within 24 h in 95%). Most units
ask surgeons to review if no meconium by 24 h
Back Check spine (midline defects)
Muscle tone Observation and holding baby prone
Reflexes Moro reflex
Hips Check for CDH (see below). Enquire if breech or family history in which case a hip USS is arranged

454
 - - --- - ···- ·- · · . . . .. .. .. . .

NEONATAL HIP EXAMINATION

The baby should be relaxed while this is carried out.
The pelvis is stabilized with one hand and the midd le finger of the other hand is placed over the greater trochanter
and the thumb around the femur. The hip is flexed. Then:
Barlow manoeuvre To check if the hip is dis locatable
The femoral head is gently pushed downwards. If dislocatable, the femoral head will be pushed
out of the acetabulum with a clunk
Ortolani manoeuvre To see if the hip is dislocated and can be relocated into the acetabulum
The hip is abducted and upward pressure applied by the finger on the greater trochanter. If the
hip was dislocated, it will clunk back into position
NB: Insignificant mild clicks due to ligaments may be hea rd.

VITAfvUN K
• Prophylactic vitamin Kis recommended for all newborns to prevent haemorrhagic disease of the newborn
• Vitamin Kis given intramuscularly, or orally shortly after birth if bottle feeding
• Oral vitamin Kgiven after birth, at 1 week and at 6 weeks if breast feeding

Haemorrhagic disease of the newborn

• Due to low vitamin K-dependent clotting factors at birth (immature liver, low gut bacteria) and a further fall in
breast-fed babies (breast milk is a poor source of vitamin K)
• Presents as bleeding on day 2-6, usually mild but may be catastrophic
• Late presentation (rarely) may occur up to 6 weeks
• If bleeding occurs, give IV vitamin K, FFP, blood and plasma as needed and check for hepatic dysfunction, e.g.
a 1-antitrypsin deficiency
_Now rare(< 10 cases per year in the UK).

GUTHRIE TEST
This is a bioche.mical screen to detect some meta bolic defects and is performed on all infants at the end of the first
week of life via a blood test (usually a heel prick sample). The screen can detect:

455
(It is often also used anonymously to determine prevalence of HIV within a population.)
Tandom mass spectroscopy is used to detect the rare metabolic conditions.

INFANT FEEDING
Infant requirements
Infant feeding Purely milk feeding for the first 4-6 months
Then solid food is gradually introduced (weaning)
Energy requirements Term 100
(kcaljkgjday) Premature 120
SGA 140
Vitamin supplementation Vitamin A (iu) 500-1500
(recommended daily dosage) Vitamin D (iu) 400
Vitamin E (iu) 5
Vitamin C (mg) 35
Folate (!-'g) 50

Breast milk
• For the first few days it is composed of colostrum (thick bright yellow-orange) with high protein, phospholipid,
cholesterol and immunoglobulin content
• Major differences to formula milk:
Casein:whey ratio (high whey in breast milk)
Fat (higher in breast milk)
Na, Ca, phosphorus }
Vitamin K Lower in breast milk
Iron
• Cow's milk is vastly different, and therefore should not be used as a substitute

Breast feeding
Establishment In the first few days after birth is critical. It is important that time and energy is used to help
the mother at this critical time
Cup feeds of formula milk should be used if additional feeding is necessary whilst tying to
establish breast feeding (to avoid nipple confusion)
Continuation Proven to benefit the baby for the first 6 months and recommended by the WHO
Many women commence well, but then stop after only a few weeks
69% of women initiated breast feeding in 2000. At 6 weeks, 42% were still breast feeding and
21% at 6 months
Higher social classes have higher rates of breast feeding
Help is available from breast-feeding councillors and health visitors in particular

Advantages
• Nutrition optimum, e.g. fatty acids, arachidonic acid and docosohexaenoic acid needed for infant brain develop-
ment
• Immunological protection transferred (IgA especially). In the developing world it gives very significant protection
against respiratory and gastrointestinal diseases
• Uterine involution (oxytocin release) and maternal weight loss expediated
• Contraceptive (lactation amenorrhoea) - as effective as the combined oral contraceptive pill during first 6
months

456
 • Convenient and cheap
• Decreases the risk of breast cancer (x 4.3 % per year of breast feeding)
• Reduces incidence of atopic disease throughout childhood and adolescence
• Helps to establish maternal-infant bonding

Problems
Social It is finally becoming socially acceptable
Fatigue The mother need not do all the feeding, as expressed breast milk can be given by other carers
Financial The mother cannot go back to work while fully breast feeding (though some milk may be expressed at
work, depending on the type of employment). It may be financially necessary for the mother to return
to work prior to 6 months after delivery, though the current direction of employment legislation is
toward providing prolonged maternity pay (up to 2 years in some countries)
Twins and higher multiples can be breast fed, though often supplemental formula feeds are necessary.

Reasons for not breast feeding

Special infant formulae

Weaning
This is the introduction of solid food and is done gradually from around 6 months (or 4 months) . Different pureed
foods are introduced every few days initially. Babies generally like sweet things (as breast milk is very sweet), but it
is important to introduce a wide variety of flavours early. Cow's milk should not be introduced before 1 year.

457
BIRTH INJURIES

HEAD INJURIES
Caput succedaneum Very common. Bruising and oedema of the presenting part of the head
Chignon Bruising from a Ventouse suction cap.
Cepha/haematoma A bleed beneath the periosteum due to torn veins (therefore limited to one skull bone)
Resolves spontaneously over a few weeks
Complications: Neonatal jaundice
Underlying skull fractu re (present in 20% but rarely needs treatment)
Associated intracranial haemorrhage
Eventual calcification (leaving permanent bump on head)
Subaponeurotic haemorrhage An uncommon bleed beneath the occipitofrontalis aponeurosis
This may spread over the scalp to become large and result in shock. High mortality if not
diagnosed

NERVE INJURIES
Erb palsy Common injury (1:2000 deliveries) to the upper nerve roots of the brachial plexus (C5, 6 ± 7)
Often follows shoulder dystocia
Arm held in adduction, elbow extended, internally rotated, forearm pronated and wrist flexed
('waiter's tip' position)
A few also have phrenic nerve involvement (causing ipsilateral diaphragmatic paralysis, a
pneumothorax andjor Horner syndrome)
Fadal nerve palsy Mostly LMN due to forceps injury, prolonged pressure on maternal sacral promontory
A few are UMN secondary to brain injury or nuclear agenesis (Moebius syndrome)
The lesions are difficult to distinguish clinically and result in an asymmetrical face when crying
and inability to close the eye on the affected side
Klumpke palsy Injury to the lower (C7 + 8 + Tl) nerve roots of the brachial plexus
A wrist drop and paralysis of the small muscles of the hand result in 'claw hand'
Around 30% also have a Horner syndrome

Management
Physiotherapy is given to prevent contractures. If there is no improvement at 2-3 months, refer to specialist unit. For
facial nerve injury, eye patching and artificial tears are needed if eye closure incomplete.

MUSCLE INJURY
Sternomastoid tumour Injury to the sternocleidomastoid muscle. May be from traumatic delivery or secondary to
position in utero
Manifest as a firm swelling within the sternomastoid muscle and a torticollis
Swift and regular physiotherapy (taught to parents) results in resolution of the swelling over
a few weeks.
The preferential turning of the head to one side only can result in plagiocephaly and
permanent postural deformity

458
BONE INJURIES
Clavicle fracture Most common delivery injury, often not detected.
Heals on its own but may need analgesia
Seen in large babies with impacted shoulders, e.g. infant of diabetic mother
Humerus fracture Usually upper third fractured. Radial nerve injury may occur
Heals on its own but may need analgesia and immobilization

INTRAPARTUM AND POSTNATAL INFECTIONS

Infections which may be acquired during delivery

GROUP B p-HAEMOLYTIC STREPTOCOCCUS (GBS)

Colonization of the vagina with Group B[3-haemolytic streptococcus occurs in approximately 30% of women. At least
10% of babies will become colonized during delivery. 1% of colonized babies develop Group Bstrep sepsis, with about
a 10% mortality(= 70 deaths in the UK/year).
Risk factors for sepsis are maternal pyre-xia, premature rupture of membranes or the infant is preterm and inadequate
labour prophylaxis was given (the infant should be treated).
Group B streptococcal neonatal infection causes serious disease with :
• Early lethargy, poor feeding, temperature instability, irritability, apnoeas, jaundice. Then features of sepsis and
shock, meningitis and pneumonia
• Late~onset from 48 h

Investigations
• PBC, CRP and septic screen (blood culture in particular)
• CXR (diffuse or lobular changes)
• Check maternal high vaginal swab result

Treatment
Tntravenous antibiotics, e.g. gentamicin and penicillin.
!here is now increasing pressure to establish a mother's Group B streptococcus status before delivery and to give
intrapartum prophylaxis with penicillin or clindamycin to colonized mothers.
NB: Any neonate in whom serious infection is suspected should be covered for Group B ~-haemolytic streptococcus.

459
Causes of neonatal sepsis and meningitis

NEONATAL HERPES 5Ifv1PLEX INFECTION

Rare. In the UK the incidence is approximately 2:100 000 live births.
Acquired from the birth canal during delivery (in most cases the mother is asymptomatic). Primary maternal infection
(with the greatest risk to the infant) during pregnancy is rare.
• Primary maternal infection - up to 50% infants infected
• Recurrent maternal infection - 3% infants infected
• Increased risk of neonatal infection with IUGR, prematurity, prolonged rupture of membranes (> 6 h) ·and fetal
scalp monitoring (direct viral skin inoculation)
Infection may be localized skin vesicles only or widespread vesicles develop within the first week of life and rapid CNS
involvement develops (meningoence-phalitis). Infection in neonates may be severe (mortality 80% untreated).
Treatment is intravenous aciclovir.

CHlAf.WDIA TRACHOMATIS
Chlamydia is found in the vagina in 4% of pregnant women and 70% of infected babies are asymptomatic.

Clinical features
• Conjuctivitis (purulent, like gonococcal) presenting in the znd week; cf. gonococcal presenting on days 1-2
• Pneumonia (may be present at 1-3 months of age), middle ear infection

Diagnosis
Organism identified on Giemsa staining and culture on special medium and immunofluorescence.

Treatment
• Oral erythromycin
• Tetracycline eye drops

UMBILICAL INFECTION
Omphalitis is umbilical stump infection. Funisitis is umbilical cord infection.
Usually due to Staph. aureus or E. coli. May lead to portal vein infection with subsequent portal hypertension .

Management
• Swab umbilicus (M, C & S)
• Gentle cleansing
• IV antibiotics if signs of spread (cellulitis around umbilicus)

460
~ :! __
NEONATAL INTENSIVE CARE
The neonatal intensive care unit (NICU) is a specialist unit to provide care to premature and sick neonates.

HiERMAL STABILITY
Incubators provide a stable warm environment designed to be thermoneutral, i.e. neither too hot requiring the
neonate to expend energy to keep cool, nor too cool requiring the neonate to expend energy to keep warm.

~WNITORING

Heart rate
Respiratory rate
Temperature
(ambient and that of infant)
BP Via umbilical artery or peripheral arterial line
Or BP cuff (less accurate)
Oxygenation Pulse oximetry (0 2 saturation)
Transcutaneous (0 2 tension)
C02 levels Transcutaneous (C0 2 tension)
Blood gases Transcutaneous, via arterial line or capillary analysis from heel prick samples
Bloods Regular samples (heel prick, venous or via arterial line) to monitor gases and
blood glucose

Blood gas acid-base monitoring

The following disturbances may exist:
Acidosis Respiratory acidosis (high CO), e.g. underventilated
Metabolic acidosis (low bicarbonate), e.g. sick infant
Alkalosis Respirat~ry alk~losis (low C0 ), e.g. overventilated
2
Metabolic alkalosis (high bicarbonate)
These will be compensated for (but never enough to bring the pH to normal) by:
• Metabolic means by altering the bicarbonate level
• Respiratory means by altering the C0 2 level
To calculate the disturbance present:
1. Loo'k at the pH to decide if acidosis or alkalosis
,, Z. Look at the C0 2 and bicarbonate to see which one has caused this primary defect
3. Look at the other agent (C0 2 or bicarbonate) to confirm that it is trying to compensate (if not, a mixed picture
'exists)

VENTILATION
Ambient oxygen (room air) or oxygen via head box/in incubator may be sufficient.
Continuous positive airway pressure (CPAP)
Continuous flow of oxygen via nasal cannulae, face mask, or endotracheal tube. This keeps the terminal bronchials
open in respiration and prevents them from collapsing.

461
Intermittent positive pressure ventilation (IPPV)
There are different types of IPPV:
Continuous mandatory ventilation (CMV) Full ventilation
Intermittent mandatory ventilation (IMV) Only occasional breaths given by the ventilator
Used to wean a baby who is making some respiratory effort off the
ventilator
Patient triggered ventilation (PTV) Ventilator assists breath after triggered by baby
Used to wean babies off the ventilator
Paralysis and sedation may be required for ventilation if a baby is struggling and 'fighting' the ventilator.

Ventilators
Ventilators are pressure and time cycled. Adjustments may be made to:
Fi02 As low as able to avoid retinopathy of prematurity
Rate A fast rate will reduce C0 2
Pressure PIP Peak inspiratory pressure
PEEP Positive end expiratory pressure. Used while ventilating, acts as CPAP does
High pressures needed for stiff lungs (low compliance) but risk of pneumothorax
Time Inspiratory and expiratory times and their relative ratio may be altered

High frequency oscillatory ventilation (HFOV)

Very high frequency rate (10 Hz or 600/min) ventilation via ETT. Useful in infants with severe lung disease, e.g.
meconium aspiration syndrome.

Extracorporeal membrane oxygenation (ECMO)

Used only if other ventilatory methods fail in severe cases, and particularly useful for meconium aspiration syndrome
in which the lungs are very stiff, and for ventilation perfusion (V:Q) mismatch. The extracorporeal circuit oxygenates
the blood outside of the body. It can only be used on infants > 2.5 kg, and is only available in a few UK centres.
Complications and contraindications include intracranial haemorrhage (heparinization is necessary for ECMO).

Nitric oxide
A specific vasodilator acting particularly on the pulmonary artery smooth muscle. Produced by vascular endothelium
and macrophages. It also acts as a vasodilator via increasing cGMP levels. Therefore used in persistent pulmonary
hypertension of the newborn (PPHN) to decrease pulmonary hypertension (see p. 470).
Side-effects Methaemoglobinaemia
Platelet function affected

CIRCULATORY SUPPORT
Intravenous fluids given as 10% dextrose with added electrolytes (sodium 2-3 mmolfkg/day, potassium 2 mmoljkg/
day and calcium 1 mmolfkg/day). The daily amount of fluid (mlfkg/day) increases over the first few days of life, and
then stabilizes. Inotropes, e.g. dopamine and dobutamine, given if needed (if the mean arterial pressure is low). TPN
can be given from day 1 if a long stay is anticipated.

462
FEEDING
Enteral feeds Breast or formula milk.
Given by breast or bottle (usually able if> 34 weeks' gestation) or bolus nasogastric feeds if
unable to feed
NB: Special formulae exist for premature infants who require a very high calorie intake
Total parenteral Used if enteral feeds are not tolerated or contraindicated, e.g. extreme prematurity, NEC)
nutrition (TPN) Given via umbilical venous catheter (UVC) or a peripheral long line
High calorie feed individually prepared to provide each infant's nutritional requirements (fat,
carbohydrate, protein, elements, iron, calcium and trace metals)
Complications: Sepsis
TPN cholestasis
Microemboli

Supplements
Children's vitamin drops Started when enteral feeds commenced until age 5 years
Iron Commence oral supplements (if bodyweight < 2.5 kg or< 36 weeks' gestation) when 4
weeks old until on solid feeds

INTRAUTERINE GROWTH RETARDATION (IUGR)

Growth may be restricted in utero for many reasons. This is sometimes defined as growth < 3'd centile and sometimes
< 10th centile.
The term IUGR (also known as small for gestational age [SGA]) should be reserved for those infants who have not
reached their genetic potential.
These babies may be:
Asymmetrical Weight on lower centile than head circumference due to relative sparing of the brain
Due to pl_acental failure late in pregnancy
Have rapid weight gain after birth
Causes: Pre-eclampsia
Multiple gestation
Maternal cardiac or renal disease
Uterine malformation
Symmetrical Head and body equally small
Results from prolonged intrauterine growth failure
Fetus is usually normal, though may be abnormal
Postnatal growth is also poor
Causes: Smoking, malnutrition, chronic illness
Chromosomal disorder
Congenital infection

Associated problems
• Hypoglycaemia (small fat and glycogen stores). Need frequent feeds
• Hypothermia (large surface area:weight ratio and not much fat insulalion)
• Infection
• Hypoxic-ischaemic encephalopathy (HIE)
• Hypocalcaemia
• Polycythaemia

463
LARGE FOR GESTATIONAL AGE {LGA)
Large for gestational age (LGA) is newborn weight> got" percentile.
Causes
• Diabetic mother
• Familial, i.e. large parents
• Beckwith-Wiedemann syndrome

Associated problems
• Hypoglycaemia (hyperinsulinism)
• Birth trauma (difficult delivery)
• Hypoxic ischaemic encephalopathy (difficult delivery)
• Polycythaemia

PREMATURITY
Prematurity is birth at < 37 weeks' gestation. Many premature infants are small but appropriate for gestational age
(AGA) due to prematurity.
Survival rates have increased dramatically over recent years but a significant proportion of extremely premature infants
will have chronic disability if they survive.

SPECIFIC PROBLE~1S ASSOCIATED WITH PREMATURITY

Temperature Thermal instability. Temperature regulations mechanisms not fully developed and low body fat
Lungs Apnoeas, respiratory distress syndrome (RDS), pneumothorax, pulmonary haemorrhage, broncho-
pulmonary dysplasia (BPD)
Cardiac Patent ductus arteriosus (PDA) (see p. 93), persistent pulmonary hypertension of the newborn
(PPHN)
CNS Apnoeas, hypoxic-ischaemic encephalopathy (HIE), intracranial haemorrhage, lack of primitive
reflexes, e.g. sucking
Gastrointestinal Intolerance of enteral feeds, gastro-oesophageal reflux, necrotizing enterocolitis (NEC)
Liver Jaundice
Kidneys Inability to concentrate urine, inability to excrete acid load
Immunity Immature immune system, with susceptibility to infections
Eyes Retinopathy of prematurity (seep. 384)
Metabolic Hypoglycaemia, electrolyte imbalances, e.g. hypocalcaemia, osteopenia of prematurity
Haematological Iron-deficiency anaemia, physiological anaemia
Surgical Inguinal and umbilical hernia

RESPIRATORY DISORDERS
Features of respiratory distress in a neonate
• Tachypnoea (RR > 60/min)
• Expiratory grunting
• Nasal flaring
• Recession (intercostals, subcostal and suprasternal)
• Cyanosis

464
Investigations of respiratory distress
• Oxygen saturation (pulse oximetry and blood gas)
• Chest transillumination with cold light (? pneumothorax)
• Pass NG tube (if choana[ or oesophageal atresia suspected)
• CXR
• Nitrogen washout test (to differentiate cause of cyanosis; see p. 97)
• Infection screen (blood, CSF, gastric aspirate for bacterial and viral culture; umbilical, ear and throat swabs). Also
check maternal high vaginal swab result
• Other bloods: FBC, haematocrit and serology

RESPIRATORY DISTRESS SYNDROME

Respiratory distress syndrome (RDS) is a specific disease due to insufficient surfactant. In RDS the neonates lungs are
non-compliant, or 'stiff'. A low alveolar compliance leads to hypoxia and acidosis and, if severe, causes PPHN

Surfactant
• Lowers surface tension and increases compliance in alveoli
• Is a phospholipid composed of lecithin and sphingomyelin
• Produced by type II pneumocytes
• Lecithin:sphingomyelin (LS) ratio is altered in RDS (less lecithin, LS ratio low, < 2)

Predisposing factors Prematurity, hypoxia, acidosis, shock, asphyxia

Diabetic mother, APH, second twin, male
Protective factors Prolonged intrauterine stress, e.g. IUGR), maternal drug addiction, maternal steroids

Clinical features
• Respiratory distress from 6 h of age
• Worsens over 2-3 days then improves over 1-2 weeks .
• CXR:; fine reticular 'ground glass' appearance, air bronchograms
'l
Management
Surfactant replacement Administered via the ETI
There are different formulations and more than one dose may be necessary
Ventilatory support Oxygen, CPAP or positive pressure ventilation as needed
Antibiotics If infection suspected
Minimal handling
Complications Pneumothorax, intraventricular haemorrhage, bronchopulmonary dysplasia (late)
Prevention If early delivery is planned, maternal oral dexamethasone is commenced 48 h prior to delivery

465
PNEUMOTHORAX

Causes
• Idiopathic (1% term infants)
• Secondary to ventilation (especially if 'stiff' lungs in RDS or meconium aspiration)

Clinical features
• Mostly asymptomatic
• If large, causes respiratory distress (see above)
• NB: Rapid deterioration suggests a tension pneumothorax

Diagnosis
• Chest transillumination with fibre-optic 'cold' light (this does not damage the infant's skin)
• CXR

Management
Insertion of chest drain (anterior axillary line, 41h intercostal space).

PULMONARY HAEMORRHAGE
Haemorrhagic pulmonary oedema due to elevated pulmonary capillary pressure from acute left ventricular failure or
lung injury.
Associations Prematurity, RDS, asphyxia
Pneumonia, acute cardiac failure (PDA), coagulopathies

Clinical features
• Frothy pink sputum (in ET tube if ventilated)
• Acutely unwell neonate
• Low haematocrit

Management
• Ventilation
• Antibiotics
• Correct any coagulation defect

BRONCHOPUlfV10NARY DYSPLASIA (BPD}

Bronchopulmonary dysplasia is a condition of chronic lung damage with persistent X-ray changes. It is defined as
either an oxygen requirement on day 28 of life or at 36 weeks' gestation.

466
It occurs after:
• Severe RDS
• Other neonatal lung disease

Clinical features
• Chest hyperinflation, intercostals and subcostal recession
• Crepitations on auscultation
• Oxygen requirement

CXR
• 'Honeycomb lung' (cystic pulmonary infiltrates in reticular pattern)
• Areas of emphysema and collapse, and fibrosis and thickening of the pulmonary arterioles

Management
• Steroids and diuretics if ventilator dependent. Steroids may have an adverse effect on long-term neurodevelop-
mental outcome
• Bronchodilators if wheezy
• May need long-term home oxygen

WilSON-MIKITY SYNDROME
Clinical features
Respiratory distress, hypoxia and apnoea developing slowly during the first month in premature infants who have no
history of severe respiratory disease.

CXR
Streaky infiltrates and cysts.

Management
• Respiratory support, long-term oxygen may be required
• Resolves over weeks- months usually, with susceptibility to chest infections for the first few years of life

APNOEA
Apnoea is cessation of breathing for> 20 s. It may be accompanied by bradycardia and cyanosis. It may be due to:
• Central factors (chemoreceptor or respiratory centre failure)
• Airway obstruction
• Reflex protective mechanisms
Premature neonates have poorly developed central chemoreceptors and respiratory centres and therefore frequently
have apnoeas.

467
Causes

Investigations
These depend on the clinical condition. Gastro-oesophageal reflux is important to exclude. Investigations may also
include screen for sepsis, CXR, arterial blood gas, cranial USS, barium swallow and neurological investigations.

Management
• Treat the underlying cause
• Acute episode: stimulation, manual ventilation if necessary, apnoea monitoring
• Recurrent episodes: CPAP, methylxanthines, e.g. caffeine, theophylline
Intubation and ventilation if severe
Resuscitation skills for the parents
Home apnoea monitor if parents wish or hypoventilation syndrome

TRANSIENT TACHYPNOEA OF THE NEWBORN (TTN)

This is due to excessive retained fetal lung fluid and is a self-limiting condition. Incidence 1-2% of newborns.
Predisposing fadors Elective caesarean section (as no stress and fluid not squeezed out of lungs during delivery)
Heavy maternal analgesia, infant of diabetic mother

Clinical features
Respiratory distress from birth resolving over the first 24 h.

CXR
• Generalized streakiness
• Fluid in the fissures
• Pleural effusions

Treatment
• Oxygen (ambient, CPAP if necessary, rarely ventilation needed)
• Antibiotics until pneumonia and sepsis excluded

468
 PNEUMONIA
Causes
Common Group B ~- haemolytic strep. Gram-negative bacteria (f. coli, klebsiella, pseudomonas, serratia), Staph.
saprophyticus aspirated blood/meconium and obstetric cream
Rarer Listeria, chlamydia, mycoplasma, CMV, coxsackie, RSV, congenital surfactant deficiencies
Clinical features
Non-specific, respiratory distress features.

CXR
Patchy opacification.

Treatment
Antibiotics, physiotherapy and respiratory support.

MECONIUM ASPIRATION SYNDROME

Meconium is present in 10% of deliveries. If resuscitation is required, then the airway must be aspirated prior to
ventilation.
Inhaled meconium can produce:
• Airway plugging with distal atelectasis, air leaks and secondary pneumonia
• Chemical pneumonitis (it is toxic to the lung tissue)
• Hypoxia, respiratory and metabolic acidosis, and PPHN if severe

Clinical features
• Respiratory distress from birth, worsening, hyperinflated chest (due to air trapping)
• Severe acidosis
• Signs of cerebral irritation

CXR
Hyperinflation and diffuse patchy opacification.

Management
1
' • Respiratory support (high pressures or high-frequency oscillatory ventilation may be needed)
• A9tibiotics and physiotherapy
• Management of PPHN

CARDIAC DISORDERS
For detail on congenital heart disease, see Chapter 13. General cardiac conditions are discussed below.
Causes of cyanosis
• Severe lung disease
• Cyanotic congenital heart disease
• PPHN
• Methaemoglobinaemia

469
 • Others: Sepsis, airway problem
Neurological, e.g. asphyxia, seizures, neuromuscular
See p. 93 .

