Osteogenesis imperfecta (OI)

General features of osteogenesis imperfecta

 Osteogenesis imperfecta (OI)
o Most common form of heritable bone fragility
o Group of disorders mainly characterized by – Bone fragility
 Broad spectrum of clinical severity in OI
o From multiple fractures in utero and perinatal lethality
o To near-normal adult stature and low fracture incidence

Epidemiology of osteogenesis imperfecta

 Estimated incidence – 0.5 to 1 in 10,000 live births
 Population prevalence – Ranges from 2.35 – 4.7 in 100,000 worldwide
o However, it is possible that some mild forms of OI – Remain undiagnosed

Pathogenesis of osteogenesis imperfecta

 Most OI
o Due to defects in genes involved in – Production, folding, stability, processing, and
secretion of type 1 collagen, osteoblast function, or bone matrix mineralization (
o Interruption of any of these processes
 May cause a pathologic phenotype with decreased or abnormal type I collagen
produced  Result in OI
 Approximately 85% of OI
o Caused by – Pathogenic variants in genes encoding type 1 collagen (COL1A1/ COL1A2)
 Can be associated with – A range of phenotypes, from mild to severe
 Dependent on – How protein folding and structure are affected
 Type I collagen
o Encoded for by – COL1A1 and COL1A2 genes
 Located on – Chromosomes 17 and 7, respectively
o Function – Formation of bones
o As with all collagens, type I is a heterotrimer
 Consisting of 3 chains – 2 alpha 1 chains (coded for by COL1A1) and 1 alpha 2 chain
(coded for by COL1A2)
Genetics of osteogenesis imperfecta
 Defects within genes involved in type 1 collagen production and processing  Result in OI
o Autosomal dominant (most people)
 Often a positive family history of – Fractures, short stature, and early-onset
osteoporosis in extended family members when this is explored
o Can also occur sporadically
 Without any previous affected family members (de novo variant)
 Autosomal dominant OI (60%)
o Pathogenic variant in
 COL1A1 or COL1A2 gene (85 – 90%)
 Which encode the pro-alpha 1 and pro-alpha 2 chains of type I collagen
 Interferon-induced transmembrane protein 5 (IFITM5)
 Identified in all patients with – Type V OI
 Other dominant forms of bone fragility include pathogenic variants in
 Low-density lipoprotein receptor-related protein 5 (LRP5)
 Protooncogene (Wnt family member 1, WNT1) genes that cause primary
osteoporosis
 Autosomal recessive OI
o Typically result in – More severe phenotype
 X-linked bone fragility
o Affect males more than females
o Genes involved – e.g. Plastin 3 (PLS3) and membrane-bound transcription factor
peptidase, site 2 (MBTPS2)
o Important to distinguish X-linked forms of bone fragility for
 Provision of accurate recurrence risk information
 Ensuring that carrier females are monitored for early-onset osteoporosis
Clinical manifestations of osteogenesis imperfecta
 Fractures
o Hallmark feature in OI – Low-impact fractures with very minimal trauma
o Detailed fracture history – Number, site, nature of injury, and age at first fracture
o Milder forms of OI – Fractures tend to first occur once a child begins standing and as they
become more active in the preschool years
 Series of fractures occurring in – Prepubertal years
 Decrease in frequency – Seen in adult life
 May have some degree of gross motor delay and short stature due to long bone
deformities
 But most have normal adult stature (or relative short stature for family)
o More severe forms of OI
 Fractures and bony deformities – May start antenatally
 Result in – Significant effects on the skeleton and subsequent growth
 Scleral hue
o Color of the sclerae – Can be subjective
