Cryptorchidism and hypospadias are the most common congenital malformations among boys.1–3 Despite extensive research, their etiology remains largely unknown. Both malformations have been associated with common prenatal and gestational factors such as low birth weight, intrauterine growth retardation, low parity and low maternal age, as well as urogenital disorders such as germ cell testicular cancer and infertility.4–15 Furthermore, both entities tend to aggregate within families. In a previous study, we found that the recurrence risk ratios in male twin pairs and in first-, second-, and third-degree relatives of a hypospadias case were 51 (95% confidence interval [CI] = 34–76), 12 (9.8–14), 3.3 (2.5–4.3), and 1.3 (0.94–1.9), respectively.16 The recurrence risk ratios in male twin pairs and first- (brothers), second- (half brothers), and third-degree (first cousins) relatives of a cryptorchidism case were 10 (7.8–13), 3.5 (3.3–3.8), 1.7 (1.4–1.9), and 1.3 (1.2–1.3), respectively.17 Thus, either of these disorders increases the risk of the other on an individual level.15
It has been suggested that these disorders are symptoms of a testicular dysgenesis, which may be caused by a common pathologic pathway during fetal life.18–20
An underlying pathogenetic mechanism might well be heritable. Should this be the case, it would be expected that having a family history of either of the disorders would result in an excess risk of any of the disorders.
The aim of this large, nationwide study was to address the heritability of a common underlying testicular dysgenesis that causes cryptorchidism and hypospadias by examining the extent to which a family history of cryptorchidism increases the risk of hypospadias (and vice versa) in male twin pairs, and in first-, second-, and third-degree relatives.
We assessed the risk of cryptorchidism in persons with a family history of hypospadias and the risk of hypospadias in persons with a family history of cryptorchidism in Denmark, using a cohort consisting of all boys born between 1 January 1977 and 31 May 2005. The boys in the cohort were identified in the Civil Registration System.21 This System has existed since 2 April 1968, and since then all residents living in Denmark have been assigned a unique personal identification number (PIN). Information from various sources, including Danish population-based health registers, can be linked via the PIN. Furthermore, information on date and place of birth, sex and continuously updated information on date of death and emigration are registered.
Identification of Relatives
Relatives were identified from the Danish Family Relations Database updated to 31 May 2005. The database is based on the parental links as registered in the Civil Registration System. Parents were identified by shared address for persons living at home at the establishment of the Registration System in 1968. Persons not living with their parents in 1968 generally have no parental link. All people born in Denmark in 1968 or later has parental links reflecting the legal parents. Consequently, the identities of the father and thereby of half/full brothers and same-sex twins were known for all Danish-born boys in the cohort. By using the parents' parental link, one can identify grandfathers and thereby cousins and uncles/nephews. However, due to the above-described construction of parental links, only boys born in 1990 or later in Denmark had an almost-complete registration of grandparents, whereas for boys born between 1968 and 1989, 53% had at least one known grandparent. It should be emphasized that, although the cohort was restricted to boys born from 1977 to 2005, there was no restriction on the birth cohorts of the relatives besides the one imposed by the way in which the parental links were constructed in the Civil Registration System.
Identification of Cryptorchidism and Hypospadias Cases
Information on cryptorchidism and hypospadias status, other congenital malformations, chromosomal abnormalities, and surgeries in the cohort and among relatives was obtained from the Danish Hospital Discharge Register. This register contains nationwide registration of all hospital discharge diagnoses and operations performed from 1977 to 2008, as well as outpatient diagnoses since 1995.22 Hypospadias status was defined as children with a diagnosis for hypospadias registered in the Danish Hospital Discharge Register. Cryptorchidism status was defined as children who had a diagnosis for cryptorchidism registered in the Danish Hospital Discharge Register after 6 months of age. Further classification according to severity, laterality, or congenital cryptorchidism versus ascending testis was not available.
Data on cryptorchidism/hypospadias were not recorded for hospitalizations before 1977. However, many cases who were born before 1977 but hospitalized in 1977 or later, have been recorded in the register at the time of treatment, which occurs in adolescence or later in a large proportion of cases. We used information on cryptorchidism/hypospadias status in persons born prior to 1977 only to identify affected relatives. Thus, only relatives with a registration from 1977 or later were regarded as affected. As these disorders are congenital malformations, the date of diagnosis was set to the date of birth. Information on hypospadias and cryptorchidism in children born later than 31 May 2005 was not used in this study as these children are not yet included in the Danish Family Relations Database.
