Campomelic dysplasia

AD; SOX9 (17q24.3). Heterozygous loss-of-function variants (usually nonsense, frameshift, splice, or whole-gene deletion). Translocations and inversions disrupting the long-range regulatory region upstream of SOX9 cause the same phenotype.

• ~95% de novo. Recurrence in unaffected parents is from gonadal mosaicism (~5%).
• SOX9 has two essential roles, which together explain the phenotype:
  1. Master regulator of chondrogenesis → skeletal dysplasia
  2. Downstream of SRY, drives testis determination in 46,XY embryos → sex reversal when haploinsufficient

The name "campomelic" comes from the Greek for "bent limb."

• Skeletal (radiographic clues):
  • Bowed (angulated) long bones, especially femur and tibia; pathognomonic when present
  • 11 pairs of ribs instead of 12 (frequently called out on neonatal CXR)
  • Hypoplastic scapulae (small, wing-like)
  • Bell-shaped narrow chest → pulmonary hypoplasia
  • Vertically narrow iliac wings, hypoplastic pubic rami
• Craniofacial:
  • Macrocephaly with flat midface
  • Pierre Robin sequence: micrognathia + glossoptosis + cleft palate
• Airway:
  • Tracheobronchomalacia is the dominant cause of morbidity and neonatal mortality
• Genitourinary (the SOX9 sex-determination tell):
  • ~75% of 46,XY infants have female or ambiguous external genitalia from defective testis differentiation
  • Karyotype every phenotypic female with this skeletal phenotype; discordance is the rule, not the exception
• Variant: acampomelic campomelic dysplasia (~10%): same gene, same syndrome, with minimal or no long-bone bowing. Diagnosis rests on the other radiographic features (ribs, scapulae, chest shape) plus SOX9 sequencing.

• Prenatal ultrasound may catch short, bowed long bones, a small chest, and micrognathia; offer karyotype and SOX9 analysis on amniocytes if suspected.
• Postnatal: clinical + skeletal survey (11 ribs, bowed femora, hypoplastic scapulae) + SOX9 sequencing and del/dup analysis.
• If SOX9 sequencing is negative, evaluate for balanced translocations or inversions disrupting the upstream regulatory region; these account for a minority of cases.
• Karyotype every infant regardless of phenotypic sex.

• Airway is the priority. NICU admission, prepare for difficult intubation; tracheomalacia may need CPAP, prolonged ventilation, or tracheostomy.
• Cleft / Pierre Robin team for airway and feeding.
• Orthopedics for limb angulation, scoliosis surveillance, and progressive cervical spine instability (a recurring late issue in survivors).
• Endocrinology / urology for the 46,XY sex-reversed infant: gonadectomy is often recommended because dysgenetic gonads carry malignancy risk (gonadoblastoma).
• Hearing assessment (mixed sensorineural and conductive hearing loss is common).
• Genetic counseling: AD with high transmission risk in the rare survivor; gonadal mosaicism is a real recurrence consideration in apparently de novo families. Recommend prenatal diagnosis in subsequent pregnancies even when parents test negative.

Historically considered lethal in infancy, primarily from respiratory failure. With modern neonatal airway management a meaningful fraction now survive past the neonatal period, but airway, orthopedic, and developmental challenges persist. The acampomelic variant has a less severe course.