Genetics for the Orthopedist

1. Genetics for the Orthopedist Charles J. Macri MD Division of Reproductive and Medical Genetics Department of OBGYN National Naval Medical Center

2. Introduction • Many syndromes involving bone or cartilage abnormalities • Classic phenotypic appearance • Molecular diagnosis • Matching type questions

3. Why do we want to know this? • Intellectual • Wardsmanship - having the right answers on rounds • Providing information to patients and families re: recurrence risks, etiology, and diagnostic/therapeutic issues • Resident training examinations • Board Examinations

4. Resources Utilized to Prepare • Smith’s Recognizable Patterns of Human Malformation • Color Atlas of Congenital Malformations • McKusick’s Heritable Disorders of Connective Tissue • Orthopedic Knowledge Update 5 • Miller’s Review of Orthopedics

5. How will we do this? • Skeletal Dysplasias • Chromosomal disorders • Single gene disorders • Metabolic disorders • Syndromes

6. Skeletal Dysplasias • osteochondrodysplasias • inherited disorders of bone and cartilage growth and development • chondrodysplasias - defective cartilage growth • disproportionate short stature • deformities of extremities and spine • diagnosis is usually made with combination of • physical appearance • radiographic characteristics • bone or physical physiology

7. Skeletal Dysplasias • most are named descriptively based on phenotypic or x-ray features • some referred to by eponym • “families” of chondrodysplasias are being identified with same presumed etiology • eg: mutation in gene for type II collagen • spondyloepiphyseal dysplasia • hypochondrogenesis • Stickler syndrome

8. Skeletal Dysplasias • heterogeneous • many have common problems such as: • short stature and deformities of limbs and spine • respiratory problems • chest wall or upper airway abnormalities • central nervous system problems • hydrocephaly • spinal stenosis • spinal cord injury from cervical spine and/or cervicovertebral junction instability • muscle hypotonia, contractures, intrinsic muscle disease • hearing loss, dental problems, myopia, retinal detachment are also more common with some of the skeletal dysplasias

9. Bone Dysplasias • Achondroplasia • Hypochondroplasia • Thanatophoric dysplasia • Achondrogenesis Types I and II • Hypochondrogenesis • Atelosteogenesis Type I

10. Bone Dysplasias • Achondroplasia • Hypochondroplasia • Thanatophoric dysplasia • Achondrogenesis Types I and II • Hypochondrogenesis • Atelosteogenesis Type I • Diastrophic dysplasia • Camptomelic dysplasia

11. Bone Dysplasias • Kyphomelic dysplasia • Osteogenesis imperfecta Type I • OI Type II • Hypophosphatasia • Jeune syndrome • Ellis-Van Crevald syndrome

12. Fibrodysplasia Ossificans Progressiva • Clue to dx in neonatal period is hypoplasia of great toe • Absent skin crease - single phalynx - deviation laterally • Progressive ossification - birth to 10 years • initial subcutaneous lump - ?preceeded by traum? • Baldness and deafness • Synovial osteochondromatosis • Autosomal dominant

13. Craniometaphyseal Dysplasia • Progressive nasal obstruction and mouth breathing in childhood • Later - craniotubular bone dysplasia can be seen on skeletal X-ray • sclerosis of skull, vault and base • abnormal metaphyseal modeling of the long bones

14. Craniometaphyseal Dysplasia • Bony overgrowth involving the supraorbital ridges giving visor-like appearance • Tibia are curved backwards with mild valgus deformity of knees • Extension and rotation is limited at elbows • Deafness and cranial nerve entrappment occur

15. Achondroplasia • Diagnosed at birth • rhizomelic limb shortening • large head with broad, prominent forehead • fingers are short, tapered and splayed (a “trident” hand)

16. Achondroplasia - X-ray findings • Pelvis is abnormal with small, square iliac wings • Horizontal acetabular roots and narrowing of the greater sciatic notch • long bones are short and the metaphyses slope • because of narrow chest - respiratory problems are not infrequent • translucent area at proximal ends of the femora in neonatal period

17. Achondroplasia • Autosomal dominant • most cases are fresh mutations • in these cases recurrence risk is small • germ-line mosaicism - small risk to normal parents of having recurrence • if both parents affected - homozygotes can occur • infants more severely affected and usually die early from compression of foramen magnum and respiratory failure

18. Achondroplasia • Autosomal dominant • Gene maps to chromosome 4p • mutation identified in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene

19. Hypochondroplasia • Diagnosis might be difficult in the neonatal period • Clinical features include: • presence of mild rhizomelic limb shortening • less severe than in achondroplasia / some bossing of the forehead • fibula seem to be disproportionately long • Interpedicular distance in the spine narrows caudally • Findings may not be present or noted until second or third year of life • Autosomal dominant inheritance - FGFR3 receptor mutations

20. Thanatophoric Dwarfism • Limbs are very short • Chest is narrow • Most infants die within a few hours of birth from respiratory failure • Clinical features: • head is large with prominent forehead • depressed nasal bridge

