DSDs: genetics, underlying pathologies and psychosexual differentiation

Key Points

  • Disorders of sex development (DSDs) are defined as congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical

  • Mutations in genes that encode transcription factors, signalling components and epigenetic modifiers that are involved in sex determination can result in 46,XX and 46,XY DSDs

  • At 6–8 weeks post-conception in human fetal development, upregulated expression of SRY in the bipotential gonad promotes testis determination, whereas activation of WNT4 and RSPO1 signalling promotes ovary determination

  • Gonadal phenotypes in patients with DSDs range from gonadal dysgenesis (in which the gonads are fibrous streak gonads) to varying degrees of ovotesis (in which both ovary and testicular tissue are present)

  • The complexity and interrelatedness of factors that contribute to the aetiology and the medical and psychological outcomes of DSDs demand a multidisciplinary team approach to health care

  • In contrast to gender differences in activities and interests, associations between prenatal exposure to androgens and development of gender identity or sexual orientation are unclear

Abstract

Mammalian sex determination is the unique process whereby a single organ, the bipotential gonad, undergoes a developmental switch that promotes its differentiation into either a testis or an ovary. Disruptions of this complex genetic process during human development can manifest as disorders of sex development (DSDs). Sex development can be divided into two distinct processes: sex determination, in which the bipotential gonads form either testes or ovaries, and sex differentiation, in which the fully formed testes or ovaries secrete local and hormonal factors to drive differentiation of internal and external genitals, as well as extragonadal tissues such as the brain. DSDs can arise from a number of genetic lesions, which manifest as a spectrum of gonadal (gonadal dysgenesis to ovotestis) and genital (mild hypospadias or clitoromegaly to ambiguous genitalia) phenotypes. The physical attributes and medical implications associated with DSDs confront families of affected newborns with decisions, such as gender of rearing or genital surgery, and additional concerns, such as uncertainty over the child's psychosexual development and personal wishes later in life. In this Review, we discuss the underlying genetics of human sex determination and focus on emerging data, genetic classification of DSDs and other considerations that surround gender development and identity in individuals with DSDs.

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Figure 1: Genetic pathophysiology of human sex determination.

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Acknowledgements

Funding for this project was from the Doris Duke Foundation and the National Institute of Child Health and Human Development RO1HD06138 DSD-TRN (Platform for Basic and Translational Research) grant to E.V. and D.E.S, University of California Los Angeles institutional funds to V.A.A. and Patient-Centered Outcomes Research Institute contract funds to D.E.S.

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Arboleda, V., Sandberg, D. & Vilain, E. DSDs: genetics, underlying pathologies and psychosexual differentiation. Nat Rev Endocrinol 10, 603–615 (2014). https://doi.org/10.1038/nrendo.2014.130

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