Cryptorchidism Linked to Specific Genetic Mutations

Laurie Barclay, MD

November 18, 2008

November 18, 2008 — Persistent cryptorchidism and bilateral cryptorchidism are statistically significantly associated with genetic mutations, according to the results of a study reported in the November 19 issue of JAMA.

"Cryptorchidism is the most frequent congenital birth defect in male children and represents an important risk factor for infertility and testicular cancer," write Alberto Ferlin, PhD, from the University of Padova in Italy, and colleagues. "Major regulators of testicular descent are the hormones insulin-like factor 3 (INSL3) and testosterone, and disruption of these pathways might cause cryptorchidism."

The goal of this study was to assess the frequency of genetic alterations, specifically karyotype anomalies and INSL3, INSL3 receptor, and androgen receptor gene mutations associated with cryptorchidism. Between January 2003 and March 2005, 600 male infants with cryptorchidism in 2 departments of pediatric surgery in Italy were evaluated and followed up for 2 to 3 years, through January 2008. Boys who were persistently cryptorchid underwent orchidopexy. The investigators analyzed 300 male children aged 1 to 4 years without cryptorchidism as control patients.

Boys with cryptorchidism had a low frequency of genetic alterations (17 [2.8%] of 600; 95% confidence interval [CI], 1.7% – 4.5%). However, boys with persistent cryptorchidism had a higher frequency of genetic alterations (16 [5.3%] of 303; 95% CI, 3.0% – 8.4%; P = .001), as did those with bilateral cryptorchidism (10 [8.3%] of 120; 95% CI, 4.1% – 14.8%; P = .001), compared with control patients (1 [0.3%] of 300; 95% CI, 0.1% – 0.8%).

Odds of having a genetic alteration were 17-fold greater in boys with persistent cryptorchidism (odds ratio, 16.7; 95% CI, 2.2 – 126.5) and 27-fold times greater in boys with bilateral persistent cryptorchidism.

In boys with cryptorchidism, the most common genetic findings were 8 cases of Klinefelter syndrome and 5 cases of mutations in the INSL3 receptor gene, which regulates testicular descent. Genetic alterations were not observed in boys with low birth weight or low gestational age, who frequently had spontaneous testicular descent.

Limitations of this study include those inherent in a case-control study and the small number of genetic abnormalities found.

"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," the study authors write.

The Italian Ministry of University supported this study. The authors have disclosed no relevant financial relationships.

JAMA. 2008;300(19):2271–2276.


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