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AT L A S OF X- L INK E D IN T E L L EC T UA L
DIS A BIL I T Y S Y NDROME S
This page intentionally left blank
ATLAS OF X-LINKED INTELLECTUAL
DISABILIT Y SYNDROMES
SECOND EDITION

Roger E. Stevenson, M.D.

SENIOR CLINICAL GENETICIST

GREENWOOD GENETIC CENTER

GREENWOOD, SOUTH CAROLINA

Charles E. Schwartz, Ph.D.

DIRECTOR OF RESEARCH

GREENWOOD GENETIC CENTER

GREENWOOD, SOUTH CAROLINA

R. Curtis Rogers, M.D.

SENIOR CLINICAL GENETICIST

GREENWOOD GENETIC CENTER

GREENWOOD, SOUTH CAROLINA

1
 3
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electronic, mechanical, photocopying, recording, or otherwise,
without the prior permission of Oxford University Press.

Library of Congress Cataloging-in-Publication Data

Stevenson, Roger E., 1940-
Atlas of X-linked intellectual disability syndromes/Roger E. Stevenson, Charles E. Schwartz, and R. Curtis Rogers.–2nd ed.
p. ; cm.
Rev. ed of: X-linked mental retardation / Roger E. Stevenson, Charles E. Schwartz, Richard J. Schroer. 2000.
Includes bibliographical references and index.
ISBN 978–0–19–981179–3 (alk. paper)
1. X-linked mental retardation–Atlases. I. Schwartz, Charles E. II. Rogers, R. Curtis (Richard Curtis), 1953-
III. Stevenson, Roger E., 1940-X-linked mental retardation. IV. Title.
[DNLM: 1. Mental Retardation, X-Linked–Atlases. QS 17]
RC574.S77 2012
616.85'88042—dc23
2011024318

135798642
Printed in the United States of America
on acid-free paper
This Atlas is dedicated to all persons with X-linked
intellectual disability, to their families, to the physicians
that provide medical care, to the scientists that seek to
understand the underlying biology, and to the memory of
Ethan Francis Schwartz 1996–1998.
This page intentionally left blank
 TABLE OF CONTENTS

FOREWORD XI CEREBRO-PALATO-CARDIAC SYNDROME (SEE ALSO RENPENNING

SYNDROME) 53
PREFACE XIII
CHARCOT-MARIE-TOOTH NEUROPATHY, COWCHOCK VARIANT 55
AARSKOG SYNDROME 1
CHARCOT-MARIE-TOOTH NEUROPATHY, IONASESCU VARIANT 56
ABIDI SYNDROME 4
CHASSAING-LACOMBE CHONDRODYSPLASIA 57
ADRENOLEUKODYSTROPHY 6
CHRISTIAN SYNDROME 59
AGENESIS OF THE CORPUS CALLOSUM, X-LINKED 9
CHRISTIANSON SYNDROME 61
AHMAD SYNDROME 11
CHUDLEY-LOWRY SYNDROME (SEE ALSO ATRX-ASSOCIATED XLID) 64
AICARDI SYNDROME 12
CK SYNDROME 66
ALLAN-HERNDON-DUDLEY SYNDROME 14
CLARK-BARAITSER SYNDROME 68
ALPHA-THALASSEMIA INTELLECTUAL DISABILIT Y
(SEE ALSO ATRX-ASSOCIATED XLID) 17 COFFIN-LOWRY SYNDROME 70

AP1S2-ASSOCIATED XLID 20 CORNELIA DE LANGE SYNDROME, X-LINKED 73

APAK ATAXIA-SPASTIC DIPLEGIA SYNDROME 22 CRANIOFACIOSKELETAL SYNDROME 76

ARMFIELD SYNDROME 24 CREATINE TRANSPORTER DEFICIENCY 78

ARTS SYNDROME 26 DUCHENNE MUSCULAR DYSTROPHY 80

ARX-ASSOCIATED XLID 28 DYSKERATOSIS CONGENITA 82

ATAXIA-DEAFNESS-DEMENTIA, X-LINKED 30 EPILEPSY-INTELLECTUAL DISABILIT Y IN FEMALES (EIDF) 84

ATKIN-FLAITZ SYNDROME 32 FITZSIMMONS SYNDROME 85

ATRX-ASSOCIATED XLID 34 FLNA-ASSOCIATED XLID 87

BERGIA CARDIOMYOPATHY 37 FRAGILE X SYNDROME 89

BERTINI SYNDROME 39 GIUFFRÈ-TSUKAHARA SYNDROME 91

BÖRJESON-FORSSMAN-LEHMANN SYNDROME 41 GLYCEROL KINASE DEFICIENCY 92

BRANCHIAL ARCH SYNDROME, X-LINKED 44 GOLABI-ITO-HALL SYNDROME: (SEE ALSO RENPENNING SYNDROME) 94

CANTU SYNDROME 46 GOLDBLATT SPASTIC PARAPLEGIA SYNDROME 96

CARPENTER-WAZIRI SYNDROME (SEE ALSO ATRX-ASSOCIATED XLID) 47 GOLTZ SYNDROME 97

CEREBRO-CEREBELLO-COLOBOMA SYNDROME 49 GRAHAM ANOPHTHALMIA SYNDROME 99

CEREBRO-OCULO-GENITAL SYNDROME 51 GUSTAVSON SYNDROME 101

vii
HALL OROFACIAL SYNDROME 103 ORAL-FACIAL-DIGITAL SYNDROME I 166

HEREDITARY BULLOUS DYSTROPHY, X-LINKED 104 ORNITHINE TRANSCARBAMOYLASE DEFICIENCY 168

HOLMES-GANG SYNDROME (SEE ALSO ATRX-ASSOCIATED XLID) 106 OTOPALATODIGITAL SYNDROME I (SEE ALSO FLNA-ASSOCIATED XLID) 170

HOMFRAY SEIZURES-CONTRACTURES 108 OTOPALATODIGITAL SYNDROME II (SEE ALSO FLNA-ASSOCIATED XLID) 172

HYDE-FORSTER SYNDROME 109 PAINE SYNDROME 174

HYDRANENCEPHALY WITH ABNORMAL GENITALIA PALLISTER W SYNDROME 176

(SEE ALSO ARX-ASSOCIATED XLID) 110
PARTINGTON SYNDROME (SEE ALSO ARX-ASSOCIATED XLID) 178
HYDROCEPHALY-CEREBELLAR AGENESIS SYNDROME 112
PELIZAEUS-MERZBACHER SYNDROME 180
HYDROCEPHALY-MASA SPECTRUM 113
PERIVENTRICULAR NODULAR HETEROTOPIA (SEE ALSO
HYPOPARATHYROIDISM, X-LINKED 115 FLNA-ASSOCIATED XLID) 182

INCONTINENTIA PIGMENTI 116 PETTIGREW SYNDROME 184

JUBERG-MARSIDI-BROOKS SYNDROME 118 PHOSPHOGLYCERATE KINASE DEFICIENCY 186

KANG SYNDROME 120 PLOTT SYNDROME 187

LENZ MICROPHTHALMIA SYNDROME 122 PORTEOUS SYNDROME (SEE ALSO RENPENNING SYNDROME) 188

LESCH-NYHAN SYNDROME 125 PPM-X 189

PRIETO SYNDROME 191

LISSENCEPHALY AND ABNORMAL GENITALIA, X-LINKED
(SEE ALSO ARX-ASSOCIATED XLID) 127
PROUD SYNDROME (SEE ALSO ARX-ASSOCIATED XLID) 193
LISSENCEPHALY, X-LINKED 129
PYRUVATE DEHYDROGENASE DEFICIENCY 195
LOWE SYNDROME 132
RENPENNING SYNDROME 197
LUJAN SYNDROME 134
RETT SYNDROME 200
MARTIN-PROBST SYNDROME 136
RETT-LIKE SEIZURES-HYPOTONIA 202
MEHMO SYNDROME 138
ROIFMAN SYNDROME 204

MENKES SYNDROME 140

SAY-MEYER SYNDROME 206

MIDAS SYNDROME 143

SCHIMKE SYNDROME 208

MILES-CARPENTER SYNDROME 145

SHASHI SYNDROME 210

MOHR-TRANEBJAERG SYNDROME 148 SHRIMPTON SYNDROME 212

MONOAMINE OXIDASE-A DEFICIENCY 150 SIMPSON-GOLABI-BEHMEL SYNDROME 214

MUCOPOLYSACCHARIDOSIS IIA 151 SMITH-FINEMAN-MYERS SYNDROME 216

MYOTUBULAR MYOPATHY 153 SNYDER-ROBINSON SYNDROME 217

N-ALPHA-ACET YLTRANSFERASE DEFICIENCY 155 STOCCO DOS SANTOS SYNDROME 219

NANCE-HORAN SYNDROME 157 STOLL SYNDROME 221

NORRIE DISEASE 159 SUTHERLAND-HAAN SYNDROME (SEE ALSO RENPENNING SYNDROME) 223

OPITZ FG SYNDROME 161 TARP SYNDROME 225

OPTIC ATROPHY, X-LINKED 164 TELECANTHUS-HYPOSPADIAS SYNDROME 227

viii TABLE OF CONTENTS

TURNER XLID (SEE ALSO AP1S2-ASSOCIATED XLID) 229 XLID-PSORIASIS 288

URBAN SYNDROME 231 XLID-RETINITIS PIGMENTOSA 290

VACTERL-HYDROCEPHALUS SYNDROME 233 XLID-ROLANDIC SEIZURES 292

VASQUEZ SYNDROME 235 XLID-SPASTIC PARAPLEGIA, T YPE 7 293

WAISMAN-LAXOVA SYNDROME 237 XLID-SPASTIC PARAPLEGIA-ATHETOSIS 295

WARKANY SYNDROME 239 XLID-SPONDYLOEPIMETAPHYSEAL DYSPLASIA 297

WIEACKER-WOLFF SYNDROME 240 XLID-THYROID APLASIA-CUTIS VERTICIS GYRATA 299

WILSON-TURNER SYNDROME 242 XLID WITH THYROXINE-BINDING GLOBULIN DEFICIENCY 300

WITTWER SYNDROME 244 YOUNG-HUGHES SYNDROME 301

XLID-ARCH FINGERPRINTS-HYPOTONIA SYNDROME

(SEE ALSO ATRX-ASSOCIATED XLID) 246
APPENDICES
XLID-ATAXIA-APRAXIA 248
I. GENES INVOLVED IN X-LINKED INTELLECTUAL DISABILIT Y
(BY ORDER OF DISCOVERY) 303
XLID-ATAXIA-DEMENTIA 250

