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Malformation syndromes associated with disorders of sex development

Key Points

  • Nongenital malformation syndromes in patients with disorders of sex development (DSDs) can be classified into two subtypes

  • In the first subtype, patients have abnormalities of hormonal function; in the second subtype, they have normal sex hormones but have a primary morphological defect of genital development

  • So-called nonhormonal morphological syndromes can be recognised by the presence of abnormal anatomy beyond a narrow range of external genital structures on a spectrum between normal male anatomy through to normal female anatomy

  • The genetic causes of many hormonal DSDs with malformation syndromes are now often known

  • Many nonhormonal DSDs with morphological changes do not have known genetic causes, but expected advances in the field are likely to change this situation in the future

Abstract

When embryological development of the internal and/or external genitalia is disrupted, the patient presents with a disorder of sex development (DSD) in the neonatal period or sometime later in life. Some of these patients have other, nongenital malformations, which makes their overall management more complex than if they just had a DSD. This Review summarises these malformation syndromes and discusses the recent research into their aetiology. The genetic causes of these malformation syndromes, when they are known, will also be described. Many specific genetic mutations are now known in malformation syndromes with a defect in hormonal function. By contrast, the genetic causes remain unknown in many nonhormonal morphological anomalies that affect the genitalia.

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Figure 1: Sex determination and sexual differentiation of the internal genital ducts is under the control of testosterone and AMH, as well as estrogen in the later gestation of female fetuses.
Figure 2: Sexual differentiation of the external genitalia, which is regulated by androgens via conversion of testosterone to dihydrotestosterone by aromatase in the peripheral tissues.
Figure 3: Features of Denys–Drash syndrome.
Figure 4: The three clinical presentations of persistent Müllerian duct syndrome.

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J.M.H. and S.D.P. contributed to all aspects of the manuscript. S.R.G. and M.O'C. contributed to discussion of the content, wrote the article and reviewed/edited the manuscript before submission.

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Correspondence to John M. Hutson.

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Hutson, J., Grover, S., O'Connell, M. et al. Malformation syndromes associated with disorders of sex development. Nat Rev Endocrinol 10, 476–487 (2014). https://doi.org/10.1038/nrendo.2014.83

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