Campomelic dysplasia is a rare, often lethal congenital osteochondrodysplasias associated with skeletal malformations and sex-reversal. The term “campomelia” derives from Greek, meaning bent or curved limb. The incidence of campomelic dysplasia is reported to be 0.05–0.9 per 10,000 births.
GENETICS/BASIC DEFECTS
1. Inheritance: autosomal dominant 2. Etiology
a. Assignment of a locus CMPD1 to 17q24.3-q25.1 was based on characterization of three independent de novo chromosome 17 translocations in campomelic dysplasia patients
b. XY sex reversal of two of these translocation patients placed an autosomal sex-determining locus, SRA1, in the same region
c. SOX9, a gene related to the mammalian Y chromo- some sex-determining gene SRY, was mapped to this region and found to be near the translocation break- point of a sex-reversed campomelic dysplasia patient.
d. Subsequent identification of de novo mutations in sex-reversed campomelic patients demonstrated that SOX9 is the gene responsible for both campomelic dysplasia and autosomal sex reversal
e. SOX9 mutations
i. Disrupt skeletogenesis and chondrocytic differ- entiation
ii. Produce defective testicular development often resulting in sex reversal with female phenotype in chromosomal XY males
f. Proof of SOX9 being responsible for both cam- pomelic dysplasia and XY sex reversal: demonstra- tion of de novo heterozygous loss-of-function mutations within the SOX9 coding region in non- translocation campomelic dysplasia patients
g. Isolation of the SOX9 gene on chromosome 17q by positional cloning in combination with positional candidate information from the vicinity of break- points in campomelic dysplasia patients with recipro- cal de novo translocations
CLINICAL FEATURES
1. Clinically a heterogeneous disorder a. Long-limbed variety
i. Bent bones of normal thickness, may be slightly shortened
ii. Rarely involves the upper limbs b. Short-limbed variety
i. Bent bones are short and wide ii. Two skull types
a) Craniosynostotic type with cloverleaf skull b) Normocephalic type
c. Acampomelic campomelic dysplasia
i. The eponymous feature ‘campomelia’ (the bend- ing of the long bones): not an obligatory feature of the syndrome
ii. Absence of campomelia in about 10% of cam- pomelic dysplasia cases
2. Prenatal history
a. Polyhydramnios (30% of cases) in the 3rd trimester common
b. Growth retardation 3. Extreme hypotonia at birth 4. Characteristic craniofacial features
a. Frequent macrodolichocephaly b. Cloverleaf skull
c. Wide fontanel
d. Short, narrow, and upslanted palpebral fissures e. Ocular hypertelorism
f. Flat nasal bridge g. Long philtrum
h. Micrognathia (Pierre Robin sequence) i. Cleft palate in 2/3rd of the cases j. Low-set and posteriorly rotated ears k. Prominent nuchal folds
l. Hearing loss (deaf) in survivors
5. Prominent and characteristic musculoskeletal features a. Congenital bowed lower limbs (anterior bowing of
the tibiae) with pretibial skin dimples. Pretibial dim- ples appear to result from the loss of subcutaneous tissue secondary to marked stretching of the skin overlying the apexes of the bony curvatures during fetal life
b. Short limbs c. Short neck d. Pterygium coli e. Narrow thorax f. Kyphoscoliosis g. Talipes equinovarus h. Hand anomalies
i. Brachydactyly ii. Clinodactyly iii. Camptodactyly
i. Congenital dislocation of the hips j. Winging of the scapula
k. Fewer ribs 6. Genitalia
a. Genotypic XY males (3/4th of karyotypic males with sex reversal)
i. External genitalia: range from unambiguous female external genitalia to hypospadias with a bifid scrotum and an enlarged clitoris
ii. Internal genitalia: various combinations of inter- nal Mullerian and Wolffian duct structures b. Genotypic XX females: remain phenotypic female 131
7. CNS
a. Mental retardation in survivors b. Large brain
c. Hydrocephalus (25%) d. Polygyria
e. Absent olfactory bulbs and/or tracts f. Dysgenesis of the corpus callosum
g. Gross cellular disorganization, especially of cerebral peduncle, thalamus, and caudate nucleus
8. Respiratory insufficiency secondary to a. Robin sequence
b. Narrow airways due to laryngotracheobronchomala- cia (the most characteristic finding)
c. Hypoplastic lungs
d. A small bell-shaped thorax 9. Occasional abnormalities
a. Congenital heart diseases i. Patent ductus arteriosus ii. Ventricular septal defects iii. Coarctation of the aorta
iv. Tetralogy of Fallot b. Renal anomalies
i. Hydronephrosis ii. Hydroureter iii. Renal hypoplasia
iv. Renal cortical and medullary cysts c. Ear anomalies
i. Hypoplastic cochlea and semicircular canals ii. Anomalies in incus and stapes
10. Cause of death
a. Usually due to respiratory insufficiency
