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Skeletal Dysplasias

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Skeletal Dysplasias Skeletal Dysplasias North Carolina Ultrasound Society Keisha L.B. Reddick, MD Wilmington Maternal Fetal Medicine Development of the Skeleton • 6 weeks – vertebrae • 7 weeks – skull • 8 wk – clavicle and mandible – Hyaline cartilage • Ossification – 7-12 wk – diaphysis appears – 12-16 wk metacarpals and metatarsals – 20+ wk pubis, calus, calcaneus • Visualization of epiphyseal ossification centers Epidemiology • Overall 9.1 per 1000 • Lethal 1.1 per 10,000 – Thanatophoric 1/40,000 – Osteogenesis Imperfecta 0.18 /10,000 – Campomelic 0.1 /0,000 – Achondrogenesis 0.1 /10,000 • Non-lethal – Achondroplasia 15 in 10,000 Most Common Skeletal Dysplasia • Thantophoric dysplasia 29% • Achondroplasia 15% • Osteogenesis imperfecta 14% • Achondrogenesis 9% • Campomelic dysplasia 2% Definition/Terms • Rhizomelia – proximal segment • Mezomelia –intermediate segment • Acromelia – distal segment • Micromelia – all segments • Campomelia – bowing of long bones • Preaxial – radial/thumb or tibial side • Postaxial – ulnar/little finger or fibular Long Bone Segments Counseling • Serial ultrasound • Genetic counseling • Genetic testing – Amniocentesis • Postnatal – Delivery center – Radiographs Assessment • Which segment is affected • Assessment of distal extremities • Any curvatures, fracture or clubbing noted • Are metaphyseal changes present • Hypoplastic or absent bones • Assessment of the spinal canal • Assessment of thorax. Skeletal Dysplasia Lethal Non-lethal • Thanatophoric • Achondroplasia • OI type II • OI type I, III, IV • Achondrogenesis • Hypochondroplasia • Campomelic • Focal femoral dysplasia deficiency • Diastrophic dysplasia Achondroplasia • Occurs 5-15 in 10,000 births • Mutation of FGFR-3 (Chromosome 4) • Autosomal Dominant (80% new mutation) • Ultrasound Findings – Frontal bossing – Megalocephaly – Micromelia – Low nasal bone – Trident hand Achondroplasia • Ultrasound – Short limbs (below the 5th percentile) in 3rd trimester – Brachycephaly – Polyhydramnios – Detectable after 24 weeks Achondroplasia • Differential diagnosis – Thanatophoric (typically more severe) – Severe IUGR (AFI is normal or low) – Hypochondroplasia (cataracts and postaxial polydactyly) – Diastrophic dysplasia (hitchhiker thumb) • Pregnancy management – Offer amniocentesis – Medical geneticist – Postnatal skeletal radiographs – Fetal echocardiogram Achondroplasia Hypochondroplasia Ultrasound Images Achondroplasia Achondroplasia Achondroplasia Achondroplasia Achondroplasia Diastrophic Dysplasia • Diastrophic dysplasia – Short limbs, club feet and progressive joint/spinal deformity – Ultrasound findings • Micromelia • Ulnar deviation (hitchhiker thumb) • Micrognathia • Cleft lip/palate • Congenital heart defects Diastrophic Dysplasia Focal Femoral Dysplasia • Shortening and/or deformity of the femur • Ultrasound findings – Absence of the proximal femur – Absent or partial absence of other long bones – Can occur with other syndromic findings • Differential diagnosis: OI (fractures) • Prenatal management – Fetal echocardiogram – Surgery consultation Focal Femoral Dysplasia Lethal Skeletal Dysplasias Lethal Skeletal Dysplasias • Earlier onset/severe phenotype • Predication of lethality – Thoracic circumference – T/A circumference – Bell shaped thorax – FL/AC less than 0.16 – Short ribs Lethal Skeletal Dysplasia • Most common types: – Thanatophoric dysplasia (29%) – Osteogenesis imperfecta Type 2 (14%) – Achondrogenesis (9%) – Others • Campomelic dysplasia • Asphyxiating thoracic dysplasia Prenatal Diagnosis • Ultrasound Findings – Increased nuchal translucency – Skeletal evaluation • Short femur • Pattern of limb shortening • Assessment of other bones Ultrasound evaluation • Short Femur – Defined as less than the 5th percentile – FL/AC (less than 0.16) • Pattern of limb shortening – Assess all long bones • Assessment of other bones – Assess shape, contour, mineralization, bowing, fractures, absence of bones. – Spine, Hands/Feet, Calvarium, Face Thanatophoric Dysplasia • FGFR3 mutation • Incidence 0.27 in 10,000 • Auto Dom • Type I (telephone receiver shaped femur) • Type II (cloverleaf skull) Thanatophoric Dysplasia • Ultrasound Findings: – Cloverleaf skull – Curved