The genetics of cryptorchidism

Cryptorchidism is one of the most frequent congenital abnormalities, with a recorded frequency of 3-4% among newborn males. Before sex determination, both female and male embryonic gonads are located in the same high intra-abdominal position. The developing testes migrate through a multiphase process of testicular descent (TD), first into a low abdominal position and then into the developing scrotum. A critical role in TD belongs to the gubernacular ligaments. Analysis of mouse mutants revealed a number of genes involved in this process. Insulin-like factor 3 (Insl3) controls the first abdominal phase of TD through its receptor, leucine-rich-containing repeats G protein-coupled receptor (Lgr8). The inguinoscrotal stage of TD is believed to be controlled by the hypothalamic-pituitary-gonadal axis, and specifically by androgens. Additionally, the targeted ablation of several transcription factors, such as Hoxa10, Hoxa11, and Desrt, causes cryptorchidism in mice, suggesting an involvement of multiple signaling pathways in TD. In this chapter, we review the mutation analysis and allele association studies for the candidate genes in human patients with cryptorchidism.