Familial coaggregation of cryptorchidism and hypospadias in twins and in first-, second-, and third-degree relatives was evaluated as the ratio between the risk of cryptorchidism/hypospadias for boys with an affected relative (a relative with a diagnosis of hypospadias/cryptorchidism) and the risk in boys with known (ie, registered in the Danish Family Relations Database) relatives of the same type, of whom none was affected. Thus, for example, the risk ratio (RR) in brothers was estimated as the risk for brothers with an affected brother compared with the risk for brothers with known and only unaffected brothers. First-degree relatives were defined as sons or brothers; second-degree relatives as grandsons, half-brothers or nephews/uncles; and third-degree relatives as first cousins. The association between cryptorchidism and hypospadias on the individual level was evaluated by the RR of cryptorchidism according to a personal status of hypospadias and vice versa.
The RRs were estimated by binomial log-linear regression with adjustment for birth period (5-year categories). In additional analyses of the RR of hypospadias in those with a family history of cryptorchidism, adjustment was made for personal status of cryptorchidism (yes/no) in the person at risk, and vice versa for the analyses of RR of cryptorchidism given a family history of hypospadias. Defining exposure on the basis of outcomes from other individuals in the cohort does not induce correlation between outcomes in this model.
Of the 41,887 identified cases of cryptorchidism registered in the Danish Hospital Discharge Register during 1977–2008, 25,655 (61%) had surgical confirmation and 1767 (4%) cases had other congenital malformations registered. Of 6393 identified cases of hypospadias registered in the same period, 2945 (46%) had surgical confirmation and 785 (12%) had other congenital malformations registered.
Of the 1,018,517 males in the study cohort, 4832 were diagnosed with hypospadias, 27,762 had a diagnosis of cryptorchidism, and 327 had a diagnosis of both hypospadias and cryptorchidism. Of all cryptorchidism cases in the study cohort, 414 had at least one relative with a diagnosis of hypospadias; of all hypospadias cases in the study cohort, 500 had at least one relative with a diagnosis of cryptorchidism. The distribution of cases according to type of relative affected with cryptorchidism/hypospadias is presented in the Table.
Persons diagnosed with hypospadias had an increased RR of cryptorchidism and vice versa. The RR for hypospadias in boys born with cryptorchidism was 3.0 (95% CI = 2.7–3.3) and the RR for cryptorchidism in boys born with hypospadias was 2.9 (2.6–3.2).
First-, second-, and third-degree relatives of a cryptorchidism case did not have an increased risk of hypospadias, and first-, second-, and third-degree relatives of a hypospadias case did not have an increased risk of developing cryptorchidism (Table). Same-sex twins of a hypospadias case had a RR of 1.8 (0.86–3.7) of cryptorchidism and same-sex twins of a cryptorchidism case had a RR of 2.0 (0.96–4.3) of developing hypospadias, compared with twin brothers who did not have a cotwin with hypospadias or cryptorchidism. However, when these estimates were adjusted for personal status of hypospadias or cryptorchidism, respectively, in the individual at risk, the RRs decreased to 1.2 (0.59–2.5) and 1.5 (0.70–3.1), respectively.
We performed several additional analyses to assess the robustness of the results. First, we used 2 alternative case definitions: (1) only cases of hypospadias/cryptorchidism with no other congenital malformations or chromosomal abnormalities and (2) only cases in the cohort who had confirmatory surgery for hypospadias/cryptorchidism (according to the registers) in addition to the hypospadias/cryptorchidism diagnosis. The results did not change markedly in these analyses. Furthermore, stratified analyses composing the 2 components of the cohort born before and after 1985 differed very little (data not shown).
Finally, the risk of hypospadias given a family history of cryptorchidism was also estimated in a cohort restricted to those who did not have a personal history of cryptorchidism and/or a family history of hypospadias. Similar but opposite restrictions were made for the analyses of cryptorchidism given a family history of hypospadias. In first-, second-, and third-degree relatives the risk of hypospadias was 1.0 (0.82–1.2), 0.91 (0.76–1.1), and 1.0 (0.87–1.8), and the risk of cryptorchidism was 0.92 (0.72–1.2), 0.85 (0.68–1.1), and 1.0 (0.88–1.2), respectively.
