Campomelic Dysplasia
The most likely diagnosis is campomelic dysplasia, a rare autosomal dominant skeletal disorder caused by SOX9 gene mutations or deletions that characteristically presents with severe micromelia, XY sex reversal manifesting as ambiguous or female external genitalia despite 46,XY karyotype, and craniofacial anomalies including hypoplastic nasal bone. 1, 2, 3
Diagnostic Reasoning
Key Clinical Features Matching Campomelic Dysplasia
Severe micromelia with limb bowing: Campomelic dysplasia characteristically presents with angular bowing and shortening of the long bones, particularly the femora and tibiae, which can be detected as early as the first trimester on ultrasound. 1, 3
XY sex reversal with ambiguous genitalia: Up to two-thirds of affected 46,XY individuals have a spectrum of genital abnormalities ranging from ambiguous genitalia to complete phenotypic female external genitalia, despite having a male karyotype. 2, 3, 4
Hypoplastic nasal bone and craniofacial features: Affected individuals typically present with dysmorphic facial features including low nasal bridge (consistent with hypoplastic nasal bone), prominent forehead, micrognathia, and cleft palate. 2
Normal cell-free DNA testing: The low-risk result for common aneuploidies (trisomies 13,18,21) is expected, as campomelic dysplasia is not caused by aneuploidy but rather by mutations or deletions in the SOX9 gene on chromosome 17q24. 5, 4
Genetic Mechanism
SOX9 gene alterations: Campomelic dysplasia results from three distinct mechanisms: (1) intragenic mutations within the SOX9 coding region (most common), (2) deletions upstream of SOX9 removing critical regulatory elements (517 kb to 1.5 Mb upstream), or (3) balanced chromosomal rearrangements disrupting SOX9 expression. 3, 5, 4
Dual role of SOX9: The SOX9 transcription factor is essential for both chondrocyte differentiation (explaining the skeletal dysplasia) and testicular development (explaining the sex reversal in XY individuals). 3
Differential Diagnosis Considerations
Why Other Skeletal Dysplasias Are Less Likely
Osteogenesis imperfecta type II: Would present with undermineralized skull, beaded ribs, and multiple fractures—not typically associated with ambiguous genitalia or sex reversal. 6, 7
Thanatophoric dysplasia: Characterized by "telephone receiver" femurs and normal bone mineralization, but does not cause sex reversal or ambiguous genitalia. 6, 7
Achondrogenesis types: Present with absent vertebral body ossification and profound undermineralization, without the sex reversal phenotype. 6, 7
Recommended Diagnostic Workup
Immediate Genetic Testing
Chromosomal microarray analysis (CMA): Should be performed first to detect SOX9 deletions, as deletions ranging from 606 kb to 1.5 Mb upstream of SOX9 have been identified in campomelic dysplasia cases. 5, 4
Whole exome sequencing (WES): If CMA is negative, proceed with WES to identify intragenic SOX9 mutations, including frameshift mutations that alter the C-terminal transactivation domain. 3, 5
Combined CMA and WES strategy: When cystic hygroma or skeletal dysplasia is detected in the first trimester, a comprehensive approach using both CMA and WES maximizes diagnostic yield. 5
Important Caveats
Timing of prenatal detection: While severe cases may be detected in the first trimester, most campomelic dysplasia cases are diagnosed between 12-32 weeks gestation, with skeletal dysplasia and limb bowing being the primary ultrasound findings. 1
Parental testing considerations: Most cases result from de novo mutations; however, familial cases with inherited deletions have been reported, including a case where the mother carried a 960 kb deletion and was affected with the acampomelic form. 4
Postmortem confirmation: If pregnancy is terminated, postmortem radiographic examination should confirm characteristic skeletal deformities including narrow thoracic cage, hypoplastic scapulae, scoliosis, and limb bowing. 2
Prognostic Implications
Lethality assessment: The presence of severe micromelia (≥3 SD below mean) combined with a femur length-to-abdominal circumference ratio <0.16 predicts lethal skeletal dysplasia with high accuracy. 6, 7
Respiratory complications: Narrow thoracic cage and hypoplastic scapulae lead to respiratory failure at birth, which is the primary cause of early mortality in campomelic dysplasia. 2