Cryptorchidism May be Associated with Genetic Mutations

Cryptorchidism, a common congenital defect of the male genitalia that affects 3-4% of full-term infants and 30% of those born prematurely, poses a risk for infertility and testicular cancer. However, the exact etiology and pathogenesis of cryptorchidism are not clearly known. Now, a recent study published in the Journal of the American Medical Association has identified a potential link between cryptorchidism and genetic alterations such as insulin-like factor 3 (INSL3) receptor gene mutations and Klinefelter syndrome.
Alberto Ferlin from the Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, Italy, and coworkers, conducted the case-control study on 600 male infants in Italy during 2003 to 2005, to investigate the rate of genetic alterations in cryptorchidism. Three hundred noncryptorchid boys between 1 to 4 years were selected as controls. Follow-up of the subjects was done for 2 to 3 years and those with persistent cryptorchidism were treated with orchidopexy.
Study results showed that mutations ranged from low in boys with cryptorchidism (2.8%), to high in those with persistent cryptorchidism (5.3%) and bilateral cryptorchidism (8.3%), compared to controls (0.3%). The calculated odds for having genetic alteration in boys with persistent cryptorchidism were more than 17 times; however, there was lack of mutations in boys with low gestational age or low birth weight and those who had spontaneous descent of the testes. The researchers found that Klinefelter syndrome and INSL3 receptor gene mutations were most frequently associated with cryptorchidism, suggesting a significant relationship between the disease and genetic alterations.
Early studies have indicated that INSL3 plays a key role in testicular descent, with mutations in the gene or its G protein-coupled receptor (leucine-rich repeat, containing G protein-coupled receptor (LGR8)) likely to be associated with cryptorchidism.
Ferlin, et al. (Molecular Human Reproduction, 2006) conducted a study to investigate the hypothesis pertaining to the relationship between INSL3 mutations and the signs of testicular dysgenesis syndrome (TDS), characterized by undescended testis, poor semen quality, testis cancer, and hypospadias. The analysis was performed on 967 subjects with maldescended testes and/or infertility and/or testicular cancer and 450 controls. The researchers also conducted in vitro functional analysis of genetic alterations (R4H, W69R, and R72K) by observing the increase of INSL3-dependent cAMP (cyclic adenosine monophosphate) in cells that express LGR8. It was found that 1.9% of the subjects had 6 INSL3 mutations, with no similar finding in the controls. Based on the findings, it was suggested that a significant link may exist between INSL3 gene alterations and TDS syndrome signs; although, a definite causative role was not established.
Although cryptorchidism or undescended testicle may occur bilaterally, it commonly affects the right testes. A combination of factors such as maternal health, genetics, and environment may play an important role in its development, but the exact cause is unknown. Generally, the condition resolves by itself but sometimes may require orchidopexy to relocate the testis into the scrotum.
Substantiating the current research, which identifies the association between undescended testicles and genetic mutations in INSL3 receptor gene and Klinefelter syndrome, with further larger studies, may help to elucidate the underlying disease mechanism. Further, this may facilitate in developing novel therapeutic strategies for patients with persistent and bilateral cryptorchidism, thereby reducing the burden associated with male infertility.
References
1. Ferlin A, Zuccarello D, Zuccarello B, Chirico MR, Zanon GF, Foresta C. Genetic alterations associated with cryptorchidism. JAMA. 2008 Nov 19;300(19):2271-6.
2. Ferlin A, Bogatcheva NV, Gianesello L, et al. Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization. Mol Hum Reprod. 2006 Jun;12(6):401-6. Epub 2006 May 10.