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Alberto Ferlin, PhD; Daniela Zuccarello, MD; Biagio Zuccarello, MD; Maria Rosaria Chirico, MD; Giovanni Franco Zanon, MD; Carlo Foresta, MD

JAMA. 2008;300(19):2271-2276.

Context  Cryptorchidism is the most frequent congenital birth defect in male children and represents an important risk factor for infertility and testicular cancer. Major regulators of testicular descent are the hormones insulin-like factor 3 (INSL3) and testosterone, and disruption of these pathways might cause cryptorchidism.

Objective  To determine the frequency of genetic alterations in cryptorchidism.

Design and Setting  Case-control study in 2 departments of pediatric surgery in Italy between January 2003 and March 2005.

Patients  Six hundred male infants with cryptorchidism. Boys were followed up for 2 to 3 years (through January 2008) and orchidopexy was performed in those who were persistently cryptorchid. We analyzed 300 noncryptorchid male children aged 1 to 4 years as controls.

Main Outcome Measures  Karyotype anomalies and INSL3, INSL3 receptor, and androgen receptor gene mutations.

Results  The frequency of genetic alterations in boys with cryptorchidism was low (17/600 [2.8%; 95% confidence interval {CI}, 1.7%-4.5%]) and was significantly higher in participants with persistent cryptorchidism (16/303 [5.3%; 95% CI, 3.0%-8.4%]; P = .001) and those with bilateral cryptorchidism (10/120 [8.3%; 95% CI, 4.1%-14.8%]; P = .001) than in controls (1/300 [0.3%; 95% CI, 0.1%-0.8%]). Boys with persistent cryptorchidism had a 17-fold greater odds of having a genetic alteration (odds ratio, 16.7; 95% CI, 2.2-126.5). The most common genetic findings in those with cryptorchidism were 8 cases of Klinefelter syndrome and 5 cases of mutations in the INSL3 receptor gene. Genetic alterations were not found in boys with low birth weight or low gestational age, who had frequent spontaneous descent of the testes.

Conclusion  In a small percentage of the study population, there was a statistically significant association between bilateral and persistent cryptorchidism and genetic alterations, including Klinefelter syndrome and INSL3 receptor gene mutations.

Author Affiliations: Section of Clinical Pathology and Centre for Male Gamete Cryopreservation, Department of Histology, Microbiology, and Medical Biotechnologies (Drs Ferlin, D. Zuccarello, and Foresta), and Department of Pediatric Surgery (Dr Zanon), University of Padova, Padova, Italy; and Unit of Pediatric Surgery, Department of Medical and Surgical Pediatric Sciences, University of Messina, Messina, Italy (Drs B. Zuccarello and Chirico).