PERSISTENT PUU40NARY HYPERTENSION OF THE NEWBORN (PPI-lN)

This is also known as persistent fetal circulation. It is the most difficult condition to distinguish clinically from
cyanotic congenital heart disease.
In PPHN there is a failure of the pulmonary vascular resistance to fall after birth, and blood is therefore shunted away
from the lungs via the ductus arteriosus (right to left) and the foramen ovale. This results in central cyanosis.
Predisposing factors Hypoxia-ischaemia, acidosis
Metabolic disturbance
Severe lung disease, e.g. severe RDS, meconium aspiration syndrome
Hypothermia/acidosis

Clinical features and diagnosis

• Central cyanosis
• Loud P2 heart sound
• Arterial blood gases: P0 2 low, PC0 2 relatively normal
• Little improvement in saturations with 100% 02
• Pre-ductal blood P0 2 is> 5 mmHg higher than postductal P0 2 (demonstrate by transcutaneous P0 2 measurements
on right chest and lower abdomen)
• CXR: normal heart and well-expanded oligaemic lung fields
• Echocardiogram: structurally normal heart, high pulmonary artery pressures

Management
It is managed with PPV or HFOV and inhaled nitric oxide (a vasodilator), prostacyclin IV or tolazoline IV. ECMO may
be necessary if ventilation fails.

PERSISTENT DUCTUS ARTERIOSUS (POA)

Commonly seen in premature infants. For features and treatment, see p. 93.

CARDIAC FAILURE
Common complication of PDA. Seen in certain congenital heart diseases. For features and treatment, see p. 90.

DUCT-DEPENDENT CIRCULATIONS
Emergency treatment includes prostaglandin E2 (seep. 104).

NEUROLOGICAL DISORDERS

HYPOXIA-ISUlAH~IA

Hypoxia is insufficient arterial oxygen concentration. Ischaemia is insufficient blood flow to the cells.
Fetal hypoxia-ischaemia can occur as an intrauterine or intrapartum event (a minority of cases are due to birth
asphyxia). After birlh, hypoxia may result from several causes including severe shock, failure to breath adequately and
severe anaemia.

470
Intrauterine hypoxia May be acute, presenting with fetal distress, or chronic presen~ng as IUGR
Intrapartum hypoxia May be acute or acute on chronic (an elevated nucleated red cell count indicates that
there has been an insult for long enough for the marrow to respond)

Causes
Maternal Pre-eclampsia, eclampsia, acute hypotensive episode
Placental Placental abruption, cord prolapse, chronic insufficiency (many causes, e.g. pre-eclampsia)
Fetal Prematurity, postmaturity, obstructed labour
After birth, hypoxia may result from several causes including severe anaemia, severe shock, failure to breathe adequately
or cyanotic cardiac disease.

Effects of hypoxia-ischaemia
Hypoxia-ischaemia can result in damage to all organs, but initially there is preferential sparing of the brain at the
expense of other organs. The effects of hypoxia-ischaemia in the different organs:
Kidneys Acute tubular necrosis
Gut NEC
CNS Hypoxic-ischaemic encephalopathy
Heart Ischaemic changes, heart failure
Lungs RDS, pulmonary haemorrhage, PPHN
Metabolic effects Metabolic acidosis, hypoglycaemia, hyponatraemia
Other Adrenal haemorrhage, DIC

Hypoxic-ischaemic encephalopathy (HIE)

This is a disturbance of neurological behaviour due to ischaemic damage to the brain. The areas affected are the
'watershed zones' between the major arteries (those most susceptible to hypoperfusion). The condition can result in
cortical and subcortical necrosis and cysts, and periventricular leukomalacia (PVL) . (In premature infants germi-
nal matrix haemorrhages occur, with intraventricular haemorrhage.)
PVL is ,cystic changes in the white matter, with later reduction in myelin around the ventricles. Diagnosis is on USS,
CT and MRI scan. A high risk of cerebral palsy follows.
HIE is classified as mild, moderate or severe. The condition develops over a period of a few days. The infants are floppy
after birth, with seizures and irregular breathing, and may become hypertonic over a period of days. Mild disease
generally resolves over a few days, but in severe HIE there is a 50% mortality and an 80% risk of cerebral palsy.

471
Clinical severity

Management
• Initial resuscitation
• General support as necessary, e.g. metabolic balance, glucose homeostasis renal support
• Management of brain oedema (fluid restriction, ventilatory control)
• Seizure management
• Management of complications

PERIVENTRICULAR HAEI\'10RRHAGE (PVH)

The term periventricular haemorrhage encompasses several types of intracranial haemorrhage. Neonates develop PVH
as a result of an unstable cerebral circulation, most commonly into the germinal matrix at the head of the caudate
nucleus.

Risk factors
• Prematurity
• Low birth weight
• Hypercapnoea
• RDS
• IPPV
• Metabolic acidosis
• Coagulation disorder

Clinical features
• Asymptomatic
• Subtle neurological signs, e.g. roving eye movements
• Slow deterioration - apnoeas, bradycardias, metabolic acidosis, seizures, anaemia
• Massive collapse - bulging fontanelle, hypotension

Diagnosis and grading

Made on cranial USS.

472
Complications
• Hydrocephalus
• Porencep haly
• Cerebra l palsy

Management
Supportive shunt for hydrocephalus.

NEONATAL CONVULSIONS AND JITTERINESS

Neonates fairly commonly show signs of 'jitteriness' with rapid fine shaking of the limbs, which must be differentiated
from seizures (which have different causes and management).

Causes

Clinical features ·
I

NB: Neonatal seizures are not always obvious and may manifest, for example, as apnoea.

473
Investigations
Infection screen Blood, CSF and urine microscopy and culture, and serology
(NB: CSF is persistently blood-stained throughout the CSF in IVH)
Electrolyte disturbance U&E, including Ca and Mg
Metabolic screen Glucose, metabolic work-up if indicated
USS brain
EEG

Treatment
1. Treat the cause, e.g. IV glucose, IV calcium, IV magnesium, IV antibiotics, IV pyridoxine
2. Give anticonvulsants for seizures if necessary. Anticonvulsants used in neonatal seizures include:
Phenobarbitone
Phenytoin
Paraldehyde
Clonazepam and midazolam

DRUG WITHDRAWAL {MATERNAL DRUG ABUSE)

Clinical features
Wakefulness
Irritability
Temperature instability, tachypnoea
Hyperactivity, high-pitched cry, hypertonia, hyperreflexia
Diarrhoea, disorganized suck
Respiratory distress, rhinorrhoea
Apnoea, autonomic dysfunction
Weight loss, failure to thrive
Alkalosis
Lacrimation
Sneezing

Management
This includes close observation for the above signs. Naloxone contraindicated at delivery.
Conservative measures Encourage mothers to breast feed, decrease sensory stimuli, swaddling
Drug treatment These include opiates, e.g. morphine, and sedatives, e.g. diazepam, chlorpromazine.
These are weaned over a few weeks
Consider immunization against Hep B and BCG. Screen mother for other blood-borne viruses (Hep C, HIV).
NB: Increased incidence of SIDS.

GASTROINTESTINAL DISORDERS

NECROTIZING ENTEROCOLITIS (NEC)

Necrotizing enterocolitis is a disease of bowel wall inflammation, ulceration and perforation due to many causes. It
may be secondary to an ischaemic or hypoxic-insult to the gut. There is mucosal damage leading to bacterial invasion
and gastrointestinal gangrene and perforation.

474
Risk factors
• Prematurity
• Hypoxia
• Sepsis
• Hypovolaemia
• Hyperosmolar feeds
• Venous and umbilical catheters
• Exchange transfusion
• Polycythaemia

Clinical features
General Apnoeas, lethargy, vomiting, temperature instability, acidosis and shock
Abdominal Distended> shiny abdomen, bile aspirates, rectal fresh blood

Complications
Short-term Perforation, obstruction, gangrenous bowel, intrahepatic cholestasis, sepsis, DIC
Long-term Stricture, short bowel syndrome (due to resection of diseased bowel), lactose intolerance

Diagnosis
AXR Fixed loops of bowel, pneumostasis intestinalis (intramural gas), portal vein gas, pneumoperitoneum, bubbles
in portal vein on ultrasound
FBC Neutrophils (i or 1), platelets (1), DIC

Management
• Manage shock, acidosis, electrolyte and clotting disturbance and anaemia, and ventilate if necessary
• SydClmic :mtibiotics
• Gastrointestinal decompression (NG tube with aspiration)
• Only parenteral nutrition until gut recovered
• Surgical intervention (perforation, clinical picture not improving with medical management, and secondary
strictures) if surgical complication occurs

Prognosis
There is a 10% mortality, and higher if perforation occurs.

'
INTESTIN,AL OBSTRUCTION
Causes
'
• Atresia: Oesophageal
Duodenal
Jejunal
Colonic
Imperforate anus
• Congenital hypertrophic pyloric stenosis
• Hirschsprung disease
• Volvulus neonatorum (malrotation)
• Meconium plug, e.g. cystic fibrosis
• Hernial obstruction (internal or external)
• Duplication cyst

475
 • NEC (stricture, ileus)
• Annular pancreas

Clinical features
• Polyhydramnios
• Bile-stained vomiting
• Abdominal distension
• Visible peristalsis
• Delayed or absent passage of meconium
• Features of dehydration

Investigations
AXR and contrast studies, abdominal USS (and metabolic alkalosis in pyloric stenosis).

Management
Dependent on the condition (often surgical).

MECONIUM ILEUS
Intestinal obstruction of terminal ileum due to thick, inspissated meconium. There is failure to pass meconium within
48 h of birth and clinical features of obstruction; may perforate in utero. 10% of cases of cystic fibrosis present with
meconium ileus.

Diagnosis
AXR Foamy pattern seen around plug abdominal calcification with in utero perforation
Gastrograffin enema Microcolon
Immune-readive trypsin NB: This falls after surgery
Sweat test At 2-3 months to confirm diagnosis
Genetics Genotype for cystic fibrosis

Management
1. Conservative
2. Gastrograffin enema or surgical decompression
NB: Meconium plug syndrome is a lower bowel obstruction or delayed passage of meconium due to a plug of
meconium around 10 em long. Seen in premature infants, Hirschsprung disease and cystic fibrosis.

OSTEOPENIA OF PREMATURITY
This is a generalized demineralization (osteopenia) seen in premature and low birthweight infants compared to a fetus
of the same gestation. It is classically seen in immature infants who are solely breast fed.

Causes
Mineral deficiency, particularly phosphate due to placental insufficiency, and/or inadequate phosphate levels in breast
milk, or low phosphate feeds.

Risk factors
• VLBW
• Severe IUGR and prematurity

476
, ...
 • Inadequate milk intake or insufficient phosphate in feeds
• Chronic lung disease
• Drugs - steroids, long term diuretics

Clinical features
It is asymptomatic, diagnosed on long bone X-ray. Clinical rickets is rare, but rib fractures are not uncommon in babies
with chronic lung disease.
Calcium normal, phosphate t, PTH i, alkaline phosphatase i.
Treatment
• Low birthweight formula (contain increased phosphate)
• Supplement breast milk with phosphate

HAEMATOLOGICAL DISORDERS

HYDROPS FETALIS
This is severe oedema, ascites and pleural effusions at birth.

Causes
Immune Severe intrauterine anaemia, e.g. severe haemolytic disease of the newborn (rhesus, other blood
group incompatibilities)
Non-immune Severe anaemia: Chronic twin- twin transfusion
Fetomaternal haemorrhage
HB Barts
Congenital injection, e.g. parvovirus B19
Cardiac failure, e.g. uncontrolled fetal SVT, severe CHD, premature closure of ductus arteriosus
and foramen ovale
Hypoproteinaemia, e.g. congenital nephropathy Finnish, maternal pre-eclampsia
Congenital malformations, e.g. anomalies of lymphatics - lymphagiectasia (Turner syndrome),
obstructive uropathy, pulmonary adenoma, fetal or placental angioma

Investigations of cause
Establish cause is not haemolysis (Coombs' test).
If anaemic; Look for evidence of feto-maternal haemorrhage (Kleihauer test)
Serum for parvovirus serology
If not anaemic Chromosomes, metabolic studies and cardiac USS
The prognosis is significantly better if you can find a cause that can be treated.

Management
1. Resuscitation- transfusions, abdominal and chest drainage as necessary, ventilatory support
2. Treat Lhe cause

HYPOGLYCAEMIA
Normal newbor'ns can have intermittent low blood ~Jlucose levels but hypoglycaemia is frequently seen in small and
premalure infants, and also in unwell 11eonates. I here is no accepted universal definition, however, blood glucose
levels< 2.6 mmoljl at any age are hypoglycaemic. Persistent neonatal hypoglycaemia is unusual (see below) .

477
TRANSIENT NEONATAL HYPOGLYCAEMIA

Causes
Substrate defidency (ketotic) IUGR, prematurity, asphyxia, hypothermia, sepsis, malformation
Hyperinsulinism (non-ketotic) Diabetic mother, gestational diabetes, rhesus isoimmunization

Clinical features
• Asymptomatic
• Apnoeas, jitteriness, seizures, lethargy, hypotonia

Investigations
Check BMStix (immediate idea) and blood glucose (for accuracy).
If persistent and recurrent, screen for ketones, hormone levels and metabolic disorders.

Management
If able to feed Oral glucose (breast milk or formula), then hourly feeds with monitoring of blood glucose levels
If unable to feed IV 10% glucose 5 mljkg bolus, then 10% glucose infusion 60-90 mljkg/day, with frequent blood
or reduced glucose monitoring
consdousness If the glucose remains low, may need 15-20% glucose infusion

PERSISTENT NEONATAL HYPOGLYCAEMIA (RARE)

Causes
Hyperinsulinism Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI, nesidioblastosis)
Beckwith-Wiedemann syndrome
Insulinoma
Metabolic disorder Carbohydrate metabolism disorder, e.g. galactosaemia, hereditary fructose intolerance
Organic acidaemia, e.g. maple syrup urine disease
Persistent hypoglycaemia is managed according to cause.

FURTHER READING
Levene M, Tudehope D, Sinha SK Essentials of Neonatal Medicine, 4 th edn, Oxford: Blackwell Sciences, 2008
MacDonald MG, Mullet MD, Seshia MMK Avery's Neonatology. Pathophysiology and Management of the Newborn, 6th edn.
Baltimore: Lippincott, Williams & Wilkins, 2005
Rennie JM Roberton's Textbook of Neonatology, 41h edn. Edinburgh : Churchill Livingstone, 2005

478
• Neonatal surgical conditions • Orthopaedic conditions
• Gastrointestinal conditions • Consent
• Genitourinary conditions

NEONATAL SURGICAL CONDITIONS

CONGENITAL ATRESIAS
Choanal atresia
This is a lailure of the bucconasal membrane to cannulate during ·development. As babies are obligate nasal breathers
unless they are crying, it presents as breathing difficulties from birth. It may be unilateral or bilateral.

Diagnosis
Inability to pass a nasogastric tube in the affected nostril(s).

Management
'
Provide an airway (pharyngeal or ETI) until surgery performed (urgently) .

Oesophageal atresia and trachea-oesophageal fistula

'
Overall incidence is 1:3000 live births.
A condition of oesophageal atresia usually associated with trachea-oesophageal fistula. There are five different
variations.
Associations VACTERL =Vertebral, Anal, Cardiac, Trachea-oEsophageal, Renal- and Limb abnormalities
VATER = Vertebral, Anal, Trachea-oEsophageal, Renal or Radial anomalies

479
 Proximal oesophageal atresia, Pure oesophageal atresia H-type trachea-oesophageal
distal trachea-oesophageal fistula
fistula

Oesophageal atresia, Oesophageal atresia,

proximal trachea-oesophageal double trachea-oesophageal
fistula fistula

Figure 19.1 Types of oesophageal artresia and trachea-oesophageal atresia

Clinical features
Presentation varies depending on the type:
• Maternal polyhydramnios (60%)
• Recurrent aspiration pneumonia
• Coughing episodes with cyanosis
• Abdominal distension (air passing into gut from lungs)
• Choking with feeds intermittently (H-type fistula) (these are notoriously difficult to diagnose)
480
Diagnosis
1. Inability to pass a radio-opaque catheter into the stomach (except for H-type)
z. AXR- no gas in stomach (types A and B)
3. CXR - areas of collapse
4. Non-irritant radio-opaque contrast study (to define the lesion)
5. Cine contrast swallow with prone oesophagogram (for H-type fistula)

Management
1. Nurse head up and prone
2. Surgical correction: division of fistula and anastomosis of oesophageal segments. If large defect, temporary
oesophagostomy and gastrostomy may be made, with definitive surgery later

Congenital intestinal atresias

These may occur anywhere along the gastrointestinal tract. Features are those of obstruction, which vary according
to the level of obstruction.

Features of obstruction
• Polyhydramnios
• Bile-stained vomiting
• Abdominal distension
• Visible peristalsis
• Delayed or absent passage of meconium
• Features of dehydration
Diagnosis is made on imaging studies, in particular:
Duodenal atresia 'Double bubble' of air seen beneath diaphragm on plain AXR
Imperforate anus Air bubble seen on AXR after first 12 h with baby held inverted
Duodenal atresia is associated with Down syndrome.
Management is with initial resuscitation and then surgical-repair.

Imperforate anus
Incidence 1:2500.
• Low and high forms exist± fistula to urethra or vagina
• Air bubble is seen on AXR after first 12 h of life with baby inverted
I

, • Management is often with an initial colostomy with further repair later

1
• Rectal inertia is a long-term problem.

GASTROSCHISIS AND EXOMPHALOS

Exomphalos
Incidence 1:5000.
An evisceration of gastrointestinal contents through the umbilicus covered by peritoneum.
Associations (common) Trisomy 13, trisomy 18
. Beckwith-Wiedemann syndrome
Renal malformations including bladder exstrophy, Wilms tumour (40% incidence)
Congenital heart disease

481
Gastroschisis
Incidence 1:30 000.
This is evisceration of gastrointestinal contents through a right paraumbilical defect. There is no peritoneal covering
and hypoalbuminaemia occurs.
Associations Bowel atresias adhesions
Strictures
Stenosis

Complications Short bowel syndrome

Faltering growth

Management
Pre-operative Abdominal contents wrapped in moist antibiotic-soaked gauze
Gastric decompression, resuscitation with IV albumin, antibiotics, TPN
Operative Small lesions (< 5 em) are surgically treated with primary closure. Larger defects treated with a staged
repair, using a non-reactive silicon sheeting to cover bowel contents in gastroschisis

Figure 19.2 (a) Exomphalos (an umbilical defect) and (b) gastroschisis (a para-umbilical defect)

CONGENITAL DIAPHRAGMATIC HERNIA

This sporadic condition is seen in 1:4000 live births. They may be:
• Posterolateral (Bochdalek) type: common type, 80% on the left side
• Anteromedial (Morgagni) type

Clinical features
• Severe respiratory distress at birth
• Cyanosis .
• Scaphoid abdomen (as intestine in chest)

482
, ...
 • Apex displaced to the right
• Complications of pulmonary hypoplasia, pulmonary hypertension and PPHN may be present (due to lack of space
for fetal lung development)

Diagnosis
CXR and AXR Loops of bowel in the thorax

Management
Resusdtation NG tube and aspiration
Intubation and ventilation (IPPV), and circulatory support
PPHN management
Surgical correction When fully resuscitated

CONGENITAL LOBAR EMPHYSEMA

Uncommon condition due to a cartilaginous defect of a lobar bronchus. Upper lobe most commonly affected.

Clinical features
• Insidious onset respiratory distress in first few weeks
• Medi9stinum displaced away from lesion
• Hyper-resonant with decreased breath sounds over affected lobe

Management
Lobectomy.

GASTROINTESTINAL CONDITIONS

THE ACUTE ABDOMEN

An acute abdomen is a clinical diagnosis indicating serious intra-abdominal pathology and requires urgent manage-
ment through r.esuscitation and usually surgical intervention.
;

Peritonitis is an inflammation or irritation of the peritoneum resulting in clinical signs either localized to a specific
area or generalized throughout the abdomen .

Clinical'features
General Unwell, fever, rigors (sometimes)
Abdominal Abdominal pain - location, duration, severity, intermittent or constant?
Other' Anorexia, nausea, vomiting, dysuria, haematuria, altered bowel habit (diarrhoea, blood in stool,
constipation)

Examination
Fever
Vital signs Pulse (tachycardia), BP (hypotension?), RR (tachypnoea)
Peripheral shutdown with capillary refill time < 2 s

483
Abdominal signs Tenderness (location and severity)
Guarding
Rebound tenderness
Rigid abdomen (unable to
'blow out' abdomen to meet Features of peritonitis (inflammation of the peritoneum)
examiner's hand when held
a few em above)
Abdominal mass
Rectal examination to be done by experienced paediatric surgeon or physician (tenderness,
blood, mucus)
General signs Jaundice (gallstones)
Anaemia (bleed)

Investigations
These will depend on the probable cause, but important investigations are:
Un"ne Urinalysis and microscopy if indicated, pregnancy test
Bloods FBC U&E and creatinine, amylase, glucose, sickle cell status if indicated. Arterial blood gas, LFT.
Bone profile (Ca and POJ
CXR Erect (chest infection - usually lower lobe, gas under the diaphragm)
AXR Supine (dilated loops of bowel)
USS abdomen (Pyloric steno-sis, intussusception, ovarian pathology)

Surgical causes of an acute abdomen

484
Medical causes mimicking an acute abdomen

INTESTINAL OBSTRUCTION

Clinical features
• Features of an acute abdomen
• No passage of faeces or flatus per rectum
• Vomiting: Non-bile stained (high obstruction above bile duct entry)
Bile stained (obstruction below bile duct entry)
Faecal (very low obstruction large bowel)

Causes

ACUTE APPENDICITIS
Peak age 10- 20 years. Rare < 5 years.

Typical clinical features

• Abdominal pain commencing para-umbilically and then moving to the right iliac fossa (McBurney's point). Worse
on movement, gradually worsening. Guarding indicates peritonitis
• Nausea, vomiting and anorexia
• Low-grade fever, flushed, tachycardic, fetor
• Perforation is common in younger children
• In young children the pain is poorly localized and features of peritonism may be absent
• A retro-caecal and pelvic appendix may present with atypical signs

485
Investigations
• Diagnosis is clinical and difficult as classical signs are often not present. All the above causes of an acute abdomen
(both medical and surgical) are in the differential diagnosis
• FBC (mild neutrophilia may be present)
• Urinalysis (to exclude UTI). NB: Pyuria may be seen in appendicitis, and so misdiagnosis of UTI should be
avoided

Complications
Appendix mass, abscess or perforation.

Management
Urgent appendicectomy.

MESENTERIC ADENITIS
This inflammation of the mesenteric lymph nodes can mimic appendicitis with non-localized abdominal pain and is
thought to be due to a viral infection, e.g. adenovirus or bacterial infection, e.g. Yersinia enterocolitica.

CONGENITAL HYPERTROPHIC PYLORIC STENOSIS

This is due to hypertrophy of the muscle layer of the pylorus of unknown cause.
Associations Males > females
Caucasian
Positive family history (especially maternal)
Syndromes: trisomy 18, Turner syndrome, Cornelia de Lange syndrome

Clinical features
• Usually presents at 4-6 weeks in first-born males
• Persistent vomiting (may be projectile, not bile-stained)
• Thin but hungry infant
• Abdominal examination: Visible peristalsis
Olive-shaped tumour in the right upper abdomen

Investigations
Diagnosis is made on a test feed or USS, both of which are operator-(lependent.
Test feed Palpate the abdomen while infant feeding milk for olive-shaped tumour and observe for peristalsis
across upper abdomen from left to right± vomiting
Abdominal USS This may outline the tumour as a 'doughnut' ring (muscle thickness > 4 mm, pyloric length
> 14 mm)

Blood electrolytes and pH must be done to look for:

• Signs of dehydration
• Jaundice (5-10%)
• Hypochloraemic hypokalaemic metabolic alkalosis (due to vomiting)
• NB: Serum Kis usually maintained but total body Kis depleted

486
Management
1. Resuscitation Initial resuscitation with IV fluids is essential
0.45% dextrose saline with 40 mmol KCljL is given over the first 12 h until the bicarbo-
nate is corrected and then standard fluid replacement
Nasogastric tube with suction
Regular U&E and ABG measurements
2. Surgery When rehydrated and the alkalosis is corrected, a pyloromyotomy (Ramstedt's
procedure) is performed

ACHALASIA
This is a motility disorder of the oesophagus with lack of normal peristalsis in the oesophagus and a relative gastro-
oesophageal junction obstruction. It generally pres~nts in adolescence or adulthood. The underlying pathology is of a
decrease in the number of ganglion cells in the oesophagus, with an increase in inflammatory cells.
Associations Chagas disease
Adrenal insufficiency

Investigations
Upn"ght CXR Air-fluid level in dilated oesophagus and/or absence of gastric air bubble
Barium swallow Abnormal motility and dilatation of oesophagus
Oesophageal manometry Abnormal

Management
Medical Calcium-channel blockers, e.g. nifedipine }
Temporary measures only
Intrasphincteral botulinum toxin injection
Surgical Heller myotomy (division of the muscle fibres at gastro-oesophageal junction)
Balloon dilatation (less effective than myotomy in childhood)
NB: Surgical management often results in gastro-oesophageal reflux.

