title: Aetiology of hypospadias: a systematic review of genes and environment.
abstract: BACKGROUND
  Hypospadias is a common congenital malformation of the male external genitalia. Most cases have an unknown aetiology, which is probably a mix of monogenic and multifactorial forms, implicating both genes and environmental factors. This review summarizes current knowledge about the aetiology of hypospadias.
  
  
  METHODS
  Pubmed was used to identify studies on hypospadias aetiology published between January 1995 and February 2011. Reference lists of the selected manuscripts were also searched to identify additional studies, including those published before 1995.
  
  
  RESULTS
  The search provided 922 articles and 169 articles were selected for this review. Studies screening groups of patients with hypospadias for single gene defects found mutations in WT1, SF1, BMP4, BMP7, HOXA4, HOXB6, FGF8, FGFR2, AR, HSD3B2, SRD5A2, ATF3, MAMLD1, MID1 and BNC2. However, most investigators are convinced that single mutations do not cause the majority of isolated hypospadias cases. Indeed, associations were found with polymorphisms in FGF8, FGFR2, AR, HSD17B3, SRD5A2, ESR1, ESR2, ATF3, MAMLD1, DGKK, MID1, CYP1A1, GSTM1 and GSTT1. In addition, gene expression studies indentified CTGF, CYR61 and EGF as candidate genes. Environmental factors consistently implicated in hypospadias are low birthweight, maternal hypertension and pre-eclampsia, suggesting that placental insufficiency may play an important role in hypospadias aetiology. Exogenous endocrine-disrupting chemicals have the potential to induce hypospadias but it is unclear whether human exposure is high enough to exert this effect. Other environmental factors have also been associated with hypospadias but, for most, the results are inconsistent.
  
  
  CONCLUSIONS
  Although a number of contributors to the aetiology of hypospadias have been identified, the majority of risk factors remain unknown.
authors.affiliation: Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. l.vanderzanden@ebh.umcn.nl
authors.forename: L F M
authors.initials: LF
authors.lastname: van der Zanden
authors.forename: I A L M
authors.initials: IA
authors.lastname: van Rooij
authors.forename: W F J
authors.initials: WF
authors.lastname: Feitz
authors.forename: B
authors.initials: B
authors.lastname: Franke
authors.forename: N V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: N
authors.initials: N
authors.lastname: Roeleveld
mesh_terms: D005260:Female; D059647:Gene-Environment Interaction; D005801:Genes, Homeobox; D006801:Humans; D007021:Hypospadias / Q000209:etiology* / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic; D011225:Pre-Eclampsia; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology* / Q000235:genetics