Disorders of Sexual Development: Current Status and Progress in the Diagnostic Approach

Abstract

Disorders of sexual development (DSD) are conditions with an atypical chromosomal, gonadal or phenotypic sex, which leads to differences in the development of the urogenital tract and different clinical phenotypes. Some genes have been implicated in the sex development during gonadal and functional differentiation where the maintenance of the somatic sex of the gonad as either male or female is achieved by suppression of the alternate route. The diagnosis of DSD requires a structured approach, involving a multidisciplinary team and different molecular techniques. We discuss the dimorphic genes and the specific pathways involved in gonadal differentiation, as well as new techniques for genetic analysis and their diagnostic value including epigenetic mechanisms, expanding the evidence in the diagnostic approach of individuals with DSD to increase knowledge of the etiology.

Keywords: Bipotential gonad; Differential development; Disorders of sexual development; Genetic pathway; Sex differences.

Fig. 1

Proposed scheme of gene regulation in gonadal development. No sexual difference can be observed in the gonads until the 6th week of embryonic life in humans. Genes related to testicular development (blue) and genes related to ovarian development (red). Arrows do not necessarily imply direct actions. In XY gonads, *SOX3 may act in development of male gonad by acting like SRY. SOX9 expression is subsequently upregulated by SRY and SF-1 binding to TESCO region of this gene. SOX9 regulates the expression of genes required for testis formation, also suppresses the expression of ovarian genes such as RSPO1 and FOXL2. In XX gonads *SOX3 may act in development of female gonad by inhibition of SOX9. The genes RSPO1, FOXL2, WNT4 and β-catenin are also expressed in a female-specific manner, promoting ovarian development and preventing differentiation of testis by repressing SOX9 expression. Hypothesis of interaction of SOX3 was proposed in reference to animal models of sex development and few reports of human with pathogenic variants in this gene [48].