II. XLID SYNDROMES WITH MICROCEPHALY 309

XLID-BLINDNESS-SEIZURES-SPASTICIT Y 252

III. XLID SYNDROMES WITH MACROCEPHALY 310

XLID-CHOREOATHETOSIS 254

IV. XLID SYNDROMES WITH OCULAR ANOMALIES AND/OR

XLID-CHOROIDEREMIA-ECTODERMAL DYSPLASIA 255
VISUAL IMPAIRMENT 311
XLID-CLEFT LIP/CLEFT PALATE 256
V. XLID SYNDROME WITH HEARING LOSS 314
XLID-EPILEPSY (XIDE) 258
VI. XLID SYNDROMES WITH FACIAL CLEFTING 315
XLID-HYDROCEPHALY-BASAL GANGLIA CALCIFICATIONS
VII. XLID SYNDROMES WITH CARDIAC MALFORMATIONS OR OTHER
(SEE ALSO AP1S2-ASSOCIATED XLID) 259
CARDIOVASCULAR ABNORMALITIES 316
XLID-HYPOGAMMAGLOBULINEMIA 261
VIII. XLID SYNDROMES WITH UROGENITAL ANOMALIES 317
XLID-HYPOGONADISM-TREMOR 263
IX. XLID SYNDROMES WITH NEURONAL MIGRATION DISTURBANCE 318
XLID-HYPOSPADIAS 266
X. XLID SYNDROMES WITH SPASTIC PARAPLEGIA 319
XLID-HYPOTONIA-RECURRENT INFECTIONS 267
XI. XLID SYNDROMES WITH SEIZURES 320
XLID-ICHTHYOSIS-HYPOGONADISM 270
XII. XLID SYNDROMES WITH HYPOTONIA 322
XLID-INFANTILE SPASMS (SEE ALSO ARX-ASSOCIATED XLID) 271
XIII. XLID SYNDROMES PREDOMINANTLY AFFECTING FEMALES 323
XLID-ISOLATED GROWTH HORMONE DEFICIENCY 273
XIV. DUPLICATION OF XLID GENES AND REGIONS OF THE
X-CHROMOSOME GENOME 324
XLID-MACROCEPHALY 275
XV. X-INACTIVATION 327
XLID-MACROCEPHALY-MACROORCHIDISM 277
XVI. SYNDROMAL XLID GENES 331
XLID-MICROCEPHALY-TESTICULAR FAILURE 279
XVII. SYNDROMAL XLID (LINKAGE LIMITS) 332
XLID-NAIL DYSTROPHY-SEIZURES 281
XVIII. NONSYNDROMAL XLID FAMILIES 333
XLID-NYSTAGMUS-SEIZURES 283
XIX. NONSYNDROMAL XLID FAMILIES 334
XLID-PANHYPOPITUITARISM 285

XLID-PRECOCIOUS PUBERT Y 287 INDEX 339

TABLE OF CONTENTS ix
This page intentionally left blank
 FOREWORD

The Greenwood Genetic Center in South Carolina was multigene sequencing panel that includes all genes associ-
established in 1974 through the efforts of Roger Stevenson ated with XLID. This is a service now offered not on by
and his associates to provide a diagnostic and assessment Greenwood Genetic Center but is also available in through
service for the state for those with intellectual disability other laboratories. A result comes back reporting a muta-
(ID). During the eighties and nineties the major contribu- tion in gene ABC. This atlas can provide both the infor-
tion of X-linked genes to ID became accepted. This stim- mation of the clinical features associated with mutations in
ulated the Center to publish in 2000 a now classic book that gene with some idea of the prognosis and references
entitled X-Linked Mental Retardation. The first half gave to more detailed clinical reports. The classical sequence of
an account of the history of X-linked ID and the second clinical diagnosis to causal mutation has given way to causal
half was an atlas with pictures and clinical details of the mutation to clinical diagnosis.
affected males from published families. It included 125 dif- This will lead to major changes in clinical practice. There
ferent syndromes. In many, linkage studies had identified will be far less discussion, in the clinic and at meetings as to
the gene location but in only very few had the responsible whether a particular set of clinical findings fits in with one
gene mutation been identified. syndrome as opposed to another. The laboratory will often
This second edition of the Atlas is a marvelous 10-year be able to settle the matter. All undiagnosed males with ID
update. It will be essential not only as a reference book will have a molecular karyotype and, if necessary, will be fol-
for medical geneticists but also for molecular laboratories lowed by a screen of the genes on the X chromosome, soon
providing a gene screening service. Over the past ten years to be followed by looking for de novo mutations. Is this the
since the publication of the previous edition, around 100 death knell of the clinical dysmorphologist? Lay and profes-
genes and their mutations have been identified in those sional support groups will be known more by their muta-
with clinical syndromes and over 33 in 95 families with tions than by their eponymous or anatomical syndromes as
nonsyndromic XLID. Some clinical diagnoses have now is happening with chromosomal disorders. The Internet will
been recognized as different manifestations of the same provide increasingly accurate clinical and molecular data.
gene as in the 24 base-pair duplications in the ARX gene. Molecular testing is rapidly becoming less expensive.
There has also been a merging of the syndromic with the This will allow the introduction of pre-pregnancy test-
non-syndromic, as families have been found in which dif- ing for carriers of X-linked ID to be added to the routine
ferent affected members may have features of either syndro- screenings. This Atlas of X-Linked Intellectual Disability
mic or non-syndromic ID but carry the same mutation. Syndromes will be invaluable in interpreting the findings.
Atlas of X-Linked Intellectual Disability Syndromes will The authors are to be congratulated on producing a
have two main functions. The first is as a help in clinical major new reference similar in importance today as was
diagnosis when the facial gestalt or a cluster of clinical fea- the publication of Dave Smith’s Recognizable Patterns of
tures brings a particular diagnosis to mind. A quick look at Human Malformations in the sixties. Information in this
the atlas will help confirm this suspicion and the clinician field continues to accumulate rapidly and we look forward
know whether the gene has been identified. to the next edition in less than 10 year’s time. This atlas is
The second, more important function is just becoming one more step in the mission of the Greenwood Genetic
apparent. In the immediate past if one made a clinical diag- Center of having all babies born free of physical and mental
nosis of an X-linked ID condition and if the gene had been disabilities.
identified, the next step was to look for a laboratory willing
to test for that mutation. Now the scene has been reversed. Gillian Turner OA Mb.Ch.B MRCPE. D.Sc.
In investigating a singleton male with ID or someone from University of Newcastle
a family that might have a mutation in a gene coded on the New South Wales
X, one can order an X gene screen covering most of the a Australia

xi
This page intentionally left blank
 PREFACE

In the early days of human development, the brain domi- recognition of the causes can specific strategies for treat-
nates the embryological landscape. As other organ sys- ment and prevention be devised. From a practical clinical
tems develop and the fetus grows, the brain becomes less standpoint, knowledge of causes gives the clinician a basis
formidable anatomically, but progressively more complex to judiciously select diagnostic tests, predict natural history,
functionally. Soon after postnatal life begins, it engages the calculate recurrence risks, direct counseling, and make rea-
environment and issues responses that bind the child to sonable medical and educational plans.
parents and to others. It enables the acquisition of skills that A pervasive finding among persons with intellectual
serve as benchmarks of developmental progress. Ultimately, disability has been the excess of males. In most popula-
the brain defines the essence of human existence through tions, the excess is about 20–40%. The biological ineq-
the control of thought processes, neurological function, uity between males and females conferred by the different
and behavior. number of sex chromosomes has been considered primarily
A certain fragility of the developing brain is suggested responsible for the excess. Accepting a male excess of 30%,
by the high prevalence in the population of significant one would estimate that XLID constitutes one of the most
impairment of cognitive and adaptive performance. Such common causal categories of intellectual disability, equal-
impairments may be associated with faulty formation or ing that of chromosome aberrations. However, the current
function of the brain, occur in one to three percent of the ability to identify intellectual disability due to X-linked
population, and are considered collectively under the gen- genes in clinical populations accounts for only a fraction
eral term intellectual disability. The high frequency with of this number.
which developmental failure of the brain occurs is found X-linked intellectual disability has been divided into
in no other organ system. The developing brain may, thus, two broad categories, syndromal and nonsyndromal (or
be easily damaged or minor damage may be more readily nonspecific). In syndromal X-linked intellectual disability,
expressed. Alternatively, other organ systems may have somatic, neurologic, behavioral, or metabolic abnormalities
structural or functional redundancy that gives greater accompany the intellectual disability and often constitute a
capacity in reserve. recognizable pattern. In nonsyndromal X-linked intellec-
Intellectual disability – significant impairment of cog- tual disability, males have no somatic, neurologic, behav-
nitive and adaptive functions – exists as a human phenome- ioral, or metabolic findings that distinguish them from
non with numerous dimensions. For the affected individual, nonaffected brothers or from other males with intellectual
it represents a cloak that limits capacity to learn, ability disability.
for expression, freedom of movement, and achievement of A large number of families with syndromal and non-
goals. For society, it represents a disability characterized by syndromal forms of XLID have been reported, primarily
reduced productivity, some measure of dependency, and during the past 50 years. Although there have been recent
vulnerability to discrimination and exploitation. For pub- advances to confirm diagnoses with biochemical or molec-
lic health, it is a common abnormality, one that is distrib- ular testing, the clues to identification of most XLID syn-
uted throughout all strata of the population, and imposes dromes come from the family history and phenotype. This
a costly and lifelong burden. For medicine, intellectual dis- Atlas of X-Linked Intellectual Disability is intended to pro-
ability represents an aberration in the formation and/or vide the clinicians, scientists, and students with a resource
function of the central nervous system that demands evalu- to differentiate the various types of XLID on the basis of
ation and explanation. craniofacial or other somatic findings, neurologic signs or
Partition of intellectual disability by cause is informa- symptoms, behavioral manifestations, brain imaging, and
tive on several counts. Scientifically, it confirms that the laboratory testing. Separate genes exist for many, but not
developing brain is susceptible to a wide variety of insults all, of the 150 syndromal forms of XLID.
including faulty genetic instructions, environmental influ- Delineation of the various forms of XLID has been
ences, and a combination of these two forces. Only with possible only through the contributions of affected families

