Genetic pathway of external genitalia formation and molecular etiology of hypospadias

Hypospadias is one of the most common congenital disorders in males. Impaired fetal androgen action interferes with masculinization, including external genitalia formation, and can result in this anomaly; however, the molecular etiology remains unknown. Recent molecular approaches, including gene-targeting approaches in mice and single nucleotide polymorphisms analyses in humans, might provide an opportunity to identify the causative and risk factors of this anomaly. Several genes, such as sonic hedgehog, fibroblast growth factors, bone morphogenetic proteins, homeobox genes, and the Wnt family regulate external genitalia formation. Mastermind-like domain containing 1/chromosome X open reading frame 6 mutation and activating transcription factor 3 variants have been shown to be associated with the incidence of isolated hypospadias. In addition, this anomaly may be associated with a specific haplotype of the gene for estrogen receptor alpha, which mediates the estrogenic effects of environmental endocrine disruptors, and the effects of these disruptors on external genitalia formation might depend on individual genetic susceptibility. These molecular studies will refine our knowledge of the genetic mechanism involved in external genitalia formation, and lead to new strategies for the clinical management of hypospadias.