Clinical, genetics and bioinformatics characterization of a campomelic dysplasia case report

Campomelic dysplasia is a rare disorder characterized by skeletal and extraskeletal defects. Up to two-thirds of affected XY individuals have a gradation of genital defects or may develop as phenotypic females. This syndrome is caused by alterations in SRY-related HMG-Box Gene 9 (SOX9), a transcription factor essential in both chondrocyte differentiation and sex determination. We report a 27-week fetus with ambiguous genitalia and upper and lower extremities bone malformations. Gross photographs, radiologic and pathological studies led the clinical diagnosis to campomelic dysplasia. A new frameshift mutation (p.Pro415Serfs*163) was identified in the SOX9 gene by genetic analysis. This mutation not only alters almost the entire sequence of the C-terminal transactivation (TA) domain of SOX9, but also enlarges it. This altered sequence does not resemble any other existing sequence. Since TA domain is entirely affected, SOX9 could not establish its normal function. The comparison between p.Pro415Serfs*163 and other frameshift mutations that enlarges SOX9 showed the same nucleotides added. This new sequence is not conserved either. We speculate that the fact of adding a sequence downstream of the C-terminal domain alters SOX9 and leads to campomelic dysplasia. The clinical information is essential not only to achieve a correct diagnosis in fetuses with pathologic ultrasound findings, but also to offer a proper genetic counseling.