ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 12 S22

Molecular and phenotypic features of disorders of sex development (DSD) in humans

JC Achermann


UCL Institute of Child Health, London, United Kingdom.


It is now 15 years since the discovery of Sry as the primary “testis-determining gene” and Koopman et al.’s classic experiment showing that transgenic expression of Sry in XX mice results in testis development and a male phenotype. Although studies in mice are continuing to provide exciting information about the biology of sex development, significant progress is also being made in our understanding of the molecular mechanisms of gonad development in humans. The identification and characterization of patients with disorders of sex development (DSD) is helping to elucidate some of these basic biological processes.

Disorders of sex development are typically divided into:

  1. disorders of chromosomes (chromosomal DSD)
  2. disorders of gonad development (gonadal DSD, sex determination)
  3. disorders of sex steroid synthesis and action (phenotypic/anatomic DSD, sex differentiation)

I will first provide a brief overview of sex chromosomes and gonad development, focussing on Klinefelter syndrome (47,XXY and variants), mixed gonadal dysgenesis (45,X/46,XY) and ovotesticular DSD (true hermaphroditism). I will then review conditions associated with gonadal (testicular) dysgenesis in humans (e.g. WT1, SF1, SRY, SOX9, DHH, DMRT, SIDDT, ARX). Finally, I will review phenotypes associated with disorders of steroid synthesis and action, with a particular focus on conditions that can result in 46,XY underandrogenization together with abnormalities of adrenal steroid synthesis (e.g. STAR, CYP11A, HSD3B2, CYP17). Significant progress has been made in our understanding of the role of these factors in human disease, but phenotypic variability can occur, and considerably more research is now needed to translate this new knowledge into effective patient care. Developing a classification system based wherever possible on precise genetic information will be a useful starting point in enabling us to structure long-term outcome studies appropriately.

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