Minor hypospadias: the "tip of the iceberg" of the partial androgen insensitivity syndrome

PLoS One. 2013 Apr 30;8(4):e61824. doi: 10.1371/journal.pone.0061824. Print 2013.


Background: Androgens are critical in male external genital development. Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome (AIS).

Objective: The aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR.

Materials and methods: Two hundred and ninety-two Caucasian children presenting with isolated hypospadias without micropenis or cryptorchidism and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1-8) was performed. In silico and luciferase functional assays were performed for unreported variants.

Results: Five missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n = 5), penile midshaft (n = 2) and penile posterior (n = 2) hypospadias, i.e., 3%: p.Q58L (c.173A>T), 4 cases of p.P392S (c.1174C>T), 2 cases of p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G). None of these mutations was present in the control group. One mutation has never been reported to date (p.D551H). It was predicted to be damaging based on 6 in silico models, and in vitro functional studies confirmed the lowered transactivation function of the mutated protein. Three mutations have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patient.

Conclusion: AR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration may be important for proper diagnosis and longer follow-up is necessary to find out if the mutations cause differences in sexual function and fertility later in life.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Androgen-Insensitivity Syndrome / complications
  • Androgen-Insensitivity Syndrome / genetics*
  • Animals
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • HeLa Cells
  • Humans
  • Hypospadias / complications
  • Hypospadias / genetics*
  • Infant
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Mutation
  • Mutation, Missense
  • Penis / metabolism
  • Penis / pathology
  • Prospective Studies
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / genetics*
  • Sequence Alignment


  • Receptors, Androgen

Grants and funding

This study was funded by a Programme Hospitalier de Recherche Clinique Inter-Régional (PHRC number UF 8270) provided by the CHU de Montpellier and by a grant from the Fondation pour la Recherche Médicale FRM110309. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.