Genetic control of typical and atypical sex development.

Sex development relies on the sex-specific action of gene networks to differentiate the bipotential gonads of the growing fetus into testis or ovaries, followed by the differentiation of internal and external genitalia depending on the presence or absence of hormones. Differences in sex development (DSD) arise from congenital alterations during any of these processes, and are classified depending on sex chromosomal constitution as sex chromosome DSD, 46,XY DSD or 46,XX DSD. Understanding the genetics and embryology of typical and atypical sex development is essential for diagnosing, treating and managing DSD. Advances have been made in understanding the genetic causes of DSD over the past 10 years, especially for 46,XY DSD. Additional information is required to better understand ovarian and female development and to identify further genetic causes of 46,XX DSD, besides congenital adrenal hyperplasia. Ongoing research is focused on the discovery of further genes related to typical and atypical sex development and, therefore, on improving diagnosis of DSD.

FGF9 variant in 46,XY DSD patient suggests a role for dimerization in sex determination.

46,XY gonadal dysgenesis (GD) is a Disorder/Difference of Sex Development (DSD) that can present with phenotypes ranging from ambiguous genitalia to complete male-to-female sex reversal. Around 50% of 46,XY DSD cases receive a molecular diagnosis. In mice, Fibroblast growth factor 9 (FGF9) is an important component of the male sex-determining pathway. Two FGF9 variants reported to date disrupt testis development in mice, but not in humans. Here, we describe a female patient with 46,XY GD harbouring the rare FGF9 variant (missense mutation), NM_002010.2:c.583G > A;p.(Asp195Asn) (D195N). By biochemical and cell-based approaches, the D195N variant disrupts FGF9 protein homodimerisation and FGF9-heparin-binding, and reduces both Sertoli cell proliferation and Wnt4 repression. XY Fgf9D195N/D195N foetal mice show a transient disruption of testicular cord development, while XY Fgf9D195N/- foetal mice show partial male-to-female gonadal sex reversal. In the general population, the D195N variant occurs at an allele frequency of 2.4 × 10-5 , suggesting an oligogenic basis for the patient's DSD. Exome analysis of the patient reveals several known and novel variants in genes expressed in human foetal Sertoli cells at the time of sex determination. Taken together, our results indicate that disruption of FGF9 homodimerization impairs testis determination in mice and, potentially, also in humans in combination with other variants.

A clinical algorithm to diagnose differences of sex development.

The diagnosis and management of children born with ambiguous genitalia is challenging for clinicians. Such differences of sex development (DSDs) are congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. The aetiology of DSDs is very heterogenous and a precise diagnosis is essential for management of genetic, endocrine, surgical, reproductive, and psychosocial issues. In this Review, we outline a step-by-step approach, compiled in a diagnostic algorithm, for the clinical assessment and molecular diagnosis of a patient with ambiguity of the external genitalia on initial presentation. We appraise established and emerging technologies and their effect on diagnosis, and discuss current controversies.