The genetic factors contributing to hypospadias and their clinical utility in its diagnosis

J Cell Physiol. 2019 May;234(5):5519-5523. doi: 10.1002/jcp.27350. Epub 2018 Sep 21.


Hypospadias is among the most common congenital malformations in male neonates. It results from abnormal penile and urethral development, but is a multifactorial disorder that is highly heterogeneous, with several genetic and environmental determinants. Monogenic and chromosomal abnormalities are present in approximately 30% of cases, although the genetic factors contributing to hypospadias remain unknown in 70% of cases. While defects in androgen synthesis can lead to this malformation, mutational analyses have shown several genes, such as sonic hedgehog, fibroblast growth factors, bone morphogenetic proteins, homeobox genes, and the Wnt family, are involved in the normal development of male external genitalia. Mutations in the genes of penile development (e.g., HOX, FGF, Shh) and testicular determination (e.g., WT1, SRY), luteinizing hormone receptor, and androgen receptor have also been proposed to be implicated in hypospadias. Here we review the recent advances in this field and discuss the potential genes that could determine the risk of hypospadias.

Keywords: environmental factors; genetics; hypospadias; polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • DNA Mutational Analysis
  • Genetic Markers*
  • Genetic Predisposition to Disease
  • Genetic Testing*
  • Humans
  • Hypospadias / diagnosis*
  • Hypospadias / genetics*
  • Hypospadias / physiopathology
  • Male
  • Molecular Diagnostic Techniques
  • Mutation*
  • Phenotype
  • Predictive Value of Tests
  • Risk Factors


  • Genetic Markers