xiii
and their physicians. To them, we are indebted and to them imprecision with which clinical evaluations are carried
we dedicate this monograph. Researchers worldwide have out, it is inevitable that some individuals with X-linked
followed up the clinical observations with systematic bio- intellectual disability will be incorrectly included in exist-
logical investigations, including a wide variety of imaging, ing diagnostic categories while others will be incorrectly
histologic, molecular and cytogenetic studies, which have excluded. The extent to which individuals/families can be
permitted delineation of the phenotype and localization evaluated is dependent on the setting, access to historical
of the majority of the X-linked intellectual disability syn- information, availability and ages of affected and nonaf-
dromes. The responsible genes have now been identified in fected family members, and the experience and expertise
two-thirds of the syndromes. of the observers. Differences in phenotype can result from
Prior to publication of X-Linked Mental Retardation mutations in different domains of a gene and by contribu-
in 2000, the laboratory approach to gene localization and tions from the balance of the genome. The identification of
identification was limited to pursuit of genes where the gene many causative XLID genes has provided the opportunity
products were known (enzymes in all cases: HPRT, PGK1, to compensate for some of these variables, resulting in the
OTC, and PHDA1), exploration of chromosome rearrange- lumping of entities previously considered to be separate
ments (predominately X-autosome translocations), and and the splitting of other entities previously considered
linkage analysis in large families in which XLID appeared the same. At the same time, the phenotypic limits of some
to segregate. Since that time, the study of breakpoints in XLID entities have been established with some degree of
chromosome rearrangements and linkage analysis coupled objectivity.
with candidate gene testing, have continued to be the Several XLID entities have been most instructive.
most productive means of gene identification. Brute force Discovery that mutations in the ATRX gene (Xq21.1) cause
sequencing of the X chromosome and genomic microar- Alpha-Thalassemia Intellectual Disability allowed testing
rays for copy number variants coupled with candidate gene of large number of males with hypotonic facies, intellectual
testing, have been added to these technologies in recent disability, and other features (Gibbons et al. 1995a, 1995b;
years. Prior to 2000, 30 XLID genes had been identified; Villard and Fontes 2002). Five named XLID syndromes –
since then an additional 72 XLID genes have been identi- Carpenter–Waziri, Holmes–Gang, Chudley–Lowry and
fied. Among families suspected to have XLID, 40–50% of XLID–Arch Fingerprints–Hypotonia – have been found
the responsible mutations can now be identified with the to be allelic variants of Alpha-Thalassemia Intellectual
most commonly affected genes, besides FMR1, being ARX Disability as have certain families with spastic paraplegia
(5–6%), and MECP2, OPHN1, PQBP1, and KDM5C and nonsyndromal XLID (Abidi et al. 1999, Lossi et al.
(each 1–4%). Mutations are detected in a much lower per- 1999, Stevenson et al. 2000, Guerrini et al. 2000, Yntema
centage of sporadic males with ID. et al. 2002, Abidi et al. 2005). One family clinically diag-
Segmental duplications involving one or more genes on nosed as Juberg–Marsidi syndrome was found to have an
the X chromosome have been associated with intellectual ATRX mutation (Villard et al. 1996). This is now known
disability. The most common of the segmental duplica- to be based on misdiagnosis of Juberg–Marsidi syndrome
tions involves the PLP1 gene at Xq22 and is responsible since the original family with this syndrome has a mutation
for the majority of cases of Pelizaeus–Merzbacher disease in HUWE1 at Xp11.22 (Friez et al. 2011). One family clin-
(Mimault et al. 1999). A second important duplication ically diagnosed as Smith–Fineman–Myers syndrome was
occurs in Xq28 and includes MECP2 with or without also found to have an ATRX mutation, although the gene
adjacent genes. The phenotype includes severe intellectual has not been analyzed in the original family (Villard et al.
disability (sometimes with co-occurring autism or autistic 2000). A clinically similar condition, Coffin–Lowry syn-
manifestations), hypotonia, absent or limited speech, absent drome, was found to be separate from Alpha-Thalassemia
or limited ambulation, spasticity, seizures, and recurrent Intellectual Disability and due to mutations in the ser-
respiratory infections (Van Esch et al. 2005, Friez et al. ine–threonine kinase gene, RPS6KA3 (RSK2) located at
2006). In some cases of X chromosome segmental dupli- Xp22.13 (Trivier et al. 1996).
cations, it is unclear whether the whole gene duplication, Kalscheuer et al. (2003) found mutations in PQBP1
partial duplication of adjacent gene or other position effect (Xp11.23) in two named XLID syndromes – Sutherland–
is most important in the causation of ID. In many cases of Haan syndrome and Hamel Cerebro-Palato-Cardiac
clinically important segmental duplication of the X chro- syndrome – and in MRX55 and two other families with
mosome, marked skewing of X-inactivation has been docu- microcephaly and other findings. Lenski et al. (2004),
mented in carrier females. Stevenson et al. (2005), and Lubs et al. (2006) added
The clinical re-evaluation of families with XLID previ- Renpenning, Porteous, and Golabi-Ito-Hall syndromes
ously reported, observations in more recently ascertained to the list of XLID syndromes caused by mutations in
families, and the incorporation of molecular technologies PQBP1. As with the ATRX phenotypes, a wide variety of
in diagnosis have resulted in lumping, splitting and reclas- phenotypic expressions result from different mutations in
sification of a number of XLID. With the variability and PQBP1 and we remain challenged to better understand

xiv PREFACE
the molecular and developmental mechanisms leading to OPHN1 and ARX mutations) reexamination has found
these differences (Germanaud et al. 2011, Sheen et al. 2010, syndromal manifestations in families previously considered
Musante et al. 2010). to have nonsyndromal XLID (Turner et al. 2002, Frints
ARX (Xp22.11) was also found to be an impor- et al. 2002, Bergmann et al. 2003, Philip et al. 2003).
tant XLID gene encompassing multiple phenotypes. The frequency with which the process of lumping and
Mutations, most commonly a 24 bp expansion of a polyala- splitting in this limited field of investigation has occurred
nine tract, were found in a number of nonsyndromal fami- has been extremely instructive to both clinical and molecu-
lies (MRX29, 32, 33, 36, 38, 43, 54, and 76), an X-linked lar investigators. The underlying mechanisms or pathways
dystonia (Partington syndrome), X-linked infantile spasms by which mutations in different genes result in similar
(West syndrome), X-linked lissencephaly with abnormal phenotypes and different mutations in a single gene result
genitalia, hydranencephaly and abnormal genitalia, and in disparate phenotypes, however, remain to be fully
Proud syndrome (Strømme et al. 2002a, 2002b; Bienvenu elucidated.
et al. 2002, Frints et al. 2002, Kitamura et al. 2002, Uyanik An exponential increase in the understanding of
et al. 2003, Kato et al. 2004, Stepp et al. 2005). molecular pathways and neuronal complexes involved in
Perhaps the most prominent example of syndrome split- brain function has occurred in the past decade. Many of
ting is FG syndrome. This syndrome, initially described in the genes and their protein products involved in the criti-
1974 by Opitz and Kaveggia, is manifest by macrocephaly cal processes of proper brain development and function
(or “relative macrocephaly”), downslanting palpebral fis- – neurogenesis, neuronal migration, and synaptic connec-
sures, imperforate anus or severe constipation, broad and tivity – have been identified. It has become obvious that
flat thumbs and great toes, hypotonia, and intellectual the “brain genes” may play multiple roles in these areas of
disability. In the ensuing years, the manifestations attrib- central nervous system development at different critical
uted to FG syndrome have become protean, but none was developmental periods. Neurogenesis is likely affected by
pathognomonic or required for the diagnosis (Opitz et al. many X-linked genes given the finding of microcephaly in
1988, Romano et al. 1994, Ozonoff et al. 2000, Battaglia et over 40 of the syndromes described in this text. Neuronal
al. 2006). Clinical heterogeneity was thus introduced and migration abnormalities are a common pathogenic finding
as a result different families were found to have different on cranial imaging studies in individuals with mutations of
localizations on the X chromosome (Briault et al. 1997, ARX, DCX, and FLNA. Synaptic connectivity has emerged
2000; Piluso et al. 2003, Dessay et al. 2002, Jehee et al. as the single most important functional deficit in individu-
2005, Tarpey et al. 2007, Unger et al. 2007). als with ID and the synapse is the site of expression for a
In 2007, Risheg et al. found a recurring mutation, majority of the associated X-linked genes. Gene products
pR961W, in MED12 (Xq13.1) in six families with the FG are involved in pre- and post-synaptic processes of synaptic
phenotype, including the original family reported by Opitz vesicles (SYN1, SYP), cellular adhesion (L1CAM, NLGN3,
and Kaveggia. In addition to the above noted manifesta- NLGN4, PCDH19), neurotransmitter release and receptor
tions, two other findings, small ears and friendly behavior, function (GRIA3, IL1RAPL1), neurite outgrowth and
were consistently noted. dendritic spine maturation (FMR1, PAK3, OPHN1), and
Although most patients that have carried the FG diag- cytoskeletal homeostasis (CASK, FLNA). Additionally,
nosis have one or more findings that overlap with those in several X-linked genes function as transporters: ATP7A,
FG syndrome, they do not have MED12 mutations (Lyons MED12, SLC16A2 (MCT8) and SLC6A8, and transcrip-
et al. 2009, Clark et al. 2009). Some have been found tion regulation and chromatin remodeling: ARX, MECP2,
to have other X-linked gene mutations (FMR1, FLNA, KDM5C, RPS6KA3, BRWD3 and ATRX. Rho GTPase
ATRX, CASK, MECP2) and others have had duplications genes – ARHGEF6, ARHGEF9, OPHN1, GDI1, FGD1
or deletions of the autosomes (Lyons et al. 2009, Clark et and PAK3 – mediate organization of the cytoskeleton, cell
al. 2009). So great is the currently existing heterogeneity shape, and motility. The RAS-MAPK transcription-sig-
within FG syndrome, that the vast majority of individuals naling cascade includes proteins encoded by ARX, PHF6,
so designated should best be considered to have intellectual ZNF41, PAK3, and RPS6KA3. Some genes are involved in
disability of undetermined cause. The designation of mul- basic cellular processes, including RNA splicing (PQBP1),
tiple loci on the X chromosome for FG syndrome appears translation (FTSJ1), energy metabolism (SLC6A8), endo-
to be ill conceived (Opitz et al. 2008) and illustrates the cytosis (DLG3, AP1S2), ubiquitination (CUL4B, UBE2A)
hazards involved in nosology without a laboratory basis. and nonsense mediated decay (UPF3B). Elucidation of
In a number of instances, certain mutations of genes the molecular etiology of Fragile X syndrome has allowed
have been associated with nonsyndromal XLID while greater understanding of the interplay and balance neces-
other mutations of the same genes have caused syndromal sary between both excitatory glutaminergic and inhibitory
XLID. Seventeen genes that may cause either type of XLID, GABAergic neurons, and provided insight to possible treat-
depending on the mutation, have been identified (www. ments targeted at restoring this balance, an approach that
ggc.org/xlmr.htm, Figure 2). In some cases (e.g., those with may also be applicable to other types of ID and autism.