In this nationwide cohort study, we investigated the risk of hypospadias in boys with a family history of cryptorchidism and vice versa. Our findings show an association between hypospadias and cryptorchidism on an individual level. However, there was little evidence that having a twin brother or a first-, second-, or third-degree relative with a history of cryptorchidism was associated with a higher risk of having hypospadias and vice versa.
In an initial analysis among twins, there appeared to be such an association. However, the observed association between cryptorchidism and hypospadias in twin brothers shrank with adjustment for personal status of the opposite disorder. These results imply that the main effect is carried by the familial aggregation of hypospadias or cryptorchidism rather than by a coaggregation of the 2 disorders in male twin pairs.
Only a few small studies, have investigated the familial coaggregation of cryptorchidism or hypospadias. In a case–control study including 374 cryptorchidism cases and 374 controls, Elert et al23 found that a family history of hypospadias was less frequent among cryptorchidism cases (0.5%) than among controls (1.9%). In contrast, Weidner et al15 found no association between a history of hypospadias in a brother and the development of cryptorchidism, and vice versa.
It has been hypothesized that cryptorchidism and hypospadias, together with testicular germ cell cancer and infertility, are all symptoms of the same syndrome (the so-called testicular dysgenesis syndrome). In addition to genetic susceptibility genes, this syndrome is believed to be caused by environmental factors such as estrogenic or antiandrogenic chemicals.19 However, thus far there has been no direct evidence that exposure of humans to environmental chemicals can induce testicular dysgenesis or impair masculinization.24 We would expect to find a familial coaggregation of the different clinical manifestations of the syndrome if the testicular dysgenesis syndrome were caused by shared susceptibility genes, familial environmental factors, or gene-environment interactions. This would be most obvious for male twin pairs who, on average, share more than 50% of their genes and also share common gestational and maternal factors, related to the intrauterine milieu. However, we did not find strong evidence for coaggregation of cryptorchidism and hypospadias among male twins.
A possible explanation for the coaggregation of these disorders on an individual level could be a cascade of seemingly unrelated consequences proceeding from one primary defect. During intrauterine life, this primary abnormality within the urogenital system may interfere with normal embryologic and fetal developmental processes, so that by the time of birth, the child is found to have several urogenital defects.25,26 However, as we did not find any familial coaggregation, it is unlikely that this primary defect is due to a genetic predisposition. Furthermore, a possible causative environmental agent must represent single exposures related to the present pregnancy rather than a factor that aggregates within families (eg, smoking or social class) or a factor that characterizes the specific woman (eg, obesity); as such factors most likely would result in an increased risk of both disorders in family members or in successive pregnancies.
Our study had several strengths. The introduction of a personal identification number to all citizens allowed us to create a cohort comprising the entire population of Denmark, which provides good power. Furthermore, the combination of a Danish health care system that is free of charge to all residents and the establishment of a mandatory Danish Hospital Discharge Register minimized selection bias and gave good validity to the congenital malformation diagnoses.22,27,28 Finally, the exposure information (eg, cryptorchidism in a relative) was obtained independently of the outcome (eg, hypospadias in a cohort member) and based on registry linkages, which eliminated problems related to recall bias.
As described above, the registration in the Danish Family Relations Database of relatives in older birth cohorts is not complete. However, a potential bias is reduced by comparing only boys with the same type of relatives. In addition, this approach adjusts the RRs for the effect of having a specific relative. For example, the RR for twins is adjusted for an effect per se of being twin on the risk of cryptorchidism/hypospadias. Another potential limitation was the collection of affected relatives diagnosed prior to 1977, as cryptorchidism/ hypospadias were not recorded until 1977. However, Andersen and Andersen29 have shown that the bias due to incomplete registration of the relatives decreases with a decreasing prevalence of the disease. As both hypospadias and cryptorchidism are rare disorders, this misclassification is of minor importance in our study. Another possible source of misclassification is the classification of ascending testes cases as congenital cryptorchidism cases. However, ascending testis make up only a small proportion (2%–20%) of cases operated for cryptorchidism; most of these cases experience spontaneous descent during puberty. Therefore, we would expect that the estimates among operated cases would differ from the overall estimates if the inclusion of ascending testes cases had an impact on our result. We did not find any difference in the 2 estimates.
