• PMID: 23637914
• Gene Name: AR
• Condition: Hypospadias without micropenis, cryptorchidism
• Association: 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
• Mutation: p.Q58L (c.173A>T), p.P392S (c.1174C>T), p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G)
• Population size: 637
• Population details: 637 (292 children presenting with isolated hypospadias without micropenis or cryptorchidism, 345 controls)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Hypospadias without micropenis, cryptorchidism

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

Kalfa N, Philibert P, Werner R, Audran F, Bashamboo A, Lehors H, Haddad M, Guys JM, Reynaud R, Alessandrini P, Wagner K, Kurzenne JY, Bastiani F, Bréaud J, Valla JS, Lacombe GM, Orsini M, Daures JP, Hiort O, Paris F, McElreavey K, Sultan C.

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. FAU - Kalfa, Nicolas AU - Kalfa N AD - Service de Chirurgie Viscérale et Urologique Pédiatrique, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France. FAU - Philibert, Pascal AU - Philibert P FAU - Werner, Ralf AU - Werner R FAU - Audran, Françoise AU - Audran F FAU - Bashamboo, Anu AU - Bashamboo A FAU - Lehors, Hélène AU - Lehors H FAU - Haddad, Myriam AU - Haddad M FAU - Guys, Jean Michel AU - Guys JM FAU - Reynaud, Rachel AU - Reynaud R FAU - Alessandrini, Pierre AU - Alessandrini P FAU - Wagner, Kathy AU - Wagner K FAU - Kurzenne, Jean Yves AU - Kurzenne JY FAU - Bastiani, Florence AU - Bastiani F FAU - Bréaud, Jean AU - Bréaud J FAU - Valla, Jean Stéphane AU - Valla JS FAU - Lacombe, Gérard Morisson AU - Lacombe GM FAU - Orsini, Mattea AU - Orsini M FAU - Daures, Jean-Pierre AU - Daures JP FAU - Hiort, Olaf AU - Hiort O FAU - Paris, Françoise AU - Paris F FAU - McElreavey, Kenneth AU - McElreavey K