Disorders of sex development: new genes, new concepts

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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.

Key Points

  • The development of a testis or an ovary from common gonadal primordia is governed by complex molecular networks of gene expression

  • The products of male-specific and female-specific genes promote testis and ovary development, and antagonize each other; disturbance of this fine balance can lead to disorders of sex development (DSDs)

  • A specific molecular diagnosis is currently made in only 20% of patients with DSDs; however, advanced genetic technologies could identify new causes of DSDs and their molecular basis

  • DSD diagnosis and management are complex; an experienced multi-disciplinary team is required to work with the patient and their family, placing the patient's quality of life at the forefront

  • New terminology for and classification of DSDs, built around genetic concepts and systematic approaches to lifelong care, have been embraced by health professionals, families and the academic literature

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Figure 1: Gene regulatory networks in embryonic gonadal development.

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Acknowledgements

The authors thank P. Bernard, S. Bagheri-Fam, R. Lavery, J. Ryan, D. Alankarage and R. Sreenivasan at Prince Henry's Institute, Melbourne, Australia for critical reading of this manuscript, and A. Greenfield of the Medical Research Council, Harwell, UK and E. Turbitt at Murdoch Children's Research Institute, Melbourne, Australia for fruitful discussions of its content. The authors' research work was supported by National Health and Medical Research Council Program Grant 546517 and Fellowship 1020034 to V. R. Harley and the State of Victoria Operational Infrastructure Support Program, Australia.

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Both authors contributed equally to researching data for the article, discussing the content, writing the manuscript, and reviewing and/or editing the manuscript before submission.

Correspondence to Vincent R. Harley.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information Table 1

Classification of DSDs (DOC 44 kb)

Supplementary information Table 2

Genes and proteins implicated in disorders of sex development (DOC 94 kb)

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Ono, M., Harley, V. Disorders of sex development: new genes, new concepts. Nat Rev Endocrinol 9, 79–91 (2013) doi:10.1038/nrendo.2012.235

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