Citation[N1] The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute (NCI).

[N2] Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Skakkebæk, NE, E Rajpert-De Meyts and KM Main. 2001. Human Reproduction 2009; 16(5): 972-978.

CitationFamilial Coaggregation of Cryptorchidism, Hypospadias, and Testicular Germ Cell Cancer: A Nationwide Cohort Study . Tine H. Schnack, Gry Poulsen, Charlotte Myrup, Jan Wohlfahrt, and Mads Melbye. The Journal of the National Cancer Institute 2009; ePub ahead of print. doi:10.1093/jnci/djp457

Abstract

Background. Cryptorchidism, hypospadias, and testicular germ cell cancer (TGCC) may be symptoms of a testicular dysgenesis syndrome that manifests during fetal life. To address the inheritability of this syndrome, we examined whether family history of cryptorchidism or hypospadias is associated with an increased risk of TGCC.

Methods. A total of 2 159 883 men born since 1953, identified through Danish health registers, were followed from April 2, 1968, through May 31, 2008. First-, second-, and third-degree relatives were identified in the Danish Family Relations Database; cryptorchidism and hypospadias patients were identified in the Danish Hospital Discharge Register; and TGCC patients were identified in the Danish Cancer Register. Poisson regression was used to calculate the risk ratio for TGCC by family history of cryptorchidism or hypospadias.

Results. A total of 5441 patients developed TGCC. A personal history of cryptorchidism or hypospadias was associated with an increased relative risk (RR) of developing TGCC (RR = 3.71, 95% confidence interval [CI] = 3.29 to 4.19; and RR = 2.13, 95% CI = 1.26 to 3.61, respectively). For example, in men in their thirties, the overall rate per 100 000 is 25.1 in the cohort, but 88.6 and 55.4 in men born with cryptorchidism or hypospadias, respectively. In contrast, relatives of a hypospadias patient did not have a statistically significantly increased risk of TGCC nor did the first- and second-degree relatives of cryptorchidism patients. However, we found a small increased risk of TGCC for third-degree relatives of patients with cryptorchidism.

Conclusions. Having hypospadias or cryptorchidism was associated with an increased risk of developing TGCC. However, our finding that family history of hypospadias or cryptorchidism generally was not associated with increased risk of developing TGCC does not support the hypothesis of shared inheritability of cryptorchidism, hypospadias, and TGCC.

Keywords: environmental disrupters, infertility, male reproduction, testicular cancer, testicular development.

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Contexts and Caveats

Prior knowledge. Although a personal history of cryptorchidism or hypospadias is associated with a risk of developing testicular germ cell cancer (TGCC), it is not known whether all three are part of an inheritable dysgenesis syndrome.

Study design. A cohort of all men living in Denmark between 1968 and 2008 was matched with health information from Danish health and hospital registries to identify boys who were born with cryptorchidism or hypospadias. Relatives of these patients were then identified through the Danish Family Relations Database to assess the risk of TGCC in relatives of cryptorchidism or hypospadias patients.

Contribution. These results confirm that boys with hypospadias are at risk of developing TGCC, but their first-, second-, and third-degree relatives are not. The first- and second-degree relatives of boys with cryptorchidism are also not at risk of developing TGCC.

Implications. Large linked databases such as those in Denmark are useful for assessment of population-level genetics of disease. Access to a national cohort allowed this study to rule out a strong familial predisposition to developing TGCC when some family members are born with hypospadias or cryptorchidism.

Limitations. Misclassification of legal and biological fathers because of privacy could lead to bias in coding of relatives. Diagnoses of cryptorchidism and hypospadias were not recorded for births until 1977, and only later diagnoses made during adolescence could be used. The very small risk of developing TGCC by third-degree relatives of cryptorchidism patients is not biologically realistic, given that it is not found in closer relatives and thus may be because of chance.