Ambiguous genitalia in both female and male infants is observed in association with syndromes of multiple congenital malformations. These associations are due to the fact that many of the transcription factors involved in sex development and differentiation are also involved in other developmental functions. For example, mutations of the WT-1 gene (11p3) can result in a number of syndromes including WAGR, Denys-Drash or Frasier syndromes (43-45). SOX-9 (17q24-25) mutations can result in camptomelic dysplasia (46). Mutations of DMRT1/DMRT2 (9p24.3), EMX-2 (10q25.3q26.13), ATRX (Xq13.3) and WNT-4 (1p35) are often associated with mental retardation (47). SF-1 (9q33) and DAX-1 (Xp21.3) play roles in early formation of the adrenals, anterior pituitary and parts of the hypothalamus and their mutations result in abnormalities of these organs (1). Abnormal development of the lower abdominal wall with pubic diastesis results in urogenital anomalies in the VATER and CHARGE syndromes as well as bladder and cloacal exstrophy (48). These examples demonstrate the complexities of the anomalies that can be associated with DSDs.

Ovotesticular DSD refers to the presence of both ovarian and testicular tissue in the same individual (1). Most newborns with ovotesticular DSD possess a 46,XX chromosome complement and present with ambiguous genitalia; however, some possess a 46,XY chromosome complement or 46,XX/46,XY mosaicism. Similar to other types of abnormal sex differentiation, the degree of testicular development will dictate the extent of Wolffian duct development and Müllerian duct regression in newborns affected by ovotesticular DSD (23). In newborns with ovotesticular DSD the risk of germ cell tumors is believed to be low (3%) and no recommendation of testicular tissue removal is offered at this time (1).

In Klinefelter (47,XXY) and 47,XYY syndromes, normal male external genitalia are typically present at birth. However, rare cases of the syndromes have presented with ambiguous genitalia. In newborns affected by Turner (45,XO) syndrome the external genitalia appear female whether the remaining X chromosome is maternal or paternal in origin. Rare cases of genital ambiguity observed with Turner syndrome are probably related to a hidden 46,XY cell line (23).