MALROTATION
This is due to incomplete rotation of the intestine around the superior mesenteric artery during the third month
of gestation. The most common type involves incomplete rotation with the caecum in the midline. In this case the
duodenum does not pass posteriorly to the superior mesenteric artery. The base of the small bowel is not fixed from
the liganjent of Treitz to the caecum but is anchored on the superior mesenteric artery and the caecum is fixed in the
r;ight upper quadrant by fibrous tissue (Ladd's bands) crossing the second part of the duodenum. Obstruction may occur
due to Ladd's bands crossing the second part of the duodenum or a volvulus occurring around the superior mesenteric
artery.
Associations Diaphragmatic hernia
Gastroschisis and exompholos

Clinical presentation
• Acute neonatal obstruction
• Intermittent childhood obstruction - distension, bilious vomiting, pallor, abdominal mass; bloody stools
• Midgut volvulus
• Protein-losing enteropathy (secondary to bacterial overgrowth)
• Asymptomatic to adolescence (up to 50%)

487
~-.,-
Investigations
Radiological AXR (abnormal gas pattern, signs of obstruction)
Contrast studies (upper gastric series and enema)
Afailure of the third part of the duodenum to cross the midline may be seen

Management
This is surgical, with release of Ladd's bands and fixation of the bowel. NB: If an asymptomatic malrotation is
discovered, it should always be treated surgically to avoid volvulus in the future.

INTUSSUSCEPTION
Intussusception is invagination of a dilated segment of bowel into an adjacent proximal segment. The blood supply
to the intussuscepted bowel is compromised and will become necrotic if not reduced rapidly. Usually occurs proximally
to the ilea-caecal valve.

Intussusceptum
- Intussuscipiens

Figure 19.3 Intussusception

Most common 6-9 months of age. Male > female.

Associations Meckel diverticulum
Henoch-Schonlein purpura
Intestinal polyps
Lymphoma
Cystic fibrosis
Inflamed Peyer's patches

Clinical features
• Episodic abdominal pain with screaming and pallor, and infant draws their knees up. Often well in between
attacks
• Abdominal distension, abdominill tenderness, sausage-shaped abdominal mass
• Blood stained mucus on rectal examination ('red-currant jelly sto_ols') - a late sign
• Vomiting and diarrhoea
• Infant may be very unwell, dehydrated and progressing to shock

488
Investigations
Abdominal USS May reveal the mass if the radiologist is skilled ('target' appearance)
Plain AXR Signs of small bowel obstruction (fluid levels, dilated loops of small bowel)
Air enema May be therapeutic as well as diagnostic

Management
• Initial fluid resuscitation as needed
• Air (or contrast) enema reduction (successful in 75%)
Contraindications to enema: Rectal bleeding
Peritonism
• Surgical reduction ± resection if enema contraindicated or unsuccessful

MECKEL DIVERTICULUM
Meckel diverticulum is an ileal remnant of the vitellointestinal duct, which may contain ectopic gastric mucosa or
pancreatic tissue.
Approximately:
• 2% of people are affected
• 2 inches long
• 2 feet from the ileocaecal valve

Clinical features
• Mostly asymptomatic
• May present with rectal bleeding, intussusception, volvulus or acute appendicitis

Investigations
Technetium scan Increased uptake by gastric mucosa identifies 75%
NB: Should be performed 4 weeks post-bleed to avoid false-negatives (as the gastric mucosa is
often ulcerated post-haemorrhage)

Management
Surgical resection.

GENITOURINARY CONDITIONS

UND~SCENDED TESTES (CRYPTORCHIDISM)

The testes descend through the inguinal canal to the scrotum in the third trimester of pregnancy.
• Approximately 3.5% of boys have undescended testes at birth
• Approximately 1.5% of boys have undescended testes at 3 months of age (as some descend after birth)
• After 9 months of age they rarely descend spontaneously
Undescended testes have an increased rate of malignant transformation even after orchidopexy. They may be:
• Bilateral or unilateral
· ·Palpable or impalpable
• Somewhere along the normal line of descent or ectopic

489
NB: Undescended testes most commonly lie in the superficial inguinal pouch.
Undescended testes should not be confused with retractile testes, which can be massaged fully into the scrotum with
no tension but retract back into the inguinal canal.
If possible, the testis is examined after massaging it gradually down the inguinal canal into the scrotum.
Karyotype should be done if bilateral impalpable testes or bilateral/unilateral impalpable testes associated with
abnormal genitalia. Check P-hCG if bilaterally impalpable.

Investigations and management

Palpable Inguinal orchidopexy
Impalpable Laparoscopy to make the diagnosis and then proceed according to findings

Present
t t
Dysplastic Absent
t
Orchidopexy Excision laparoscopically Fix remainlng contralateral testis in
(usually in two stages and fix remaining testis the scrotum to avoid the small
laparoscopically 3 (as for absent testis) risk of torsion
months apart)

Orchidopexy (surgical correction)

This is usually done before age 2 years, either as a one- or two-staged procedure, depending on the length of the
testicular artery. It is done for:
• Cosmetic reasons
• To optimize testicular development and theoretically to increase fertility
• To allow early detection of malignant change
If the testis is abnormal or a unilateral intra-abdominal and unable to be corrected, it is removed (orchidectomy).

SCROTAL/INGUINAL SWELLINGS

Inguinal hernia
Males > females. Right side > left side.
Usually indirect in children, i.e. due to a wide patent processus vaginalis that allows omentum or bowel to pass into
it.
Associations Undescended testes
Prematurity
Connective tissue disorders, e.g. Marfan syndrome

CLinicaL features
• Intermittent scrotal swelling, more prominent on crying or straining
• If an irreducible hernia: Painful
Risk of bowel obstruction or strangulation
Must be reduced urgently by a combination of firm pressure on the fundus,
combined with co-ntrol of the neck of the hernia. Alternatively, analgesia and
Gallow's traction may be effective

490
_,.,.._ _...
 Figure 19.4 Inguinal hernia

Management
• Emergency repair- indicated if incarcerated (irreduceable), tender and any signs of bowel obstruction or bowel
damage (perforation and peritonitis are rare but life-threatening complications). Children, especially babies, must
be carefully resuscitated with fluids prior to the operation.
• Elective surgical repair once reduced (with minimum delay as incarceration may occur in the meantime)

HYDROCOELE
A hydrocoele in infancy is due to a narrow patent processus vaginalis that only permits peritoneal fluid to drain to
the scrotum. It is common after birth.

Clinical features
• Scrotal swelling, usually fluctuant (may be tense)
• Variation in size of testes
• Transilluminates with a torch
• In an older child will characteristically increase in size during the day and reduce over night

Manage111ent
Small hyd/-ocoeles
'i
Usually observed for 1 year as most spontaneously resolve
Large and persistent hydrocoeles Treated with surgical ligation of the processus vaginalis (herniotomy)

TESTICUlAR TORSION
Testicular torsion is a rotation of the testis which causes vascular compromise by kinking the testicular pedicle.

Clinical features
• Acute scrotal pain, nausea and vomiting
• Firm dusky red scrotal swelling
• Pain may be a dull abdominal ache
• Usuatly tender on palpation
• Testis may be high in the scrotum and the spermatic cord feels thickened

491
The diagnosis is clinical. Doppler ultrasound of the testes can demonstrate the blood flow but it is relatively inaccurate
and should not be relied on.

Management
• Any suspected testicular torsion should be taken to theatre to be explored
• Torted testis is untwisted and fixed. If it is non-viable it is excised
• Other testis should be fixed at the same time to prevent future torsion
NB: Testicular torsion is a surgical emergency and must be operated on within 6 h of onset of symptoms in order to
save the testis.

TORTED TESTICULAR APPENDAGE (HYDATID OF MORGAGNI)

• Commonest cause of acute scrotum in younger boys
• Due to torsion of the appendix testis - at the upper pole of the testis
• Mimics torsion, so diagnosis is often made at exploration
Early examination may reveal the 'blue dot' sign, with a visible lump at the upper pole of the testis. When this is seen
by an experienced surgeon, it may be treated conservatively.

IDIOPATHIC SCROTAL OEDEMA

• Oedema of the scrotal wall, extending to the groin and perineum
• Not tender although may mimic torsion
• Testes characteristically feel normal
• Important to exclude other causes of scrotal/testicular pathology

EPIDIDYMO-ORCHITIS
This is inflammation of the epididymis and/or testis.
Associations UTI
Secondary to viral infection, e.g. mumps, or STD
The symptoms mimic testicular torsion but:
• More gradual onset of testicular pain
• Nausea and vomiting uncommon
• Usually associated with dysuria, pyuria and discharge
• Often febrile
Treatment is with antibiotics. In equivocal cases, surgical exploration must be performed to exclude torsion.

HYPOSPADIAS
Hypospadias is a common congenital abnormality due to a failure in midline fusion of the urethral folds. Degrees
of severity are described according to the position of the urethral meatus.

492
{:
j% of casesj jTypej j Associated chordee j

[
Glandular
70 Minimal
Coronal

10 Penile Moderate

20
Penile/scrotal • Severe
[
Perineal ..
(check for intersex and
anorectal anomalies)

Figure 19.5 Hypospadias

There are three problems:

1. Ventral urethral meatus (this may lie anywhere from the base of the penis to just below the normal opening on
the tip of the glans)
2. Hooded prepuce (due to a failure of the foreskin to form completely on the under surface of the penis)
3. Chordee (a ventral curvature of the penis)
Hypospadias is associated with a higher incidence of inguinal hernia and undescended testis. Unilateral or bilateral
impalpable testis and hypospadias raise the possibility of an intersex condition so a karyotype and specialist review
is indicated.

Surgical correction
• Based on straightening the penis and lengthening the urethra to the tip of the penis
• More severe forms are often repaired in two stages
'I • Foreskin hood is often used in the repair and boys are usually left with a circumcised appearance. NB : Parents must
be told not to have their sons circumcised as the foreskin may be used in the repair
• Sdrgery is usually performed in the second year of life with a good long-term outcome from specialist centres

THE FORESKIN AND CIRCUMCISION

A non-retractile foreskin is normal in infants and young boys. In its early development the foreskin is conical in shape
and cannot be retracted over the glans. In addition the under surface of the foreskin is adherent to the outer surface
of the glans (physiological adhesions). During childhood the tip of the foreskin widens and the adhesions resolve at a
variable rate, leading to retraction for around 70% by 5 years of age.
• I n young children parents are reassured and advised that gentle retraction in the bath may help produce a
retractile foreskin
• Phimosis (meaning muzzling) describes a tight foreskin which is non-rectractile

493
 • Non-retraction may persist at puberty in around 1% of boys. In most of these there is a secondary scarring of
the tip preventing its retraction. This is no longer a physiological narrowing but a pathological entity of the skin
known as lichen sclerosus et atrophicans (also known as balanitis xerotica et obliterans [BXO] or posthitis
[PXO]). This is the only true indication for medical circumcision which cures the condition. Other foreskin prob-
lems tend to be transient, with no long-term sequelae for foreskin development or general health, so they are only
relative indications for circumcision

Balano-posthitis
Inflammation of the glans (balano) and foreskin (posthitis)- self-limiting. Rarely, severe cases may result in urinary
retention but most resolve in a few days with bathing. Systemic or topical antibiotics and antifungals are non-
contributory.

Ballooning
This is seen during voiding in young boys. The foreskin distends due to turbulence of urine beneath it. Although it
may appear spectacular, it is rarely painful and resolves with foreskin retraction.

Paraphimosis
This occurs when a narrow foreskin becomes stuck behind the glans and restricts the venous and lymphatic drainage
of the distal penis. The glans and inner-prepuce swell and become quite painful. Urgent reduction is needed and is
achieved after prior compression of the oedema, usually without anaesthetic. The foreskin may continue to develop
normally after this.

Circumcision
Circumcision is performed for medical reasons and also by some religious groups.

Medical reasons
• True phimosis - usually BXO and an absolute indication due to the abnormal foreskin
• Recurrent balano-posthitis (dependent on severity and frequency of symptoms)
• Symptomatic ballooning
• Paraphimosis (rare)
In addition, recurrent UTis may be resolved by circumcision, due to reduction of paraurethral organisms. This is
indicated in boys with severe urinary tract anomalies.

ORTHOPAEDIC CONDITIONS

CAUSES OF LIMP

NB: Any child with knee pain may have hip pathology presenting with referred pain to the knee.
494
INFECTIONS
Septic arthritis
• Infection in the joint space
• Usually occurs ~ 2 years
• From haematogeneous spread, but also direct extension from osteomyelitis or abscess
• Serious joint destruction can occur if not promptly treated
• Neonatal disease may be multifocal

Organisms
Children Staphylococcus aureus and streptococci are the most common agents
Enterococci, salmonella (in sickle cell disease). Haemophilus now rare
Meningococcus, yersinia (iron overload)
TB (prolonged indolent arthritis with stiff joint)
Neonates Staph. aureus, Group B streptococcus, Escherichia coli, gonococcus, enterobacteria

Clinical features
Joint Hot, red, tender swollen joint
Pain at rest and with movement
. Markedly reduced range of movement (pseudo paresis in infant)
Joint position due to maximum joint relaxation or muscle spasm
Child Toxic and febrile
NB: Osteomyelitis may have a sympathetic joint effusion, but tenderness is over the bone. Hip disease may present
with referred pain to the knee.

Investigations
Bloods Neutrophils t
ESR, CRP t
Serial blood cultures and antigens
X-ray Normal initially but helpful to eliminate trauma
Joint USS Useful for hips in infants
Bone scan 'Hot spots' at involved joints
Joint aspiration Under USS guidance forM, C & S, and pain relief

Managerryent
Antibiotics Prompt and prolonged IV course, e.g. flucloxacillin +third-generation cephalosporin
Surgical Athroscopic or open joint washout for hip disease and if delayed response to antibiotics
Physiotherapy Initially joint immobilization for pain relief, then mobilized to prevent deformity

Osteomyelitis
• Acute, subacute and chronic depending on virulence of organism and efficacy of treatment
• Most commonly affects the proximal tibia and distal femur
• Usually due to haematogenous spread
• Occasionally multifocal
• Ineffective treatment results in discharging sinus and limb deformity

495
Organisms
Similar to those of septic arthritis, with Staph. aureus the most common.

Clinical features
• Site dependent with point tenderness
• Overlying skin is warm, red and swollen
• Toxic, febrile child
• Painful immobile limb± muscle spasm
• May have adjacent sympathetic joint effusion or extension to joint
• Older children may present with limp or back pain

Investigations
Bloods CRP, ESR 11, neutrophilia
Blood cultures and rapid antigen tests
X-rayjUSS Normal initially
Periosteal reaction > 2 weeks
Subsequent lucent areas in bone
Bone scan 'Hot spots'
Aspiration In atypical cases or immunocompromised child to identify organism

Management
1. Prolonged course (several weeks) of IV antibiotics
2. Surgical drainage/decompression if rapid response to antibiotics not seen

CONGENITAL DYSPLASIA OF THE HIP (CDH)

Also known as developmental dysplasia of the hip (DDH), this condition is due to incomplete shallow development of
the acetabulum, allowing the femoral head to dislocate. Optimal hip development in utero and postnatally requires
abduction and external rotation. The following factors affect such positionin~1:
• Breech position (especially extended breech)
• Oligohydramnios
• Muscular or neurological problem, e.g. spina bifida
• Positive family history (polygenic inheritance. Recurrence risk 1:30)
Incidence 2:1000, female > male. Left side > right side.

Diagnosis
• Emphasis on screening by identifying risk factors and from examination (Ortolani and Barlow te~;ts) at birth and
6-week check
• USS to confirm diagnosis ± orthopaedic examination
• Clinically obvious when walking develops, by which time too late

Management
Detected early, the hip is immobilized by casts or splints in abducted position with hips and knees flexed to keep the
head of the femur in the acetabulum and allow development of the acetabulum and Ligaments. Late diagnosis often
requires major orthopaedic surgery.

496
 .. .... . · · ·· ··· ··· ···· ··· ··· ···· ········· ·· ··· ·- ·

OSTEOCHONDRITWES
Boys > girls. Usual age 3-12 years.
A group of idiopathic acquired localized disorders of bone and cartilage, typically affecting the primary or second-
ary ossification centre in the growing child which undergoes aseptic necrosis with resorption of the dead bone and
replacement by new osseous tissue. They are characterized by localized pain and are possibly associated with trauma
of the affected area.

Perthes disease (Legg-Calve-Perthes)

This is an osteochondrosis caused by avascular necrosis of the femoral head, often due to compromise of the nutrient
artery.
Males> females, 5:1. Usually 4-10 years at presentation. 10-20% have bilateral disease.

Clinical features
• Intermittent referred pain to anterior thigh or knee
• Limp (may be painless)
• Decreased internal rotation, abduction and extension of the hip (at rest semi-flexed and externally rotated)
• Leg length ,i nequality

In vestigations
Hip X-rays Fragmented, flattened femoral head, often of increased density
Increase in the medial joint space, subchondral fra cture
MRI hip May illustrate above features earlier
Radionucleotide scan Reduced femoral head uptake (but increased when neovascularization)

Management
Varies between centres and depends on severity.
If< 6 years Conservative - splints and bed rest
If> 6 years Abduction exercises and bed rest
Abduction casts and femoral osteotomy if necessary

497
Kyphosis
Postural kyphosis Bad posture. Smooth back contour on examination. Correctable by child.
X-rays normal
Idiopathic kyphosis X-rays show kyphosis
Scheuermann disease (this is not the same thing as such, but may be associated)
Congenital Vertebral malformations, e.g. VATER/VACTERL. Often present in infancy

Scheuermann disease
• Osteochondritis of the spine occurring during pubescent growth spurt
• Pain in mid-thoracic (75%) or thoracolumbar spine, or
• Painless round shoulders and kypho(scolio)sis
• Due to wedging of vertebrae caused by loss of anterior vertebral height

X-rays
• Wedging of 1-3 adjacent vertebrae
• Schmorl's nodes (irregular end-plates)
• Kyphosis

Management -
• Conservative management (physiotherapy) usually as generally self-limiting with good outcome
• Casting or surgical fusion may be necessary

SCOLIOSIS
Structural
Congenital Due to vertebral malformations: Vertebral body anomaly
Failure of segmentation
Generally presents in infancy
Associated with renal abnormalities in 20%
Idiopathic Most common form
Us ually mild disorder (< 20°, M= F), often spontaneously corrects
Severe and progressive in 1:20 cases (F > M, progressive in adolescence with growth)

Postural
No spinal rotation and normal alignment when flex spine.
May be secondary to:
• Neuromuscular disease, e.g. muscular dystrophy, unilateral paralysis
• Osteoid osteoma
• Leg length discrepancy

Management
• Enquire about bowel and bladder function and examine neurological system
• Management directed at any cause plus: Brace for moderate deformity (20-40°)
Surgical intervention if more severe

498
,_ SUPPED UPPER FEMORAL EPIPHYSIS (SUFE)
The epiphysis of the femoral head 'slips' off the femoral neck. Seen in adolescence when growth plate at its weakest
due to excess growth hormone relative to sex hormones.
Characteristically either
Fat boys with relative hypogonadism (small testes) but normal growth, or
Tall thin girls with increased growth hormone and normal sex hormone
Associations Hypogonadism
Hypothyroidism
Pituitary dysfunction

Clinical features
• Acute presentation - pain on hip movement (possibly referred knee pain only) and limited hip movement
• Chronic presentation - antalgic limp, hip externally rotated
• 25% bilateral
• On examination, decreased internal rotation of the hip

Complications
• Osteonecrosis
• Chondrolysis (articular cartilage degeneration)
• Early arthritis

X-ray hip ('Frog-leg lateral view')

• Widened growth plate
• Femoral neck anteriorly rotated
• Femoral epiphyses slipped down and back

Management
Surgical pinning of the femoral head.

IRRITABlE HIP

• Self-limiting transient reactive synovitis associated with, e.g., gastrointestinal illness, EBV, influenza, myco-
plasma, streptococcus
• Common cause of acute hip pain in children aged 2- 6 years
• Diagnqsis of exclusion and, if doubt regarding septic arthritis, aspirate joint
Clinical features
• Sudden onset joint pain (possibly referred to knee, but no pain at rest) or lim p
• Decreased range of movement
• Child is well± mild fever

Investigations
• ESR/CRP/neutrophils normal or mildly elevated
• Blood cultures negative
• Joint X-ray or USS - small effusion may be present

499
Management
Brief bed rest, NSAIDs and remobilize.

PUlLED ELBOW
• Distal dislocation of radial head through the annular ligament
• Common injury in toddlers
• Caused by rapid pull/rotation on child's forearm, e.g. when lifting child by one arm
• Pseudo-paralysis at the elbow with arm extended, forearm pronated and held at the side
• Often non-tender but apparent 'paralysis' of limb
• X-rays - radial head away from socket and no fracture

Management
Treatment is manipulation back into socket (hold flexed elbow in one hand and forearm in other ha~d, supinate
forearm and place thumb over radial head and push it into the elbow).

POSTURAL VARIANTS IN TODDLERS

Postural variants of the developing skeleton are attributable to different load bearing at different ages and so resolve
with time. Pathological skeletal variations are fixed and associated with identifiable pathology.

500
 BlOUNT DISEASE
Idiopathic disorder resulting from abnormal growth of medial proxima l tibial epiphysis. Common in Africans.
If< 4 years Females > males, 20% unilateral
If> 4 years Males > females, 50% unilateral
Associations Obesity

Clinical features
• Leg length discrepancy
• Internal tibial torsion

Investigations
'Beaking' of the medial metaphysis of the tibia
Management
If< 4 years Splinting or surgical treatment
If> 4 years Surgical osteotomies

TALIPES
Talipes is a positional deformity of the foot of which the re are two types.
Talipes equinovarus The most common form
May be positional or fixed
Foot supinated with heel inward ly rotated
Forefoot adducted
Talipes calcaneovalgus Foot everted and dorsiflexed

{a) (b)

figure 19.6 Talipes equinovarus (a) and calcaneovalgus (b)

501
Positional talipes Will correct to normal anatomical position during manual examination and responds to
physiotherapy
Fixed talipes Requires diagnosis of underlying cause, e.g. muscular or neurological problems, oligohydram-
nios, and genetic conditions, and correction by conservative (serial plasters) or surgical means
NB: Congenital vertical talus causes 'rocker bottom' feet and is seen in Edwards syndrome.

CONSENT

THE C0~1PETENT CHILD

• Children over 16 years of age are regarded as adults for the purposes of consent
• A child under 16 years may give consent if they are deemed competent. However, a competent child cannot with-
hold consent (because a refusal to give consent can be countermanded by those with parental responsibility)
• A child under 16 years old will be considered competent to give consent to a particular intervention if they have
'sufficient understanding and intelligence to enable him or her to understand fully what is proposed' (known as
Frazer competence)

THE INCONlPETENT CHILD

If a child does not have the capacity to provide consent a proxy may do so. The proxy is expected to act in the best
interests of the child and they can include the following :
• A parent who has 'parental responsibility' for the child
• A local authority that has acquired 'parental responsibility' and the power of consent. A local authority can only
usurp this power by restricting the parents' power
• The court can act as a proxy in wardship, under inherent jurisdiction or via court orders. In this way it can
review a parent's decision, e.g. the refusal of a life-giving blood transfusion for a child of a Jehovah's Witness

FURTHER READING
Spitz L, Coran AG, eds Paediatn·c Surgery, 5th edn. London: Chapman & Hall Medical,_ 1995

502
 - - --------- - -- --- - - - - - - - - · --- · - ---------

,,

• Resusdtation • Apparent life-threatening events

• Reduced consciousness and coma • Sudden infant death syndrome
• Management of major trauma • Childhood accidents
• Head injury • Non-accidental injury
• Shock • The Law
• Anaphylaxis

RESUSCITATION
Whatever the underlying cause, in a seriously unwell child the basic initial management is the same (see below). Any
compror:nise of the Airway, Breathing or Circulation must be attended to immediately using basic resuscitation measures.
Advanced resuscitation is proceeded to when necessary and the equipment is available.
The procedures•for basic and advanced life support are regularly updated by the European and the UK Resuscitation
Committees, and thus the current guidelines should be checked.

MANAG~MENT OF A SERIOUSLY ILL CHILD (SUMMARY)

~ppid pnmary assessment and resuscitation
Check area is SAFE Shout for help
Approach with care
Free from danger
Evaluate ABC
Assess responsiveness
Assessment and resuscitation:
A Airway Basic life support
B Breathing
C Circulation
D Disability:
Pupillary assessment (size and reaction)
Conscious level AVPU (see p. 508)
E Exposure
503
Secondary assessment
Detailed history
Detailed examination
Emergency investigations

Emergency treatment
Definitive further treatment (including investigations, monitoring and management as appropriate)

BASIC LIFE SUPPORT

, .:: ·
·.::.. · ·. :. . _ - · .. ., :_.. ._._.
__ -_ _ ,

H~~·J :~ltt:po~i~~n, .
Check patency

LOOK for chest and/or abd()minal movements

LISTEN for breath sounds
FEEL for breathing

Mouth to mouth-and-nose Mouth to mouth

504
Check pulse, Carotid
(no pulse or inadequate< 6o bpm' with poor perfusion)

-- ~ '
·:.-.. -_ . "·( ,;:f,----.. -·-.
•-- ..· - :,: -

..•;.~~:~r'~t~~~r~.~~ftw .
riippte·hqe{· ~., :.; · · ··' .••
Heel of one hand
<{finger breadth
·.·. above xiphisternum
.Cqrnpress\o ·iA'depth.of cheh .

Go for. help affgr~~elllinute i(n~one has arrived (take a s~all child withyoy) :

Important differences between infants and children in resuscitation

Head position is neutral in infants (not sniffing) as this will keep the airway open (due to their different anatomy)
Mouth to mouth-and-nose in infants- because they are so small this is the easiest way to get air into them
Check brachial or femoral pulse (radial pulse is too difficult to feel in infants)

Choking
If a child is choking (foreign body aspiration suspected) back blows or chest thrusts are used to dislodge the object
in an infant; abdominal thrusts are also used in a child 1 year old. (A finger sweep in the mouth used in adults is not
recommended in children as the soft palate can easily be damaged or foreign bodies can be forced further down the
airway.)

