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Genetic control of typical and atypical sex development

Nature Reviews Urology volume 20, pages 434–451 (2023)Cite this article

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Abstract

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.

Key points

  • Sex development is a complex developmental process that relies on the actions of positive and negative genetic signals, and occurs in three sequential stages: development of the bipotential gonad, sex determination and sex differentiation.

  • Differences in sex development (DSD) are a heterogeneous group of conditions in which chromosomal, gonadal or anatomical sex is atypical. Most forms remain genetically unexplained.

  • DSD are classified according to sex chromosomal constitution into three types: sex chromosome DSD, 46,XY DSD and 46,XX DSD.

  • The most frequent 46,XY DSD is androgen insensitivity syndrome, and the most frequent 46,XX DSD is congenital adrenal hyperplasia.

  • Ongoing research is focused on the discovery of causative genes for DSD to improve clinical diagnosis and management.

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Fig. 1: Gonadal ridge formation, primary gonadal sex determination and sex differentiation in humans.
Fig. 2: Genetic network required during testis and ovarian determination.
Fig. 3: 46,XY differences in sex development: androgen insensitivity syndrome, gonadal dysgenesis and 5α-reductase deficiency.
Fig. 4: 46,XX congenital adrenal hyperplasia.

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Acknowledgements

This research was funded by the National Health and Medical Research Council (NHMRC, Australia) Program Grant 1074258 and the NHMRC Research Fellowship 441102, both awarded to V.R.H. This work was supported by a clinical fellowship awarded to A.P.R. from the Board of the Hospital Infantil de México Federico Gómez. The Hudson Institute is supported by the Operational Infrastructure Scheme of the State Government of Victoria, Australia.

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  1. Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, Victoria, Australia

    Alejandra P. Reyes, Nayla Y. León, Emily R. Frost & Vincent R. Harley

  2. Genetics Department, Hospital Infantil de México Federico Gómez, Mexico City, Mexico

    Alejandra P. Reyes

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All authors searched the literature, wrote the manuscript, prepared the tables and developed the figures. All authors made substantial contributions to discussion of content, and reviewed and edited the article before submission.

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Correspondence to Vincent R. Harley.

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Related links

Human Gene Mutation Database: https://www.hgmd.cf.ac.uk/ac/index.php

Online Mendelian Inheritance in Man: https://www.omim.org

PubMed: https://pubmed.ncbi.nlm.nih.gov

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Reyes, A.P., León, N.Y., Frost, E.R. et al. Genetic control of typical and atypical sex development. Nat Rev Urol 20, 434–451 (2023). https://doi.org/10.1038/s41585-023-00754-x

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