The role of sonic hedgehog homologue signal pathway in hypospadias aetiology.

Summary Introduction Hypospadias is one of the most common congenital anomalies of the male genitalia. Sonic hedgehog homologue (SHH) signalling pathway is believed to be involved in the development of the male genital system. Objective In this clinical prospective study, the role of the SHH pathway in hypospadias aetiology was investigated. Study design In this study, 200 healthy children (boys without hypospadias, control group), 118 patients (boys with distal hypospadias) and 82 patients (boys with proximal hypospadias) of age 0–16 years were included. The expression of the genes suppressor of fused protein (SUFU), SHH, protein patched homologue (PTCH; PTCH1 and PTCH2), glioma-associated oncogene homologue (GLI; GLI1, GLI2, GLI3 and GLI4), smoothened, frizzled-class receptor (SMO) and serine/threonine-protein kinase 36 (STK36) that are involved in SHH pathway were investigated. Furthermore, polymorphism analyses of GLI2, SHH and PTCH1 genes were performed. The history of hypospadias in the first and second-degree relatives of the patients in boys with distal hypospadias and boys with proximal hypospadias was inquired. Results Ten patients in the boys with distal hypospadias and twenty patients in the boys with proximal hypospadias had a history of hypospadias in first or second-degree relatives (p   0.05). Discussion SHH expression is required for the growth and differentiation of the genital bulge. Developmental defects in the external genital organs were demonstrated in mice with SHH deletion. It has been demonstrated that SHH mainly plays a role in the formation of sinusoid morphology of the penis. In the present study, although SHH and PTCH gene expressions were found to be decreased only in the penile tissues of proximal hypospadias, GLI2 gene expression was decreased in penile tissues of boys with both distal hypospadias and boys with proximal hypospadias. Conclusion Genes involved in the SHH pathway might play a role in the aetiology of hypospadias. Furthermore, there is a correlation between molecular defects in this pathway and severity of hypospadias. Summary Table . Fold-changes in mRNA expression in genes examined in penile tissue among cases with distal hypospadias and with proximal hypospadias. No Cases with distal hypospadias Cases with proximal hypospadias Gene name mRNA fold-change p-value∗∗∗ mRNA fold-change p-value 1 SUFU 1035 0.898 1028 0.922 2 SHH 1087 0.753 0451 0.044∗ 3 PTCH1 1087 0.754 0441 0.041∗ 4 PTCH2 1035 0.899 1035 0.901 5 GLI1 1157 0.586 1133 0.639 6 GLI2 0,330 0021∗ 0,302 0018∗ 7 GLI3 1181 0.537 1117 0.676 8 GLI4 0.818 0457 0.877 0609 9 SMO 0.920 0746 0.986 0948 10 STK36 1214 0.475 1275 0.378 p calculated as One way anowa test. ∗p