Sex determination and differentiation.

N Engl J Med 2004;350:367-78. Copyright © 2004 Massachusetts Medical Society. ex determination, which depends on the sex-chromosome complement of the embryo, is established by multiple molecular events that direct the development of germ cells, their migration to the urogenital ridge, and the formation of either a testis, in the presence of the Y chromosome (46,XY), or an ovary in the absence of the Y chromosome and the presence of a second X chromosome (46,XX). Sex determination sets the stage for sex differentiation, the sex-specific response of tissues to hormones produced by the gonads after they have differentiated in a male or female pattern. A number of genes have been discovered that contribute both early and late to the process of sex determination and differentiation. In many cases our knowledge has derived from studies of either spontaneous or engineered mouse mutations that cause phenotypes similar to those in humans. We will examine how mutations in these genes cause important clinical syndromes (Table 1 and Fig. 1) and discuss clinical entities that continue to elude classification at the molecular level. Knowledge of the molecular basis of disorders of sex determination and differentiation pathways will continue to have a strong influence on the diagnosis and management of these conditions. Terminology, when possible, adheres to that used in the Online Mammalian Inheritance in Man data base developed by the National Center for Biotechnology Information of the National Library of Medicine (http://www.ncbi.nlm.nih.gov).