 Depending upon – Lighting and age of the person amongst other factors and
 ∴ Should be considered as an additional clinical feature rather than a defining
feature in OI
o Blue/ bluish-grey/ grey scleral hue
 Have all been described in OI
 But can also be a normal finding in the neonatal period
 AR forms of OI
 Tend to have a more whitish sclerae
 More classical forms of OI
 Tend to have a bluish scleral hue
 Dentinogenesis imperfecta
o Inherited dentine anomaly
o Teeth – Discolored, chip and wear easily
 Have abnormal crown and root development
 Facial features
o Not typical, BUT certain facial features aid in making a diagnosis of OI on initial evaluation
 Triangular face
 Frontal bossing
 Broad forehead
 Deep-set eyes
 Beaked nose
o Persons with OI – May also have a distinctive high-pitched voice
 Growth
o Short stature
 Common but not invariable feature in OI
 Several contributing factors including
 Bony deformities following healing of repeated fractures
o Esp. of the long bones
 Defects in primary development of long bones during the intrauterine and
postnatal period
 Intraosseous calcification at growth plates
 Scoliosis
o High BMI or obesity
 Prevalent finding BUT is not always attributable to reduced mobility and activity in
these patients
 Hearing loss
o Does not occur until adulthood
o Hearing loss in OI
 Very similar to that found in otosclerosis
 Often a mixed sensorineural and conductive hearing loss
 Joint hypermobility and ligament laxity
o Joint hypermobility – Increased risk of premature joint degeneration, osteoarthritis, and
chronic musculoskeletal pain is
o Can result in increased fatigability and intractable pain
 Skin laxity and easy bruising
 Chest and spine disorders
o Respiratory insufficiency
 Potentially due to – Primary effect of OI on lung tissue and pulmonary function
 In severe form
 Can often result in – Death
o Esp. in the perinatal period
 In the milder forms
 Risk of restrictive lung disease – ∵ Thoracic kyphoscoliosis and vertebral
collapse/ fractures
o Sternal deformities
 e.g. Pectus carinatum and excavatum
 Can result in – Respiratory difficulties
o Curvature of the spine
 Needs careful monitoring – Esp. in the rare forms of OI, due to significant risk of
rapidly developing scoliosis resulting in respiratory compromise
 Cardiovascular manifestations
o OI-related valvular insufficiencies and aortic dilatation – Well documented
o Aortic (more common) and mitral regurgitation
 Most commonly described valvular insufficiencies
 Cranial abnormalities and neurologic manifestations
o OI is commonly associated with – Relative macrocephaly
o Comorbidities seen in association in OI
 Platybasia – Flattening of the skull base
 Basilar impression – Softening of the bone at the foramen magnum
 Basilar invagination – Upward displacement of the upper cervical spine and clivus
into the foramen magnum
 High frequency in patients with severe OI
 Can progress slowly in childhood and take years before symptoms develop
 Typical symptoms of basilar invagination
o Which requires urgent intervention
o Include headaches, nystagmus, ataxia, and altered facial sensation
Diagnosis of osteogenesis imperfecta
General principles
 OI should be suspected in a patient with
o Recurrent fractures
o Bone deformities (AND/OR) Short stature
o Finding of short long bones in a fetus on ultrasound or in a baby or child with a family
history of OI
 However, OI encompasses a wide range of presentations, ranging from mild to sever
o ∴ Diagnosis is determined when there is a combination of skeletal and extraskeletal
manifestations consistent with OI

