Skeletal dysplasia Flashcards
ACHONDROPLASIA
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible gene: FGFR3
Protein: Fibroblast growth factor recepter 3
Cytogenetic locus: 4p16.3
Inheritance: AD; 80% de novo
Clinical Features and Diagnostic Criteria: short stature, rhizomelic
shortening, trident hand, frontal bossing, midface hypoplasia, macrocephaly,
OSA, spinal cord compression
Clinical Tests: Narrowing of interpediculate distance, caudal spine; notch-like
sacroiliac groove, circumflex or chevron seat on the metaphysis
Molecular Tests: 98% FGFR3 G1138A; ~1% FGFR3 G1138C
Disease Mechanism: Constitutive activation of FGF R (GOF mutations)-
activation of negative growth control
Treatment/Prognosis: achondroplasia growth curves, surgery or CPAP for
OSA, role of GH unclear, leg lengthening, suboccipital decompression, spinal
fusion, LPA support group
CLEIDOCRANIAL DYSPLASIA
Responsible gene:
Protein:
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Inheritance:
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Responsible gene: RUNX2
Protein: Runt-related transcription factor 2
Cytogenetic locus: 6p21
Inheritance: AD (high proportion de novo)
Clinical Features and Diagnostic Criteria: delayed closure of the cranial sutures, hypoplastic
or aplastic clavicles, multiple dental abnormalities. Abnormally large wide open anterior
fontanel, midface hypoplasia, brachydactyly, recurrent OM, hearing loss, normal intellect.
Clinical Tests: X-ray: clavicular hypoplasia, open sutures, wormian bones, poor or absent
sinus pneumatization, hypoplastic scapulae, wide symphysis pubis and sacroiliac joints, large
femoral neck and epiphyses, pseudoepiphyses of the metacarpals and metatarsals, deformed
and short middle phalanges, osteopenia.
Molecular Tests: RUNX2 sequencing and array for microdeletions (60-70%).
Disease Mechanism: Independently mediates DNA binding and protein heterodimerization;
mutations abolish DNA binding
Treatment/Prognosis: Hearing test, dental referral, ear tubes, helmets if large skull defects
DIASTROPHIC DYSPLASIA
Responsible gene:
Protein:
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Molecular Tests:
Disease Mechanism:
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Responsible gene: SLC26A2 Protein: Sulfate transporter
Cytogenetic locus: 5q32-q33.1 Inheritance: AR
Clinical Features and Diagnostic Criteria: limb shortening, normal-sized skull, hitchhiker thumbs,
small chest, large joint contracture, cleft palate, cystic ear swelling, ulnar deviation of fingers, clubfoot,
low tone, normal IQ
Clinical Tests: x-ray: cervical kyphosis, incomplete thoracic vertebrae ossification, coronal clefting of
lower thoracic and lumbar vertebrae, narrowed interpedicular distance L1 to L5, distal humerous can be
bifid or v shaped, rounded distal femur, advanced bone age. Cartilage histopathology: paucity of
sulfated proteoglycans in cartilage matrix. Abnormal incorporation of sulfate into macromolecules in
cultured chondrocytes
Molecular Tests: SLC26A2 targeted mutation analysis (65% one of 5 mutations), SLC26A2
sequencing(>90%)
Disease Mechanism: Undersulfation of proteoglycans affects the composition of the extracellular matrix
and leads to impaired proteoglycan deposition which is necessary for proper enchondral bone formation
Treatment/Prognosis: Maintain joint positioning and mobility as much as possible, clubfoot deformities
tend to recur after surgical correction, scoliosis surgery best if postponed until after puberty. Joint
contractures and spine deformity worsen with age. Total arthroplasy may diminish joint pain.
FGFR-RELATED CRANIOSYNOSTOSIS
(Pfeiffer, Apert, Crouzon, Beare-Stevenson, FGFR2-related Isolated Coronal Synostosis, Jackson-Weiss, Crouzon with Acanthosis Nigricans, and Muenke)
Responsible genes:
Proteins:
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Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible genes: FGFR1, FGFR2, FGFR3
Proteins: Basic fibroblast growth factor receptor 1, 2, and 3
Cytogenetic loci: 8p11.2-p11.1, 10q26, 4p16.3
Inheritance: AD
Clinical Features and Diagnostic Criteria: All but Muenke and FGFR2-related Isolated Coronal
craniosynostosis are associated with bicoronal craniosynostosis or cloverleaf skull, distinctive facial
features, and variable hand and foot anomalies (broad and/or syndactylous). Developmental delay/ID,
hearing loss, and visual impairment common.
Clinical Tests: Brain CT or MRI for hydrocephalus, spinal x-rays for vertebral anomalies
Molecular Tests: FGFR1 sequencing (5% Pfeiffer 1); FGFR2 sequencing (100% Crouzon, JacksonWeiss, Apert, Pfeiffer 2 and 3, and FGFR2-related isolated coronal synostosis); FGFR3 sequencing
(100% Crouzon with Acanthosis Nigricans); FGFR3 targeted mutation analysis (100% Muenke)
Disease Mechanism: Mutations cause increased R affinity thought to promote excessive receptor
down-regulation.
