AN AUTOSOMAL OR X-LINKED MUTATION RESULTS IN TRUE HERMAPHRODITES AND 46,XX MALES IN THE SAME FAMILY

It is now well established that the differentiation of the primitive g onad into the testis during early human embryonic development depends on the presence of the SRY gene. However, the existence of total or pa rtial sex reversal in 46,XX males with genetic mutations not Linked to the Y chromosome suggests that several autosomal genes acting in asso ciation with SRY may contribute to normal development of the male phen otype. We report a family in which four related 46,XY 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 de grees of sexual ambiguity and were found to be 46,XX true hermaphrodit es. The presence of male sexual development in genetic females with tr ansmission through normal male and female parents indicates that the c ritical genetic defect is most likely to be an autosomal dominant muta tion, the different phenotypic effects arising from variable penetranc e. Other autosomal loci have been implicated in male sexual developmen t but the genetic mechanisms involved are unknown. In this family ther e may be an ''activating'' mutation which mimics the initiating role o f the SRY gene in 46,XX subjects.