505
Figure 20.1 Protocol for management of choking
Adapted from Resuscitation Guidelines 2005. Resuscitation Council. www.resus.org.uk

ADVANCED LIFE SUPPORT

This involves basic life support with the addition of:
Airway Oral airway or
Nasal airway (not if risk of basal skull fracture) or
Endotracheal intubation if necessary ~ ETT internal diameter= [age of
child/4] + 4
ETT length = [ age/2] + 12
Suctioning and nasogastric tube insertion
Breathing Bag and mask/mechanical ventilation with 100% oxygen
_Monitor with pu.lse oximeter and ECG leads
Circulation Assessment of cardiac output and rhythm (clinically and on ECG monitor)
Give drugs and defibrillate as per protocols
Fluid replacement (intravenous or intra-osseous)

Cardiac arrest protocols

Most cardiac arrests in children are respiratory in origin, with a secondary cardiac arrest.
Three basic cardiac arrhythmias are seen in cardiac arrest:
• Ventricular fibrillation (and pulse less VT)
• Asystole
• Pulseless electrical activity
The blood sugar must be monitored during cardiac arrest as children have low glycogen stores and thus rapidly become
hypoglycaemic.
506
 .-. ~- ,·.. _, .. . . ~- . ·-;, .,

:P~B;~~" f~~.~c~tf;!X~gd'.,". };._ · . · · : .... :·

• . ccirrecfreversible 'caus·es ~ . . . \f.:-,:>

,1The European Resuscitation Council regularly revises the protocols for cardiac arrest, and the latest guidelines should be viewed.

Figure 20.2 Cardiac arrest protocols for VFjpulseless VT and asystolejpulseless electrical activity
Adapted from Resusdtation Guidelines 2005. Resusdtation Coundl. www.resus.org.uk

507
REDUCED CONSCIOUSNESS AND COMA
Consciousness is awareness of oneself and surroundings in a state of wakefulness.

Coma is a state of unrousable unresponsiveness.

Causes of reduced conscious Levelfcoma

CNS Epilepsy (post-ictal)
Traumatic brain injury (accidental or NAI)
Infection, e.g. meningoencephalitis
Subarachnoid haemorrhage
Hypoxic ischaemic brain injury
Acute i ICP, e.g . intracranial mass, CSF obstruction; coning
Brainstem neoplasm, trauma or infarction
Toxins E.g. alcohol, glue, CO, lead, salicylates
Metabolic imbalance E.g. glucose, Ca, Na (i or 1)
Temperature instability Hypothermia or hyperthermia
Systemic organ failure E.g. sepsis, liver failure, Reye syndrome, renal failure, respiratory failure
Inborn error of metabolism

COMA SCALES
These are important rapidly to assess depth of coma in a consistent way. A very rapid assessment is the AVPU coma
scale, but the Glasgow and Children's Coma Scales are more comprehensive. The Children's Coma Scale (unlike the
Glasgow Coma Scale) has not been validated.

Eye op,e~fng Eye opening ·

Spontaneous Spon_taneous ..
To speech 3 To speech
To pain 2 To pain 2
None 1 None 1

508
::;·

~;~~~~~£u~e*og~:Ys;;c6m·· :•· .·..

Localizes pain
Withdraws from pain
Abnormal flexion to pain .·
Abnormal extension to' pain
None · · ·

sest verbacrespanse
Alert, babbles as usuat _. ...·. ·. > • : , . .
FewersouhOs/wo'rds than -~s~'a( i.tn-tafit~Tf9 >
Cries to pain only . · · ··
Moans 'topajri <-·
None

MANAGEMENT OF DECREASED CONSCIOUS STATE

The initial management of an unconscious child is to assess and stabilize them. While this is being done, further
history, examination and investigations to establish the cause of the coma can be performed.

Rapid primary assessment (ABCDE) and resuscitation

Pay particular attention to:
• Securing the airway (give 100% oxygen and intubate and ventilate if necessary)
• Establish IV access, check glucose stick (and treat any hypoglycaemia)
• Initial blood samples
• Give IV fluids 20 mljkg initial bolus if in shock
• Give broad-spectrum antibiotic if meningitis or sepsis suspected
• Rapid coma scale (AVPU), pupillary assessment, posture
• Check all over for other signs including temperature and rash

Secondary assessment
History Specific points:
•I Where discovered and by whom. Any witnesses?
Resuscitation history with accurate timings
Enquire about trauma, poisons, possible self-harm, infectious disease exposure, travel, preceding
fit, febrile illness, pre-existing disease (neurological, metabolic) and social history (NAI)
Further examination Check for any 'medic alert' bracelet
Detailed neurological examination (including full coma scale score)
Signs of injury (including nasal discharge)
Signs of meningism (fundi - retinal haemorrhages, papilloedema, neck stiffness)
Skin rash (petechial rash, bruising, jaundiced)
Abnormal smell, e.g. ketones, organic solvents, metabolic disorder
General examination - signs of other systemic disease

509
Investigations
Blood BMStix, blood cultures, FBC, clotting studies, cross-match, U&E, creatinine, LFT, glucose, CRP,
toxicology, lactate, ammonia and blood gas.
Urine Glucose, protein, microscopy and culture, toxicology, amino and organic acids
Keep sample for rarer inborn errors of metabolism especially if hypoglycaemic at time of
presentation (store at- 70°C).
Brain scan (CT If no identifiable cause found
or MRI)
CXR ± AXR (Post intubation)
Lumbar puncture Should not be done on a comatose child. It can be performed later when the condition allows

Further treatment
• Monitor vital signs (pulse, temperature, BP, respiration, oxygen saturation, neurological observations)
• Treat on paediatric intensive care unit if GCS < 8.
• Site NG tube and aspirate (keep initial contents for analysis)
• Catheterize
• Monitor and stabilize blood sugar and electrolytes
• Treat any epileptic seizures with anticonvulsants
• Consider aciclovir (if herpes encephalitis a possibility)
• Monitor and treat any i ICP (mannitol IV± hyperventilation to induce hypocapnoea)
• Further detailed investigations to establish the cause and treat specific conditions as necessary

BRAIN DEATH
Brain death is the irreversible loss of consciousness and the capacity to breathe. This is accepted to occur when
there is permanent functional death of the brainstem.
• Diagnosis of brain death requires the absence of brainstem function (no brainstem reflexes) for at least 24 h
• Child must be unconscious with no drugs acting that affect consciousness or respiratory function
• Coma state must: Be apnoeic despite hypercapnoiec drive, i.e. PaC0 2 > 6.7 kPa
Be of diagn·osed cause
Exclude drugs, poisons, hypothermia (< 35 °C}, and biochemical disturbance
There must be no treatable metabolic or endocrine cause
• Assessment of brainstem reflexes, tested by two senior physicians working independently. The reflexes must be
retested at least 1/2 h apart

Brainstem reflexes

510
MANAGEMENT OF MAJOR TRAUMA

Primary survey and resuscitation (ABCDE)

Life-threatening conditions are identified and treated immediately.
Pay particular attention to:
• Securing airway with cervical spine control (assume spinal injury until excluded)
• Check for pneumothorax and haemothorax
• Estimation of blood Loss (heart rate, BP, capillary refill, respiratory rate, temperature, skin colour and mental status)
• IV access and give 20 mljkg fluid bolus, repeat if necessary. If> 40 mljkg needed, give blood and obtain urgent
surgical opinion
• Rapid neurological status assessment (AVPU and pupillary size and reactivity)
• Complete examination to check for other injuries (and then cover with blanket)
During the resuscitation take a more detailed history and basic investigations.

Detailed history of accident and medical history

Allergies
Medications
Previous illness/ injury (PMH)
Last oral intake
Environment in which the injury occurred

Investigations
X-rays CXR, pelvis, (-spine
Blood tests ABG, FBC, Cross-match, glucose, U&Es

Further treatment
• Catheterize if necessary
• NG tube and aspiration (pass tube orally if basal skull fracture suspected)
• Give analgesia if necessary (IV morphine)

Secondary survey
When the child is stabilized a detailed secondary survey can be done, from top downwards:
• Head } Assess for injuries
,, • Face
• Neck - assume spinal injury until excluded
• Chest - open wound, tension pneumothorax, haemothorax
• Abdomen - ruptured organs (kidneys, liver, spleen, bowel)
• Pe~vis } Assess for injuries
• Sp1ne
• Extremities - open wounds, fractures

Emergency treatment
Treatment of any injuries discovered during secondary survey.

511
HEAD INJURY
This is the single most common cause of trauma death in children. Minor head injuries are common.

Causes
• Road traffic accidents
• Falls, e.g. windows, trees, walls
• NAI (usually infants)

Forms of head injury

Concussion A brief reversible impairment of consciousness
Extradural haematoma A bleed in the middle meningeal space due to rupture of the middle meningeal artery
or dural veins
A convex lesion is seen on CT scan
Subdural haematoma A bleed between the dura and cerebral mantle, due to rupture of cortical veins
Seen in shaken infants (NAI)
May be chronic, with gradual enlargement and a history of irritability, poor feeding
and lethargy
A concave lesion is seen on CT scan
Intracerebral contusions An insult to the brain substance
NB: A skull fracture is not always present with severe cerebral injury. Subdural haematoma is most common in head
injuries without skull fracture.

Figure 20.3 Extradural (top) and subdural (bottom) haematoma

512
Skull fractures
Non-depressed, linear Most common fracture seen
Depressed Need surgical treatment if ~ 3-5 mm depressed
Basal skull fracture CSF rhinorrhoea (can check with dextrostix to differentiate from mucus) and bilateral
eyelid ecchymoses ('panda eyes')
Difficult to demonstrate on SXR, CT views helpful

Suspect severe head injury if:

• Substantial injury, e.g. RTA, fall from great height
• Loss of consciousness at time of injury
• Impaired level of consciousness
• Neurological signs
• Penetrating injury

Management

Primary survey and resuscitation (as for major trauma)

• Immobilize neck until cervical spine injury ruled out
• AVPU, pupil size and reactivity, temperature and glucose

Secondary survey
Head examination Lacerations, compound or depressed fractures
Check for basal skull fracture ('panda eyes', CSF leak from ear or nose - check glucose Level,
bruising over mastoid [Battle's sign])
Full neurological Glasgow coma scale; neurological examination, fundi
examination Especially check for localizing signs
Investigations FBC, . U&E, cross-match, ABG } Dunng · pnmary
· survey
C-spme, CXR, pelvis
Do CT brain scan once stable if indicated (GCS < 12, loss of consciousness at time of
incident, skull fracture, retrograde amnesia or neurological symptoms or signs, significant
injury). If GCS < 12, an anaesthetist should assess for elective intubation for the CT

Emergency treatment
• Monjtor closely to detect any change in clinical state and conscious level, recording regular neurological observa-
tions using the appropriate coma scale
'r • Treat seizures and raised ICP as necessary
• Check for and treat any other injuries
• Assessment for surgical intervention by neurosurgeons if necessary (focal neurology, deteriorating neurological
signs, ICP I, abnormal CT, penetrating injury, basal skull fracture, depressed skull fracture)

SHOCK
Shock is the failure of adequate perfusion of the tissues.

Causes
• Hypovolaemic, e.g. blood loss, gastrointestinal fluid loss, ketoacidosis, skin Loss (burns)
• Distributive, e.g. septicaemia, anaphylaxis, spinal cord injury
• Cardiogenic, e.g. arrythmias, cardiac failure, myocardial infarction

513
 • Obstructive, e.g. tension pneumothorax, cardiac tamponade, pulmonary embolism
• Dissociative, e.g. profound anaemia, carbon monoxide poisoning

Three stages of shock

It is important to recognize the early stages (compensated) shock because early treatment of shock is vital.
1. Compensated shock Perfusion to vital organs is maintained at the expense of non -essential tissues
(capillary refill time (CRT) may be normal or poor, core-peripheral differential of
< 20C)
2. Uncompensated shock Mechanisms start to fail, tissue hypoxia and acidosis occur. Poor CRT.
Core- peripheral differential of> 2°C
Preterminal Situation is becoming irreversible

Clinical features of the stages of shock

Management
Immediate management is the same for all types of shock:

Primary assessment and resuscitation (ABCDE)

Pay particular attention to cardiovascular status:
• Pulse rate, pulse volume, capillary refill, blood pressure

514
 Effects of drculatory compromise on other organs (sighing respirations, pale skin, mental status, urine output)
Features of heart failure
• Give 100% oxygen via face mask
• Obtain IV or IO access. Fluid replacement in boluses of 20 mljkg (crystalloid or colloid, then blood) as required.
• Low threshold for broad-spectrum antibiotics as sepsis is the most common cause in children

Secondo!}' assessment (jncluding detailed neurological status with detailed histol}' and examination)
If there is no improvement, or if improvement requires> 40 mljkg fluid, then consider mechanical ventilation, inotropic
support, intensive monitoring, catheterization and correction of any biochemical and haematological abnormalities
as necessary.

ANAPHYLAXIS
This is a severe, life-threatening, generalized systemic hypersensitivity reaction . It is an IgE mediated acute reaction
to an allergen . The clinical features and severity are variable and include:
Airway and breathing Bronchospasm, upper airway obstruction (stridor, wheeze, cyanosis), respiratory arrest
Circulation Tachycardia, shock, cardiac arrest
Skin Urticaria, flushing, angioedema, facial swelling

Management
Anaphylactic reaction?
Airway, Breathing, Circulation, Disability, Exposure
Diagnosis - look for: Acute onset of illness
Life-threatening Airway and/or Breathing and/or Circulation problems 1
And usually skin changes
• Call for help
• Lie, patient flat
• Raise patient's legs
Adrenaline (IM unless experienced with IV)
When skills and equipment available:
• Estabilish airway
• High flow oxygen Monitor:
• IV fluid challenge (crystalloid) Pulse oximetry
• Chlorphenamine (IM or slow IV) ECG
,r• Hydrocortisone (IM or slow IV) Blood pressure
1 Life-threatening
r
problems:
Airway: swelling, hoarseness, stridor
Breathing: rapid breathing, wheeze, fatigue, cyanosis, Sp0 2, <92%, confusion
Circulation: pale, clammy, low blood pressure, faintness, drowsy/coma

APPARENT LIFE-THREATENING EVENTS (ALTE)

Apparent life-threatening events are unexpected episodes in infants that may involve:
• Apnoea
• Unresponsiveness
• Choking
• Central cyanosis or pallor

515
There are often no other obvious symptoms. Aserious underlying disorder needs to be excluded but no cause may be
found.

Causes
• Infection - sepsis, viral infection
• Seizure
• Gastro-oesophageal reflux
• Hypoglycaemia
• Central apnoea
• Cardiac - arrhythmia, cyanotic spell
• Encephalopathy - metabolic upset
• Suffocation (fictitious or induced illness)

Management
• Initial survey (ABCDE) and resuscitation as necessary
• Secondary survey: Thorough history (in particular check social situation)
Full examination
• Admit to hospital for close monitoring (oxygen saturations, ECG, respiration)
• Investigate further as appropriate: ABG, glucose, FBC, U&E, creatinine
Infection screen .
Reflux investigations (pH study)
Cardiac screen (CXR, ECG, echocardiogram)
Metabolic screen
Toxicology screen
• Teach parents resuscitation

SUDDEN INFANT DEATH SYNDROME (SIDS)

Sudden infant death syndrome is the sudden unexplained death of a previously well infant in whom no cause is found
after postmortem examination .

It most commonly occurs at 2- 4 months. The risk of SIDS for subsequent children is increased.
There has been a significant decrease in the numbers of SIDS cases with the advice:
• Put the baby to sleep on their back
• Avoid overheating the baby
• Tuck the baby in with their feet to the base of the cot (so the risk of sl1pping under the cover is reduced)
• Use blankets with holes in them and not duvets for infants
• Avoid smoking while pregnant and after pregnancy
• Avoid smoking in the house
• Have the baby sleep in the parents' bedroom for the first 6 months at least
• Do not put the baby in the parents' bed when the parents are tired or have taken drugs or alcohol
Basic resuscitation skills should be taught to parents of children at risk. Home apnoea monitoring for infants at risk
may be considered, though in some cases this can prove anxiety-provoking for the parents and has not been proven
to be of benefit.

CHilDHOOD ACCIDENTS
Accidents are the commonest cause of death in children aged 1-14 years, and they are broadly predictable and
therefore often preventable.

516
Causes of fatal accidents
o Road traffic accidents (50%)
• Fire (30%)
• Drowning (10%)
• Suffocation and choking
• Falls
• Poisoning

ROAD TRAFFIC ACCIDENTS

Road traffic accidents are the cause of most accidenta l childhood deaths in the UK. They may involve:
Car passenger Well fitting car seats and seat belts are preventative
Pedestn'an Young school boys at highest risk. Environmental measures most preventive
Bicyclist Most common in boys. Crash helmets significantly reduce severity
For management, see Major Trauma and Head Injury, p. 511.

NEAR DROWNING
The third commonest cause of accidental death in children in the UK. Up to 70% will survive if basic life support is
provided at the scene.
Near drowning If any recovery following immersion
Drowning No recovery after immersion
Effects of submersion:
• Breath-holding -7 bradycardia (diving reflex) -7 hypoxia -7 tachycardia, BPi, acidosis
• Then breathing movements occur(< 2.5 min) -7 laryngeal spasm and secondilry apnoea
• Then involuntary breathing efforts, bradycardia, arrythmias,_cardiac arrest
• Hypothermia common (this protects against hypoxic brain damage)
• Fresh wat~r and ~alt water both cause (via different mechanisms) pulmonary oedema and hypoxaemia, and have
the same prognosis

Management'
• Initial survey (ABCDE) and resuscitation. Assume cervical spine injury. Early intubation and nasogastric tube
placement with aspiration to remove swallowed water
• Rewarming (passive, e.g. blankets and active, e.g. radiant lamps, warm IV flu ids)
~
• Do not stop resuscitation if .core temperature< 32°(
' • Secondary survey (full history and examination). Commence advanced life support when able
• Ir}vestigations: ABG, U&Es, glucose, blood cultures, CXR
• Definitive care in hospital
• NB: Initial examination may be normal (including CXR and blood gas) as progressive pulmonary oedema and
respiratory failure can develop over 72 h
• Good prognostic indicators: Short time to first gasp on resuscitation(< 3 min)
Hypothermia< 33°( core temperature

BURNS
Causes of burns and scalds
• Hot liquids
• Fire
517
 • Smoke inhalation
• Electrical injury
• Chemical burns

Electrical burns
Lightning Direct current (DC), very high voltage (200 000-2 billion V) over milliseconds
Causes asystole, respiratory arrest, minimal tissue damage
High voltage wires Alternating current (AC) usually < 70 000 Vover longer time
Causes ventricular fibrillation, deep tissue injury, muscle necrosis, renal failure
Low voltage household AC: causes tetanic muscle contractions, victim unable to let go, and thus sustains
substantial damage
DC (or high voltage AC): causes single forceful muscle contraction, throwing th_e
victim away

Assessment
Burns are assessed by:
Depth Partial thickness (pink or mottled skin, blistering, painful)
Full thickness (white or charred skin, painless)
Extent Expressed as a percentage of body surface area
Location Airway involvement in smoke inhalation must be checked for
Hand and face burns are of particular cosmetic and functional significance

Figure 20.4 Assessment of burns

Management
Burn management is coordinated by the plastic surgical team, and if treated as an inpatient this should be on a burns unit.

518
 .. . ·· ·· · ··· · ...... . .... -··· ·- ··· · ··-· ·

Pn'maty survey and resuscitation (ABCDE)

Pay special attention to:
• Airway - if inhalation injury intubation by expert may be necessary.
• Exposure - rapid heat loss occurs from burnt areas
Secondary survey
Assess the burn (as above).

Emergency treatment
Analgesia Burns are very painful so strong IV analgesia required for all but minor burns
Initial shock IV fluids via two large cannulae as skin fluid loss may be extensive
Burns > 10% body surface area will need additional IV fluid replacement:
Additional fluid requirement == percentage burn x weight (kg) x 4
Monitor urine output
Wound care Removal of dead tissue, then placement of sterile dressings
Significant burns must be managed on a burns unit, i.e. full thickness burns, > 10% body surface
area, inhalational burns, hand and face burns

Definitive care
Carried out on a paediatric burns unit.

POISONING
Poisoning in young children is usually accidental, though deliberate poisoning is seen in adolescents and in fictitious
or induced illness (FII).

General management
Take history Including:
Substance(s) ingested
Amount
Exact timing
Examination ABCDE asse~ sment and resuscitation
In particular: Level of consciousness
Orophayrnx
Features specific to various poisons (see below)
Investigations Drug levels, e.g. salicylates, paracetamol
U&Es, creatinine, LFTs, clotting profile, ABGs, FBC
Elimination Contact the Regional Poisons Information Centre for advice
Specific antidotes, investigations and therapy for particular poisons
There are two methods of elimination:
Activated charcoal This is considered if ingestion is recent
Charcoal is given orally (via nasogastric tube if necessary), and works by absorbing the
drug itself, thereby reducing the intestinal absorption of drugs
Gastric lavage Rarely indicated in children
Most effective <1 h of ingestion
Airway must be protected during the procedure
Contraindicated after ingestion of corrosives and hydrocarbons due to potential for
aspiration pneumonitis
519
Specific poison remedies

520
Lead poisoning
This is usually chronic poisoning from the ingestion of lead-containing paint or water in lead pipes. Rare in the UK.
It may result in permanent mental retardation .
Chronic illness Bone features, developmental delay, gum involvement, constipation, neuropathy
Acute Vomiting, ataxia, seizures, coma, anaemia, renal involvement

Clinical features
Gastrointestinal Anorexia, nausea, vomiting, constipation, abdominal pain
Haematological Hypochromic microcytic anaemia with basophilic stippling on red cells
Neurological Peripheral neuropathy, e.g. wrist drop, foot drop
Lead encephalopathy (seizures and reduced consciousness)
Skeletal Dense metaphyseal bands at the growfng end of long bones - 'lead lines'
Renal Fanconi syndrome
Other Blue line on gums

Diagnosis
Serum Lead levels
FBC (basophilic stippling, hypochromic microcytic anaemia)
Urine Proteinuria, glycosuria, aminoaciduria

Management
Chelation therapy with dimercaptosuccinic acid (DMSA). Calcium EDTA and dimercaprol may be used instead. Removal
of source.

NON-ACCIDENTAL INJURY {NAI)

Types
• Physical abuse
• Sexual abuse
• Emotional abuse and neglect
• Fabricated or induced illness (FII) (used to be termed Munchausen syndrome by proxy)

P,HYSICAL
',
ABUSE
Following accidental injury, parents would normally be very concerned and bring their child straight to medical atten-
tion ind give a consistent and plausible history of events. The following features of the history should raise suspicion
of physical abuse:
• Unexplained or multiple injuries
• Inconsistent history
• Lale presentation
• lJmisual parental behaviour, P.g. hostile, unconcerned
• Anxious withdrawn child (termed 'frozen watchfulness')
Injuries seen in physical abuse:
Lacerated oral frenulum (Due to carer forcing bottle in infant's mouth)
Cigarette bums
521
Bruises Finger tip bruises
Belt mark bruises
Bite marks
Unexplained multiple bruises (especially when not occurring over bony prominences)
Head injuries Retinal haemorrhages (caused by shaking injury 'shaken baby', see p. 385)
Subdural haematoma (from shaking injury)
Wide skull fractures (> 3 mm displacement)
Fractures Unexplained or multiple fractures
Spiral fractures
Old fractures not previously brought to medical attention

Differential diagnosis

SEXUAL ABUSE
In most cases of sexual abuse the perpetrator is male and the abused child female, although all variations exist.
Features of sexual abuse include:
• Sexually transmitted infection
• Genital injury with no plausible explanation
• Urinary tract infection, enuresis
• Anal fissure, pruritis ani, constipation, encopresis
• Inappropriate sexual behaviour, i.e. sexualized behaviour
• Behavioural disturbance
• Direct allegation of abuse

EMOTIONAL ABUSE AND NEGLECT

This can be difficult to identify. Features include general neglect, dirty child, scruffy clothing, a miserable child and
growth faltering.

FABRICATED OR INDUCED ILLNESS (FII)

This is an uncommon form. of abuse in which illness in the child is fabricated by the parents(s) or carer.
Features of the disorder include:
• Condition which is difficult to diagnose
• Features are only present when the parent is present
• Multiple hospital admissions
• Mother often has healthcare connections, e.g. a nurse
Examples Feeding salt to the child
Putting blood in the urine, stool or vomit
Putting sugar in the urine
522
The child can come to serious harm from these activities, not least from protracted unnecessary medical investigations
to determine the source of the fictitious symptoms.

