Familial Sex Reversal: A Review

Since 1905, it has been recognized that a gene on the Y chromosome, originally termed TDF (for “testes-determining factor”) acted in a dominant fashion to promote male sexual development (1). In 1990, the SRY (sex-determining region Y) gene was identified as TDF (2). This gene was cloned, and its identity was confirmed by studying individuals with sex reversal (phenotypic sex of one type, genetic sex of the other). Subsequent studies of sex-reversed individuals have shown that this gene is neither necessary nor sufficient to promote testis development (3–10). This review will highlight the many observed cases of sex-reversal that have led to the identification of genes other than SRY that promote testicular development and that have suggested a rudimentary genetic pathway. However, rather than focusing on work that has been well-summarized in other reviews, this article will delve into the analysis of cases of sex reversal that are likely to be informative for identifying new genes in the testis-determining pathway (11–13). These cases fall into two categories; either they are associated with novel genetic syndromes or they are familial, with multiple affected individuals within a pedigree. The frequent occurrence of familial sex-reversal suggests that family members other than the proband may be at risk for sex reversal themselves or for having offspring with sex reversal.