Disorders of Sex Development Loci

Abstract

Disorders of sex development (DSDs) are defined as congenital conditions in which chromosomal, gonadal, or anatomic sex is atypical. They occur at a frequency of 1–3% (including hypospadias). A patient is diagnosed with a DSD if sex determination and differentiation are incomplete or mixed, or if phenotypic and genotypic sex do not match. DSDs can be classified into three major categories: (1) sex chromosome DSDs, (2) 46,XY DSDs (disorders of testicular development (eg, complete/partial gonadal dysgenesis, ovotesticular DSD, and gonadal regression) and disorders of androgen synthesis or action), and (3) 46,XX DSDs (disorders of ovarian development (eg, gonadal dysgenesis, ovotesticular DSD, and testicular DSD) and disorders of androgen excess). The genetic causes for around 70% of DSDs affecting gonadal development are still unknown. Mutations in several loci have been identified in DSD patients in genes that are required for gonadal development and endocrine function. Complex genetic pathways control the development of the gonads. For example, in the XY gonad, the expression of specific genes promotes testis development and inhibits ovarian development. In the XX gonad, the converse situation occurs. In this article, we will review genes that have been implicated in 46,XY and 46,XX DSDs.