[Genetic heterogeneity and phenotypic variability in 46,XY sex reversal]

The discordance between the chromosomic and the gonadal-phenotypic sex is known as sex reversal (XX males and XY females). We review the XY pure gonadal dysgenesis characterized by female phenotype, primary amenorrhea and absence of secondary sexual development. Bilateral streak gonads are always present in the complete form of this syndrome, while variable degrees of virilization are found in the partial forms, depending on the severity of the testicular damage. A plausible explanation for this pathology are SRY mutations that interfere with the testicular differentiation. However, only 10-15% of the patients with the complete form show SRY mutations, particularly in the HMG box. The remaining cases are probably due to mutations in different autosomal or X-linked genes which are also involved in the sex differentiation cascade. Recently, it has been shown that mutations in several genes responsible of well known genetic entities as WT1, SOX9, DSS and SF1, result in sex reversal. These findings reveal the genetic heterogeneity and clinical variability of XY sex reversal and provide the basis establishing a hierarchy of genes and their participation in the sex determination pathway.