Abstract

BackgroundAndrogens 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).ObjectiveThe 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 MethodsTwo 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.ResultsFive 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.

Highlights

  • Hypospadias is defined as a malformation of the penis due to an incomplete development of the ventral part of the penis

  • androgen receptor gene (AR) mutations may play a role in the cause of isolated hypospadias, even in the most minor forms

  • The recommendations for the appropriate use of genetic testing in male children with genital malformation state that AR mutation analysis, along with karyotyping and hormonal work-up, should be performed in children with (1) a phenotype of uncertain sex at birth, (2) severe hypospadias, and (3) hypospadias associated with another sign of DSD that could be a manifestation of partial androgen insensitivity syndrome, such as micropenis or cryptorchidism [19]

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Summary

Introduction

Hypospadias is defined as a malformation of the penis due to an incomplete development of the ventral part of the penis. This may include (1) a defect in the developing urethra leading to the localization of the urinary meatus on the ventral aspect of the penis in a variable position from the glans to the perineum [1], (2) a defect in the ventral part of the prepuce, and (3) an inconstant ventral penile curvature mainly related to a defect in the ventral skin or, more rarely, the development of the corpus cavernosum. In addition to the surgical challenge of correcting this malformation and reducing the non-negligible risk of complications, the clinical challenge today is to elucidate the pathophysiology. 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)

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