genetics for the orthopedist charles j. macri md division of reproductive and medical genetics...
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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 21-22– 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