Antenatal diagnosis
 Abnormal ultrasound
o Ultrasound findings should be re-evaluated periodically
 Typically repeat ultrasound every 2 – 3 weeks
 Esp. if there is suspicion of “short” long bones at 20-week scan
o Frequency determined by – Fetal growth measurements
o Imaging is repeated postnatally if pregnancy is continued
 To ensure a precise diagnosis is made, esp. in the absence of genetic confirmation
of diagnosis
 Early presentation
o Short long bones identified on a 20-week anomaly scan
 Usually suggest – A more severe skeletal disorder
 Esp. if seen in association with other findings such as
o Large head circumference
o Reduced chest capacity
o Abnormal brain imaging – e.g. Hydranencephaly, ventriculomegaly,
and poorly ossified skull
  Later presentation
o May also identify abnormal findings of milder OI at a later gestation such as
 Short long bones
 Bowing of femur
 Fractures
o Some of the severe forms of OI (not lethal) may be diagnosed at a later gestation
 Need further discussions with metabolic bone specialists to
 Inform mode of delivery
 Transfer to a specialized clinical service
 Institution of early treatment and care when pregnancy is continued

Biochemical tests
 Biochemical parameters in OI – Tend to be normal
o Serum calcium – Normal
 Although hypercalciuria – Has been reported in some patients with OI with no
kidney dysfunction or nephrocalcinosis
o Serum 25-OH vitamin D levels – May be low
 But are not typical and are attributable to lack of sunlight exposure
o Markers for bone turnover
 Do not provide information on bone structure
 But may be useful in monitoring children with OI
 Esp. response to treatment
 Measurement of bone production and resorption markers
 e.g. Urine N-terminal telopeptide (urine NTx)
 Corrected for age and sex
 May be useful in – Monitoring response to treatment
Management of osteogenesis imperfecta
 Mainstay of management
o Targets – Improving bone health, muscle strength, mobility, function, and quality of life
o Multidisciplinary and consists of
 Physical therapy
 Surgical interventions
 Bone-targeted therapy
 Medical therapy
o Bisphosphonates
 Used commonly in moderate-to-severe forms of OI with a high risk of fractures
 Ongoing monitoring and assessment for extraskeletal features, including
o Routine dental examination
o Early diagnosis of hearing loss
o Monitoring growth
o Cardiovascular assessment for valvular abnormalities and aortic root measurements
o Neurodevelopmental assessments for hydrocephalus and basilar impression
Iatrogenic pseudoaneurysm
General features of iatrogenic pseudoaneurysm
 Iatrogenic pseudoaneurysm (IPA)
o False aneurysm that occurs after localized arterial wall injury related to an incomplete
hemostatic plug at the injury site
o Localized extravasation of blood outside the arterial wall
 Confined and controlled by the pseudocapsule that develops
o Any arterial site used for arterial puncture  Can develop a pseudoaneurysm
 But IPA secondary to femoral arterial access for percutaneous-based diagnostic and
interventional procedures – By far the most common etiology and site
 Most uncomplicated IPAs
o Can be managed without open surgery
 Observational management
 (OR) By using ultrasound-guided or, occasionally, endovascular techniques to effect
closure
 Complicated IPAs and those failing non-surgical management
o Surgical repair of the artery ± Patch closure

Risk factors for iatrogenic pseudoaneurysm

 Well-described risk factors for IPA include
o Female sex
o Increasing age
o Concomitant venous puncture
o Hypertension
o Severely calcified vessels
o Larger access sheath size (>6 Fr)
o Use of anticoagulation either at the time of arterial cannulation or in the immediate
postprocedure period
Diagnosis of iatrogenic pseudoaneurysm
History taking and physical examination
 Pseudoaneurysms
o Represent a spectrum of extravasation of blood from the artery
o With a wide range of findings
 Depending upon – Size of the pseudoaneurysm and its duration
 Clinical suspicion for iatrogenic pseudoaneurysm (IPA)
o Should be ↑ after any percutaneous femoral access that results in significant groin pain or
swelling
 Particularly among those with risk factors
 Clinical findings suggestive of IPA
o Noted soon after the procedure
 Often within the first 24 hours after sheath removal
 However, IPA can develop as patient activity ↑
 Delayed presentations – Have been reported 7 – 10 days after the initial
procedure
o Most commonly associated with
 Pain at the access site
 Skin ecchymosis
 Subcutaneous hematoma of varying size
 Presence of a femoral bruit or thrill
 But the absence of a bruit – Does not exclude pseudoaneurysm
 DDx – Arteriovenous (AV) fistula
o Embolization from thrombus that might develop within the pseudoaneurysm
 Rarely occurs in the absence of IPA manipulation
o Complicated IPA
 Should prompt surgical evaluation and management
 Defined as the presence of any of the following clinical features
 Hemodynamic instability
 Neurologic deficit (motor or sensory) or pulse deficit attributable to the IPA
 Expanding hematoma
  Extensive skin and subcutaneous damage
 Concern for soft tissue infection – e.g. Fever, cellulitis, purulent drainage

Radiological tests
 Imaging is required to confirm IPA
 Arterial duplex ultrasound evaluation
o Recommended as – Initial imaging modality
o Accuracy – Near 100% for the diagnosis of IPA and other access-related pathology (e.g. AV
fistula)
o B-mode imaging – Identify hypoechoic fluid collections (i.e. hematoma)
o Color flow Doppler – To assess for arterial flow outside the boundaries of the femoral artery
o Typical ultrasound characteristics include
 Yin-yang sign – Classic swirling bidirectional color flow outside of the femoral artery
 To-and-fro waveforms within the tract leading to the sac
 When a pseudoaneurysm is identified, the following anatomic features are
documented
 Pseudoaneurysm sac size (cm2)
 Dimensions of active flow outside the femoral artery (cm2)
 Aneurysm sac morphology (single or multiple lobes)
 Pseudoaneurysm neck diameter and length
  CT angiography or catheter-based angiography (i.e. digital subtraction angiography)
o Obtained from a contralateral femoral access site
 Can also be used to – Document IPA
o Provide additional value
 In cases where – Duplex ultrasound is equivocal or technically limited (e.g. obesity),
or if there are other anatomic issues (e.g. high arterial puncture)

