An autosomal or X linked mutation results in true hermaphrodites and 46,XX males in the same family

Abstract

It is now well established that the differentiation of the primitive gonad into the testis during early human embryonic development depends on the presence of the SRY gene. However, the existence of total or partial sex reversal in 46,XX males with genetic mutations not linked to the Y chromosome suggests that several autosomal genes acting in association with SRY may contribute to normal development of the male phenotype. We report a family in which four related 46,XX subjects with no evidence of Y chromosome DNA sequences underwent variable degrees of male sexual differentiation. One 46,XX male had apparently normal male external genitalia whereas his brother and two cousins had various degrees of sexual ambiguity and were found to be 46,XX true hermaphrodites. The presence of male sexual development in genetic females with transmission through normal male and female parents indicates that the critical genetic defect is most likely to be an autosomal dominant mutation, the different phenotypic effects arising from variable penetrance. Other autosomal loci have been implicated in male sexual development but the genetic mechanisms involved are unknown. In this family there may be an "activating" mutation which mimics the initiating role of the SRY gene in 46,XX subjects.