Disorders of sex development: new genes, new concepts

Abstract

Formerly known as 'intersex' conditions, disorders of sex development (DSDs) are congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. A complete revision of the nomenclature and classification of DSDs has been undertaken, which emphasizes the genetic aetiology of these disorders and discards pejorative terms. Uptake of the new terminology is widespread. DSDs affecting gonadal development are perhaps the least well understood. Unravelling the molecular mechanisms underlying gonadal development has revealed new causes of DSDs, although a specific molecular diagnosis is made in only ∼20% of patients. Conversely, identification of the molecular causes of DSDs has provided insight into the mechanisms of gonadal development. Studies of N-ethyl-N-nitrosourea mutagenesis in the mouse, and multigene diagnostic screening and genome-wide approaches, such as array-comparative genomic hybridization and next-generation sequencing, in patients with DSDs are accelerating the discovery of genes involved in gonadal development and DSDs. Furthermore, long-range gene regulatory mutations and multiple gene mutations are emerging as new causes of DSDs. Patients with DSDs, their parents and medical staff are confronted with challenging decisions regarding gender assignment, genital surgery and lifelong care. These advances are refining prognostic prediction and systematically improving the diagnosis and long-term management of children with DSDs.

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

“…In the bipotential stage of development, transcription factors such as Wilms' tumor 1, nuclear receptor subfamily 5 group A member 1 (NR5A1) and GATA-binding protein 4 (GATA4) lead to upregulation of the sex-determining region Y gene (SRY) in the male embryo, thereby initiating the male developmental signaling cascade, with the expression of other male-specific genes such as SRY-box 9 (SOX9). 1 In addition, several reports indicate an important role for the mitogen-activated protein kinase (MAPK) pathway in the early phases of (male) sex determination. [2][3][4] In female embryos lacking the Y chromosome, female-specific genes like R-spondin 1 and forkhead box L2 (FOXL2) are expressed among others.…”

“…[2][3][4] In female embryos lacking the Y chromosome, female-specific genes like R-spondin 1 and forkhead box L2 (FOXL2) are expressed among others. 1,5 Animal studies have revealed multiple and long-lasting interactions between these male and female pathways; for instance, the loss of Foxl2 or Dmrt1 in murine adult granulosa and Sertoli cells, respectively, results in trans-differentiation to an opposite cell fate. 6,7 Subtle imbalances of this strictly regulated sex-specific gene network can lead to disorders or differences of sex development (DSD).…”

“…6,7 Subtle imbalances of this strictly regulated sex-specific gene network can lead to disorders or differences of sex development (DSD). 1 Currently, mutations in genes known to be involved in sex development explain the molecular pathogenesis in only a minority of 46,XY DSD cases. 1,7 Nextgeneration-sequencing-based approaches such as wholeexome sequencing improve the identification of causal genetic defects, and the discovery of new genes and signaling pathways implicated in sex development.…”

“…1 Currently, mutations in genes known to be involved in sex development explain the molecular pathogenesis in only a minority of 46,XY DSD cases. 1,7 Nextgeneration-sequencing-based approaches such as wholeexome sequencing improve the identification of causal genetic defects, and the discovery of new genes and signaling pathways implicated in sex development. 8,9 Elucidating the underlying causes of DSD can facilitate sex assignment and lead to improved management, a better prognosis and a more accurate evaluation of gonadal function and gonadal germ cell cancer risk.…”

The role of signalling pathways in urogenital ridge differentiation

“…Disorders of Sex Development (DSD) in human, formerly known as "intersex disorders", are defined as congenital conditions in which the development of the chromosomal, gonadal, or anatomical sex is atypical (Lee et al, 2006; reviewed by Ono and Harley, 2013). These disorders may affect up to 1:1000 newborns and encompass a range of phenotypes including ambiguous genitalia, complete sex reversal (phenotypic sex different to chromosomal sex), ovotestis, gonad dysgenesis, androgen insensitivity and can lead to infertility (reviewed by Ostrer, 2014).…”