Management of iatrogenic pseudoaneurysm

Complicated pseudoaneurysm
 Complicated femoral IPA is defined as the presence of any of the following clinical features
o Hemodynamic instability
o Neurologic deficit (motor or sensory) or pulse deficit attributable to the IPA
o Expanding hematoma
o Extensive skin and subcutaneous damage
o Concern for soft tissue infection – e.g. Fever, cellulitis, purulent drainage
 Generally require – Open surgical repair
 o Endovascular repair (in the absence of infection) – Can be considered if the patient is
deemed high surgical risk

Uncomplicated pseudoaneurysm
 Most patients – Can be managed with ultrasound-guided treatment or observation
o Uncomplicated femoral IPA + ≥3 cm + Asymptomatic or symptomatic
 Suggest intervention
o Uncomplicated femoral IPA + <3 cm
 Suggest observation
 Most uncomplicated IPAs – Resolve with time
 Given that patient will be compliant with serial imaging and follow-up
o Patients under observation + Develop acute symptoms (in the setting of an IPA ≥1 cm), IPA
enlargement, or persistent IPA ≥1.0 cm by 6 weeks
 Suggest intervention
 Uncomplicated femoral IPA that requires treatment
o 1st line – Ultrasound-guided thrombin injection (UGTI)
o Alternative – Ultrasound-guided compression (UGC)
 For pseudoaneurysms that fail UGTI
o Repeat UGTI, UGC, or endovascular treatment – Can be considered
o But if these are unsuccessful  Proceed to open surgical repair

Graft-versus-host-disease (GVHD)
General features of GVHD
 GVHD
o Refers to multi-organ syndromes of tissue inflammation and/or fibrosis
 Primarily affect – Skin, GI tract, liver, lungs, and mucosal surfaces
o Arises from – One of the principal functions of the immune system
 Distinguishing between self and non-self
 Occurs when immune cells transplanted from a non-identical donor (graft) into the
recipient (host)  Recognize the host cells as “foreign”  Initiating a graft-versus-
host reaction
o Major cause of morbidity and non-relapse mortality
 In patients after allogeneic hematopoietic cell transplantation (HCT)
 Clinically
o Comprises 3 syndromes
  Acute GVHD (aGVHD)
 Rapid onset and acute disease course
 Primarily manifest as
o Inflammatory immune cell infiltrate, including T cells, neutrophils,
and monocytes, with tissue destruction
o Maculopapular rash, weight loss, diarrhea, and/or hepatitis that
typically occurs within the first 100 days after transplantation
 Chronic GVHD (cGVHD)
 Chronic disease course
 Can involve virtually all organs with variable manifestations, including
sclerosis
 Tissue response – Relatively acellular and reveals fibroproliferative findings
 Manifest as
o Fibrosis and chronic inflammation of skin, lungs, GI tract, and soft
tissues that generally presents ≥100 days after transplantation
 GVHD overlap syndrome – Simultaneous features of both cGVHD and aGVHD
o Various GVHD syndromes – Defined by clinical manifestations according to National
Institutes of Health consensus criteria
 X Time of onset – i.e. Before or after day 100 of transplantation, as was used
previously

