title: Minor hypospadias: the "tip of the iceberg" of the partial androgen insensitivity syndrome.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Service de Chirurgie Viscérale et Urologique Pédiatrique, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France.
authors: Nicolas
authors: N
authors: Kalfa
authors: Pascal
authors: P
authors: Philibert
authors: Ralf
authors: R
authors: Werner
authors: Françoise
authors: F
authors: Audran
authors: Anu
authors: A
authors: Bashamboo
authors: Hélène
authors: H
authors: Lehors
authors: Myriam
authors: M
authors: Haddad
authors: Jean Michel
authors: JM
authors: Guys
authors: Rachel
authors: R
authors: Reynaud
authors: Pierre
authors: P
authors: Alessandrini
authors: Kathy
authors: K
authors: Wagner
authors: Jean Yves
authors: JY
authors: Kurzenne
authors: Florence
authors: F
authors: Bastiani
authors: Jean
authors: J
authors: Bréaud
authors: Jean Stéphane
authors: JS
authors: Valla
authors: Gérard Morisson
authors: GM
authors: Lacombe
authors: Mattea
authors: M
authors: Orsini
authors: Jean-Pierre
authors: JP
authors: Daures
authors: Olaf
authors: O
authors: Hiort
authors: Françoise
authors: F
authors: Paris
authors: Kenneth
authors: K
authors: McElreavey
authors: Charles
authors: C
authors: Sultan
mesh_terms: D000595:Amino Acid Sequence; D013734:Androgen-Insensitivity Syndrome / Q000150:complications / Q000235:genetics*; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D006367:HeLa Cells; D006801:Humans; D007021:Hypospadias / Q000150:complications / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010413:Penis / Q000378:metabolism / Q000473:pathology; D011446:Prospective Studies; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D011944:Receptors, Androgen
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