The Genetics of Ovotesticular Disorders of Sex Development

Abstract

Disorders of sex development (DSD) encompass a very large spectrum of phenotypes, from minor malformations of the genitalia (hypospadias, cryptorchidism, and hypertrophy of the clitoris) to sexual ambiguity. Taken altogether, these anomalies have an estimated frequency of 0.5–1%. Moreover, sexual ambiguity has a major impact on quality of life. Recently, the debate about the management of patients with DSD has intensified over issues of gender assignment and the indication for early genital surgery. Yet the scientific data on patient outcome have remained poor. The main obstacles to the optimal management of patients with DSD have been a combination of the lack of controlled outcome data and the lack of understanding of their pathophysiology, which prevents precise diagnostic categorization of patients. Despite much progress in the past 15 years, the molecular mechanisms underlying mammalian sex determination are still far from understood, and the molecular basis of sex reversal in a large number of patients cannot yet be explained. Apart from XX testicular DSD, mainly caused by an X–Y translocation including SRY, the genetic etiology of XY gonadal dysgenesis and of ovotesticular DSD (OT-DSD) remains unknown for a majority of patients. The genetic causes of the latter, involving the presence of both testicular and ovarian tissues in the same patient, are particularly unappreciated.