i. Primarily owing to airway and pulmonary defects, lack of laryngotracheobroanchial carti- lages and hypotonia
ii. Resulting in apneic spells, atelectasis, aspiration, and pneumonia
b. A high rate of neonatal death
i. Most deaths occurring neonatally (77%) ii. 90% of deaths before 2 years
11. Life expectancy varies depending on the severity of the phenotype
a. Young infants who survive i. Feeding difficulties ii. Stridor
iii. Retractions
iv. Frequent otitis media v. Bronchitis
vi. Poor growth
b. Infants who survive several years i. May be mentally retarded
ii. May show variable breakpoints within the vicin- ity of chromosome 17 (q21-q25)
iii. Oldest reported survivor: 17 years of age with an IQ of 45
c. Complications of survivors of campomelic dysplasia i. Recurrent apnea
ii. Upper respiratory infections iii. Progressive kyphoscoliosis
iv. Mild to moderate learning difficulties
v. Short stature
vi. Dislocation of the hips
d. Possible explanations for the survival of patients with campomelic dysplasia
i. Mosaicism of the SOX9 mutations
ii. Chromosomal rearrangements involving chro- mosome 17q (q23.3-q25.1) shown to cause cam- pomelic dysplasia without disrupting the SOX9 gene, resulting in a milder phenotype
DIAGNOSTIC INVESTIGATIONS
1. Radiography a. Affected infants
i. Tubular bones
a) Bowed femora and tibiae b) Short fibulae
c) Radioulnar dislocation ii. Thorax
a) Severe hypoplastic, bladeless scapulae b) Thin short clavicles
c) Nonmineralized sternum
d) Small thoracic cage with slender and/or decreased number of ribs (usually 11 pairs) iii. Spine
a) Abnormal cervical vertebrae b) Kyphoscoliosis
c) Non-mineralized thoracic pedicles iv. Pelvis
a) Dislocation of the hips b) Narrow iliac wings
c) Poorly developed ischiopubic rami d) Coxa vara
v. Hands and feet
a) Short first metacarpal bone b) Talipes equinovarus vi. Skeletal maturation
a) Delayed bone age
b) Delayed ossification of proximal tibial and distal femoral epiphysis and talus
b. Survivors
i. Hypoplastic scapulae
ii. Defective ischiopubic ossification iii. Absent or hypoplastic patellae
iv. Spinal dysraphism
c. Considerable radiographic overlap with ischiopubic- patella syndrome
2. Gonadal histology
a. Similar to XY gonadal dysgenesis
b. Ranging from dysplastic testicular tissue to poorly differentiated ovarian tissue with a few primordial follicles
3. Histology of growth plate: unremarkable epiphyseal rest- ing cartilage
4. Cytogenetic analysis
a. Identification of the sex reversal
b. Identification of the chromosomal rearrangement involving 17q
5. Molecular analysis of SOX9 mutation
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: not increased unless gonadal mosaicism in one of the parent
b. Patient’s offspring: 50% if the patient can survive to the reproductive age
2. Prenatal diagnosis
a. Possible by ultrasonography as early as 18 weeks of gestation
i. Ultrasonographic findings
a) Symmetrical anterior bowing of femurs and tibias
b) Hypoplastic or absent scapulae
c) Small thorax compared to the abdomen d) Bilateral talipes equinovarus
e) External genitalia not compatible with 46,XY karyotype
f) Polyhydramnios g) Fetal growth retardation
h) Large head with internal hydrocephalus i) Sagittal scan of the face showing a flat nasal
bridge, elongated philtrum, and micrognathia ii. Major differential diagnosis of ultrasonographic
features
a) Osteogenesis imperfecta b) Hypophosphatasia
c) Unclassifiable varieties of congenital bow- ing of the long bones
b. Amniocentesis result of 46,XY with ultrasonographic finding of a female external genitalia
c. Identification of SOX9 mutation in the fetus 3. Management
a. Supportive medical care
b. Orthopedic treatment of the musculoskeletal malfor- mations to prevent additional morbidity
i. Hip dislocation
ii. Bracing or spinal fusion for spinal deformity iii. Serial casting or surgical correction for foot
deformity
c. Gonadodectomy advocated in surviving phenotypic females with Y chromosome fragments owing to the increased risk of gonadoblastoma
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Fig. 1. Radiograph of an infant with campomelic dysplasia showing bowed femurs.
Fig. 2. An infant with campomelic dysplasia showing bowing of the limbs with pretibial skin dimples, hypoplasia of cervical vertebra and scapula, 11 pairs of ribs, non-mineralized pedicles, vertical/narrow iliac wings, and bowing of femurs.
Fig. 3. A neonate with campomelic dysplasia showing large head, flat face, flat nasal bridge, low-set ears, micrognathia, and bowed lower legs with pretibial dimples. The radiographs show bowing of the femora, tibia, and fibulas.