or straight femurs – Generalized micromelia – Small narrow thorax – Polyhydramnios – Frontal bossing – Platyspondyly – Brachydactyly – “Telephone receiver” femur – No fractures Ultrasound Images (TD) Thanatophoric Dysplasia Thanatophoric Dysplasia Thanatophoric Dysplasia Thanatophoric Dysplasia Thanatophoric Dysplasia Thanatophoric Dysplasia Thanatophoric Dysplasia Thanatophoric Dysplasia Campomelic Dysplasia • Auto Dom • SOX9 gene mutation, 17q – (SRY-related HMG box 9) • Sex-reversal in males • Ultrasound findings – Campomelia/micromelia – Club feet – Ventriculomegaly – Micrognathia – Hypoplastic scapula Campomelic Dysplasia • Ultrasound findings – Bell shape chest – Micrognathia – Club feet with brachydactyly – Hypoplastic scapulae – Ambiguous genitalia • Prognosis – lethal • Differential diagnosis – Osteogenesis imperfecta (do not see club feet or cranial findings) • Prenatal management – Amniocentesis – Fetal echocardiogram Campomelic Dysplasia Osteogenesis Imperfecta • Type I – moderate fractures • Type II – severe, lethal • Type II – progressive deforming disorder • Type IV – variable phenotype • Ultrasound findings – Type I, IV – fractures, bowing of bone – Type II – deossification of ribs, compressible head, small chest, ribs are concave – Type III – fractures, less severe than type II Osteogenesis Imperfecta Type II Osteogenesis Imperfecta Type II Osteogenesis Imperfecta Type II Osteogenesis Imperfecta Type II Osteogenesis Imperfecta Type II Osteogenesis Imperfecta Type II OI Type II at 29 weeks OI Type II at 29 weeks Osteogenesis Imperfecta Type II Osteogenesis Imperfecta Type II Osteogenesis Imperfecta Type II Osteogenesis Imperfecta Type II Osteogenesis Imperfecta Type II Achondrogenesis • Type Ia (AR) • Type Ib (AR) – DTDST • Type II (AD) – COL2A1 • Ultrasound Findings – Poorly ossified skull – Micrognathia – Micromelia – Small chest – Flared ribs – Polyhydraminos Achondrogenesis • Rare skeletal dysplasia • Mutations – DTDST • Type I (Autosomal recessive) – Minimal lumbar vertebrae ossification • Type II (new dominant mutation) – Absent ossification • Poor ossification of sacral pubic, ribs • Rib fractures • Polyhydramnios Achondrogenesis • Type 1 – Micromelia – Flared ribs and fractures – No ossification of the calvarium and spine – Micrognathia • Type 2 – No flaring of ribs or rib fractures Achondrogenesis Asphyxiating Thoracic Dystrophy • Very narrow thorax, pulmonary hypoplasia, short limbs and renal dysplasia • Ultrasound findings – Small chest and short ribs – Mildly short limbs with mild bowing – Renal cysts • Prenatal management – Genetic counseling – Associated with a 25% risk of recurrence Asphyxiating Thoracic Dystrophy Hypophosphatemia • Autosomal recessive – Severe (lethal form) – Benign • Ultrasound findings – “chromosome - appearing” bones – Micromelia – Decreased mineralization – Cranium is compressive Hypophosphatemia Chondrodysplasia Punctata • Rhizomelic and Non-rhizomelic • Findings: – Craniofacial dyspmorphism – Joint contractures – Short humerus, relatively short femurs – Caclcific stippling – Poor prognosis – Severe mental delay Other Lethal Anomalies • Fibrochondogenesis • Atelosteogenesis – Midface hypoplasia – Micrognathia – Micromelia – Narrow chest – Polyhydramnios Distal Extremity Anomalies • Upper extremities – Polydactyly – Ectrodactyly – Syndactyly – Clinodactyly • Lower extremities – Rocker bottom feet – Club foot Ectrodactyly Lower extremity • Club feet – Isolated or associated with genetic/chromosome abnormalities/syndromes – Foot is flexed or extended • Rocker bottom feet – Can be associated with chromsome abnormalities/genetic syndromes – Heels of the foot extended posterior to the leg Rare but recent… • Amniotic band – Asymmetric disruption and deformities – Sporadic – Absent digits or portions of hands – Distal extremity swollen • Fibula hemimelia Absence of distal upper extremity Absent Fibula Absent Fibula Summary • Ultrasound can be an effective method for the diagnosis in the prenatal-onset skeletal dysplasias. • 3D ultrasound - visualization of the dysmorphic findings in the skeletal dysplasias. • Final diagnosis of a prenatal-onset skeletal dysplasia should be based on radiology and histomorphology • Some diagnoses cannot be accurately made in the prenatal period. 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