MANAGEMENT OF NON-ACCIDENTAL INJURY

There are national guidelines regarding the management of NAI, emphasizing the team approach between hospital-
and community-based professionals, and dedicated child protection teams including paediatricians, social workers,
health visitors, GP, police, teachers and lawyers. Important points to remember in suspected cases are:
• Involvement of senior child protection paediatrician early
• Detailed history should be taken including direct 'quotes'. Remember to record date and time and sign notes.
Include detailed family and social history'
• Full examination with consent (ideally only once by senior paediatrician(s) and if necessary a forensic physician
from the child protection team to minimize distress to the child) . Observe child-parent interaction
• Detailed documentation of the injuries with chronology (if possible photographs with consent)
• Relevant investigations (X-rays, blood tests) and treatment of injuries
• In suspected or confirmed abuse, all cases are managed by a dedicated multidisciplinary child protection team.
The team decide whether any emergency and/or long-term action is needed
• If necessary immediate protection with admission to hospital for observation, treatment and investigation.
(Parental consent usually obtained for this but if not, legal enforcement is necessary using a child protection
order).
• Every child at risk or referred for abuse should now have a Laming Checklist in the notes, and all sections should
be signed by the responsible consultant
• A child protection conference is scheduled to decide whether further action is necessary and what. From this
there may be a decision to place the child on the Child Protection Register, and/or the development of a child
protection care plan. In some cases placement in care is necessary (in severe cases long-term foster care and/or
adoption)

If a practitioner
. . has concerns about a child's welfare

523
Emergency action to safeguard a child

TI1E CHILDREN'S ACT

The Children's Act is a document designed for the protection of children. It was fully implemented in 1991 (and given
royal assent in 1989). The act includes the following features:
• Child's welfare is the Court's paramount consideration, so any Court order made should contribute positively to
the child's welfare
• Prime responsibility for bringing up children lies with the parents
• Local authorities should provide supportive services to help parents in bringing up children
• Local authorities should take reasonable steps to identify children and families in need
• Every local authority should have a register of children in need
• Every local authority should work in partnership with the parents
The Children Act 1989 also provides protection orders for children 'at risk'. These are:
1. Emergency protection order (EPO). Any person may apply to a magistrate's court for an EPO and then would
have parental responsibility for the child if granted. The order lasts 8 days and an extension of a further 7 days
is possible. An appeal can be made after 3 days
2. Police protection provision. A police constable may take a child into police protection without assuming
parental responsibility. This lasts up to 3 days only
3. Child assessment order. This allows proper assessment of a child to be done over a period of up to 7 days.
(Removal of the child from the family home does not necessarily occur)
1~. Care and supervision orders. These allow a child to be placed in the care of or under the supervision of the
local authority. Maximum duration is 8 weeks

524
STATEMENTING
As part of the Education Act 1981 (updated 1993) the local education authority must provide a statement for a child
with special education needs to outline the special needs of the child and the consequent services that the education
authority will provide.
• An initial assessment is made of the child's particular needs and disabilities by interested professionals (includ-
ing as necessary teacher, paediatrician, educational psychologist, occupational therapist, physiotherapist and
speech therapist)
• Then a statement of special educational needs, i.e. plan of help, of the child's educational and non-educational
needs is made, which includes information given by the parents and professionals The special services to be
offered to the child are included within the statement, e.g. one-to-one tuition, special transport to school
• It is important that the statement be regularly reviewed and revised or cancelled as necessary

WARDSHIP
If a child is a 'ward of court': 'the court is entitled and bound in appropriate cases to make decisions in the interests
of the child which override the rights of its parents'.
Wardship may not be invoked by the local authority or while the child is in care, but may be made by other interested
parties, e.g. a health authority, and it ends when a child ceases to be a minor. This is a major step to take as, when
evoked, 'no important step in the life of that child can be taken without the consent of the Court'.

INHERENT JURISDICTION
This is most commonly used in medical law cases. The court does not take all the decisions relating to the child's life,
but only in certain issues, e.g. medical care. It can be invoked in an emergency and also by a local authority even
while the child is in care.

COURT ORDERS
The court has the power to make specific issue orders and prohibited step orders.
• A prohibited step order means that no step (specified in the order) can be taken by any person (including the
parent) without the consent of the court
• A specific issue order gives directions to determine a specific question in connection with any aspect of
parental responsibility for a child
These orders cannot be made if a child is in care, or in an emergency, and are rarely made if the child is 16 years old.
They do riot represent a true order as they only allow a local authority to authorize and supervise a policy. As with all
treatment, the final decision and duty of care still rests with the doctor in charge of the case.

FURTHER READING
Meadows R, ed ABC of child abuse, 3rd edn. London: BMJ Publishing Group, London, 1997
Resuscitation Council (UK) Guidelines July/Sept 2008

525
ABCDE assessment 503, 509, 511 acute lymphoblastic leukaemia (ALL) allogenic stem cell transplantation
abdominal pain, recurrent 432-3 422
functional 156-7 immunophenotype classification alopecia 303
abducens nerve 330 432 alopecia areata 303
abetalipoproteinaemia 151 prognostic indicato rs 433 a-fetoprotein (AFP) 176
absence seizures 334, 344 acute mastoiditis 119 a-thalassaemia trait 405-6
absent radii 327, 410-11 acute miliary TB 65, 66 a-thalassaemias 403, 405-6
acanthocytes 151, 389 acute monocytic leukaemia 441 a1-antitrypsi n deficiency 139, 189-90
accessory nerve 330 acute myeloid leukemia (AML) 433-4 Alport syndrome 216
accidents classification 434 alternating squint 381
causes of fatalities 516 acute myelomonocytic leukaemia 441 ambiguous genitalia 267-8
childhood 516-21 acute nephritic syndrome 213 amblyopia 373, 380
road traffic accidents 517 acute otitis media (AOM) 117 aminoacidopathies 277-9, 357
achalasia 487 acute porphyrias 287, 288 diagnosis/treatment 278
achondroplasia 325 acute renal failure {ARF) 229-30 aminophylline 133
aciclovir 47, 50 causes 229, 230 aminotransferases 176
acid-base homeostasis 202 clinical features 229 amniocentesis 445
acidosis management 230 amniodrainage 446
anion gap 202 acute tubular necrosis (ATN) 229-30 amniofusion 446
congenital lactic acidosis 285 acyl-CoA dehydrogenase amoebiasis 72
diabetic ketoacidosis 255-6 deficiencies 281 ampicillin 47
hyperkalaemic hyperchloraemic Addison disease 241 AMPLE mnemonic 511
metabolic acidosis 218 - adenomas amyloidosis 322-3
hypokalaemic hyperchloraemic familial adenomatous polyposis 165- primary 322
metabolic acidosis 218 6 secondary 323
hypokalaemic hypochloraemic pituitary 235 anaemia 390-401
metabolic acidosis 486 in thyroiditis 245 aplastic 399-400
metabolic 461 adenosine 105 haemolytic 395-9
renal tubular 218-20 adenoviridae 49 macrocytic 393-5
respiratory 461 adrenal crisis 241 microcytic hypochromic 391-3
acinar cells' 142 adrenal glands 239 red cell aplasia 400-1
acne vulgaris 293 disorders 239-4 2 sickle cell 401-2
·l
acquired cutis taxa 309 adrenocortical insufficiency 241-2 anaemic twin 448
acquirep Fanconi syndrome 221 Aicardi syndrome 344 anagen effluvium 303
acquired hypothyroidism 244 airway, checking 504, 506 anaphylaxis 515
acquired melanocytic naevi (moles) 'alabaster skin' 236 anencephaly 342
302 Alagille syndrome 89, 184, 186 aneuploidy 7
acrodermatitis enteropathica (zinc albinism 303-4 Ange lman syndrome 17
deficiency) 169-70 albumin levels 176 angio-oedema 25-6
activated partial thromboplastin time alcohol angioedema, hereditary 35
(APTI) 408, 409 poisoning 520 anion gap 202
acute abdomen 483-5 as teratogen 20, 89 dlliridia 376
medical causes mimicking 485 aldosterone antagonists 203 Ankylostoma duodenale 75
surgical causes 484 alkaline phosphatase Levels 17~ anogenital warts 296
acute appendicitis 485-6 alkylating agents 420 anomaly scan 444
acute cortical necrosis (ACN) 230 allodynia 326 anorexia nervosa 171-2

527
antenatal screening/diagnosis 444-5 ASD see atrial septal defect Babinsky reflex 338
antenatal testing 2 'ash leaf macules 353 Bad/lus spp. 59
anterior horn cell disorders 362, 364 L-asparaginase 420 bacterial infections 39, 57-70
antibiotics 420 Asperger syndrome 372 Gram-positivej-negative bacilli 59-63
antibodies Aspergillus fumigatus 73 Gram-positivej-negative cocci 57- 9
acetylcholine receptors 366 aspiration wheeze 130-1 staphylococcal 57-8, 108, 292,
antineutrophil cytoplasmic 311 aspirin use 1go 295
antinuclear 310-11 asthma 131-4 streptococcal 58-9, 107, 108, 214,
antiphospholipid 311, 316 chronic vs exacerbation vs life- 292, 295
autoantibodies 310- 11 threatening 131 impetigo 294-5
composition 22 history 131 other bacteria 63-70
factor VIII 412 management bacterial meningitis
immunoglobulin structure 22 acute 131-2 causes 46
immunoglobulin types 23 by age 132 management 47
placental transfer 449 long-term 132 partially treated 48
anticholinergics 133 medications 132-3 TB 48
antiemetics 421 delivery devices 133-4 bacterial tracheitis (pseudomembranous
antiepileptic drugs 349-50 spacer devices 134 croup) 122
anti -extractable nuclear antigens peak respiratory flow rate 126 balano-posthitis 494
(ENAs) 311 astrocytoma 430 ballooning foreskin 494
antigen-presenting cells (APCs) 21, asymmetric tonic reflex 337 'bamboo' spine 313
24 ataxia 353-5 Barlow manoeuvre 455
antimetabolites 419 ataxia telangiectasia 32-3 Barr bodies 15
antineutrophil cytoplasmic antibodies atopic eczema (atopic dermatitis) Bartonella henselae 59, 62
(ANCAs) 311 associations 294 Bartter syndrome 222-3
antinuclear antibodies 310-11 atopy 26 basal skull fracture 513
antiphospholipid antibodies 311, 316 atrial natriuretic peptides (ANP) 200 'basket weave' renal microscopy 216
antiphospholipid syndrome 316 atrial septal defect (ASD) 79, 92-3 basophilic stippling 389
at-antitrypsin deficiency 139, 189- ostium primum 92-3 basophils 21
90 ostium secundum 92 'bathing trunk' naevus 302
aorta, coarctation of 95-6 atrioventricular septal (canal) defect BCG (Bacille Calmette-Guerin)
aortic arch (AVSD) 93 · vaccination 68
interrupted 96 attention deficit hyperactivity disorder Becker muscular dystrophy 368
right -sided 81 (ADHD) 371 Beckwith-Wiedemann syndrome 17-
aortic regurgitation 79 audiograms 116 18
aortic stenosis 79, 95 autism 371-2 associations 425
Apert syndrome 339 autoantibodies 310-11 beclomethasone 133
Apgar scores 453 autoimmune haemolytic anaemia 398 Beh~et syndrome 322
aplasia cutis congenita 291 autoimmune polyglandular syndrome benign hypermobility syndrome 327
aplastic anaemia 399-400 type 1 260-1 benign intracranial hypertension 333
associations 433 autoimmune polyglandular syndrome benign paroxysmal vertigo 348
apnoea 467-8 type 2 (Schmidt syndrome) 260-1 benign rolandic epilepsy (benign partial
apparent life-threatening events autoimmune thrombocytopenia 20, epilepsy with centroternporal
(ALTE) 515-16 449 spikes) 347
APT test 165 autologous stem cell Berger nephropathy 215
APUDomas 166 transplantation 422 beriberi (thiamine (vitamin B1)
arenavirus 54 autosomal dominant/recessive deficiency) 171
Arnold-Chiari malformation 341, 342 inheritance 13-14 Bernard-Soulier syndrome 411
arrhythmias 104-7 AVPU coma scale 508 ~ - antagonists 132, 133
arthritis of IBD 314 azithromicin 62 ~-thalassaemia 403
arthrogryposis 19 major 404
Ascaris lumbricoides 74 B cell (humoral) disorders 26, 28- 30 minor 405
ascorbic acid (vitamin C) deficiency B lymphocytes 23, 24 bicarbonate resorption, failure of 219-
(scurvy) 170 · activation 24 20

528
 bile acids 143, 176 Borrelia burgdorjen· 69 exchange 247
bile secretion 176 bow legs (genu varum) 500 physiology 24 7
biliary atresia 185-6 brachycephaly 338, 339 calcium oxalate/phosphate calculi 209
bilirubin brain 328-9 calciviridae 54
conjugated 182 blood supply 328, 329 Campylobacter spp. 60
levels 176, 180, 182 functional areas of cortex 328 cancer deaths by tumour type 419
metabolism 180 ventricular system 329 cancer genes 418
unconjugated 181-2 brain anomalies, structural 338-44 cancer incidence, childhood 419
biotinidase deficiency 275 corpus callosum agenesis 343-4 cancer treatment 420-3
Birbeck granules 439 craniosynostoses 339-40 chemotherapy 419-21
birth injuries fontanelle closure disorders 340 immunotherapy 422
bone injuries 459 head shape/size, abnormal 338-9 radiotherapy 421
head injuries 458 hydrocephalus 342-3 small molecule inhibitors 422
nerve/muscle injuries 458 neural tube defects 340-2 stem cell transplantation 422-3
birthmarks, vascular neuronal migration disorders 343 surgery 421
infantile haemangiomas 301 brain death 510 Candida albicansjcandidiasis 39, 73,
Kasabach-Merritt syndrome 302 brain tumours 429-31 108, 291
Klippel-Trenaunay syndrome 300-1 brainstem glioma 430 chronic mucocutaneous 31
neonatal haemangiomatosis 302 brainstem reflexes 510 candidate genes 7
port-wine stain (naevus breast feeding 456-7 cannon a waves 80
flammeus) 300 breast milk 456 caput succedaneum 458
salmon patch 301 breast milk jaundice 183 carbamazepine 19, 349
bite cells 389 breath-holding attacks 348 carbohydrate metabolism 175
bladder exstrophy 226-7 breathing, checking 504, 506 disorders 279-81
Blalock-Taussig shunt 100 Brill-Zinser disease 70 carbonic anhydrase inhibitors 203
Blastomyces dermatitidis 73 bronchiectasis 138 carcinogenesis
bleach poisoning 520 bronchiolitis 129-30 cancer genes 418
bleeding, gastrointestinal 164-5 bronchiolitis obliterans 130 cell growth/differentiation, regulation
causes by age 164 bronchogenic cyst 128 of 417
bleeding time 408 bronchopneumonia 64 carcinogens 419
bleomycin 420 bronchopulmonary dysplasia 46ti-7 carcinoid syndrome 166
blepharophimosis 375 Brown-Sequard syndrome 361 carcinoid tumours 166
blister cells 389 Brucella spp. 59, 62 cardiac arrest protocols 506-7
blood ABO incompatibility 183-4 Brunner's glands 142 cardiac axis 83-4
blood coagulation cascade 408 Brushfield spots 8, 376 cardiac catheterization 81
blood count and film 408 Bruton XLA 28 cardiac cycle 78
blood gas acid-base monitoring 460-1 budesonide 133 heart sounds 78-9
blood glucose monitoring 255 bulimia 172 cardiac positions
blood tests, bulla 290 apex of heart 87
antenatal 444 bullous impetigo 294
·f fetal 445
visceroatrial situs 86
bundle branch block 78, 85 cardiac scars 82
blood volume, estimated 514 buphthalmos 377 cardiogenic shock 513
'bloodhound' facies 309 Burkitt lymphoma 438-9 cardiology 7 6-113
Bloom syndrome 5 burns 517-19 arrhythmias 104-7
associations 433 assessment 518 cardiac positions 86-7
Blount disease 501 cigarette 521 cardiomyopathy 110-11
blue sclera 324 emergency treatment 519 congenital heart disease 89-104
body mass index (BMI) 172 management 518-19 acyanotic 90-7
bone age (skeletal maturity) 262 Burr cells 389 cyanotic 96-104 .
bone birth injuries 459 'butterfly' rash 315 inherited conditions in 90
bone tumours 426 button batteries, ingested 520 structural 90-104
bones 496
teratogens/maternal disorders
'hoof-shaped heart 99 calcitonin 247 in 89
Bordetella spp. 59, 63, 135 calcium 247 ECG 82-6

529
cardiology - contd ceroid lipofuscinosis (late infantile chromosome 22 microdeletion see
ECG- contd Batten disease) 284, 354 DiGeorge anomaly
axis 83-4 cestodes (tapeworms) 74 chromosome banding 6
heart block 83-4 Charcot-Marie-Tooth disease chromosome rearrangements 11- 12
rate 82 (hereditary motor-sensory chronic active hepatitis (CAH) 194, 195
ventricu lar hypertrophy 85-6 neuropathy) 365 chronic bullous dermatosis of childhood
Eisenmenger reaction 88-9 CHARGE syndrome 90, 98 (linear IgA dermatosis) 307- 8
heart fai lure 88 CHD see congenital heart disease chronic granulomatous disease
infective endocarditis 108- 9 Chediak-Higashi syndrome 34, 304 (CGD) 33-4
murmurs, innocent 87 chemotherapy 419-21 chronic idiopathic pain syndrome 326
myocarditis 109 side-effects 420 chronic iridocyclitis (uveitis) 312
neonatal 469- 70 chest X-ray chronic mucocutaneous candidiasis 31
pericar~tis 112-13 Eisenmenger reaction 89 chronic myelogenous leukaemia ,
physiology 77-82 heart failure 88 (CML) 435-6
cardiac catheterization 81 silhouette 81 chronic otitis media (COM) 118 ;
cardiac cycle 78 chicken pox (varicella) 50-1 chronic persistent hepatitis (CPH) 194,
cardiac scars 82 chignon 458 195
chest X-ray silhouette 81 child assessment order 524 chronic plaque psoriasis 293
fetal circulation 77 child development chronic renal failure (CRF) 231
heart sounds 78- 9 areas 336 acidosis types 202
jugu lar venous pulse 80 milestones 336-7 'cigarette paper scars' 309
vital signs, normal 80 reflexes 337-8 circulation, checking 505, 506
rheumatic fever 107- 8 childhood absence epilepsy 345-6 cjrculation, fetal 77
cardiomyopathy childhood histiocytosis syndromes 439- cirrhosis 179
dilated 110 41 cisplatin 420
hypertrophic 110-11 Children's Act 1989 524 cleft lip/palate 124-5
carditis 107 Children's Glasgow Coma Scale 508-9 Pierre-Robin sequence 125
care and supervision orders 524 Chlamydia spp. 63, 460 surgical repair 125
carnitine palmitoyl transferase 1 choana[ atresia 479 Clostridium spp. 59, 61
deficiency 281 choking 505-6 clotting disorders 411-15
Caroli disease 184, 186 cholecystokinin-pancreozymin (CCK- investigations 408-9
Caroli syndrome 186 . PZ) 143 coagulation factors 409
Carpenter syndrome 339 cholestatic jaundice 181 COAL mnemonic 222
carrier, typhoid 63 cholesteatoma 118 coarctation of aorta 95-6
Cas als' necklace 171 cholesterol synthesis defects 281 'cobblestone' mucosa 158
cat scratch disease 62 chondrodysplasia punctata 282 cocaine 19
cataracts 377 chordee 493 Coccidioides immitis 73
catch-up growth 262 chorionic villous sampling 445 coeliac disease 149-50
cavernous haemangiomas 301 choroid plexus papilloma 343, 431 .villous atrophy 150
ceftriaxone 47 Chotzen syndrome 340 'coeur en sabot' 99
cell cycle 4 'Christmas tree' rash 294 cofactors 272
cell growth/differentiation, regulation chromosomal disorders 7-12 colloidian baby 306
of 417 abnormalities of number 7-11 coloboma 378
cellulitis abnormalities of structure 11-12 iris 376
orbital 120- 1, 382-3 chromosomes 3, 4 lid 375
pre-septal 382- 3 deletions 11-12 colon physiology 144
central nervous system 328 duplications 12 colostrum 456
cephalhaematoma 458 loci 5 coma 508
cephalosporin 47 mosaicism 9, 15 coma scales 508-9
cereb_ellar disease 331, 353, 354 non-disjunction 7, 8 combined hyperlipidacmia 286
cerebellum 331 polymorphism 5 combined pituitary provocation test 270
cerelH dl palsy 3))-6 translocations 11 common cold 120
cereurohepatorenal syndrome (Zellweger reciprocal 11 common variable immunodeficiency
syndrome) 186, 282 Robertsonian 9, 11 (CVID) 28-9

530
common w;,.rtL 206 congen1tal urinary \.1 elL\. vi rat \acute laryngotracheobronchitis)
competence 502 obstruction 206-7 122
complement 22 management 207 vs epiglottitis 123
complement deficiencies 26, 35 sites 207 Crouzon syndrome 339
complete (third degree) heart block 80, conjugated hyperbilirubinaemia 182 cryptococcosis 39, 73
84, 106 neonatal 184-5 Cryptococcus neoformans 73
complex partial seizures 345 conjunctivitis 382 cryptorchidism (undescended
concussion 512 consciousness 508 testes) 489-90
conductive deafness 115-16 brain death 510 Cryptosporidium parvum 39, 70
congenital adrenal hyperplasia loss of 510 Cullen sign 163
(CAH) 263, 268-9 reduced 508-10 Cushing disease 239
steroid biosynthesis 268 management 509-10 Cushing reflex 332
congenital atresias 479-81 consent 502 Cushing syndrome 172, 239-40
congenital defects 18-20 constipation 160-2 causes 239, 240
dysmorphology 18-19 faecal soiling 162 dexamethasone suppression tests 270
maternal illness, effects of 20 Hirschsprung disease 161-1 diagnosis/investigations 240
teratogens 19-20 continuous positive airway pressure treatment 240
congenital diaphragmatic hernia 482-3 (CPAP) 461 cutaneous diphtheria 60
congenital disorders of glycosylation convergent squint 380-1 cutaneous polyarteritis 319
(CDG) 281-2 convulsions see seizures cutaneous porphyrias 287-8
congenital dysplasia of hip 496 copper metabolism 187 cutaneous reactions
congenital Fanconi syndrome 221 copper transport 358 erythema multiforme 298- 9
congenital heart disease (CHD) 89- corneal abnormalities 376 erythema nodosum 298
104 corneal light reflection test 381 mastocytosis 299
acyanotic 90-7 coronary artery aneurysms 320 toxic epidermal necrolysis 299
cyanotic 96-104 corpus callosum agenesis 343-4 cutis laxa 309
causes 97 cortex, functional areas of 328 cyanosis
complications 97 cortical tuber 353 causes 97, 469-70
prostaglandin (PGE2) 97 corticospinal tracts (pyramidal nitrogen washout test 97
inherited conditions in 90 system) 331 cyclizine 421
structural 90-104 cortisol (hydrocortisone) 239 cyclophosphamide 420
teratogensjmaternal disorders in 89 Corynebacterium diphtheriae 59 cystic adenomatoid malformation
congenital hereditary endothelial cotrimoxazole 62 (CAM) 128
dystrophy 376 cough, chronic 134 cystic fibrosis 136- 8
congenital hereditary stromal court orders 525 associations 488
dystrophy 376 cover test 381 clinical features 136
congenital hyperbilirubinaemia 187 cow's milk protein intolerance 147-8, 150 diagnosis 137
congenital hypertrophic pyloric Coxiella burnetii 63 examination findings 137
stenosis 486-7 cranial diabetes insipidus 237-8 gene therapy 3
congenital hypertrophy of retinal cranial nerves 330 management 137-8
·! pigment epithelium (CHRPE) 165 craniofacial malformations affecting neonatal presentation 136
congenital hypothyroidism 244 development 379 review, regular 138
congenital infections 449-52 craniopharyngioma 235, 431 cystine 222
congenital intestinal atresias 481 craniosynostoses 339-40, 379 cystinosis 221-2
congenital lactic acidosis 285 mutations 339 cytogenetic abnormalities 423
congenital lobar emphysema 483 craniotabes 249 cytogenetic analysis techniques 6
congenital malformations, CREST syndrome Schirmer test 318 cytokines 22
respiratory 128 cri du chat syndrome 11, 12 cytomegalovirus (CMV) 39, 51-2, 450
congenital melanocytic naevi 30? Criqler-Najjar syndrome 187
congenital muscle fibre-type Crohn disease 158 dacryocystocele 37 6
disproportion 369 extra-abdominal features 159-60 Dandy-Walker syndrome 342
congenital myasthenia gravis 367 croup Darier's sign 299
congenital myopathies 369-70 pseudomembranous (bacterial daunorubicin 420
congenital rubella syndrome 89 tracheitis) 122 de Quervain thyroiditis 245 ·

531
deafness 115-16 dexamethasone 47 composition 3
dehydration 152 relative strength 239 defective repair 5
assessment 152 dexamethasone suppression tests 270 rep li cation 3- 4
bicarbonate calculation 153 dextrocardia 87 sequencing 6
hypernatraemic 153 diabetes insipidus 237- 8 structure 3
maintenance fluid calculation 153 diabetes mellitus 89, 253-7, 449 DNA chips 7
rehydration fluids 153 blood glucose monitoring 255 DNA repair genes 418
delayed puberty 266-7 'bronzed diabetes' 188 DNA viruses 49
delivery 453-4 clinic checks 255- 6 dolichocephaly (scaphocephaly) 338,
high-risk 454 clinical features 254 339
resuscitation 453 comp lications, long-term 255-6 donor T cells 1122
dendritic cell disorders 439-40 diabetic ketoacidosis 255-6 double inlet ventricle 100
deoxyhaemoglobin 386 diagnosis 254 Down syndrome (trisomy 21) 8.-9, 90
depressed skull fracture 513 management 254-5 associations 92, 93, 98, 161, 294,
dermatitis 291 recent developments 255 433 ~

atopic 291-3 maternal 20, 103 doxorubicin 420

herpetiformis 149 problems 255 drowning 517
irritant 291 type 1 253-7 drug abuse, maternal 474
seborrhoeic 291 type 2 253 drug metabolism 176
dermatology 289-309 dialysis, renal · 231-2 drug therapy, resuscitation 453
acne vulgaris 293 Diamond-Blackfan syndrome 401 drug withdrawal 474
alopecia 303 diarrhoea dry beriberi 171
atopic eczema (atopic bloody 152 Dubin-Johnson syndrome 187
dermatitis) 291-3 chronic 155 Duchenne muscular dystrophy 367-8
cutaneous reactions 298-9 osmotic vs secretory 154 gene therapy 3
cutis taxa 309 toddler's diarrhoea 149, 155 Duckett Jones criteria 107
DNA fragility syndromes 308 watery 152 duct-dependent circulations 104, 470
ectodermal dysplasias 308-9 DIDMOAD (Wolfram syndrome) 238 Duncan (X-linked lymphoproliferative)
Ehlers-Danlos syndrome 309 dietary protein intolerance 147-8 syndrome 30
examination 289 diethylenetriami nepenta-acetic acid duodenal atresia 481
ichthyoses, congenital 306-7 (DPTA) 204 duodenal ulcers 157
infections 294-8 diethylstilboestrol 20 duodenum/jejunum physiology 142- 3
head lice 297 diffuse cutaneous mastocytosis 299 duplex kidney 204, 226
impetigo 294-5 diffuse cutaneous systemic sclerosis 318 dynamic nuclear medicine (DTPA and
molluscum contagiosum 295 diffuse glomerulonephritis 212 MAG3) scan 204
pityriasis versicolor 297 DiGeorge anomaly (microdeletion dysplastic kidney 224-5
ringworm (tinea) 296 syndrome) 30-1, 248 dystichiasis 3 75
scabies 297-8 associations 90, 98 dystrophic epidermolysis bullosa 307
staphylococcal scalded skin dilated cardiomyopathy ( DCM) 110
syndrome 295 dimercaptosuccinic acid (DMSA) 521 Eagle-Barrett (prune belly)
viral warts 296 dimercaptosuccinic acid (DMSA) syndrome 227
keratosis pilaris 294 scan 204 ears 114-19
naevi 300, 302-3 disc pallor 379 ear conditions 117-19
nappy rash 291 disc swelling 378 hearing ~ss 115-16
neonatal conditions 290-1 discoid lupus 315 hearing tests 114-15
pigmentation disorders 303- 5 disomy, uniparental 17 eating disorders
pityriasis rosea 294 disseminated intravascular coagulation anorexia nervosa 171-2
psoriasis 293-4 (DIC) 414 bulimia 172
terminology of common lesions 290 dissociative shock 514 obesity 172-3
vasclllilr birthmarks 300-2 distributive shock 513 Ebstein anomaly 100- 1
vesicobullous disorders 307-8 diuretics 202-3 ECG see electrocardiog ram
dermatophytoses 73 divergent squint 381 ectopic kidney 226
dermoid 376 DNA ectrodactyly-ectodermal dysplasia-
developmental dysplasia of hip 496 analysis techniques 6- 7 clefti ng ( EEC) syndrome 308