Furthermore, incomplete links to grandparents and thus uncles and cousins prior to 1985 could in theory have influenced our estimates. However, we found no important differences in a subanalysis for which the links in the cohort were complete, including all men born after 1985.
In conclusion, we found no persuasive evidence that a family history of hypospadias increases the risk of cryptorchidism, or that a family history of cryptorchidism increases the risk of hypospadias. Thus, we found no support for shared heritability of hypospadias and cryptorchidism.
1. Boisen KA, Kaleva M, Main KM, et al. Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet
2. Boisen KA, Chellakooty M, Schmidt IM, et al. Hypospadias in a cohort of 1072 Danish newborn boys: prevalence and relationship to placental weight, anthropometrical measurements at birth, and reproductive hormone levels at three months of age. J Clin Endocrinol Metab
3. Paulozzi LJ. International trends in rates of hypospadias and cryptorchidism. Environ Health Perspect
4. Akre O, Lipworth L, Cnattingius S, Sparen P, Ekbom A. Risk factor patterns for cryptorchidism and hypospadias. Epidemiology
5. Aschim EL, Haugen TB, Tretli S, Daltveit AK, Grotmol T. Risk factors for hypospadias in Norwegian boys—association with testicular dysgenesis syndrome? Int J Androl
6. Depue RH. Maternal and gestational factors affecting the risk of cryptorchidism and inguinal hernia. Int J Epidemiol
7. Fredell L, Kockum I, Hansson E, et al. Heredity of hypospadias and the significance of low birth weight. J Urol
8. Hjertkvist M, Damber JE, Bergh A. Cryptorchidism: a registry based study in Sweden on some factors of possible aetiological importance. J Epidemiol Community Health
9. Hussain N, Chaghtai A, Herndon CD, Herson VC, Rosenkrantz TS, McKenna PH. Hypospadias and early gestation growth restriction in infants. Pediatrics
10. Pierik FH, Burdorf A, Deddens JA, Juttmann RE, Weber RF. Maternal and paternal risk factors for cryptorchidism and hypospadias: a case-control study in newborn boys. Environ Health Perspect
11. Pottern LM, Brown LM, Hoover RN, et al. Testicular cancer risk among young men: role of cryptorchidism and inguinal hernia. J Natl Cancer Inst
12. Prener A, Engholm G, Jensen OM. Genital anomalies and risk for testicular cancer in Danish men. Epidemiology
13. Swerdlow AJ, Higgins CD, Pike MC. Risk of testicular cancer in cohort of boys with cryptorchidism. BMJ
14. Tollerud DJ, Blattner WA, Fraser MC, et al. Familial testicular cancer and urogenital developmental anomalies. Cancer
15. Weidner IS, Moller H, Jensen TK, Skakkebaek NE. Risk factors for cryptorchidism and hypospadias. J Urol
16. Schnack TH, Zdravkovic S, Myrup C, et al. Familial aggregation of hypospadias: a cohort study. Am J Epidemiol
17. Schnack TH, Zdravkovic S, Myrup C, Westergaard T, Wohlfahrt J, Melbye M. Familial aggregation of cryptorchidism–a nationwide cohort study. Am J Epidemiol
18. Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet
19. Sharpe RM. The “oestrogen hypothesis”—where do we stand now? Int J Androl
20. Skakkebaek NE. Testicular dysgenesis syndrome: new epidemiological evidence. Int J Androl
21. Pedersen CB, Gøtzsche H, Møller JØ, Mortensen PB. The Danish Registration System. Dan Med Bull
22. Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull
23. Elert A, Jahn K, Heidenreich A, Hofmann R. [The familial undescended testis.] Klin Padiatr
24. Sharpe RM. Pathways of endocrine disruption during male sexual differentiation and masculinization. Best Pract Res Clin Endocrinol Metab
25. Aase JM. Diagnostic Dysmorphology
. New York: Plenum Medical Book Co; 1990.
26. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA
27. Christensen K, Knudsen LB. Registration of congenital malformations in Denmark. Dan Med Bull
28. Vestergaard M, Obel C, Henriksen TB, et al. The Danish National Hospital Register is a valuable study base for epidemiologic research in febrile seizures. J Clin Epidemiol
29. Andersen EW, Andersen PK. Adjustment for misclassification in studies of familial aggregation of disease using routine register data. Stat Med
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