Genetic and Molecular Aspects of Hypospadias

Abstract Hypospadias, a midline fusion defect of the male ventral urethra, is a relatively common genital anomaly occurring in 0.3 - 7 of 1000 live male births. The anatomical location of the misplaced urethral meatus determines the severity of this anomaly with the severity increasing from distal to proximal. Glandular and penile hypospadias, the most common forms, often appear as an isolated anomaly and account for the majority of hypospadias, whereas about 20 % are classified as scrotal and perineal types. These latter forms frequently occur in association with other genital anomalies such as microphallus, bifid scrotum, penoscrotal transposition, and cryptorchidism, and may represent an intersex phenotype. Besides a higher incidence in consanguineous families and a suggested recessive inheritance, in other families a dominant transmission is likely. The recurrence risk in the next generation seems to be correlated with the severity of hypospadias. Only 30 % of severe hypospadias can be attributed to defects in the synthesis of testosterone or adrenal steroid hormones, receptor defects, syndrome-associated hypospadias, chromosomal anomalies, defects in other genetic factors, or exogenous forms. To identify the underlying causes of the remaining 70 % “idiopathic” hypospadias, familial and twin studies were performed. Familial studies can help identify gene loci and, subsequently, candidate genes by mutational analysis. Either linkage analysis in large families with many affected individuals suspicious for a monogenic trait or association studies in cases of a complex inheritance in many families with a few affected individuals can be performed. Microarrays and proteomics can help detect gene expression or protein differences. Furthermore, genetically modified animal models can be used to detect phylogenetically homologous genes in man. In addition to an optimal documentation and acquisition of blood and tissue samples this requires a close cooperation between clinicians in the operative and non-operative specialities as well as geneticists.