21. Thanatophoric Dwarfism - X-ray feature • shortening of the long bones with metaphyseal flaring and cupping • characteristically curved femurs (“telephone receiver”) • Iliac wings are hypoplastic • Sacrosciatic notches are narrow • Severe flattening of vertebral bodies • gives an inverted “H” or inverted “U” shape • Incidence - 1/20,000 live births

22. Thanatophoric Dwarfism • Autosomal dominant • Mutations in FGFR3 receptor • Most cases are sporadic • Condition probably caused by a lethal AD gene

23. Thanatophoric Dwarfism with Clover-leaf Skull • Separate condition from isolated TD • In comparison with TD: • long bones are longer and may not be as bowed • histological changes in cartilage similar • skull changes are very unusual • basal and occipital bones under-developed • parietal bones form most of the back of the skull

24. Thanatophoric Dwarfism • Mutations in FGFR3 • Most cases represent new mutations although affected siblings have been reported

25. Achondrogenesis Types I and II • Type 1 - Parenti-Fraccaro - Autosomal recessive • Type 2 - Langer - Saldino - Autosomal dominant • Difficult to distinguish clinically • Both result in stillbirth or neonatal death

26. Achondrogenesis - Clinical Features • severe micromelia • relatively large head, short neck, short trunk and protuberant abdomen • flat nasal bridge • nose is short with anteverted nostrils

27. Type 2 Collagen Defects • Achondrogenesis Types 1 and 2 • Hypochondrogenesis • Lethal spondylo-epiphyseal dysplasia congenita • All form clinical spectrum

28. Hypochondrogenesis • Most AD - New mutations • mutations in Type II collagen genes • Clinical features: • flat face, depressed nasal bridge, small thorax, relatively large head • Limbs are short • Infant seems edematous

29. Atelosteogenesis Type I • Form of short limbed skeletal dysplasia • Diagnosis must be made from the radiologic appearance • Hallmark of condition is: • hypoplastic humerus that tapers distally • hypoplastic femurs, platyspondyly • vertebral coronal clefts • absent or hypoplastic carpals, tarsals, and proximal and middle phalanges • Genetics - uncertain

30. Diastrophic Dysplasia • Severe Limb Dysplasia • Short limbs, severe talipes equinovarous • hitch-hiker thumbs (abducted thumbs) • cleft palate in many • cauliflower ear - characteristic swelling of the pinnae • occasional dislocations of joints

31. Diastrophic Dysplasia • respiratory problems due to narrow chest and micrognathis can be the cause of death • X-rays - marked shortening of the first metacarpals • Bizarre ossification of hand bones • Epiphyses and metaphyses are irregular • V-shaped deformity at distal ends of the femora and tibiae • vertebral bodies are irregular

32. Diastrophic Dysplasia • Genetic Aspects: • Autosomal recessive • Gene localized to chromosome 5q • Novel sulphate transporter gene

33. Camptomelic Dysplasia • Hallmark bowing of long bones • particularly the femur and tibia • Large head, small jaw, cleft palate and flat nasal bridge • Ears may be malformed and low set • Chest narrow - respiratory distress is common

34. Camptomelic Dysplasia • Interesting Associations: • 1/3 cardiac defects (VSD, ASD, Fallot Tetrology) • 1/3 hydronephrosis - unilaterally • medullary cystic disease • Ambiguous Genitalia occur in the majority of patients with XY karyotype • Other frequent malformation include hydrocephalus, arrhinencephaly

35. Camptomelic Dysplasia • Genetics: • Autosomal dominant • Some with balanced translocations in the 17q12-25 region • Mutations in Sox 9 gene have been demonstrated • Most cases are sporadic

36. Kyphomelic Dysplasia • Short, angulated femurs • Bowing of other long bones • Face is characterized by micrognathis and a capillary hemangioma over forehead and gabella • ? bowing improves with age ? • intelligence is normal • similar to FHUFS • ? Genetics - ? AR

37. Osteogenesis Imperfecta - I • Commonest form of OI • Affected Individuals have: • blue sclera and tendency to fracture the long bones • Healing occurs without deformity • X-ray may reveal wormian bones of the skull and mild osteoporosis

38. Osteogenesis Imperfecta - I • Autosomal dominant inheritance • Cells from individuals with OI type I secret about half the normal amount of Type I procollagen • Gene linked to one of the Type I collagen loci • 7 q 21-22 • 17 q 21-22

39. Osteogenesis Imperfecta - II • Severe, usually lethal form of OI • Chest narrow, sclera blue, nose beaked • Marked reduction of ossification of cranial vault and facial bones • Beading of the ribs - indicates multiple fractures

40. Hypophoshatasia • Two forms - early and late • Both have reduced chondro-osseous mineralization • low levels of alkaline phospatase in blood, cartilage and bone • Infantile form: • stillbirth, early death due to respiratory insufficiency

41. Hypophosphatasia • Long bones - deformed and sometimes fractured • Differential diagnosis - OI bones are very poorly mineralized and irregular ossification of the metaphyses which are widened and frayed • Skull is poorly ossified • Concentration of phosphoethanolamine is elevated in urine • Late onset - AD • Early onset - AR