PREFACE xv
 We wish to thank our clinical and research colleagues epilepsy, rostral ventricular enlargement and cerebellar hypoplasia.
who have taught us about X-linked intellectual disability. In Brain 126:1537, 2003.
Bienvenu T, Poirier K, Friocourt G, et al.: ARX, a novel Prd-class-
particular, we thank Herbert Lubs (Painter, VA), Fernando homeobox gene highly expressed in the telencephalon, is mutated in
Arena (National Cancer Institute, Bethesda, MD), Hunt X-linked mental retardation. Hum Mol Genet 11:981, 2002.
Willard (Duke University, Durham, NC), Jean-Louis Briault S, Hill R, Shrimpton A, et al.: A gene for FG syndrome maps in
Mandel (Institut de Chimie Biologique, Strasbourg), Grant the Xq12–21.31 region. Am J Med Genet 73:87, 1997.
Briault S, Villard L, Rogner U, et al.: Mapping of X chromosome inver-
Sutherland (Women’s and Children’s Hospital, Adelaide), sion breakpoints [inv(X)(q11q28)] associated with FG syndrome: a
Gillian Turner, Anna Hackett, and Michael Field (Hunter second FG locus [FGS2]? Am J Med Genet 95:178, 2000.
Genetics, New South Wales), Josef Gecz (Women’s and Clark RD, Graham JM, Friez MJ, et al.: FG syndrome, an X-linked
Children’s Hospital, Adelaide), Giovanni Neri (Universitá multiple congenital anomaly syndrome: the clinical phenotype and
an algorithm for diagnostic testing. Genet Med 11:769, 2009.
Cattolica del Sacro Cuore, Rome), Patrick Tarpey and Dessay S, Moizard MP, Gilardi JL, et al.: FG syndrome: linkage analy-
Mike Stratton (Wellcome Trust Sanger Institute, Hinxton, sis in two families supporting a new gene localization at Xp22.3
Cambridge, UK), Lucy Raymond (Cambridge Institute of [FGS3]. Am J Med Genet 112:6, 2002.
Medical Research, Cambridge, UK), and Michel Fontés Friez MJ, Jones JR, Clarkson K, et al.: Recurrent infections, hypotonia,
and mental retardation caused by duplication of MECP2 and adja-
(INSERM, Marseille). Our current and former colleagues cent region in Xq28. Pediatrics 118:e1687, 2006.
at the Greenwood Genetic Center: William Allen, Ellen Friez MJ, Brooks SS, Stevenson RE, et al.: Juberg–Marsidi syndrome
Boyd, Sara Cathey, Katie Clarkson, David Everman, Joseph and Brooks syndrome are allelic X-linked intellectual disability
Geer, Michael Lyons, Robert Saul, Laurie Seaver, Richard syndromes due to a single mutation (p.G4310R) in HUWE1. 15th
International Workshop on Fragile X and Early-Onset Cognitive
Simensen, Steven Skinner, Yuri Zarate and our laboratory Disorders. September 5, 2011, Berlin, Germany.
colleagues: Fatima Monica Basehore Abidi, Lauren Cason, Frints SG, Froyen G, Marynen P, et al.: Re-evaluation of MRX36 family
Mike Chandler, Barbara DuPont, Michael Friez, Bernhard after discovery of an ARX gene mutation reveals mild neurological
Häne, Lynda Holloway, Darci Horne, Julie Jones, John features of Partington syndrome. Am J Med Genet 112:427, 2002.
Germanaud D, Rossi M, Bussy G, et al.: The Renpenning syndrome
Longshore, Melanie May, Ron Michaelis, Retecher Nelson, spectrum: new clinical insights supported by 13 new PQBP1-
Lisbeth Ouzts, Katy Phelan, Laura Pollard Anand Srivastava, mutated males. Clin Genet 79:225, 2011.
Monica Stepp, Jack Tarleton, Harold Taylor, and Tim Wood Gibbons RJ, Brueton L, Buckle VJ, et al.: Clinical and hematologic
have made important contributions to the evaluation and aspects of the X-linked α-thalassemia/mental retardation syndrome
(ATR-X). Am J Med Genet 55:288, 1995.
understanding of X-linked intellectual disability. They have Gibbons RJ, Picketts DJ, Villard L, et al.: Mutations in a putative global
made suggestions on content of this Atlas, reviewed drafts of transcriptional regulator cause X-linked mental retardation with
the manuscript and have taken on additional responsibilities α-thalassemia (ATR-X syndrome). Cell 80:837, 1995.
to give us time to devote to this effort. Guerrini R, Shanahan JL, Carrozzo R, et al.: A nonsense mutation of
the ATRX gene causing mild mental retardation and epilepsy. Ann
Numerous authors and publishers have provided fig- Neurol 47:117, 2000.
ures to illustrate the XLID syndromes. Individual credits Jehee FS, Rosenberg C, Krepischi-Santos AC, et al.: An Xq22.3 duplica-
are given in the figure legends. Literature searches, citation tion detected by comparative genomic hybridization microarray (Array-
verification, and other library resources have been provided CGH) defines a new locus (FGS5) for FG syndrome. Am J Med Genet
A 139:221, 2005.
by Rachel Collins. Karen Buchanan and Patti Broome have Kalscheuer VM, Freude K, Musante L, et al.: Mutations in the polyglu-
organized the materials used to produce this monograph tamine binding protein 1 gene cause X-linked mental retardation.
and have provided invaluable assistance and advice. Nat Genet 35:313, 2003.
The production of Atlas of X-Linked Intellectual Kato M, Das S, Petras K, et al.: Mutations of ARX are associated with
striking pleiotropy and consistent genotype-phenotype correlation.
Disability gave us the opportunity to work with Anne Hum Mutat 23:147, 2004.
Dellinger and Catherine Barnes at Oxford University Kitamura K, Yanazawa M, Sugiyama N, et al.: Mutation of ARX causes
Press. Their valuable suggestions from concept through abnormal development of forebrain and testes in mice and X-linked
production have enabled us to work with some degree of lissencephaly with abnormal genitalia in humans. Nat Genet
32:359, 2002.
efficiency and equanimity. Lenski C, Abidi F, Meindl A, et al.: Novel truncating mutations in
the polyglutamine tract binding protein 1 gene (PQBP1) cause
Renpenning syndrome and X-linked mental retardation in another
family with microcephaly. Am J Hum Genet 74:777, 2004.
REFERENCES Lossi AM, Millán JM, Villard L, et al.: Mutation of the XNP/ATR-X
gene in a family with severe mental retardation, spastic paraplegia and
Abidi F, Hall BD, Cadle RG, et al.: X-linked mental retardation with skewed pattern of X inactivation: demonstration that the mutation is
variable stature, head circumference, and testicular volume linked involved in the inactivation bias. Am J Hum Genet 65:558, 1999.
to Xq12–q21. Am J Med Genet 85:223, 1999. Lubs H, Abidi FE, Echeverri R, et al.: Golabi–Ito–Hall syndrome
Abidi FE, Cardoso C, Lossi AM, et al.: Mutation in the 5’ alternatively results from a missense mutation in the WW domain of the PQBP1
spliced region of the XNP/ATR-X gene causes Chudley–Lowry gene. J Med Genet 43:e30, 2006.
syndrome. Eur J Hum Genet 13:176, 2005. Lyons MJ, Graham JM Jr., Neri G, et al.: Clinical experience in the
Battaglia A, Chines C, Carey JC: The FG syndrome: Report of a large evaluation of 30 patients with a prior diagnosis of FG syndrome. J
Italian series. Am J Med Genet A 140:2075, 2006. Med Genet 46:9, 2009.
Bergmann C, Zerres K, Senderek J, et al.: Oligophrenin 1 (OPHN1) Mimault C, Giraud G, Courtois V, et al.: Proteolipoprotein gene analysis in
gene mutation causes syndromic X-linked mental retardation with 82 patients with sporadic Pelizaeus–Merzbacher disease: duplications,