532
ectropion 375 encephalocoele 342 enterohepatic circulation 144
eczema encephalopathy enterovirus encephalitis 48
acute/subacute 291 HIV 37 enthesitis-related arthropathy
atopic 291 - 3 hypoxic-ischaemic 471-2 (ERA) 313-14
chronic 291 lead 521 X-ray changes 313
herpeticum 292 encopresis 162 entropion 375
Education Act 1981 525 end-stage renal failure (ESRF) 231 enzymes
Edwards syndrome (trisomy 18) 9-10, endemic typhus 70 chemotherapy 420
90 endocarditis, infective 108-9 digestive 143
EEC (ectrodactyly-ectodermal dysplasia - endocrine syndromes 260-1 in metabolic disorders 272, 274
clefting) syndrome 308 endocrine tests pancreatic 142
EEG see electroencephalogram combined pituitary provocation ependymoma 431
'egg on side'-shaped heart 104 test 270 epiblepharon 375
Ehlers-Danlos syndrome 90, 309 dexamethasone suppression tests epicanthus 375
benign hypermobility syndrome 327 270 epidermolysis bullosa 307
Eisenmenger reaction 88-9 glucose tolerance test 271 epidermolysis bullosa simplex 307
Eisenmenger syndrome 88, 91 growth hormone (GH) stimulation epididymo-orchitis 492
ejection murmur 87 tests 269 epiglottitis, acute 122-3
electrical burns 518 LHRH stimulation test 270 vs viral croup 123
electro-retinogram (ERG) 375 synacthen stimulation tests 271 epilepsy
electrocardiogram (ECG) 82-6 TRH stimulation test 270 antiepileptic drugs 349-50
aortic stenosis 95 endocrinology 233- 61. 269-71 investigation 344-5
atrial septal defect 92 adrenal gland disorders 239-42 later development 348
axis 83-4 adrenocortical insufficiency seizure classification 344
deviation 84 241-2 status epilepticus 349 .
dextrocardia 87 Cushing syndrome 239-40 syndromes 345-7
Eisenmenger reaction 89 phaeochromocytoma 242 Epilim 349
heart block 83-4 primary hyperaldosteronism 240-1 epistaxis 120
patent ductus arteriosus 93 endocrine syndromes 260-1 Epstein-Barr virus 52-3
pulmonary stenosis 94 endocrine tests 269-72 Epstein's pearls 290
rate 82 glucose metabolism 252-8 Erb palsy 458
tetralogy of Fallot" 98 diabetes mellitus 253-7 erosions 290
torsade de pointes 106 hypoglycaemia 257-8 erythema
ventricular hypertrophy 85-6 hypothalamus/pituitary 233-9 chronicum migrans 69
ventricular septal defect 91 craniopharyngioma 235 infectiosum 53
electroencephalogram (EEG) 334-6 diabetes insipidus 237-8 marginatum 107
absence seizures 334 hypopituitarism 236-7 multiforme 298-9
burst suppression pattern 336 physiology 233 nodosum 298
encephalopathy, acute 335 pituitary gigantism 235 toxicum neonatorum 290
hypsarrhythmia 335 pituitary tumours 233-4 erythropoiesis/erythropoietin 387
'\nterpretation 334 prolactinoma 236 Escherichia coli 60
left temporal infarct 335 syndrome of inappropriate ADH ethambutol 67, 68
mono'clonic epilepsy 334 secretion (SIADH) 238-9 etoposide 420
electrolyte absorption/excretion 201 pancreatic tumours 259-60 Ewing sarcoma 426
electromyography (EMG) 333 parathyroid disorders 247-52 exanthem subitum 53
Ellis-van Creveld syndrome 92, 325 polycystic ovary syndrome excoriation 290
Embden-fvieyerhof pathway 388 (PCOS) 252 exomphalos 481-2
emergency protection order (EPO) 524 thyroid disorders 243-6 expiratory stridor 121
Emery-Dreifuss muscular dystrophy 368 see also growth; puberty extracorporcal membrane oxygenation
emotional abuse 522 endothelial cells 21 462
emphysema 78 Entamoeba histo/ytica 70, 72 extradural haematoma 512
en Coup de Sabre 317 enteral feeds 463 extrapyramidal system 331
encephalitis 48-9, 51 Enterobius vermicularis 74 eye lid abnormalities 375
Rasmussen 347 enterocyte secretion 142 eye movements 381

533
fabricated or induced illness (FII) 519, first degree heart block 84 gas transfer factor 128
522-3 'fish mouth' 368 gastric acid secretion 141-2
facial nerve 330 fixed talipes 502 gastric inhibitory peptide (GIP) 143
facial nerve palsy 458 flat feet (pes planus) 500 gastric ulcers 157
facioscapulohumeral muscular flaviviridae 54 gastrin 141-2
dystrophy 368 floppy baby 8, 363-4 gastrinoma (Zollinger-Ellison
factor VIII 412-13 floppy larynx (laryngomalacia) 121 syndrome) 157, 259 - 60
factor VIII antibodies 412 flow-volume curves 128 gastro-oesophageal reflux 144-5
faecal retention with overflow fluid therapy 153 gastroenteritis 151-4
incontinence 162 burns 519 bacterial/protozoal 152
faecal soiling 162 neonatal 462 causes 151- 2
faecoliths 160 flukes (trematodes) 74 clinical features/differential
Fallot's tetralogy see tetralogy of Fallot fluorescent in situ hybridization diagnosis 152
faltering growth see growth, faltering (FISH) 6 complications 154
familial adenomatous polyposis coli fluticasone 133 dehydration 152-3
(FAP) 165-6 focal segmental glomerulonephritis 212, examination findings 152
familial combined hyperlipidaemia 286 215 investigations 153
familial dysautonomia (Riley-Day focal segmental glomerulosclerosis 210 management 153
syndrome) 370 folic acid 394, 445 post-gastroenteritis intolerance 148
familial hypercholesterolaemia 286 deficiency 340, 393 viral 151
familial hypertriglyceridaemfa 286 tests 395 gastrointestinal (GI) disorders 141-73
familial hypophosphataemic (vitamin follicular dendritic cells (FDCs) 24 chronic abdominal pain 156-7
D-resistant) rickets 251 fontanelle closure disorders 340 constipation 160-3
Fanconi anaemia 400 food intolerances 147-9 diarrhoea 154-5
associations 433 Forchheimer spots (palatal eating disorders 171-3
Fanconi syndrome 221 petechiae) 55 G! bleeding 164-5
fatty acid oxidation defects 281 foreign bodies 119 gastroenteritis 151-4
febrile child 42-4 formal water deprivation test 237 growth, faltering 166-8
features of unwellness 43-4 formotorol 133 inflammatory bowel disease 158-60
history/examination 43 forward parachute reflex 338 malabsorption 147-51
management 43-4 fractures during birth 459 causes/investigations 147
prolonged fever 44 fragile Xsyndrome 16 Shwachman-Diamond
symptoms/signs 44 Frazer competence 502 syndrome 34-5
febrile convulsions 34 7-8 Friedreich ataxia 354-5 neonatal 474-6
feeding, infant see infant feeding Friedreich's sign 112 nutritional disorders 168-71
female pseudohermaphrodite 267 'frozen watchfulness' 521 pancreatitis 162-4
femoral anteversion 500 fructose intolerance, hereditary 280 peptic ulcer 157
fetal alcohol syndrome 379 fulminant hepatic failure (FHF) 177-9 physiology 141-4
fetal blood sampling 445, 447 causes 177 colon 144
fetal circulation 77 clinical manifestations 177-8 duodenum/jejunum 142-3
fetal distress 471 complications 178-9 enterohepatic circulation 144
fetal haemoglobin 388 investigations 178 ileum 143
fetal medicine 446-9 management 178 oesphagus 141
fetal therapy 446 prognostic features 178 pancreas 142
high-risk pregnancies 446, 447 fungal infections 39, 291, 296, 297 stomach 141-2
maternal illness 448-9 funisitis 460 surgical conditions 483 - 9
multiple pregnancy 446, 447, 447-8 'funny turns', non-epilepsy 348-9 tumours 165-6
fibrin 408 upper GI
fibrinolysis tests 409 gabapentin 350 gastro-oesophageal reflux 14/f-5
fictitious (fabricated) or induced illness galactosaemia 280, 377 hiatus hernia 145- 6
(FII) 519, 522 - 3 gallbladder disease 197 possetti ng 145
Fifth disease 53 gallstones 197 vomiting 146- 7
filiform warts 296 y-glutamyl transpeptidase levels 176 gastroschi sis 482
fine motor milestones 336-7 Gardner syndrome 165 Gaucher disease 284

534
genes glucagonoma 259 GH stimulation tests 269
dominant/recessive 12 glucocorticoid axis 239 growth spurts, pubertal 265
autosomal 13-14 gluconeogenesis 175, 252 Guillain-Barre disease 365-6
X-linked 14-15 glucose-6-phosphate dehydrogenase Guthrie test 137, 243, 277, 281, 455-6
gene mapping techniques 7 deficiency 397 guttate psoriasis 294
gene therapy 2-3 glucose-galactose malabsorption 149
generalized seizures 344 glucose metabolism 252-8 haem biosynthesis pathway 287
generalized tonic-clonic seizures 345 diabetes mellitus 253-7 haematology 386-416
genetics 1-20 hypoglycaemia 257-8 anaemia 390-401
basic cell genetics 3-4 glucose tolerance test 271 aplastic 399-400
clinical application 1-3 glue ear (otitis media with effusion) haemolytic 395-9
genetic carrier testing 2 117-18 macrocytic 393-5
genetic counselling 1 gluten intolerance 149 microcytic hypochromic 391-3
genetic disorders 7-20 glycogen storage diseases 279 red cell aplasia 400-1
chromosomal 7-12 glycogenolysis 17 5 haemoglobinopathies 401-6
congenital defects 18-20 glycosylation disorders 281-2 sickle cell haemoglobinopathies
multifactorial inheritance 18 goitre 246 401-3
single gene defects 12-18 Goldenhar syndrome 379 thalassaemias 403-6
genetic screening 1-2 gonadaljgerm cell tumours 428 haemostasis 407-15
genitourinary conditions, surgical 483- gonadotrophin blood coagulation cascade 408
9 delayed puberty 266 clotting disorder
genu valgum (knock knees) 500 precocious puberty 265 investigations 408-9
genu varum (bow legs) 500 Goodpasture disease 216 clotting factor disorders 411-15
German measles (rubella) 54-5 Gottron's papules 317 platelet disorders 409-11
GH see growth hormone Gower's sign 368 vasculature, disorders of 409
giant a waves 80 graft-versus-host disease 422-3 neonatal 477
giant cell arteritis 319 granulomatous vasculitis 319 physiology 386-9
Giardia Iamblia 70, 72. 150 Graves disease 245 blood coagulation cascade 408
giardiasis 72-3 Grey Turner sign 163 erythropoiesis/erythropoietin 387
Gilbert syndrome 187 gross motor milestones 336-7 haemoglobin 386-7
gingivostomatitis 50 group A ~-haemolytic streptococcal haemoglobin C 403
Gitelmah syndrome 222-3 (GAS) infection 107 methaemolgobi naemia 387
glandular fever (infectious group B ~-haemolytic streptococcal oxyhaemoglobin dissociation
mononucleosis) 52 (GBS) infection 459-60 curve 387
Glanzmann disease 411 growing pains 327 platelets 407
Glasgow Coma Scale 508-9 growth 261- 4 red blood cells 388-9
glaucoma 300 assessment 261 polycythaemia 406-7
congenital 377- 8 bone age (skeletal maturity) 262 spleen 415
gliadin intolerance 149 catch-up 262 thrombocythaemia 407
glomerular filtration 199-200 failure 236-7 haemochromatosis 188-9
glomerular filtration rate (GFR) 199- faltering 37, 166-8 neonatal 189
200 atopic children 292 transfusion-induced 189
glomefulonephritis 212-17 causes 167 haemodialysis 232
acute nephritic syndrome 213 cystic fibrosis 136 haemoglobin 386
Alport syndrome 216 medical management 167-8 in anaemia 391
Goodpasture disease 216 nutritional disorders 168-71 fetal vs adult 388
haematuria, causes of 216-17 phases 261 function 386
Henoch-Schonlein purpura 214-15 predicted eventual adult height 261 haem synthesis 387
histological classification of short stature 262-3 lack of see anaemia
pathology 212-13 tall stature 263 - 4 in thalassaemias 403
IgA (Berger) nephropathy 215 velocity 262 haemoglobin C 403
post-streptococcal 214 growth charts 261 haemoglobinopathies 401-6
SLE nephritis 216 growth hormone (GH) sickle cell haemoglobinopathies 401-3
glossopharyngeal nerve 330 deficiency 236, 263 thalassaemias 403-6

535
haemolysis 181. 403 heart shape hermaphrodite 267
haemolytic anaemia 395-9 boot 99 herpes labialis 50
autoimmune 398 'egg on side' 104 herpes simplex virus (HSV) 39, 49-50
in ~-thalassaemia major 404 snowman 103 diagnosis/treatment 50
haemolytic jaundice 180-1 heart sounds 78- 9 encephalitis 48
rhesus/ABO incompatibility 183-4 aortic stenosis 95 neonatal 460
haemolytic uraemic syndrome 217-18 atrial septal defect 92 serious infection 50
diarrhoea-positivej-negative 217 first (51) 78 herpesviridae 49
haemophagocytic lymphohistiocytosis fourth (54) 79 heterocromia 376
440 pulmonary stenosis 94 hexose monophosphate pathway 388
haemophilia A 412-13, 414 second (A2 P2) 78 HHV6 53
antenatal/carrier detection 413 tetralogy of Fallot 99 hiatus hernia 145-6
haemophilia B (Christmas disease) 413, third (53) 79 hidrotic ectodermal dysplasia 309
414 ventricular septal defect 91 high frequency oscillatory
gene therapy 3 heel prick test see Guthrie test ventilation 462
Haemophilus spp. 59 Heinz bodies 389 Hirschsprung disease 160, 161
haemopoiesis sites 388 He/icobader pylon" 60, 157 histiocytoses
haemorrhagic disease of newborn 455 heliotrope violaceous rash 317 class I: dendritic cell disorders 439-
haemostasis 407-15 Henoch-Schonlein purpura 214-15 40
blood coagulation cascade 408 associations 488 class II: macrophage disorders 440
clotting disorders 7111-15 hepadnaviridae 49 class III 441
investigations 408-9 hepatic fibrosis, congenital 191 Histoplasma capsulatum 73
platelet disorders 409-11 hepatitis HIV/AIDS 36-40
tests 414 chronic 194-5 classification 37
vasculature, disorders of 409 viral 191-4 clinical manifestations 37-8
hair Loss 303 hepatitis A (HAV) 191-2 diagnosis 36-7
hand, foot and mouth disease 54 serology 19 2 growth, faltering 37
happy-puppet syndrome see Angelman hepatitis B (HBV) 192-3 HIV encephalopathy 37
syndrome HBV particle 192 HIV structure 36
harlequin ichthyosis 306 infants of carrier mothers 193 lymphocytic interstitial pneumonitis
hay fever 383 markers 19-3 37
Hb Barts (hydrops fetalis) 405, 406 serology 193 opportunistic infections 37-8
HbH disease 405, 406 hep;ititis C {HCV) 194 therapy 40
head injuries hepatitis D (HDV) 194 transmission 36
birth 458 co-infection vs superinfection 194 vertical, reduction of 40
forms 512 hepatitis E (HEV) 194 tumours 38-9
traumatic 512-13 hepatocellular carcinoma 429 and vaccination 42
head lice 297 hepatolenticular degeneration (Wilson HOCM 79
head shape/size, abnormal 338-9 disease) 187-8 Hodgkin disease 436-7
headaches 350-1 hepatomegaly 179 Holt-Dram syndrome 90, 92
hearing loss 115-16 hepatoportoenterostomy (Kasai homocystinuria 278
hearing tests 114-15 procedure) 186 'honeycomb lung' 465
audiograms 116 heptoblastoma 429 hookworm 75
testing schedules 114 herald patch 294 hormone metabolism 176
tuning fork tests 115 hereditary angioedema 35 hormones, gastrointestinal 141-2, 143
heart block 83-4, 106 hereditary elliptocytosis 397 horseshoe kidney 226
heart murmurs hereditary fructose intolerance 280 Howell-Jolly bodies 389
aortic stenosis 95 hereditary haemorrhagic human leucocyte antigens (HLA) 24
atrial septal defect 92 telangiectasia 409 Hunter syndrome 90, 284
innocent 87 hereditary motor-sensory neuropathy Huntington disease 16
patent ductus arteriosus 93 (Charcot-Marie-Tooth disease) 365 Hurler disease 283, 284
pulmonary stenosis 94 hereditary sensory neuropathy 370 Hutchinson teeth 452
tetralogy of Fallot 99 hereditary spherocytosis 396-7 hydrocephalus 342-3
ventricular septal defect 91 Hermansky-Pudlak syndrome 304 hydrocoele 491

536
hydrocortisone (cortisol) 239 hypoglossal nerve 330 hypersensitivity reactions 24-6
hydrogen ion excretion, failure of 219 hypoglycaemia 257-8 immune activation/interaction 24
hydronephrosis 226 associations 463, 464 immunodeficiencies and infections 26
hydrops fetalis (Hb Barts) 405, 406, ketotic 258 innate immunity 21-2
477 neonatal 477-8 specific immunity 23
11 ~-hydroxylase deficiency 269 persistent 257-8 immune thrombocytopenia (idiopathic
21-hydroxylase deficiency 268-9 in resuscitation 506 thrombocytopenic purpura) 410
3~-hydroxysteroid dehydrogenase transient neonatal 257 immunization schedule 41, 61
deficiency 268-9 hypohidrotic ectodermal dysplasia 308-9 immunodeficiencies
hyper IgE (Job syndrome) 33 hypokalaemia 257 acquired 35-40
hyper IgM, X-linked immunodeficiency and ECG 86 causes 35-6
with 33 hypokalaemic alkalosis 137 HIV/AIDS 36-40
hyperaldosteronism hypokalaemic hyperchloraemic metabolic clinical features 26-8
primary 240-1 acidosis 218 examination 27
secondary 240 hypokalaemic hypochloraemic metabolic history 26-7
hyperammonaemia 276 acidosis 486 and infections 26
hyperbilirubinaemia hypomelanosis of Ito 304-5 inherited 28-35
congenital 187 hypoparathyroidism 248 B cell (humoral) disorders 26,
conjugated 182, 187 hypophosphataemia 257 28-30
neonatal 184- 5 hypopituitarism 236-7 combined humoral/cell-
unconjugated 187 congenital 236 mediated 26, 31-3
hypercalcaemia 251-2 hypoplastic left heart syndrome 101 complement deficiencies 26, 35
hypercholesterolaemia 286 hypospadias 492-3 neutrophil disorders 26, 33-5
hypercromia 376 hyposp lenism 416 T cell (cell mediated) disorders 26,
hypercyanotic spells 98 hypothalamus see pituitary/ 27, 30-1, 36
hyperglycinaemia, non-ketotic 278-9 hypothalamus disorders investigations 27-8
hyperinsulinism 477, 478 hypothyroidism 243-4 villous atrophy 150
hyperkalaemia acquired 244 immunoglobulins 22, 23, 30
and ECG 86 congenital 244 immunoglobulin deficiency 35-6
management 230 Guthrie test 243 disorders 29, 33
hyperkalaemic hyperchloraemic hypotonia, neonatal 8, 363-4 immunological function of liver 176
metabolic acidosis 218 hypovolaemia, intravascular 211 immunology 21-40
hyperlipidaemias 286 hypovolaemic shock 513 immune system components 21-6
hypermetropia 379 hypoxia - ischaemia 470-2 immunodeficiencies
hyperpigmentation 266 hypoxic-ischaemic encephalopathy acqui red 35-40
hypersensitivity reactions 24-6 471-2 clinical features 26-8
atopy 26 hypsarrhythmia 335, 346 infections associated 26
skin tests 25 inherited 28-35
in tuberc~losis 64 IBD see inflammatory bowel disease immunosuppressants in renal
urticaria/angio-oedema 25-6 ichthyoses, congenital 306-7 transplant 232
hypertelorism 379 ichthyosis vulgaris 306 immunotherapy 422
hypertension 228-9 icterus see jaundice imperforate anus 481
benign intracranial 333 idiopathic inflammatory impetigo 294-5
persistent pulmonary, of newborn 470 myopathies 316-17 impetigo contagiosa 294
portal 195-7 idiopathic scrotal oedema 492 impri nting 16-18
pulmonary 78, 80 idiopathic thrombocytopenic purpura in-toeing 500
hyperthyroidism 20, 245, 449 (immune thrombocytopenia) 410 incontinentia pigmenti 304
neonatal 245 IgA nephropathy 215 infant feeding 456-7
hypertriglyceridaemias 286 IgG subclass deficiency 30 breast milk/feeding ft56 -7
hypertrophic cilrdiomyopathy 110- 11 ileum physiology 143 requirements 456
hyperuricaemia 227 immotile cilia (Kartagener) syndrome weaning 456, 457
hypocalcaemia 248, 463 138-9 infant formula 148, 149, 457
hypocromia 376 immune system infantile acne 293
hypogammaglobulinaemias 28, 29 human leucocyte antigens (HLA) 24 infantile haemangiomas 301

537
infantile Refsum disease 282 single gene defects 16-18 bilirubin metabolism 180
infantile spasms 346 X-linked 14-15 breast milk 183
infections/infectious diseases 41-7 5, innate immunity 21-2 cholestatic 181
382-4 inspiratory stridor 121 haemolytic 180-1
bacterial 39, 57- 70 insulin 253 rhesus/ABO incompatibility
Gram-positivej-negative bacilli therapy 254 183-4
59- 63 exercise/illness 255 neonatal 181- 6
Gram-positivej-negative cocci 57- types 255 causes 182
9, 292, 294-5 insulin-like growth factor (IGF-1) 263, management 182-3
other bacteria 63-70 264 unconjugated 182
dermato logical 294-8 insulin resistance 253 physiological 183
eye 382-3 intermittent positive pressure jejunal biopsy 150
febrile child 42-4 ventilation (IPPV) 122, 462 Jervell-Lang-Neilson syndrome ;107
fungal 39, 291, 296, 297 internal tibial torsion 500 JIA see juvenile idiopathic arthritis
group A ~-haemolytic streptococcal intestinal lymphangiectasia 150-1 jitteriness 473
(GAS) 107 intestinal malrotation 487-8 Job syndrome (hyper IgE) 33
helminthic 74-5 intestinal nematode infections 74-5 jugular venous pulse 80
HIV associated 37- 8 intestinal obstruction 485 junctional epidermolysis bullosa 307
immunodeficiency associated 26 neonatal 475-6 juvenile colonic polyps 165
intrapartum/postpartum 459-61 intracerebral contusions 512 juvenile idiopathic arthritis (JIA) 311-
neonatal herpes simplex infection intracranial haemorrhage 385 15
460 intracranial pressure, raised 332-3, enthesitis-related arthropathy 313-
neurodegenerative disorders 357 429-30 14
orthopaedic 495-6 acute 332- 3 management of JIA 314- 15
prion infection 357 chronic 333 oligoarticular JIA 312
protozoal 38- 9 intrauterine/intrapartum hypoxia 471 polyarticular JIA 312
respiratory 134-6 intravascular haemolysis 396 reactive arthritis 314
seriously unwell child 44-9 intravascular hypovolaemia 211 subclassification 312
in sickle cell anemia 402 intravenous urography (IVU) 203 systemic -onset JIA 313
streptococcal infections 459-60 intussusception 488-9 X-ray changes 311
vaccination 41-2 ipratropium bromide 133 juvenile mye_lomonocytic leukaemia
viral 39, 49-57, 296-7, 357, 364-5 IPPV 122, 462 (JMML) 435
DNA viruses 49- 53 iridocyclitis, chronic (uveitis) 312 juvenile myoclonic epilepsy 346
RNA viruses 54-7 iris abnormalities 376 juvenile-onset dermatomyositis 317-7
infectious mononucleosis (g landular iris co loboma 376 juvenile psoriatic arthropathy 314
fever) 52 lrOn juvenile xanthogranuloma 440
infective endocarditis 108- 9 intake/absorption 391-2
infestations metabolism 391 Kallman syndrome 266, 306
head lice 297 overload 404 Kaposi syndrome 39
scabies · 297-8 poisoning 520 Kartagener (immotile cilia) syndrome
inflammatory bowel disease (IBD) supplementation 463 138-9
arthritis of IBD 314 iron-deficiency anaemia 391-2 karyotyping 6
Crohn disease 158, 159, 160 irritable hip 499-500 Kasabach-Merritt syndrome 302
ulcerative colitis 158-60 irritant dermatitis 291 Kasai procedure (hepatoportoenterostomy)
inflammatory linear verrucous epidermal ischaemia 359-60, 470 186
naevi 303 see also hypoxia-ischaemia Kawasaki disease 320
infratentorial tumours 430-1 ischaemic heart disease 79 Kayser-Fleischer ring 188
inguinal hernia 490, 491 islets of Langerhans 142 keratoconjunctivitis 50
inguinal swe llings 489-90 isoniazid 67, 68 keratoconus 376
inherent jurisdiction 525 isotretinoin 19 keratosis pilaris 294
inheritance isovaleric acidaemia 275 kerions 296
autosomal dominant/recessive 13- 14 kernicterus 182
Mendelian 12 Janeway lesions 108 ketoacidosis, diabetic 256- 7
multifactorial 18 jaundice (icterus) 180-6 ketotic hypoglycaemia 258

