Syndromic true hermaphroditism due to an R-spondin1 ( RSPO1 ) homozygous mutation

XX true hermaphroditism, also know as ovotesticular disorder of sexual development (DSD), is a disorder of gonadal development characterized by the presence of both ovarian and testicular tissue in a 46, XX individual. The genetic basis for XX true hermaphroditism and sex reversal syndromes unrelated to SRY translocation is still mostly unclear. We report mutational analysis of the RSPO1 gene in a 46, XX woman with true hermaphroditism, palmoplantar keratoderma, congenital bilateral corneal opacities, onychodystrophy, and hearing impairment. R-spondin1 is a member of the R-spondin protein family and its pivotal role in sex determination has been recently described. We identified a homozygous splice-donor-site mutation in the RSPO1 gene in our patient. We found that the c. 286+1G>A mutation led to an aberrantly spliced mRNA (r. 95₂86del), which is presumably translated into a partially functional protein (p. Ile32Ile95del). Our case demonstrates for the first time, to our knowledge, that XX true hermaphroditism can be caused by a single gene mutation. The reported findings represent a further step toward a complete understanding of the complex mechanisms leading to DSDs.