x vi PREFACE
 the major cause of the disease, originate more frequently in male germ Stevenson RE, Bennett CW, Abidi F, et al.: Renpenning syndrome
cells, but point mutations do not. The Clinical European Network on comes into focus. Am J Med Genet A 134:415, 2005.
Brain Dysmyelinating Disease. Am J Hum Genet 65:360, 1999. Strømme P, Mangelsdorf ME, Shaw MA, et al.: Mutations in the human
Musante L, Kunde SA, Sulistio TO, et al.: Common pathological ortholog of Aristaless cause X-linked mental retardation and epilepsy.
mutations in PQBP1 include nonsense-mediated mRNA decay Nat Genet 30:441, 2002a.
and enhance exclusion of the mutant exon. Hum Mutat 31:90, Strømme P, Mangelsdorf ME, Scheffer IE, Gécz J.: Infantile spasms,
2010. dystonia, and other X-linked phenotypes caused by mutations in
Opitz JM, Smith JF, Santoro L: The FG syndrome (Online Mendelian Aristaless related homeobox gene, ARX. Brain Dev 24:266, 2002b.
Inheritance in Man 305450): Perspective in 2008. Adv Pediatr Tarpey PS, Raymond FL, Nguyen LS, et al.: Mutations in UPF3B, a mem-
55:123, 2008. ber of the nonsense-mediated mRNA decay complex, cause syndromic
Opitz JM and Kaveggia EG: Studies of malformation syndromes and nonsyndromic mental retardation. Nat Genet 39:1127, 2007.
of man XXXIII: The FG syndrome. An X-linked recessive syn- Trivier E, De Cesare D, Jacquot S, et al.: Mutations in the kinase Rsk-2
drome of multiple congenital anomalies and mental retardation. Z associated with Coffi n–Lowry syndrome. Nature 384:567, 1996.
Kinderheilk 117:1, 1974. Turner G, Partington M, Kerr B, et al.: Variable expression of mental
Opitz JM, Richieri-da Costa A, Aase JM, et al.: FG syndrome update retardation, autism, seizures, and dystonic hand movements in two
1988: note of 5 new patients and bibliography. Am J Med Genet families with an identical ARX gene mutation. Am J Med Genet
30:309, 1988. 112:405, 2002.
Ozonoff S, Williams BJ, Rauch AM, Opitz JO: Behavior phenotype Unger S, Mainberger A, Spitz C, et al.: Filamin A mutation is one cause
of FG syndrome: cognition, personality, and behavior in eleven of FG syndrome. Am J Med Genet 143A:1876, 2007.
affected boys. Am J Med Genet 97:112, 2000. Uyanik G, Aigner L, Martin P, et al.: ARX mutations in X-linked lis-
Philip N, Chabrol B, Lossi AM, et al.: Mutations in the oligophrenin-1 sencephaly with abnormal genitalia. Neurology 61:232, 2003.
gene (OPHN1) cause X linked congenital cerebellar hypoplasia. J Van Esch H, Bauters M, Ignatius J, et al.: Duplication of the MECP2
Med Genet 40:441, 2003. region is a frequent cause of severe mental retardation and progres-
Piluso G, Carella M, D’Avanzo M, et al.: Genetic heterogeneity of sive neurological symptoms in males. Am J Hum Genet 77:442,
FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an 2005.
Italian family. Hum Genet 112:124, 2003. Villard L, Fontes M: Alpha-thalassemia/mental retardation syndrome.
Risheg H, Graham JM Jr., Clark RD, et al.: A recurrent mutation in X-linked (ATR-X, MIM #301040). ATR-X/XNP/XH2 gene MIM
MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat #300032). Eur J Hum Genet 10:223, 2002.
Genet 39:451, 2007. Villard L, Fontès M, Adès LC, Gecz J: Identification of a mutation
Romano C, Baraitser M, Thompson E: A clinical follow-up of British in the XNP/ATR-X gene in a family reported as Smith-Fineman-
patients with FG syndrome. Clin Dysmorphol 3:104, 1994. Myers syndrome. Am J Med Genet 91:83, 2000.
Sheen VL, Torres AR, Du X, et al.: Mutation in PQBP1 is associated Villard L, Gecz J, Mattei JF, et al.: XNP mutation in a large family with
with periventricular heterotopia. Am J Med Genet A 152A:2888, Juberg–Marsidi syndrome. Nat Genet 12:359, 1996.
2010. Yntema HG, Poppelaars FA, Derksen E, et al.: Expanding phenotype of
Stepp ML, Cason AL, Finnis M, et al.: XLMR in MRX families 29, 32, XNP mutations: mild to moderate mental retardation. Am J Med
33 and 38 results from the dup24 mutation in the ARX (Aristaless Genet 110:243, 2002.
related homeobox) gene. BMC Med Genet 6:16, 2005.
Stevenson RE, Abidi F, Schwartz CE, et al.: Holmes–Gang syndrome R.E.S.
is allelic with XLMR-hypotonic face syndrome. Am J Med Genet C.E.S.
94:383, 2000. R.C.R.

PREFACE x vii
This page intentionally left blank
A ARSKOG SYNDROME
(A ARSKOG -SCOT T SY NDROME, FACIOGENI TAL DY SPL A SIA ,
FACIODIGI T OGE NI TA L S Y NDROME )

O M I M 305 4 0 0 Somatic Features. Prominent forehead, widow’s peak,

hypertelorism, downslanting palpebral fissures, ptosis, short
X p11. 2 2
nose with anteverted nares, cupped ears, wide upper lip,
FGD1 indistinct philtral pillars, and small chin comprise the facial
phenotype. In adults, the face elongates and the prominent
Definition. XLID with short stature, hypertelorism, forehead and hypertelorism may not be apparent. When
downslanting palpebral fissures, joint hyperextensibility, extended, the fingers are held in flexion at the MP joints,
and shawl scrotum. The gene (FGD1), a guanine nucleo- hyperextension at the PIP joints, and flexion at the DIP
tide exchange factor, exerts its influence, at least in part, joints, presumably because of shortening of the flexor ten-
by activating Rho GTPase. More than 100 mutations, the dons. Other musculoskeletal findings include brachydactyly,
majority of which lead to truncated proteins, have been horizontal palmar crease, varus foot, and generalized joint
identified. hyperextensibility. The scrotum tends to surround the penis,

A B C

D E

Aarskog Syndrome. Four-year-old with hypertelorism, downslanting palpebral fissures, and prominent forehead (A); 17-year-old with prominent fore-
head, ptosis, and cupped ears (B); 60-year-old with balding and cupped ears but less apparent widening of midface (C); characteristic posturing of
extended fingers (D); shawl scrotum (E).

1
giving the “shawl scrotum” appearance. Protruding umbili- mutations. One family with nonsyndromal XLID had a
cus, cryptorchidism, and inguinal hernias may occur. missense mutation.
Growth and Development. From birth, linear growth fol-
lows the lower centiles. Head circumference is normal.
REFERENCES
Cognitive Function. Intelligence is usually normal but is
quite variable from normal into the mildly impaired range. Aarskog D: A familial syndrome of short stature associated with facial
dysplasia and genital anomalies. J Pediatr 77:856, 1970.
Severe intellectual impairment is the exception. Fryns JP: Aarskog syndrome: The changing phenotype with age. Am J
Neurological Findings. Hypermobility of the cervical Med Genet 43:240, 1992.
Lebel RR, May M, Pouls S, et al.: Non-syndromic X-linked mental
spine may lead to cord impingement. retardation associated with a missense mutation (P312L) in the
FGD1 gene. Clin Genet 61:139, 2002.
Heterozygote Expression. Carrier females tend to be Logie LJ, Porteous MEM: Intelligence and development in Aarskog
shorter than noncarriers and may have subtle facial features syndrome. Arch Dis Child 79:359, 1998.
(hypertelorism, fullness of tip of the nose), brachydactyly, Orrico A, Galli L, Cavaliere ML, et al.: Phenotypic and molecular char-
and unusual posturing of the fingers. acterization of the Aarskog-Scott syndrome: A Survey of the clini-
cal variability in light of FGD1 mutation analysis in 46 patients. Eur
Comment. Aarskog syndrome has one of the distinctive J Hum Genet 12:16, 2004.
recognizable somatic phenotypes with which very few con- Pasteris NG, Cadle A, Logie LJ, et al.: Isolated and characterization of
the faciogenital dysplasia (Aarskog-Scott syndrome) gene: A puta-
ditions are likely to be mistaken. Noonan syndrome shares tive Rho/Rac guanine nucleotide exchange factor. Cell 79:669,
ptosis, downslanting palpebral fissures, short stature, and 1994.
pectus excavatum. However, patients with Noonan syn- Porteous MEM, Curtis A, Lindsay S, et al.: The gene for Aarskog syn-
drome often have broad and webbed neck and a cardiac drome is located between DXS255 and DXS566 (Xp11.2-Xq13).
Genomics 14:298, 1992.
defect; patients with Aarskog syndrome often have shawl Porteous MEM, Goudie DR: Aarskog syndrome. J Med Genet 28:44,
scrotum. These findings serve as distinguishing but not 1991.
pathognomonic findings. Teebi Hypertelorism syndrome Scott CI, Jr.: Unusual facies, joint hypermobility, genital anomaly and
and Robinow syndrome – both autosomal syndromes – short stature: A new dysmorphic syndrome. Birth Defects: Orig Art
Ser VII(6):240, 1971.
should be included in the differential diagnosis. Stevenson RE, May M, Arena JF, et al.: Aarskog-Scott syndrome:
Only about one-fi fth of the individuals suspected on Confirmation of linkage to the pericentromeric region of the X
clinical findings to have Aarskog syndrome harbor FGD1 chromosome. Am J Med Genet 52:339, 1994.

2 ATL AS OF X-LINKED INTELLEC TUAL DISABILIT Y SY NDROMES

D I F F E R E N T I A L M AT R I X
Telecanthus/ Urogenital
Syndrome Hypertelorism Brachydactyly Anomaly Comments

Aarskog + + + Short stature, downslanting palpebral fissures,

ptosis, cupped ears, anteverted nares, horizontal
palmar crease, midfoot varus, joint laxity, shawl
scrotum, cryptorchidism, inguinal hernias

Atkin-Flaitz + + + Macrocephaly, short stature, downslanting

palpebral fissures, broad nasal tip, thick lower lip,
macroorchidism, seizures

ATRX-Associated XLID + + + Microcephaly, short stature, small triangular nose,

tented upper lip, open mouth, wide spacing of teeth,
musculoskeletal anomalies, hemoglobin H inclusions
in erythrocytes

Simpson-Golabi-Behmel + + + Somatic overgrowth, supernumerary nipples,

polydactyly

Kang + + 0 Microcephaly, frontal prominence, downturned

angles of mouth

Otopalatodigital I + + 0 Cleft palate, hearing impairment, short stature,

(FLNA-Associated XLID) skeletal dysplasia, mild cognitive impairment

Hall Orofacial + 0 + Normal growth, upslanted and short palpebral

fissures, prominent nasal tip, high nasal bridge,
inguinal hernia

Telecanthus- + 0 + High broad nasal root, dysplastic ears, cleft lip/

Hypospadias palate, abnormal cranial contour or symmetry

Wittwer + 0 + Microcephaly, short stature, microphthalmia, hearing

loss, vision loss, hypotonia, seizures

XLID-Psoriasis + 0 + Open mouth, large ears, hypotonia, seizures,

psoriasis

Hereditary Bullous 0 + + Microcephaly, short stature, upslanting palpebral

Dystrophy, X-linked fissures, protruding ears, short and tapered digits,
cardiac defects, bullous dystrophy, small testes,
early death from pulmonary infection

A ARSKOG SYNDROME 3
ABIDI SYNDROME

O M I M 30 0 26 2 centile. Sloping forehead and cupped ears were present in

some cases. Two affected males had cleft lip with or without
X q12- q21
cleft palate, but this was noted in nonaffected family mem-
Definition. XLID with variable manifestations, but usu- bers as well. Testicular volume was below the 10th centile
ally short stature, small head size, and small testes. The gene in four of six for whom measurements were available. Large
maps to Xq12-q21. ears, hearing loss, high foot arches, and excessive arch fin-
gerprints were present in some cases.
Somatic Features. Based on a single family, manifestations
tended to be mild and variable. The head circumference Growth and Development. Birth weights were in the
was smaller than unaffected brothers but in only one case lower centiles. Adult height and head circumference tended
was less than the 3rd centile. Stature was usually below the to be at or below the 10th centile. Developmental mile-
10th centile, again with a single case being below the 3rd stones were globally delayed in most cases.