Contributing factors of GVHD

 Histocompatibility
o GVHD arises when immune cells transplanted from a non-identical graft recognize cells in
the host as foreign
o Major histocompatibility complex (MHC)
 Provides the crucial surface upon which foreign antigens are displayed for immune
recognition by T lymphocytes
o Minor antigens
 Also contribute to tissue histocompatibility
 GVHD can develop even with grafts that are fully matched at the MHC/ HLA loci
 ∵ Mismatching of other antigens, termed minor histocompatibility antigens
(miH)
 Tissue microenvironment
o Cells, cytokines, and signaling pathways of the tissue microenvironment contribute to
GVHD and the graft-versus-leukemia (GVL) effect
o Example – Notch signaling
 Orchestrates cell fate and differentiation
 Critical in both – Acute and chronic GVHD
 Notch inhibition  Results in blockade of multiple cytokines, expansion of T regs
and decrease in pathogenic T cells without decreasing GVL
 Clinical factors
o Clinical factors that contribute to GVHD include:
 Donor type – i.e. Matched related, matched unrelated, haploidentical
 Source – Peripheral blood, bone marrow, umbilical cord
 Sex-mismatch
 Age of donor and recipient
 Conditioning regimen intensity
 Underlying malignancy – e.g. Myelodysplastic syndrome, acute or chronic myeloid
or lymphoid leukemia
 T cell depletion in vivo – e.g. Anti-thymocyte globulins, alemtuzumab
 Post-transplantation cyclophosphamide
 Infection history – e.g. CMV, EBV

 Microbiome
o Composition of GI microbiota – Has been associated with outcomes in patients who
undergo allogeneic HCT
 However, it is not clear that – This is a causal relationship or if it is possible to
manipulate the intestinal microbiome to influence outcomes
o ↑ Potentially pathogenic bacteria and ↓ of diversity in the number of bacterial taxa
 Commonly found in – Patients undergoing allogeneic HCT
o Large international study reported that
 Higher diversity of intestinal microbiota – Associated with lower mortality, lower
rates of transplant-related death, and fewer deaths attributable to GVHD [58]. The
study profiled 8767 fecal samples from 1362 patients at four institutions and used
16S ribosomal RNA sequence to stratify patients into higher-diversity (HD) and
lower-diversity (LD) groups. In a preliminary study at one of the institutions,
 compared with LD patients, patients with HD had a hazard ratio (HR) for death of
0.71 (95% CI 0.55-0.92); analysis from three other institutions reported the HR for
death was 0.49 (95% CI 0.27-0.90). Samples obtained before transplantation
already showed evidence of microbiome disruption, and lower diversity before
transplantation was also associated with poor survival. Single-institution studies
have reported similar associations between diversity of intestinal microbiota and
transplantation outcomes [59-61]. SUMMARY

Polymyalgia rheumatica (PMR, 風濕性多肌痛)

General features of PMR
 An inflammatory rheumatic condition
o Characterized clinically by – Aching and morning stiffness about the shoulders, hip girdle,
and neck
 Can be associated with – Giant cell arteritis
 When the diagnosis of PMR is considered, 2 main issues arise
o How is the diagnosis established and distinguished from other disorders that can produce
similar symptoms?
o Does the patient also have GCA?

General epidemiology of PMR

o EPIDEMIOLOGY Polymyalgia rheumatica (PMR) is almost exclusively a disease of adults
over the age of 50, with a prevalence that increases progressively with advancing age. The
peak incidence of PMR occurs between ages 70 and 80 [1]. PMR is relatively common. The
lifetime risk of developing PMR has been estimated at 2.43 percent for women and 1.66
percent for men and is second only to rheumatoid arthritis (RA) as a systemic rheumatic
disease in adults [2]. Women are affected two to three times more often than men. Cases
of familial aggregation are rare, but recognized [3]. The annual incidence varies
geographically and is highest in Scandinavian countries and in people of northern
European descent [4]. In Europe, for example, the incidence rates for the population ≥50
years are highest in northern regions (113 per 100,000 per year in Norway) and much
lower in southern areas (13 per 100,000 per year in Italy) [5,6]. In Olmsted County,
Minnesota, where the population is predominantly of Scandinavian descent, the incidence
is 63.9 per 100,000 per year, with a prevalence of 701 out of 100,000 [7-9]. PMR is
distinctly less common in Asian, African American, and Latin American populations,
though all racial and ethnic groups can be affected. Association with GCA — PMR is two to
three times more common than giant cell arteritis (GCA) and occurs in approximately 50
percent of patients with GCA [10]. The percentage of patients with PMR who experience
GCA at some point varies widely in reported series, ranging from roughly 5 to 30 percent
[1,11,12]. A figure of 10 percent seems most consistent with clinical practice. PMR can
precede, accompany, or follow GCA.