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
heterogeneous
Dysplasias
• 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