538
kidneys the law 524-5 liver disorders 17 4-98
chronic abdominal pain, causes LBBB (left bundle branch block) 79, 85 cirrhosis 179
of 156 lead encephalopathy 521 congenital hepatic fibrosis 191
development 223 lead poisoning 521 fulminant hepatic failure (FHF) 177-9
aberrant 223-4 left bundle branch block (LBBB) 79, 85 gallbladder disease 197
duplex 204 left ventricular function, impai red 78 hepatitis
physiology 199-204 left ventricular hypertrophy (LVH) 85 chronic 194-5
acid-base homeostasis 202 legal issues 524-5 viral 191-4
atrial natriuretic peptides (ANP) Legg-Calve-Perthes (Perthes disease) hepatomegaly 179
200 497 jaundice (icterus) 180-6
diuretics 202-3 Legione/la pneumophila 59 bilirubin metabolism 180
electrolyte absorption/excretion Leigh syndrome 285 cholestatic 181
201 Leishmania spp. 70 haemolytic 180-1
function 199 Lennox-Gasta ut syndrome 347 neonatal 181-6
glomerular filtration 199-200 lepromatous leprosy 68 liver disease, clinical manifestations
renal blood flow (RB F) 200 lepromin test 68 of 177
renal radiologica l investigations leprosy 68 metabolic 187-91
203- 4 Leptospira interrogans 63 a1-antitrypsin deficiency 189-90
renin -a ngiote nsi n-a ldoste ron e Lesch-Nyhan syndrome 228 haemochromatosis 188-9
system 200 leucocoria (white pupil) 377 Reye syndrome 190-1
transplantation 232 leucocyte adhesion defects (LAD) 35 Wilson disease (hepatolenticular
see also renal disorders leucocytes 21, 23 degeneration) 187-8
Klebsiella pneumoniae 60 leucocytoclastic vasculitis 319 portal hypertension 195-7
Kleeblattschadel deformity 338 leukaemias 431-6 transplantation 197-8
Klinefelter syndrome 11 acute lymphoblastic leukaemia 432-3 liver physiology/anatomy 174-6
Klippel-Trenaunay syndrome 300-1 acute myeloid leukemia 433-4 functional acinus 175
Klumpke palsy 458 chronic myelogenous leukaemia 435- functions 17 4- 6
knock knees (genu valgum) 500 6 bile 176
Kussmaul respiration 256 myelodysplastic syndromes 434-5 carbohyd rate metabolism 175
Kussmaul's sign 112 leukotriene receptor antagonists 133 hormone/drug metabolism 176
kwashiorkor 168 LHRH stimulation test 270 immunological 176
kyphosis 498 lichenification 290 investigative blood tests 17 6
lid coloboma 375 lipid metabolism 175
lacrimal system abnormalities 375-6 life support protein metabolism/degradation
lactose intolerance 148-9 advanced 506-8 74
laevocardia 87 basic 503, 504-5 liver tumours 428- 9
lamellar ichthyosis 306 lightning, burns from 518 'lizard skin' 306
lamotrigine 349 limb girdle muscular dystrophy 368 'lobster claw' deformity 308
Landau-Kleffner syndrome 347 limited cutaneous systemic sclerosis localized scleroderma (morphoea) 317
Landau reflex 338 318 loop diuretics 202
tangerhans' cell histiocytosis 439-40 limping 494 lower motor neuron (LMN) lesions 331
Langerhans' cells 24 linear IgA dermatosis (chronic bullous lumbar puncture 47
langu~ge milestones 336-7 dermatosis of childhood) 307-8 lung function tests 126-8
large v waves 80 linear scleroderma 317 flow-volume curves 128
largejvery large a waves 80 linear skull fracture 513 lung volumes/capacities 127
laryngomalacia (floppy larynx) 121 linkage analysis 7 obstructive vs restrictive lesions 127
laryngotracheobronchitis, acute (croup) lipid metabolism 175 peak respiratory flow rate 126
122 lipoprotein lipase deficiency 286 spirometry 127
late infantile Batten disease (ceroid lissencephaly (smooth brain) 343 transfer factor 128
li pofuscinosis) 354 Listeria monocytogenes 59, 446, 452 lung volumes/capacities 127
latent squint 381 lithium 20, 89 lupus erythematosus 20, 449
lateral propping reflex 338 Little's area of nasal septum 120 lupus vulgaris 66
Laurence-Moon-Biedl syndrome 172 liver 156 Lyme disease 69
associations 161 liver disease, chronic vs acute 177 lymphocytes 23

539
lymphocytic interstitial pneumonitis 37 maternal blood, swallowed 165 group 1: toxic molecule accumulation
lymphoid tissues 23 maternal drug abuse 474 aminoacidopathies 277- 9
lymphokine-activated killer (LAK) cells McCune- Albright syndrome (polyostotic organic acidaemias 274-5
23 fibrous dysplasia) 266 urea cycle disorders 275- 7
lymphokines 22 measles 55-6 group 2: lack of energy
lymphoma 40, 436-9 Meckel diverticulum 488, 489 carbohydrate metabolism
associations 488 Meckel-Gruber syndrome 342 disorders 279-81
lysosomal storage defects 282-4, 357 meconium aspiration syndrome 469 fatty acid oxidation defects 281
lysosomes 282-3 meconium ileus 476 group 3: large molecule synthesis
meconium plug syndrome 476 defects 281-2
'machinery murmur' see atrioventricular medial tibial torsion 500 group 4: large molecule metabolism
septal (canal) defect medulloblastoma 430 defects
Macleod syndrome 130 megacolon, acquired 160 lysosomal storage defects 2~2 -4
macrocephaly 338 megaloblastic anaemia 393-5 mucopolysaccharidoses 284
macrocytic anaemia 393-5 melanosis, intracranial/intraspinal 302 group 5: mitochondrial diseases
macrocytosis 393 MELAS 285 284-5
macule 290 membranoproliferative hyperlipidaemias 286
maculopapular 290 glomerulonephritis 212 parental history 273
maintenance fluid/bicarbonate membranous glomerulonephritis 213 porphyrias 286-8
calculation 153 membranous neph ropathy 210 screening investigations 27 4
major histocompatibility complex (MHC) Mende~an inheritance 12~18 metachromatic leucodystrophy 284
24 meningitis 46-8, 460 metal overload disorders 357
malabsorption 147- 51 associations 119 metastatic TB abscess 66
abetalipoproteinaemia 151 bacterial metata rsus adductus 500
causes 147 causes 46 methaemoglobinaemia 97-8, 387
coeliac disease 149- 50 management 47 methotrexate 419
food intolerances 147-9 partially treated 48 methyl xanthines 133
glucose-galactose malabsorption 149 TB meningitis 48, 66 methylmalonic acidaemia 275
intestinal lymphangiectasia 150-1 clinical features 46 metoclopramide 421
investigations 147 complications 47 microalbuminuria 213
Shwachman-Diamond syndrome 34-5, investigations 46-7 microcephaly 338
151 lumbar puncture 47 microcytic hypochromic anaemia
sucrase-isomaltase deficiency 149 prevention 48 391-3
malaria 71-2 prognosis 48 laboratory tests 393
clinical features 71-2 viral microdeletion syndrome see DiGeorge
diagnosis/treatment 72 causes 46 anomaly
parasite life cycle 71 management 47 micturating cystourethrography (MCUG)
prevention 72 meningocoele 341 203
protection by sickle trait 403 meningomyelocoele 341 migraine 351
male pseudohermaphrodite 267 Menke kinky hair disease 358 milia 290
malnutrition 168- 9 mercaptoacetylglycine (MAG3) 204 miliary TB, acute 65, 66
malrotation of intestine 487-8 6-mercaptopurine 419 Miller-Fischer syndrome 366
Mantoux test 66 mesangiocapillary glomerulonephritis minimal change nephropathy 213
maple syrup urine disease 277 212 mitochondrial chromosomes/inheritance
marasmic kwashiorkor 168 mesenteric adenitis 486 15-16
marasmus 168 metabolic acidosis 461 mitochondrial disorders 16, 357
Marfan syndrome 14, 90 metabolic alkalosis 461 inheritance 285
mast cell stabilizers 133 metabolic decompensation 276- 7 mitral regurgitation 79
mast cells 21 metabolic disorders 272-88 'mitten hand' deformity 307
mastocytoma, solitary 299 basic mechanisms 272 mixed connective tissue disease 318
mastocytosis 299 classification 273 mixed porphyrias 287 , 288
diffuse cutaneous 299 clinical feature s 273 Mobitz type I/II heart block 84
mastoiditis, acute 119 examination findings 273 molecular genetic analysis techniques
maternal age 8 features 273 6-7

540
molluscum contagiosum 295 naevi birth statistics 443
Mongolian blue spot 290 'bathing trunk' 302 cardiac disorders 469-70
mononuclear phagocytes 21 inflammatory linear verrucous congenital infections 449-52
monosomy 7 435 epidermal 303 cytomegalovirus 450
monosomy of X chromosome 10 melanocytic Listeria monocytogenes 452
monteleukast 133 acquired (moles) 302 rubella 451
morning glory disc 378 congenital 302 syphilis 452
Moro reflex 33 7 naevus flammeus (port-wine stain) toxoplasmosis 450-1
morphoea (localized scleroderma) 317 300 varice lla 451-2
Morquio syndrome 284 spitz 302 convulsions/jitteriness 473-4
motilin 143 nappy rash 291 definitions 442-3
motility disorders 154 narcolepsy 349 delivery 453-4
motor nerve system 331 nasolacrimal duct obstruction 375-6 fetal medicine 446-9
tracts 332 nasopharyngitis 120 fetal therapy 446
maya maya disease 360 natural killer (NK) cells 23 high-risk pregnancies 447
mucopolysaccharidoses 284 nausea/vomiting after chemotherapy 421 maternal illness 448-9
mucopolysaccharidosis I 283 near drowning 517 multiple pregnancy 447-8
mucosal invasion 154 Necator americanis 75 gastrointestinal disorders 47 4-6
multiple endocrine neoplasia (MEN) necrodomil 133 haematological disorders 477
MEN I 260 necrotizing enterocolitis 474-5 hypoglycaemia 477-8
MEN II 242, 260-1 neglect 522 infant feeding 456-7
multiple epiphyseal dysplasias 326 Niemann Pick disease 283 infections, intrapartum/
multiple sclerosis 358-9 Neisseria spp. 57 postpartum 459-61
mumps 56 Nelson syndrome 240 intensive care 461-3
encephalitis 48 nemaline rod myopathy 369 intrauterine growth retardation 463
muscle birth injuries 459 nematode (round worm) infections 74-5 large for gestational age 464
muscular disorders 362 Neocate 148, 149, 457 mortality rates 443
muscular dystrophies 367-8 neonatal adrenoleucodystrophy 282 neurological disorders 470-3
musculoskeletal disorders see rheumatic/ neonatal conjugated hyperbilirubinaemia normal newborn 454-6
musculoskeletal disorders 184-5 osteopenia of prematurity 476-7
mutations 4-5 neonatal examination predicted survival percentages 443
causes 5 general 454 pregnancy food/drug advice 445-6
detection techniques 6-7 hips 455 prematurity 464
germli ne cells 4 neonatal haemangiomatosis 302 osteopenia of 476-7
single cell mutation types 5 neonatal haemochromatosis 189 retinopathy of 384
somatic cells 5 neonatal hepatic syndrome 185 respiratory disorders 464-9
myasthenia gravis 20, 366-7 neonatal hyperthyroidism 245 surgical conditions 479-83
congenital 367 neonatal hypotonia 8, 363-4 nephritic syndrome, acute 213
maternaL 449 neonatal intensive care 461-3 nephritis 210
transient neonatal 367 circulatory support 462 nephroblastoma (Wilms tumour) 424-5
Mycobacterium spp. 63 feeding 463 nephrogene~s 223
M. leprae 68 monitoring 461 nephrogenic diabetes insipidus 237-8
M. t&berculosis 64 thermal stability 461 nephrotic syndrome 209-12, 213
Mycoplasma pneumoniae 63, 64 ventilation 461-2 classification 210
myelodysplasia (including monosomy 7) neonatal jaundice 181-6 clinical features/investigations 210
435 causes 182 complications/prognosis 211
myelodysplastic syndromes 434-5 management 182-3 congenital 211-12
myocarditis 109 exchange transfusion 183 management 211
myopia 380 phototherapy 183 steroid sensitivity 211
myotonia 368 unconjugated 182 nerve birth injuries 458
myotonia congenita (Thomsen neonatology 442-78 nerve conduction, peripheral 334
disease) 369 antenatal screening/diagnosis 444-5 nesidioblastosis (persistent
myotonic dystrophy 16, 368-9 invasive tests 445 hyperinsulinaemic hypoglycaemia
myotubular myopathy 369 birth injuries 458-9 of infancy) 258

541
neural tube defects 340-2 clinical features 363 non-ketotic hyperglycinaemia 278-9
neuroblastoma 423 -4 congenital myopathies 369-70 Noonan syndrome 14, 90
neurodegenerative disorders 356-9 the floppy baby 36 3- 4 associations 94, 150
infections 357 Guillain-Barre disease 365-6 nose disorders 119- 21
investigations 356-7 hereditary motor-sensory neuropathy nuchal ultrasound scan 2, 444
Menke kinky hair disease 358 (Charcot-Marie-Tooth nuclear medicine scan
multiple sclerosis 358- 9 disease) 365 dynamic (OTPA and MAG3) 204
neurometabolic disorders 357 hereditary sensory neuropathy 370 static (DMSA) 204
Rett syndrome 357-8 investigations 363 Nutramigen 148, 149, 457
subacute sclerosing panencephalitis muscular dystrophies 367-8 nutritional disorders 168-71
358 myasthenia gravis 366-7 acrodermatitis enteropathica (zinc
types 357 myotonia congenita (Thomsen deficiency) 169-70
white vs grey matter disorders 356 disease) 369 beriberi (thiamine deficiency) ;171
neuroectodermal syndromes 351-3 myotonic dystrophy 368-9 malnutrition 168- 9
neurofibromatosis 352 poliomyelitis 364-5 pellagra (niacin (nicotinamide) ;·
tuberous sclerosis 352-3 potassium-related periodic deficiency) 170
neurofibromatosis 90, 352, 385 paralysis 370 scurvy (vitamin C (ascorbic acid)
associations 242, 425 spinal muscular atrophy type 1 deficiency) 170
neurogenic tumours 166 (Werdnig-Hoffman disease) 364 vitamin A (retinol) deficiency 171
neurological disorders 328-62, 371-2 types 362
ataxia 353-5 neuromuscular junction disorders 362 obesity 78, 172-3
brain anomalies, structural 338-44 neuronal ceroid lipofuscinosis 284 obstructive shock 514
corpus callosum agenesis 343-4 neuronal migration disorders 343 obstructive sleep apnoea syndrome. 124
craniosynostoses 339- 40 neutrophils 21 ocular albinism 303
fontanelle closure disorders 340 neutrophil disorders 26, 33-5 oculocutaneous albinism 303, 304
head shape/size, abnormal 338-9 newborn, normal oculomotor nerve 330
hydrocephalus 342-3 Guthrie test 455-6 oesophageal atresia 479-81
neural tube defects 340- 2 neonatal examination types 480
neuronal migration disorders 343 genera l 454 oesphagus 141
cerebral palsy 355- 6 hips 455 'oil-drop' cataract 377
child development vitamin K, prophylactic 455 olfactory nerve 330
areas 336 niacin (nicotinamide) deficiency oligoarticular JIA 312
milestones 336-7 (pellagra) 170 oliguria 154
reflexes 337-8 night terrors 349 omphalitis 460
headaches 350- 1 Nikolsky sign 295 oncogenes 418
hypoxia-ischaemia 470- 2 nitric oxide, inhaled 462 oncology 417-41
intracranial pressure, raised 332- 3 nitrogen washout test 97 bone tumours 426
investigations 333-6 nocturnal enuresis 208 brain tumours 429-31
neonatal 470-3 nodule 290 cancer treatment 420-3
neuroectodermal syndromes 351-3 non-accidental injury (NAI) 521-4 carcinogenesis; mechanisms of 417
neurofibromatosis 352 emotional abuse/neg lect 522 cancer genes 418
tuberous sclerosis 352-3 fabricated of induced illness (FII) childhood cancer incidence 419
periventricular haemorrhage 472-3 522-3 childhood histiocytosis syndromes
seizures 344-50 guidelines 439~41
antiepileptic drugs 349- 50 for concerned practitioner 523 gonadaljgerm cell tumours 427-8
common types 345 emergency safeguarding 524 leukaemias 431-6
epilepsy 344-7 management 523-4 acute lymphoblastic leukaemia
febrile convulsions 347-8 ophthalmology 385 432- 3
non -epilepsy 'funny turns' 348-9 phy~calabuse 521-2 acute myeloid leukemia 433-4
status epilepticus 349 sexual abuse 522 chronic myelogenous leukaemia
spinal cord disorders 360-2 non-bullous ichthyosiform erythroderma 435-6
stroke 359-60 307 myelodysplastic syndromes 434- 5
neurological regression 283 non-depressed skull fracture 513 liver tumours 428- 9
neuromuscular disorders 362-70 non-Hodgkin lymphoma 437-9 lymphoma 436-9

542
 nephroblastoma (Wilms tumour) slipped upper femoral epi physis paramyxoviridae 54
424-5 (SUFE) 1.99 paraphimosis 494
neuroblastoma 423-ft talipes 501-2 parathyroid disorders 247 - 52
retinoblastoma 426-7 Ortolani manoeuvre 455 calcium physiology 247
soft tissue sarcomas 425-6 Osler's nodes 108 hypercalcaemia 251-2
ondansetron 421 osmolality mismatch 237 hypocalcaemia 248
ophthalmia neonatorum 382 osmotic diarrhoea 154 pseudohypoparathyroidism
ophthalmology 373-85 osmotic diuretics 203 (PHP) 248-9
cataracts 377 osteochondritides 497-8 rickets 249-51
corneal abnormalities 376 osteochondrodysplasias 325-6 parathyroid hormone 24 7
disc swelling 378 osteochondrosis 497 paratyphoid fever 63
eye lid abnormalities 375 osteogenesis imperfecta 323-4 paroxysmal nocturnal haemoglobinaemia
glaucoma, congenital 377-8 classification 323 399
infections/allergies 382-4 osteomalacia 249 partial seizures 344
iris abnormalities 376 osteomyelitis 495-6 si mple/complex 345
lacrimal system abnormalities 375-6 osteopenia 249 parvoviridae 49
non-accidental injury 385 of prematurity 476-7 parvovirus B19 53-4
optic atrophy 379 osteopetrosis (marble bone disease) 324 Patau syndrome (trisomy 13) 10, 90
optic nerve abnormalities 378 with precocious manifestations 324 patent ductus arteriosus (PDA) 93-4
orbital abnormalities 379 osteosarcoma 426 peak respiratory--tlow rate (PEFR) 126
phakomatoses 385 otitis externa 118 Pearson syndrome 285, 392
pupil abnormalities (anisocoria) otitis media pedigree 12-13
377 acute (AOM) 117 pellagra (niacin (nicotinamide)
refractive error 379-80 chronic (COM) 118 deficiency) 170
retinopathy of prematurity 384 with effusion (glue ear) 117-18 . pelviureteric junction obstruction (PUJ)
squint (strabismus) 380-2 out-toeing 500 207
visual acuity 373 ovarian germ cell tumours 428 pencil cells 389
testing 373-4 oxitropium 133 peptic ulcer 157
in visual impairment 374 oxygen, ambient 460-1 Peptijunior 148, 149, 45 7
visual development 373-4 oxyhaemoglobin 386 pericardiectomy 113
visual impairment 374-5 dissociation curve 387 pericarditis
optic atrophy 3i9 acute 111-12
optic nerve 330 pain syndromes, non-inflammatory 326-7 constrictive 80, 112
optic nerve abnormalities 378 palatal petechiae (Forcheimer spots) 55 pericardia[ effusion 112
optic nerve glioma 431 palmar grasp reflex 337 peripheral nerves
optic nerve hypoplasia 378 pancreas conduction 334
orbital abnormalities 379 chronic abdominal pain, causes of 156 neuromuscular disorders 362
orbital cellulitis 120-1 physiology 142 posterior columns 332
orchidopexy 490 pancreatic polypeptide (PP) 143 spinothalamic tracts 332
organic a'cidaemias 274-5, 357 pancreatictumou~ 259-60 peripheral nervous system 328
'Ornithine transcarbamylase deficiency insulinoma 259 peritoneal dialysis 231-2
277 pancreatitis peritonitis 484
orthdmyxoviridae 54 acute 162-3 periventricular haemorrhage 472-3
orthopaedics 494-502 acute haemorrhagic 163 peroxisomal biogenesis disorders 281,
Blount disease 501 chronic 163-4 282, 357
congenital (developmental) dysplasia hereditary 163 persistent hyperi nsulinaemic
of hip 496 PANDAS 59 hypoglycaemia of infancy
infections 495-6 panhypopituitarism 235 (nesidioblastosis) 258
irritable hip 499-500 Panneth cells 142 persiste nt hypoglycaemia 257-8
limping '•94 p<!povaviridae 49 persistent pulmonary hypertension of
osteochondritides 497-8 papule 290 newborn 470
postural variants in toddlers 500 para-oesophageal hiatus hernia 145 persistent pupillary membrane 376
pulled elbow 500 paracetamol poisoning 520 Perthes disease (legg-Calve-
scoliosis 498 paralytic squint 381 Perthes) 497

543
pertussis (whooping cough) 135-6 platelet function disorders 411 postural scoliosis 498
vaccine 42 platelets 21, 407 postural variants in toddlers 500
pes planus (flat feet) 500 plethoric twin 448 potassium-related periodic paralysis 370
petechiae pneumococcal pneumonia 135 potassium-sparing diuretics 203
palatal (Forcheimer spots) 55 Pneumocystis jejuni (carinii) pneumonia Potter sequence 224
petechial rash 45 (PCP) 38 poxviridae 49
Peutz-Jeghers syndrome 166 pneumonia 51, 134-5, 468, 469 PR intervals 82
Pfeiffer syndrome 340 pneumostasis intestinalis 4 74 Prader-Willi syndrome 17, 172
phaeochromocytoma 242, 260 pneumothorax 466 precocious puberty 263, 265-6
phagocytes 21 poisoning 519 - 21 gonad otro phi n-de pe nde ntj
phakomatoses 385 clinical features/causes 520 -independent 265
pharyngitis 123 remedies 520 prednisolone 239
phenobarbitone 350 police protection 524 Pregestamil 148, 149, 457
phenylketonuria 277, 449 poliomyelitis 364-5 pregnancy
maternal 20 polyarteritis 319 food/drug advice 445-6 :
phenytoin 349, 350 nodosa 320-1 high-risk 447
as teratogen 19, 89 polyarthritis 107 multiple 446, 447-8
phimosis 493 polyarticular JIA 312 reduction 446
phototherapy 183 polycystic kidneys 225-6 prematurity 464
phototherapy treatment chart 183 autosomal dominant (ADPKD) 225-6 apnoea 465
physical abuse 521-2 autosomal recessive (ARPKD) 225 osteopenia of 476-7
physiological jaundice 183 polycystic ovary syndrome (PCOS) 252 retinopathy of 384
picornaviridae 54 polycythaemia 406-7 premutation. 16
piebaldism (white spotting) 305 associations 463, 464 prenatal diagnosis 2
Pierre- Robin sequence 125, 379 polygenic hypercholesterolaemia 286 prepuce, hooded 493
pigmentntion disorders polymerase chain reaction (PCR) 6 prickle cells 389
albinism 303-4 polymorphonuclear granulocytes 21 primary hyperaldosteronism 240- 1
hypomelanosis of Ito 304-5 polyostotic fibrous dysplasia (McCune- prion infection 357
incontinentia pigmenti 304 Albright syndrome) 266 prohibited step order 525
piebaldism (white spotting) 305 polypeptide hormones, gastrointestinal proinsulin 253
vitiligo 305 143 prolactinoma 236
Waardenburg syndrome 305 polyploidy 7 prolonged QT syndrome (torsade de
pineal tumours 431 Pompe disease 90 pointes) 106-7
pituitary gigantism i35 porencephaly 343 propionic acidaemia 275
pituitary/hypothalamus disorders 233-9 porphyrias 286-8 proptosis 379
craniopharyngioma 235 acute 287, 288 pro stag la ndi n ( PG E2) 97
diabetes insipidus 237-8 classification 287 protein
hormones 234 cutaneous 287-8 formation 4
hypopituitarism 236-7 haem biosynthesis pathway 287 intolerance 147-8
physiology 233 mixed 287, 288 metabolism/degradation 74
pituitary gigantism 235 port-wine stain (naevus flammeus) 300 proteinuria, causes of 213-14
pituitary tumours 233-4 portalhyperten~on 195-7 Proteus spp. 204
prolactinoma 236 causes 196 prothrombin time (PT) 176, 408, 409
syndrome of inappropriate ADH clinical features/investigations 196 protozoal infections 38-9
secretion (SIADH) 238-9 management 196-7 proxies 502
pityriasis rosea 294 positional talipes 502 prune belly (Eagle-Barrett) syndrome
placental antibody transfer 20, 449 possetting 145 227
plagiocephaly 338, 339 post-gastroenteritis intolerance 148, pseudo-Bartter syndrome 137
plane warts 296 150 pseudochondrodysplasia 326
plantar grasp reflex 337 post-infectious arthritides 314 pseudohermaphrodites 267
plantar warts 296 post-streptococcal glomerulonephritis pseudohypoparathyroidism (PHP) 248- 9
plaque 290 214 pseudomembranous croup (bacterial
Plasmodium spp. 70, 71 posterior urethral valves (PUV) 207-9, tracheitis) 122
platelet disorders 409-11 226 Pseudomonas spp. 59