A B C

D E F

Abidi Syndrome. Facial appearance of three males ages 31, 34, and 37 years, showing sloping forehead and prominent brow (A–D) and
sloping forehead, cupped ears, and repaired cleft lip (E–F).

4
Cognitive Function. IQ measurement varied between 12 respects, the syndrome resembles Renpenning syndrome,
and 61. which maps to Xp11.
Neurological Findings. Muscle tone was normal, and
in several cases there was a mild increase in deep tendon REFERENCE
reflexes.
Abidi F, Hall BD, Cadle RG, et al.: X-linked mental retardation with
Heterozygote Expression. None variable stature, head circumference, and testicular volume linked
to Xq12-q21. Am J Med Genet 85:223, 1999.
Comment. The manifestations were so mild and variable
as to limit their usefulness in clinical diagnosis. In many

D I F F E R E N T I A L M AT R I X
Syndrome Microcephaly Short Stature Small Testes Comments

Abidi + + + Sloping forehead, cupped ears

ATRX-Associated XLID + + + Telecanthus/hypertelorism, small triangular nose,

tented upper lip, open mouth, wide spacing of
teeth, minor musculoskeletal anomalies, hypotonia,
erythrocyte HbH inclusions in some

Börjeson-Forssman- + + + Coarse face, large ears, gynecomastia, narrow sloped

Lehmann shoulders, visual impairment, tapered digits, hypotonia,
obesity

Hereditary Bullous Dystrophy, + + + Upslanting palpebral fissures, protruding ears, digits

X-linked short and tapered, bullous dystrophy, early death
from pulmonary infection, cutaneous lesions, cardiac
defects

Renpenning + + + Upslanting palpebral fissures

XLID-Microcephaly-Testicular + + + Prominent supraorbital ridges, high nasal bridge,

Failure prominent nose, macrostomia

Cornelia de Lange + + 0 Arched eyebrows, synophrys, long philtrum, thin lips,

Syndrome, X-linked cutis marmorata, small hands and feet, hirsutism,
enlarged cerebral ventricles, proximal thumbs, elbow
restriction

Miles-Carpenter + + 0 Ptosis, small palpebral fissures, open mouth, pectus

excavatum, scoliosis, long hands, camptodactyly,
rockerbottom feet, arch fingerprints, unsteady gait,
skeletal abnormality, spasticity

Roifman + + 0 Spondyloepiphyseal dysplasia, retinal pigmentary

deposits, antibody deficiency, eczema, hypotonia

Pettigrew + 0 + Dandy-Walker malformation, microcephaly or

hydrocephaly, long face with macrostomia,
contractures, choreoathetosis, cerebellar hypoplasia,
spastic paraplegia, iron deposits or calcification of
basal ganglia, seizures

XLID-Hypogonadism- 0 + + Prominent lower lip, muscle wasting of legs, abnormal

Tremor gait, obesity, seizures, tremor

ABIDI SYNDROME 5
ADRENOLEUKODYSTROPHY
(A DDISON DISE ASE AND CEREBR AL SCL EROSIS, ADRE NOM Y ELONEUROPAT H Y, SIEMERL ING -
CREU T Z F EL DT DISE ASE, BRON Z E SCHIL DER DISE ASE, MEL ANODERMIC L EUKODYS T ROPH Y )

O M I M 30 010 0 Neurological Findings. X-linked adrenoleukodystrophy

usually presents with neurological features. The neurolog-
Xq28
ical presentation, age of onset, and progression are variable.
ABCD1 Cerebral involvement predominates in childhood. Spinal
cord presentation is more common in adulthood. At any
Definition. XLID with variable and progressive vision and age, the presence of cerebral demyelination signals a more
hearing loss, spasticity, and neurological deterioration asso- rapid progression.
ciated with demyelination of the CNS and adrenal insuffi-
ciency. The gene, ABCD1, encodes a peroxisomal membrane Natural History. Cerebral adrenoleukodystrophy usually
ATP-binding cassette (ABC) protein. presents at ages 4 to 8 years but may present in adolescence.
Slowing and then arrest of motor, mental, and social devel-
Somatic Features. Malformations are not features of this opment, with behavioral changes, are followed by spastic-
peroxisomal disorder. With elevated melanocyte-stimulat- ity, vision and hearing impairments, and, in a matter of
ing hormone in overt or covert adrenal insufficiency, the years, death in an extremely debilitated state. The adult-on-
skin may become diffusely darkened. set cerebral presentation includes dementia and psychosis
and is also rapidly progressive. More commonly, however,
Growth and Development. In childhood-onset adreno-
adults present with more slowly progressive spastic parapa-
leukodystrophy, normal growth and development for the
resis (adrenomyeloneuropathy). They may develop sphinc-
first several years are followed by developmental stagnation
ter incompetence and impotence. About half will develop
or regression and growth failure.
cerebral involvement.
Cognitive Function. Cerebral demyelination during child- By the time of neurological manifestations, frank adre-
hood results in cognitive arrest and in adulthood results in nal insufficiency or, more commonly, compromise of adre-
dementia. nal reserve, may be found. About 15% of people who suffer

Adrenoleukodystrophy. T-2 axial images of the brain (image on the left is video-inverted) showing bilateral, symmetric abnormal signal in the occipi-
tal lobe white matter, and splenium of the corpus callosum caused by dysmyelineation/demyelination. Courtesy of Dr. G. Shashidhar Pai, Medical University
of South Carolina, Charleston.

6
from childhood-onset adrenoleukodystrophy present with diet in preventing the onset of neurological symptoms
adrenal insufficiency. About 40% of adrenomyeloneuropa- is under investigation. Also under study are bone mar-
thy patients have clinical adrenal insufficiency before the row and stem cell transplantation and anti-inflammatory
onset of neurologic symptoms. Of those with neurological interventions.
presentation, 85% have compromise of adrenal reserve by
ACTH provocative testing. Variable presentations within Comment. The existence of a modifier gene has been pro-
families is common. posed because the severity of the neurological involvement
does not correlate with gene mutations, very-long-chain
Heterozygote Expression. Heterozygotes may be affected fatty acid levels, or adrenal insufficiency. It is proposed that
in this condition, most commonly with adrenomyeloneu- the modifier gene may affect the cerebral inflammatory
ropathy but sometimes with cerebral involvement. One-half response.
or more of carriers show some mild neurological manifesta- X-linked adrenoleukodystrophy accounts for about
tion, and about 20% have adrenomyeloneuropathy. Adrenal 5% of the leukodystrophies, is less frequent than Pelizaeus-
insufficiency is very rare in heterozygotes. Merzbacher disease and metachromatic leukodystrophy, but
is more common than Krabbe disease and Tay-Sachs disease.
Neuropathology. Brain demyelination commences in the
parieto-occipital region and progresses anteriorly in 85%
of cerebral cases. The demyelination is accompanied by an
REFERENCES
inflammatory response. Spinal cord pathology is that of a
distal axonopathy fiber loss with minimal or no inflamma- Berger J, Pujol A, Aubourg P, et al.: Current and future pharmacologi-
tory response. Adrenal pathology is characterized initially cal treatment strategies in X-linked adrenoleukodystrophy. Brain
by cellular edema followed by atrophy. Pathol 20:845, 2010.
Bonkowsky JL, Nelson C, Kingston JL, et al.: The burden of inherited
Laboratory. Very-long-chain fatty acids are increased in leukodystrophies in children. Neurology 75:718, 2010.
blood and other tissues. Cortisol may be low or decreased Cartier N, Aubourg P: Hematopoietic stem cell transplantation
and hematopoietic stem cell gene therapy in X-linked adrenoleu-
cortisol reserve may be detected with provocative tests. kodystrophy. Brain Pathol 20:857, 2010.
Dodd A, Rowland SA, Hawkes SLJ, et al.: Mutations in the adrenoleu-
Treatment. Cortisol replacement is indicated for adrenal kodystrophy gene. Hum Mutat 9:500, 1997.
insufficiency. Evaluation of intervention for neurologic Gartner J, Braun A, Holzinger A, et al.: Clinical and genetic aspects of
features is complicated by the variability of presenta- X-linked adrenoleukodystrophy. Neuropediatr 29:3, 1998.
tion. Dietary therapy with GTO–GTE oils (glyceryl Moser HW: Adrenoleukodystrophy: phenotype, genetics, pathogenesis
and therapy. Brain 120:1485, 1997.
trioleate–glyceryl trierucate) normalizes very-long-chain Mosser J, Lutz Y, Stoeckel ME, et al.: The gene responsible for adre-
fatty acid levels but does not alter the progression of pre- noleukodystrophy encodes a peroxisomal membrane protein. Hum
existing neurological impairment. The efficacy of the Mol Genet 3:265, 1994.

