Partial duplication of chromosome 22q (duplication of bands from 22q11.2-22q13) or overexpression of the SOX10 gene at 22q13 (OMIM#602229) can also lead to testicular DSD in 46,XX subjects in the absence of SRY.54 Furthermore, mutations in the RSPO1 gene, as previously mentioned, have been associated with testicular DSD in 46,XX subjects, in the absence of SRY, together with palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin.40 However, with the exception of these few cases, SRY negative testicular DSD remains largely unexplained. The presence of familial 46,XX testicular DSD and familial 46,XX ovotesticular DSD in the same pedigree remains unexplained.55 These familial cases, in which XX ovotesticular DSD coexist with testicular DSD in the same sibship, provide evidence to support the hypothesis that these disorders constitute variable manifestations of the same genetic defect with differences in the expression and penetrance of the mutant gene.56 It should also be mentioned that an unknown interplay between several genes could be modified by still unidentified environmental factors, known as endocrine disruptors.57