544
pseudo pseudo hypo pa rathyroidi sm red blood cells 388-9 renal failure 229-32
(PPHP) 249 metabolism 388 acute 229-30
psoriasis 291, 293-4 red cell aplasia 400-1 chronic 231
psychiatric disorders 371-2 red cell fragmentation syndromes 399 dialysis 231-2
ptosis 375 'redcu rrant jelly stools' 488 end-stage 231
puberty 264-9 reflexes 331, 337-8 transplantation 232
delayed 266-7 postural 338 renal vein thrombosis 218
onset/growth spurts 265 primitive 337 tubular function disorders 218-23
precocious 263, 265-6 reflux nephropathy 206 Bartter syndrome 222-3
staging 264-5 refractive error 379-80 cystinosis 221-2
pulled elbow 500 rehydration fluids 153 cystinuria 222
pulmonary atresia 101-2 Reidel thyroiditis 245 Fanconi syndrome 221
pulmonary fibrosis 139 Reiter syndrome 314 Gitelman syndrome 222-3
pulmonary haemorrhage 466 renal agenesis 224 renal tubular acidosis 218-20
pulmonary hypertension 78, 80 renal blood flow (RBF) 200 urate metabolism 227-8
pulmonary stenosis 78, 80, 93 renal calculi 208-9 urinary tract infections (UTis) 204-6
peripheral 89 classification 209 vesicoureteric junction obstruction
pulmonary va lve stenosis 78 renal clearance 200 (VUJ) 207
'pulseless disease' 321 renal countercurrent mechanism 200 vesicoureteric reflux (VUR) 206
pulsus paradoxicus 112 renal disorders 199-232 see also kidneys
pupil abnormalities (anisocoria) 377 congenital structural malformations renal dysplasia 224
purpura fulminans 51 223-7 unilateral vs bilateral 224-5
pustule 290 bladder exstrophy 226-7 renal radiological investigations 203-4
pyramidal system (corticospinal tracts) duplex kidney 226 renal scarring 204, 206
331 dysplastic kidney 224-5 rena l tubular acidosis (RTA) 218-20
pyrazinamide 67, 68 ectopic kidney 226 type I (distal) 218, 219
pyroxidine deficiency 347 horseshoe kidney 226 type II (proximal) 218, 219-20
pyruvate kinase deficiency 397-8 hydronephrosis 226 type III 218
polycystic kidneys 225-6 type IV 218, 220
QRS durations 82 prune belly syndrome 227 renal vein thrombosis 154, 218
QTcs, maximum 82 renal agenesis 224 renin-angiotensin-aldosterone system
quinsy (peritonsillar abscess) 124 urinary tract develop ment/ 200, 201
malformations 223-4 reo vi ridae 54
rabies 56-7 congenital urinary tract respiratory acidosis 461
rachitic rosary 249 obstruction 206-7 respiratory alkalosis 461
radiotherapy 421 glomerulonephritis 212-17 respiratory disorders 126-40
rapidly progressive acute nephritic syndrome 213 a1-antitrypsi n deficiency 139
glomerulonephritis 212 Alport syndrome 216 apnoea 467-8
raschisis 342 Goodpasture disease 216 bronchiectasis 138
Rasmussen encephalitis 347 haematuria, causes of 216- 17 bronchopulmonary dysplasia 466-7
RBBB (right bundle branch block) 78, Henoch-Schiinlein purpura 214-15 chronic cough 134
85 histological classification of congenital malformations 128
reactiVe arthritis 314 pathology 212-13 cystic fibrosis 3, 136-8
recombinant erythropoietin 387 IgA (Berger) nephropathy 215 immotile cilia (Kartagener) syndrome
rectal faecoliths 160 post-streptococcal 214 138-9
recurrent functional abdominal pain proteinuria, causes of 213-14 infection 134-6
156-7 SLE nephritis 216 meconium aspiration syndrome 469
Apley's criteria 156 haemolytic uraemic syndrome 217- 18 neonatal 464-9
causes hyperten~on 228- 9 obstructive vs restrictive lesions 127
gilstrointestinaljrenal 156 nocturnal enuresis 208 physiology 126-8
liver/pancreatic 156 pelviureteric junction obstruction pneumonia 51, 469
organic 157 (PUJ) 207 pneumothorax 466
management 157 posterior urethral valves (PUV) 207-9 pulmonary fibrosis 139
recurrent (spasmodic) troup 122 renal calculi 208-9 pulmonary haemorrhage 466

545
respiratory disorders - contd management of JIA 314-15 sacrococcygeal teratoma 428
respiratory distress syndrome 465 oligoarticular JIA 312 SAFE mnemonic 503, 504
sarcoidosis 139-40 polyarticular JIA 312 salbutamol 133
transient tachypnoea of newborn 468 reactive arthritis 314 salicylate poisoning 520
wheeze 129-36 systemic -onset JIA 313 salmeterol 133
aspiration 130-1 mixed connective tissue disease 318 salmon patch 301
asthma 131-4 non-inflammatory pain syndromes Salmonella spp. 60, 63
bronchiolitis 129-30 326-7 Sanfilippo syndrome 284
causes 129 osteochondrodysplasias 325-6 sarcoidosis 139- 40
foreign body inhalation 130 osteogenesis imperfecta 323-4 SBE see subacute endocarditis
persistent, in infancy 134 osteopetrosis (marble bone disease) sea bies 29 7-8
viral-induced 131-4 324 scalds 517
Wilson-Mikity syndrome 466-7 scleroderma disorders 317-18 scales 290
respiratory distress syndrome 465 Sjogren syndrome 318-19 scaphocephaly (dolichocephaly) 338,
respiratory syncytial virus (RSV) 129 syndromes involving absent radii 339 ~

responsiveness 504 327 sea rlet fever 58-9

restriction fragment length systemic lupus erythematosus 315-16 Scheuermann disease 498
polymorphisms (RFLPs) 6 vasculitis 319-22 Schilling test 395
resuscitation 503-8 rheumatoid factor (RhF) 310 Schirmer test 319
assessment rhinitis 119 schizencephaly 343
primary 503, 509, 511 rickets 249-51 Schmidt syndrome (autoimmune
secondary 504, 509, 511 causes/features 249 polyglandular syndrome type 2)
emergency treatment 504 familial hypophosphataemic (vitamin 260-1
infants vs children 505 D-resistant) 251 sclera, blue 324
life support investigations 250 sclerocornea 376
advanced 506-8 treatment 250 scleroderma disorders 317-18
basic 503, 504-5 vitamin 0-dependent 251 scoliosis 498
seriously ill child 503-4 X-ray changes in knee 250 screening, prenatal 2
reti nat haemorrhages 385 Rickettsia spp. 63, 70 scrofuloderma 66
retinoblastoma 426-7 rifampicin 47, 48, 67, 68 scrotal swellings 490-1
retinol (vitamin A) deficiency 171 right bundle branch block (RBBB) 78, scurvy (vitamin C (ascorbic acid)
retinopathy of prematurity 384 85 deficiency) 170
retractile testes 490 right ventricular hypertrophy (RVH) 85, sebaceous gland hyperplasia 290
retroviridae 54 86 sebaceous naevus 291
Rett syndrome 357-8 Riley-Day syndrome (familial seborrhoeic dermatitis 291
reversible ischaemic neurological defect dysautonomia) 370 second degree heart block 84
(RIND) 359 ring sideroblasts 389, 392 secondary hyperaldosteronism 240
Reye syndrome 190-1 ringworm (tinea) 296 secretin 143
rhabdomyosarcoma 425-6 road traffic accidents 517 secretory diarrhoea 154
rhabdoviridae 54 Robertsonian translocation 9, 11 seizures 344- 50
rhesus disease 20, 449 Rocky mountain spotted fever 70 antiepileptic drugs 349-50
rhesus incompatibility 183-4 Romano-Ward syndrome 107 causes 473
rheumatic fever 107-8 rooting reflex 337 classification 344
rheumatic/musculoskeletal disorders Rosai-Dorfman disease 440 common types 345
310-27 'rose spots' 63 epilepsy 344-7
amyloidosis 322-3 roseola infantum (exanthem subitum) febrile convulsions 347-8
antiphospholipid syndrome 316 (HHV6) 53 neonatal convulsionsjjitteriness 473-
autoantibodies 310- 11 Roth spots 108 4
idiopathic inflammatory myopathies Rotor syndrome 187 non-epilepsy 'funny turns' 348-9
316-17 round worms (nematodes) 74- 5 status epilepticus 349
juvenile idiopathic arthritis (JIA) roundworm 74 selective IgA deficiency 29
311- 15 rubella (German measles) 54-5, /f51 sensorineural deafness 115- 16
enthesitis-related arthropathy congenital rubella syndrome 89 sensory nerve system 332
313-14 as teratogen 89 sepsis 44-5, 515

546
 causes 45 skin pathergy 322 staphylococcal scalded skin syndrome
clinical features 45 skin tests 25 294-5
management 45 skull fracture 512, 513 staphylococcal scalded skin syndrome
neonatal 460 slapped cheek disease (erythema (SSSS) 295
pathway 44 infectiosum) (Fifth disease) 53 Staphylococcus spp. 57
petechial rash 45 SLE see systemic lupus erythematosus statement of special educational needs
septic arthritis 495 sleep apnoea 124 525
septic shock 44 sliding hiatus hernia 145, 146 statementi ng 525
Septrin 40 slipped upper femoral epiphysis (SUFE) static nuclear medicine (DMSA) scan
sequences vs syndromes 19 499 204
seriously unwell child 44-9 small molecule inhibitors 422 status epilepticus 349
encephalitis 48-9 Smith-Lemli-Opitz syndrome 281, steep y descent 80
meningitis 46-8 282 Stein-Leventhal syndrome 252
se psis 44-5 smooth brain (lissencephaly) 343 stem cell transplantation 422-3
severe combined immunodeficiency snowflake cataracts 377 allogenic 422
(SCID) 31-2 'snowman'-shaped heart 103 autologous 422
ge ne therapy 3 social milestones 336-7 stepping reflex 337
sexual abuse 522 sodium chromoglycate 133 sternomastoid tumour 458
sexual differentiation disorders 267-8 sodium valproate 349 sternotomy scars 82
sexual maturity rating 264 associations 340 steroid biosynthesis 268
shagreen patches 353 aste~togen 19,89 steroids -
shaken baby syndrome 385, 522 soft tissue sarcomas 425-6 glucocorticoid axis 239
Shigella boydii 60 soluble mediators 22 inhaled 132, 133
shingles (zoster) 51 somatostatin 143 topical 292
shock 513-15 Soto's syndrome 263 Stevens-Johnson syndrome 298-9,
burns 519 Southern blotting 6 383-4
clinical features by stage 514 soya intolerance 148, 150 Stickler dysplasia 325
management 514 spasmodic (recurrent) croup 122 stomach
stages 514 specific immunity 23 gastric acid secretion 142
short stature 262-3 specific issue order 525 physiology 141-2
shunting, rig ht-to-left 98 spina bifida occulta 341 stork bites 300-1
Shwachman-Diamond syndrome 34-5, spinal cord disorders strawberry haemangiomas 301
151- complete transection 361 'strawberry tongue' 58
sick euthyroid syndrome 243 compression 360-1 streptococcal infections 58-9, 292, 295
sickle cells 389 hemisection (Brown-Sequard a-haemolytic 108
sickle cell anaemia 401-2 syndrome) 361 group A ~-haemolytic (GAS) 107
sickle cell haemoglobinopathies 401-3 syringomyelia/syringobulbia 361 group B p-haemolytic (GBS) 459-60
sickle cell trait 401. 403 transverse myelitis 361-2 post-streptococcal glomerulonephritis
sickle chest syndrome 401 spinal muscular atrophy type 1 214
sickle crises 401 (Werdnig-Hoffman disease) 364 Streptococcus spp. 57
siaeroblastic anaemia 392-3 spirochaetes 63 stridor 121, 122
simple partial seizures 345 spirometry 127 'string of pearls' sign 307
si ngle gene defects 12-18 spitz naevi 302 stroke 359-60
autosoma l dominant/recessive 13-14 splenectomy 415-16 stroke-like episode 359
imprinting 16-18 splenomegaly 416 Strongyloides stercora/is 75
mitochondrial disorders 15-16 spondyloarthropathies 313, 314 structural scoliosis 498
premutation 16 spondyloepiphyseal dysplasias 326 struvite calculi 209
uniparental disomy 17 squint (strabismus) 380-2 Sturge-Weber syndrome 300, 385
X-linked 14-15 tests for 381-2 subacute endocarditis (SBE) 108
sin us histiocytosis with massive types of squint 380 subacute sclerosing panenccphalitis 358
lymphadenopathy 440 staghorn calculi 209 subdural haematoma 512
sinusitis 120-1 staphylococcal infections 57-8, 108, subependymal glial nodules 353
Sjog ren syndrome 89, 315, 318-19 292, 295 subperiosteal abscess 120
skeletal maturity (bone age) 262 pneumonia 135 substance P 143

547
sucking blister 290 pulled elbow 500 tetanus immunization 61
sucking pad 290 scoliosis 498 tetralogy of Fallot 98-9
sucking reflex 337 slipped upper femoral epiphysis management 99
sucrase-isomaltase deficiency 149 (SUFE) 499 thalassaemia intermedia 405
sudden infant death syndrome (SIDS) talipes 501-2 thalassaemias 403-6
516 swallowed maternal blood 165 diagnosis 403
supervision orders 524 sweat test 137,163,185 thalidomide 20
supratentorial tumours 431 Sydenham chorea 107 thanatophoric dwarfism 325
supraventricular tachycardia (SVT) 104- synacthen stimulation tests 271 theophylline 133
5 syncope 348 thiamine (vitamin B1) deficiency
vs ventricular tachycardia 106 syndrome of inappropriate ADH secretion (beriberi) 171
surfactant 465 (SIADH) 238-9 thia zi de diuretics 203
surgery 421 syndromes vs sequences 19 third degree (complete) heart block 80,
surgical conditions 4 79-502 synovitis, chronic 311 84
consent 502 syphilis 69. 452 Thomsen disease (myotonia congenita)
gastrointestinal conditions 483-9 systemic lupus erythematosus (SLE) 89, 369
achalasia 487 315- 16 thoracotomy scars 82
acute abdomen 483-5 associations 316 threadworm 74
acute appendicitis 485-6 neonatal lupus 315-16 throat disorders 121-5
congenital hypertrophic pyloric nephritis 216 thrombin clotting time 409
stenosis 486- 7 systemic -onset JIA 313 thrombocythaemia 407
intestinal obstruction 485 systemic sclerosis 318 thrombocytopenia 409-10
intussusception 488-9 autoimmune 20, 449
malrotation 487-8 T cell (cell mediated) disorders 26, immune 410
Meckel diverticulum 489 30-1 thrombocytopenia absent radius (TAR)
genitourinary conditions 489-94 investigations 27 syndrome 410-11
circumcision 494 T cells, donor 422 thrombotic thrombocytopenic purpura
epididymo-orchitis 492 T-cytotoxic cells 23 (TIP) 410-11
foreskin 493-4 T-helper cells 23 'thumb-printing' colon wall 158
hydrocoele 491 T lymphocytes 23, 24 thyroid axis 243
hypospadias 492-3 activation 24 thyroid crisis 245
idiopathic scrotal oedema 492 Takayasau disease 321 thyroid disorders 243-6
scrotal/inguinal swelling> 490-1 talipes 501-2 goitre 246
testicular torsion 491-2 calcaneovalgus 501 hyperthyroidism 245
torted testicular appendage equinovarus 501 hypothyroidism 243-4
(hydatid of Morgagni) 492 tall stature 263-4 Guthrie test 243
undescended testes Tanner sexual maturity rating 264 thyroid tumours 246
(cryptorchidism) 489-90 tapeworms (cestodes) 74 thyroid gland physiology 243
neonatal 479-83 target cells 389 thyroid tumours 246
congenital atresias 479- 81 target Lesions 298 thyrotoxicosis factitia 245
congenital diaphragmatic hernia Tay Sachs disease 284 tilted discs 378
482-3 Tegretol 349 tinea (ringworm) 296
congenital lobar emphysema 483 telecanthus 375 TOBIDA scan 185
exomphalos 481-2 telogen effluvium 303 toddler's diarrhoea 149, 155
gastroschisis 482 temporal Lobe epilepsy 347 toe-walking 500
orthopaedics 494-502 tensilon test 366 togaviridae 54
Blount disease 501 tension headache 351 tonsillitis, acute 123-4
congenital (developmental) teratogens 20, 89 tonsillectomy indications 124
dysplasia of hip 496 terbutaline 133 topical steroids 292
infections 495- 6 termination 446 topiramate 350
irritable hip 499 - 500 test feeds !f86 torsade de pointes (prolonged QT
Limping 494 testicular germ cell tumours 428 syndrome) 106-7
osteochondritides 497-8 testicular torsion 491-2 torted testicular appendage (hydatid of
postural variaf.lts in toddlers 500 testosterone in sex differentiation 268 Morgagni) 492

548
total anomalous pulmonary venous Trypanosoma brucei 70
drainage (TAPVD) 102-3 tuberculoid leprosy 68
total parenteral nutrition (TPN) 463 tuberculosis (TB) 64
toxic epidermal necrolysis 299 diagnosis 66
toxic megacolon 159 direct detection of organisms 66 ~rk·. th···;:r· f.. development/
toxic shock syndrome 51, 58, 299 extrapulmonary 65- 6 m ·ons 223-4
Toxocara spp. 75 late reactivation 66 uri'rlarY halt irHections (UTis) 204-6
toxoplasmosis 70, 73, 446, 450-1 management 67, 68 causes 204
tracheitis, bacterial (pseudomembranous massive spread (acute miliary TB) clinical manifestations/diagnosis
croup) 122 65-6 205 .
trachea-oesophageal fistula 479- 81 meningitis 48 furth~r investigations in proven UTI
types 480 pu lmonary 205
'tramline' appearance of spine 313 asymptomatic 64-5 management 205
transaminases 176 symptomatic 65 preve~tion ·206
transfusion-induced haemochromatosis skin manifestations 66 urinar}/ tract ohstruction,
189 tuberous (tuberose) sclerosis 90, 352-3, congenital 206-7
transient hypogammaglobulinaemia of 385 management 207
infancy 29 tumours sites 207
transient ischaemic attack (TIA) 359 endocrine 166 urogenital tract development 223
transient neonatal hypoglycaemia 25 7, gastrointestinal 165-6 urticaria 25- 6
477-8 in hepatomegaly 179 pigmentosa 299
transient neonatal myasthenia gravis HIV/AIDS 38-9 uveitis (chronic iridocyclitis) 312
367 pancreatic 259-60
transient tachypnoea of newborn 468 in pregnancy 446 vaccination
transplantation thyroid 245, 246 contraindications 42
kidneys 232 types 419 immunization schedule 41
liver 197-8 tumour lysis syndrome 421 in meningitis 48
complications/prognosis 198 tumour suppressor genes 418 TB (BCG) 68
indicationsjcontraindications 197, tuning fork hearing tests 115 tetanus 61
198 Turcot syndrome 165 vaccines 42
urgent 198 Turner syndrome 10, 90 zoster 51
stem cells 42 2 associations 95, 150 vaccines 42
transposition of great arteries (TGA) turricephaly 338 VACTERL syndrome 98
103-4 twin-twin transfusion syndrome 448 vagus nerve 330
trauma, major 511 twins 447, 448 varicella (chicken pox) 50-1
Treacher-Collins syndrome 379 typhoid 63 congenital 451
trematodes (flukes) 74 typhus 70 maternal, around delivery 451
Treponema pallidum 63, 69 tyrosinaemia (type 1) 277-8 VZIG treatment 452
TRH stimul<Jtion test 270 varicella zoster virus (VZV) 50-1
Trichomonas vagina/is 70 ulcer 290 encephalitis 48
tnchotillomania 303 ulcerative colitis 158-60 vasculature, disorders of 409
Tricuris trichuria 74 extra-abdominal features 159-60 vasculitis 319- 22
tricuspid atresia 99-100 ultrasound scan (USS) Beh~et syndrome 322
tricuspid regurgitation 80 anomaly 444, 445 classification 319
tricuspid stenosis 80 dating/growth 444 Kawasaki disease 320
trigeminal nerve 330 nuchal 2, 444 polyarteritis nodosa 320-1 ·
trigonocepha~ 338, 339 renal 203 Takayasau disease 321
triple ultrasound scan 445 trip le test 445 Wegener granulomatosis 321-2
trisomy 13 see Patau syndrome umbilical infectio n 460 vasoactive intestinal peptide (VIP) 143
trisomy 18 see Edwards syndrome undescended testes (cryptorchidis111) venous huJll H7 ·
trisomy 21 see Down syndrome 489-90 venous sinus thrombosis 119
trochlear nerve 330 upper motor neuron (UMN) lesions 331 venous thrombosis 415
tropical sprue 150 upper oesophageal sphincter (UOS) 141 ventricular filling , restrictive 79
trunkal ataxia 331 urate metabolism 227-8 ve ntricular hypertrophy 85'-6

549
ventricular septal defect (VSD) 90-1 vitamin D-dependentj-resistant rickets whooping cough (pertussis) 135-6
ventricular tachycardia (VT) 105-6 251 vaccine 42
vs supraventricular tachycardia 106 vitamin K Williams syndrome 11, 12, 89, 90
vesicle 290 deficiency 413- 14 associations 95
vesicoureteric junction obstruction prophylactic 455 Wilms tumour (nephroblastoma) 424-5
(VUJ) 207 vitamin supplementation 463 Wilson disease (hepatolenticular
vesicoureteric reflux (VUR) 206 vitiligo 305 degeneration) 187- 8
vestibulotrochlear nerve 330 vomiting 146-7 Wilson-Mikity syndrome 466-7
Vibrio cholerae 60 von Hippel- Lindau disease 353, 385 Wiskott-Aldrich syndrome 32
vigabatrin 350 von Recklinghausen disease 352 WITHDRAWALS mnemonic 474
vinblastine 420 von Willebrand disease 413 Wolff-Parkinson-White syndrome 104-5
vinca alkaloids 420 von Willebrand factor 413 Wolfram syndrome (DIDMOAD) 238
vincristine 420 VT 80
vipoma 259 Xchromosome monosomy 10
viral-induced wheeze 131-4 Waardenburg syndrome 305, 379 Xinactivation 14
viral infections 49-57 associations 161 X-linked agammaglobulinaemia (XLA)
dermatological 295 wardship 525 (Bruton XLA) 28
DNA viruses 49-53 warfarin 19, 94 X-linked disorders 15
HIV-associated 39 warts, viral 296 X-linked immunodeficiency with hype r
neurodegenerative disorders 357 water deprivation test 237 IgM 33
neuromuscular disorders 364 'waterhammer pulse' 93 X-~nked inheritance
RNA viruses 54-7 Waterhouse-Friedrichson syndrome dominant 15
viral meningitis 46, 47 241 recessive 14-15
visual acuity 373 weaning 456, 457 X-linked lymphoproliferative (Duncan)
testing 373-4 Wegener granulomatosis 321-2 syndrome 30
in visual impairment 374 Werdnig-Hoffman disease (spinal X-linked recessive ichthyosis 306
visual development 373-4 muscular atrophy type 1) 364 X-ray, chest see chest X-ray
visual evoked responses 375 West syndrome 346 xanthine calculi 209, 228
visual impairment 374-5 wet beriberi 171 xanthinuria 228
vital signs, normal 80 wheal 290 xeroderma pigmentosum 308
vitamin A (retinol) deficiency 171 wheeze 129-36 XYY syndrome 11
vitamin B1 (thiamine) deficiency aspiration 130-1
(periberi) 171 asthma 131-4 Yersinia spp. 60
vitamin B12 394 bronchiolitis 129-30
deficiency 393 causes 129 ZDT (zidovudine) 40
tests 395 foreign body inhalation 130 Zellweger syndrome (cerebrohepatorenal
vitamin C (ascorbic acid) deficiency persistent, in infancy 134 syndrome) 186, 282
(scurvy) 170 viral-induced 131-4 zidovudine (ZDT) 40
vitamin 0 whipworm 74 zinc deficiency (acrodermatitis
metabolism 247 . white pupil (leucocoria) 377 enteropathica) 169-70
requirement 249 white spotting (piebaldism) 305 Zollinger-Ellison syndrome
in rickets 249 'white strawberry tongue' 58 (gastrinoma) 157, 259- 60
vitamin 0 analogues 248 whitlow 50 zoster (shingles) 51

550
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