Treatment/Prognosis: Coordinated neurosurgical, ORL, and dental care, follow for scoliosis, limb
anomalies rarely benefit from surgery
HEREDITARY MULTIPLE OSTEOCHONDROMAS SYNDROME
Responsible genes:
Proteins:
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Inheritance:
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Disease Mechanism:
Treatment/Prognosis:
Responsible genes: EXT1, EXT2
Proteins: Exostosin-1, Exostosin-2
Cytogenetic loci: 8q24.11, 11p11.2
Inheritance: AD
Clinical Features and Diagnostic Criteria: Exostoses (benign cartilage-capped bony
growths) arising from the growth plate of the long bones or from the surface of flat bones
(scapula). Limb length inequity and bowed long bones can develop. Short metacarpals. Can
have mass effect compression of nerves and blood vessels.
Clinical Tests: x-ray may detect mildly affected individuals
Molecular Tests: EXT1 and EXT2 sequencing: >70% detection rate, del/dup studies: 20%
Disease Mechanism: EXT1/2 encode glycosyltransferases, mutations lead to actin
accumulation and cytoskeltal abnormalities
Treatment/Prognosis: Growth ceases after skeletal maturation. 0.5-2% of cases degenerate
to chondrosarcoma. Treatment is surgical resection.
HYPOCHONDROPLASIA
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Disease Mechanism:
Treatment/Prognosis:
Responsible gene: FGFR3
Protein: Fibroblast growth factor receptor 3
Cytogenetic locus: 4p16.3
Inheritance: AD
Clinical Features and Diagnostic Criteria: Short stature, stocky build, rhizo- or mesomelia,
limited elbow extension, brachydactyly, mild joint laxity, macrocephaly, scoliosis, genu varum,
lumbar lordosis, mild-mod ID, LD, adult onset osteoarthritis
Clinical Tests: x-ray: elongated distal fibula, short lumbar pedicles, short distal ulna, chevron
deformity of distal femur metaphysis, flattened acetabular roof
Molecular Tests: Targeted mutation analysis: N540K (C1620A) (49%), N540K (C1620G)
(21%). Exon 9, 10, 13, or 15 sequencing (80%)
Disease Mechanism: unknown but mouse models suggest FGFR3 is a negative regulator of
bone growth
Treatment/Prognosis: Monitor for S/Sx spinal cord compression (MRI or CT foramen
magnum), sleep study id history c/w OSA, ortho eval if severe genu varum impairs walking
OSTEOGENESIS IMPERFECTA
Responsible genes:
Proteins:
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Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Responsible genes: COL1A1 and COL1A2
Proteins: Collagen alpha 1(I) chain, Collagen alpha 2(I) chain
Cytogenetic loci: 17q21.33, 7q21.3 Inheritance: AD and rare AR
Clinical Features and Diagnostic Criteria: Fractures with little or no trauma, relative short
stature, blue sclera, dentinogenesis imperfecta, post-pubertal HL, ligamentous laxity, easy
bruising. OI Type II: perinatal lethal, palpable callus formation on ribs, hips in “frog-leg”
position, short bowed extremities. OI Type III: severe, skull descends on cervical spinebrainstem compression, obstructive hydrocephalus, syringomyelia
Clinical Tests: x-ray: fractures of varying ages, spinal compression fracture, wormian bones,
protrusio acetabuli, osteopenia. Cultured fibroblasts (98% Type II, 87% all others)
Molecular Tests: COL1A1 and COL2A1 sequencing: ~100% Type I, 98% Type II, 60-70%
Type III, 0-80% Type IV
Disease Mechanism: Type I: premature stop codon->unstable mRNA->dec amount type I
collagen. Types II, III, IV: mutations alter collagen structure
Treatment/Prognosis: Bisphosphonate to decrease bone resorption, GH to increase linear
growth and bone formation
SAETHRE-CHOTZEN SYNDROME
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
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Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible gene: TWIST1 Protein: Twist-related protein 1
Cytogenetic locus: 7p21 Inheritance: AD
Clinical Features and Diagnostic Criteria: coronal synostosis, facial asymmetry, ptosis, 2/3
hand syndactyly, mild-moderate developmental delay in a minority, short stature, parietal
foramina, vertebral fusions, radioulnar synostosis, cleft palate, maxillary hypoplasia,
congenital heart defect
Clinical Tests: echo, x-ray for vertebral abnormalities, audiologic testing, and karyotype:
translocations, inversions, or ring chromsome 7 have been reported
Molecular Tests: TWIST1 sequencing: >50%, del/dup testing: complete deletion of the
TWIST1 gene 11-28%
Disease Mechanism: haploinsufficiency by gene deletion, rapid degradation of abnormal
protein, or altered subcellular localization of abnormal protein
Treatment/Prognosis: endocrine eval if plateau in growth, craniofacial team management,
surgical repair of cleft palate and craniosynostosis, eye exams to monitor for evidence of
increase ICP
