To the Editor:
It has been postulated that cryptorchidism, hypospadias, and testicular cancer, as components of the “testicular dysgenesis syndrome,” may have a shared etiology.1 Recent increases in the birth prevalence of cryptorchidism and hypospadias and in the incidence of testicular cancer have been reported.2 Geographic variation is apparent in the birth prevalence of cryptorchidism and hypospadias.3,4 Furthermore, there is limited evidence for space–time clustering among cases of testicular cancer who are age 15 to 19 years.5 Together this evidence provides tentative evidence for the involvement of environmental factors in etiology.6
If environmental exposures (especially infections) are involved in the etiology of cryptorchidism and hypospadias, then the distribution of these births may exhibit space–time clustering. Space–time clustering occurs when excess numbers of cases are observed within small geographic locations for limited periods of time. We have analyzed population-based data to test for the presence of space–time clustering.
The study included all cases diagnosed with cryptorchidism or hypospadias between 1993 and 2000 and who resided in Northern England, identified from Hospital Episode Statistics data. The study area has a predominantly white population of 3.1 million with approximately 37,000 live births per year.
The residential addresses at the first hospital treatment episode (taken as a proxy for birth addresses) were geocoded and used as the basis for the analyses. We applied Knox space–time clustering tests to the data with thresholds fixed as, for close in space, less than 5 km, and for close in time, less than 1 year apart.7 The Knox test regards a pair of cases as being in “close proximity” if they are both born at addresses that are simultaneously close in space and time. The number of case pairs observed (O) and expected (E) to be in close proximity was obtained and the magnitude of the excess estimated by S = [(O − E)/E] × 100. To adjust for the effect of varying population density, tests were repeated replacing fixed geographic distances with nearest neighbor thresholds. This approach also provides a better metric for space–time clustering that might arise from person-to-person transmission rather than from fixed spatial sources.
An underlying problem with the Knox test is the arbitrary choice of thresholds. We used a simplification of a second-order procedure based on K functions to partly overcome this limitation.8 Fixed geographic distance and NN thresholds were both used in the K function analyses.
The study included 1144 boys diagnosed with cryptorchidism and 537 boys diagnosed with hypospadias (14 had both conditions), who were born during 1993–2000, identified from a population-based register that covered the Northern Region of England. Operations were performed for 1056 cases of cryptorchidism and 447 cases of hypospadias. Overall, there was statistically significant space–time clustering for cases of cryptorchidism and hypospadias. Further analysis showed that clustering was restricted to cases of hypospadias with no evidence of clustering for cryptorchidism (Table 1).
If cryptorchidism, hypospadias, and testicular cancer constitute the “testicular dysgenesis syndrome,” then there may be etiologic factors that are common to all 3 conditions.1 The findings from the present study, together with tentative results from a study of space–time clustering of testicular cancer,5 suggest that there may be an environmental component to the etiology of hypospadias and testicular cancer, at least for some cases.
The occurrence of space–time clustering is consistent with an etiologic agent that displays a temporary occurrence at a number of different locations. Infections would be a highly plausible candidate. It is not suggested that the condition itself would arise from person-to-person transmission. Rather, the infection may precipitate the condition in a small number of individuals. The infection may act in combination with other environmental exposures and genetic predisposition.
Richard J. Q. McNally
Nor A. Abdullah
Mark S. Pearce
John R. Wilkinson
Newcastle upon Tyne, U.K.
1.Skakkebaek NE, Raipert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod
2.Xu Q, Pearce MS, Parker L. Incidence and survival for testicular germ cell tumor in young males: a report from the Northern Region Young Persons’ Malignant Disease Registry, United Kingdom. Urol Oncol
3.Joffe M. Are problems with male reproductive health caused by endocrine disruption? Occup Environ Med
4.EUROCAT. An Assessment and Analysis of Surveillance Data on Hypospadias in Europe
. EUROCAT; 2003:1–86 (Anomalies 2003).
5.McNally RJQ, Pearce MS, Parker L. Space–time clustering analyses of testicular cancer amongst 15–24-year-olds in Northern England. Eur J Epidemiol
6.Toppari J, Haavisto AM, Alanen M. Changes in male reproductive health and effects of endocrine disruptors in Scandinavian countries. Cad Saude Publica
7.Knox EG. The detection of space–time interactions. Appl Stat
8.Diggle PJ, Chetwynd AG, Haggkvist R, et al. Second-order analysis of space–time clustering. Stat Methods Med Res