ADRENOLEUKODYSTROPHY 7
D I F F E R E N T I A L M AT R I X
Spastic Vision Hearing
Syndrome Paraplegia Loss Loss Comments

Adrenoleukodystrophy + + + Adrenal insufficiency, diffuse skin pigmentation, progressive

neurological deterioration and dementia, elevated very-long-
chain fatty acids in plasma

Gustavson + + + Microcephaly, short stature, optic atrophy with blindness,

large ears, joint contractures, rockerbottom feet, brain
undergrowth, hydrocephaly, cerebellar hypoplasia, seizures

Mohr-Tranebjaerg + + + Neurological deterioration with childhood onset, dystonia

Schimke + + + Microcephaly, sunken eyes, downslanting palpebral fissures,

narrow nose, wide spacing of teeth, cupped ears, hypotonia,
abducens palsy, choreoathetosis, contractures

Paine + + + Microcephaly, short stature, optic atrophy, seizures

Proud (ARX-Associated XLID) + + + Microcephaly, agenesis of corpus callosum, cryptorchidism,

inguinal hernias, ataxia, seizures

Ataxia-Deafness-Dementia, + + + Optic atrophy, ataxia, hypotonia, seizures, childhood death

X-linked

Cerebro-Oculo-Genital + + 0 Microcephaly, hydrocephaly, short stature, agenesis of

corpus callosum, microphthalmia, ptosis, hypospadias,
cryptorchidism, clubfoot

Goldblatt Spastic + + 0 Optic atrophy, exotropia, nystagmus, ataxia, dysarthria,

Paraplegia muscle hypoplasia, contractures

Pelizaeus-Merzbacher + + 0 Optic atrophy, nystagmus, hypotonia, ataxia, dystonia, CNS

dysmyelination

XLID-Blindness- + + 0 Poor growth, postnatal microcephaly, clubfoot, seizures,

Seizures-Spasticity contractures, scoliosis, hypomyelination

XLID-Spastic + + 0 Nystagmus, reduced vision, absent speech and ambulation,

Parapleglia, type 7 bowel and bladder dysfunction, spastic quadriplegia

Wittwer 0 + + Microcephaly, short stature, microphthalmia, hypertelorism,

genitourinary anomalies, hypotonia, seizures

8 ATL AS OF X-LINKED INTELLEC TUAL DISABILIT Y SY NDROMES

AGENESIS OF THE CORPUS CALLOSUM, X-LINKED
(ME N K E S - K A P L A N S Y N DROM E )

O M I M 30 410 0 agenesis of the corpus callosum that experienced severe

developmental impairment and seizures beginning in the
Maldevelopment of the corpus callosum may occur as an neonatal period. Kaplan (1983) reported a 2-year-old boy
isolated and perhaps asymptomatic finding or may co- with developmental disability, small head size, enlarged
exist with other anomalies. XLID syndromes that may ventricles, hypoplasia of the inferior vermis and cerebel-
have dysgenesis of the corpus callosum include Aicardi, lum, right ptosis, adducted thumbs, upper limb weakness,
ARX-Associated XLID, Bertini, Cerebro-Oculo-Genital, and Hirschsprung disease. The child’s maternal uncle had
Hydrocephaly-MASA Spectrum, Juberg-Marsidi-Brooks, intellectual disability, microcephaly, and agenesis of the
Kang, Lujan, MIDAS, Optiz FG, Oral-Facial-Digital corpus callosum.
I, Pyruvate Dehydrogenase Deficiency, and X-Linked
Lissencephaly. Although a number of families with appar-
ently X-linked partial or complete agenesis of the corpus REFERENCES
callosum have been reported, it is not clear that they do not
Boyd E, Schwartz CE, Schroer RJ, et al.: Agenesis of the corpus cal-
represent one of these syndromes. losum associated with MASA syndrome. Clin Dysmorphol 2:332,
Boyd et al. (1993) and others have noted that dys- 1993.
genesis of the corpus callosum may be a frequent fi nding Kaplan P: X linked recessive inheritance of agenesis of the corpus callo-
in some families with X-Linked Hydrocephaly-MASA sum. J Med Genet 20:122, 1983.
Menkes JH, Philippart M, Clark DB: Hereditary partial agenesis of
Spectrum. The families reported by Menkes et al. (1964) corpus callosum. Arch Neurol 11:198, 1964.
and Kaplan (1983) may, in fact, be examples of this Serville F, Lyonnet S, Pelet A, et al.: X-linked hydrocephalus: clinical
spectrum. Menkes et al. (1964) reported five cases with heterogeneity at a single gene locus. Eur J Pediatr 51:515, 1992.

9
A B C D

E F

Agenesis of the Corpus Callosum, X-Linked. Seven-year-old male with total agenesis of the corpus callosum (A – B). Brother of patient in A and
B at age 9 years with total agenesis of the corpus callosum (C, D); sagittal MRI scan of patient shown in C and D showing absence of the corpus
callosum (E). Sagittal brain section showing absence of the corpus callosum [arrows] (F); sagittal MRI scan of a child with macrocephaly and
normal-appearing corpus callosum (G). Illustrations A–E courtesy of Dr. E.M. Honey, University of Pretoria, Republic of South Africa.

10 ATL AS OF X-LINKED INTELLEC TUAL DISABILIT Y SY NDROMES

AHMAD SYNDROME

O M I M 30 0 218 177 centimeters, weight between 80 kilograms and 120

kilograms.
X p11. 3 - q 2 3
MRXS7 Cognitive Function. IQ scores ranged between 40 and 50.
Heterozygote Expression. No intellectual impairment.
Defi nition. XLID with short stature, obesity, and
hypogonadism. Comment. This X-linked hypogonadism syndrome most
Somatic Features. The tetrad of findings – short stature, resembles Wilson-Turner syndrome, which maps to the
obesity, hypogonadism, and severe intellectual disabil- same region. Gynecomastia is typically present in Wilson-
ity – are present in most affected males. Hypogonadism is Turner syndrome and absent in Ahmad syndrome. Borjeson-
manifest by small penis and testes and absent or scant body Forssman-Lehmann and MEHMO syndromes map outside
hair. Facial hair is present and gynecomastia conspicuously the linkage region.
absent. The fingers are tapered and strength is diminished.
Obesity is constant. Hormone levels – FSH, LH, testoster- REFERENCE
one – are normal.
Ahmad W. De Fusco M, ul Haque MF, et al.: Linkage mapping of a
Growth and Development. Prenatal growth is not new syndromic form of X-linked mental retardation, MRXS7, asso-
known. Adult height varies between 145 centimeters and ciated with obesity. Eur J Hum Genet 7:828, 1999.

D I F F E R E N T I A L M AT R I X
Short
Syndrome Stature Hypogonadism Obesity Comments

Ahmad + + + Tapered fingers

Börjeson-Forssman- + + + Microcephaly, coarse face, large ears, gynecomastia,

Lehmann narrow sloped shoulders, visual impairment, tapered
digits, hypotonia

Urban + + + Small hands and feet, digital contractures, osteoporosis,

hypotonia

Vasquez + + + Microcephaly, gynecomastia, hypotonia

XLID-Hypogonadism- + + + Prominent lower lip, muscle wasting of legs, abnormal gait,

Tremor seizures, tremor

Young-Hughes + + + Small palpebral fissures, cupped ears, ichthyosiform

scaling, hypogenitalism

ATRX-Associated XLID + + 0 Microcephaly, telecanthus/hypertelorism, small triangular

nose, tented upper lip, open mouth, wide spacing of teeth,
abnormal genitalia, minor musculoskeletal anomalies,
hypotonia, erythrocyte HbH inclusions in some

Wilson-Turner 0 + + Normal growth, small hands and feet, tapered digits,

gynecomastia, emotional lability, hypotonia

11
AICARDI SYNDROME
(AGENESIS OF CORPUS CAL LOSUM - L ACUNAR CHORIORE T INOPAT H Y SY NDROME )

O M I M 30 4 05 0 resulting in microcephaly. Developmental milestones are

globally delayed.
Xp22.3-p22.2 ( TEN TATIVE)
Cognitive Function. Severe impairment, with few achiev-
Definition. XLID with agenesis of the corpus callosum,
ing the rudiments of speech.
lacunar chorioretinopathy, costovertebral anomalies, and
seizures in females. The tentative location of the responsi- Neurological Findings. Severe impairment of neurolog-
ble gene is based on an X:3 translocation with the X break- ical function is obvious from early infancy. Seizures of a
point at p22.3-22.2. wide variety (infantile spasms, generalized seizures, staring
spells) occur, in some cases beginning as early as the first
Somatic Features. More than any other manifestation,
day of life. The EEG shows the characteristic burst-suppres-
lacunar chorioretinopathy serves to distinguish Aicardi syn-
sion pattern of hypsarrhythmia, other seizure discharges,
drome from other conditions with agenesis of the corpus cal-
and asynchrony between the cerebral hemispheres.
losum and seizures. Bilateral punched-out areas of pigment
epithelium occur near the optic disc, appear yellow-white, Imaging. Agenesis of the corpus callosum, cerebral asym-
and have little surrounding pigment deposition. Deposition metry with cortical dysplasia, neuronal migration abnor-
of pigment around and within the lacunae increases with malities, enlarged lateral ventricles, choroid plexus cysts,
age. Microphthalmia, iris synechiae, optic atrophy, and cerebellar hypoplasia, and posterior fossa cysts may be
colobomas may occur as well. Cranial size varies depending demonstrated.
on whether enlarged ventricles are present. Isolated cortical
Comment. Microcephaly, chorioretinopathy, seizures,
heterotopias occur in at least half of cases. Hemivertebrae,
and developmental delay calls to mind prenatal infection,
scoliosis, and absent or malformed ribs are found in one-
especially prenatal toxoplasmosis. The distinctive lacunar
third of those affected. Cleft lip and cleft palate, hiatal her-
retinopathy serves best to distinguish Aicardi syndrome
nia, and hip dysplasia have been described in a few cases.
from these infections. As a rule, Aicardi syndrome occurs
Growth and Development. Normal intrauterine and sporadically and only in females. No affected female has
postnatal growth is the rule. Cephalic growth may slow reproduced. Consideration that the syndrome is X-linked

A B C

Aicardi syndrome. One-year-old female with microphthalmia (A); lacunar choreoretinopathy (B); cranial CT showing high third ventricle consistent
with agenesis of the corpus callosum (C). Courtesy of Dr. Alan Donnenfeld, Pennsylvania Hospital, Philadelphia.

