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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 –17 q 21-22

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

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

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