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

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

• 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

• 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

• Skeletal Dysplasias
• Chromosomal disorders
• Single gene disorders
• Metabolic disorders
• Syndromes

• 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

• 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

• 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

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

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

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

• 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

• 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

• 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

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

• 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

• 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

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

• 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

• 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

• 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

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

• 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

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

• Type 1 - Parenti-Fraccaro - Autosomal recessive
• Type 2 - Langer - Saldino - Autosomal dominant
• Difficult to distinguish clinically
• Both result in stillbirth or neonatal death

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

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

• 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

• 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

• 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

• 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

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

• 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

• 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

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

• 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

• 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

• 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

• 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

• 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

• 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