12
dominant with expression in females and gestational Aicardi J, Lefebvre J, Lerique A: Spasms in flexion, callosal agene-
lethality in males is based on the increased abortions and sis, ocular abnormalities: a new syndrome. Electroenceph Clin
Neurophysiol 19:609, 1965.
decreased male:female ratio in at risk sibships. An increase Chen T-H, Chao M-C, Lin L-C, et al.: Aicardi syndrome in a 47,XXY
in skewing of X-inactivation has been reported. The few male neonate with lissencephaly and holoprosencephaly. J Neurol
males reported have had atypical chorioretinal findings, lis- Sci 278:138, 2009.
sencephaly or other structural brain anomalies, may repre- Donnenfeld AE, Packer RJ, Zackai EH, et al.: Clinical, cytogenetic,
and pedigree findings in 18 cases of Aicardi syndrome. Am J Med
sent phenocopies, or may result from somatic mosaicism. In Genet 32:461, 1989.
some cases, a 47, XXY karyotype has been demonstrated. Kroner BL, Preiss LR, Ardini M-A, et al.: New incidence, prevalence,
and survival of Aicardi syndrome from 408 cases. J Child Neurol
23:531, 2008.
Sutton VR, Hopkins BJ, Eble TN, et al.: Facial and physical features of
REFERENCES Aicardi syndrome: infants to teenagers. Am J Med Genet 138A:254,
2005.
Willis J, Rosman NP: The Aicardi syndrome versus congenital infec-
Aicardi J: Aicardi syndrome. Brain Dev 27:164, 2005.
tion: diagnostic considerations. J Pediatr 96:235, 1980.
Aicardi J, Chevrie J-J, Rousselie F: le syndrome spasmes en flexion,
agenesie calleuse, anomalies chorio-retiniennes. Arch Franc Ped
26:1103, 1969.

D I F F E R E N T I A L M AT R I X
Ocular CNS Vertebral or
Syndrome Abnormality Anomalies Rib Defects Comments

Aicardi + + + Lacunar retinopathy, costovertebral anomalies, agenesis

of corpus callosum, seizures

Cerebro-Cerebello- + + 0 Hydrocephaly, cerebellar vermis hypoplasia, retinal

Coloboma coloboma, hypotonia, seizures, abnormal respiratory
pattern

Cerebro-Oculo-Genital + + 0 Microcephaly, hydrocephaly, short stature, agenesis of

corpus callosum, microphthalmia, ptosis, hypospadias,
cryptorchidism, clubfoot, spasticity

MIDAS + + 0 Microphthalmia, corneal opacification, dermal aplasia,

dysgenesis of corpus callosum, cardiac defects,
cardiomyopathy

Chassaing-Lacombe + 0 + Spondylometaphyseal dysplasia, hydrocephaly, and

Chondrodysplasia microphthalmia in males. Spondylometaphyseal dysplasia
with rhizomelic shortening of limbs and learning disability
in females

Lenz Microphthalmia + 0 + Microcephaly, microphthalmia, malformed ears, cleft

lip/palate, cardiac and genitourinary anomalies, thumb
duplication or hypoplasia, narrow shoulders

Roifman + 0 + Microcephaly, short stature, spondyloepiphyseal

dysplasia, retinal pigmentary deposits, antibody
deficiency, eczema, hypotonia

AICARDI SYNDROME 13
ALL AN-HERNDON-DUDLE Y SYNDROME
(A L L AN - HERNDON SY NDROME )

O M I M 30 0 5 2 3 and head circumference appears normal. Puberty occurs at

the usual age, and external genitalia are normal.
X q13. 2
SLC16A2 (MCT8) Cognitive Function. Severe cognitive impairment and
attentive friendly countenance.
Definition. XLID with generalized muscle hypoplasia,
Heterozygote Expression. None
childhood hypotonia, ataxia, athetosis, dysarthria, and
spastic paraplegia. The gene (SLC16A2) is responsible for Imaging. Magnetic resonance imaging of the brain in a
transporting triiodothyronine into neurons. 1-year-old was normal; in a 58-year-old showed prominence
of the cortical sulci and mild dilation of the ventricular
Somatic Features. Marked hypotonia and paucity of skele-
system.
tal muscle mass permits diagnosis in infancy. Although the
facies do not appear distinctive in childhood, there is a ten- Laboratory. Peripheral nerve (peroneal) conduction in
dency in adult life toward elongation of the face, cupping or one affected male was mildly impaired and showed some
abnormal folding of the ears, and large ears. In one family, spontaneous motor potential, but muscle microscopy
bitemporal narrowness and midface hypoplasia was noted. showed no pathologic changes. Serum free and total T3 are
No malformations have been noted. Spastic paraplegia and elevated, and T4 may be in the low normal range. TSH is
contractures of the small and large joints become evident in normal.
adult life. Shallow pectus excavatum, ulnar deviation of the
hand, scoliosis, and valgus position of the great toe may be Treatment. Several patients have been treated with T4 and
seen. Excessive drooling and dysarthria continue into adult propylthiouracil without psychomotor improvement.
life, deep tendon reflexes become hyperactive, and clonus
and Babinski signs may be seen. Fungal infections appear Comment. Allan-Herndon-Dudley syndrome is one
common. of several XLID syndromes that present initially with
hypotonia and later transition to spasticity. Although
Growth and Development. Some affected males never the T3 is elevated, there are no systemic signs of thyroid
develop speech or independent ambulation. Adult stature dysfunction.

Allen-Herndon-Dudley Syndrome. Five affected males from original family in childhood and late adult life (A).

14
B C D

G H I

Forty-nine-year-old with long face, bitemporal narrowing, flat midface, and myopathic appearance (B); 61-year-old with bitemporal narrowing, midface
hypoplasia, and simple cupped ears (C); and 65-year-old with bitemporal narrowing, cupped ears, and marked hypoplasia of musculature (D,E);
Two cousins and their uncles from another family showing hypotonic face in 22-month-old child (F); muscle hypoplasia and spasticity in 4-year-old
cousin (G); gaunt face in 38-year-old uncle (H), and gaunt face and open mouth in 39-year-old uncle (I).

ALLAN-HERNDON-DUDLE Y SYNDROME 15
REFERENCES Schwartz CE, May MM, Carpenter NJ, et al.: Allan-Herndon-Dudley
syndrome and the monocarboxylate transporter 8 (MCT8) gene.
Allan W, Herndon CN, Dudley FC: Some examples of the inheritance Am J Hum Genet 77:41, 2005.
of mental deficiency: Apparently sex-linked idiocy and microceph- Schwartz CE, Ulmer J, Brown A, et al.: Allan-Herndon syndrome.
aly. Am J Ment Defic 48:325, 1944. II. Linkage to DNA markers in Xq21. Am J Hum Genet 47:454,
Bialer MG, Lawrence L, Stevenson RE, et al.: Allan-Herndon-Dudley 1990.
syndrome: Clinical and linkage studies on a second family. Am J Stevenson RE, Goodman HO, Schwartz CE, et al.: Allan-Herndon
Med Genet 43:491, 1992. syndrome. I. Clinical studies. Am J Hum Genet 47:446, 1990.
Dumitrescu AM, Liao X-H, Best TB, et al.: A novel syndrome combin- Wémeau JL, Pigeyre M, Proust-Lemoine E, et al.: Beneficial effects
ing thyroid and neurological abnormalities is associated with muta- of propylthiouracil plus L-thyroxine treatment in a patient with a
tions in a monocarboxylate transporter gene. Am J Hum Genet mutation in MCT8. J Clin Endocrinol Metab 93:2084, 2008.
74:168, 2004.
Friesema ECH, Grueters A, Biebermann H, et al.: Association between
mutations in a thyroid hormone transporter and severe X-linked
psychomotor retardation. Lancet 364:1435, 2004.

D I F F E R E N T I A L M AT R I X
Spastic Muscle
Syndrome Ataxia Paraplegia Hypoplasia Comments

Allan-Herndon-Dudley + + + Childhood hypotonia, dysarthria, athetosis, large ears with

cupping or abnormal architecture, contractures

Apak Ataxia-Spastic + + + Short stature, clubfoot, dysarthria, nystagmus

Diplegia

Goldblatt Spastic + + + Optic atrophy, exotropia, nystagmus, dysarthria, contractures

Paraplegia

XLID-Spastic + + + Nystagmus, weakness, dysarthria, muscle wasting,

Paraplegia-Athetosis contractures

Adrenoleukodystrophy + + 0 Adrenal insufficiency, diffuse skin pigmentation, progressive

neurologic deterioration and dementia, elevated very-long-chain
fatty acids in plasma

Hydrocephaly- + + 0 Ophthalmoplegia, lack of speech and ambulation, incontinence

MASA Spectrum

Pelizaeus-Merzbacher + + 0 Optic atrophy, nystagmus, hypotonia, dystonia, CNS

dysmyelination

Pettigrew + + 0 Microcephaly or hydrocephaly, long face with macrostomia

and prognathism, Dandy-Walker malformation, small testes,
contractures, choreoathetosis, iron deposits in basal ganglia,
seizures

Ataxia-Deafness-Dementia, + + 0 Optic atrophy, deafness, hypotonia, hyperreflexia, recurrent

X-linked episodes of choking and vomiting, seizures, childhood death

XLID-Ataxia- + + 0 Adult-onset dementia

Dementia

XLID-Spastic + + 0 Nystagmus, reduced vision, absent speech and ambulation,

Paraplegia, type 7 bowel and bladder dysfunction

Arts + 0 + Growth deficiency, poor muscle development, hypotonia,

areflexia, seizures, childhood death

Christianson + 0 + Microcephaly, short stature, long narrow face, contractures,

seizures

XLID-Hypogonadism- + 0 + Short stature, prominent lower lip, muscle wasting of legs,

Tremor abnormal gait, hypogonadism, obesity, seizures, tremor

Fitzsimmons 0 + + Pes cavus, hyperkeratosis of palms and soles, dystrophic nails

16 ATL AS OF X-LINKED INTELLEC TUAL DISABILIT Y SY NDROMES

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