Risk of Urological Cancer Among Boys and Men Born with Hypospadias: A Swedish Population-based Study.

Background: Hypospadias is a common genital malformation among boys. Studies indicate that hypospadias is associated with a higher risk of testicular cancer. Other forms of urological cancer may be linked to hypospadias via a mutual aetiology, hormonal dysfunction, or hypospadias complications, but this has not yet been studied. Objective: To investigate the association between hypospadias and testicular cancer and the risk of other urological cancers among individuals born with hypospadias. Design setting and participants: The study used a population-based male cohort born in Sweden in 1964-2018. Exposure was hypospadias diagnosis in national registers. Outcomes were defined using the Swedish Cancer Register. An extended cohort born from 1940 was used to study cancers among older men. Biological brothers and fathers were linked to investigate familial coaggregation. Outcome measurements and statistical analysis: Associations were assessed using Cox proportional-hazards regression analysis, with results presented as hazard ratios. Results and limitations: We found that hypospadias was associated with a higher risk of testicular cancer (hazard ratio 2.04, 95% confidence interval 1.42-2.92), especially for proximal hypospadias, but did not observe any clear familial coaggregation of hypospadias and testicular cancer. Hypospadias was associated with Wilms' tumour in childhood. We also found an association between hypospadias and bladder and urethral cancers, but not prostate cancer. The number of cases with hypospadias was small and the results for cancers among older men may be impacted by limitations in register coverage. Conclusions: Our study supports the hypothesis of a higher risk of testicular cancer for men with hypospadias, especially with proximal phenotypes. Hypospadias may also be associated with a higher risk of lower urinary tract cancers, although this requires further investigation in older cohorts. Patient summary: Boys and men in whom the opening of the urethra is not at the end of the penis (called hypospadias) at birth are at higher risk of developing testicular cancer, although their overall risk is still low. They may also have a higher risk of developing other forms of cancer in the urinary tract.

Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation.

Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities, dysmorphic features, short stature, obesity, and hypogonadism. PWS is not a known cancer predisposition syndrome, but previous investigations regarding the prevalence of cancer in these patients suggest an increased risk of developing specific cancer types such as myeloid leukemia and testicular cancer. We present the results from a Swedish national population-based cohort study of 360 individuals with PWS and 18,000 matched comparisons. The overall frequency of cancer was not increased in our PWS cohort, but we found a high frequency of pediatric cancers. We also performed whole-genome sequencing of blood- and tumor-derived DNAs from a unilateral dysgerminoma in a 13-year-old girl with PWS who also developed bilateral ovarian sex cord tumors with annular tubules. In germline analysis, there were no additional findings apart from the 15q11.2-q13 deletion of the paternal allele, while a pathogenic activating KIT mutation was identified in the tumor. Additionally, methylation-specific multiplex ligation-dependent probe amplification revealed reduced methylation at the PWS locus in the dysgerminoma but not in the blood. In conclusion, our register-based study suggests an increased risk of cancer at a young age, especially testicular and ovarian tumors. We found no evidence of a general increase in cancer risk in patients with PWS. However, given our limited observational time, further studies with longer follow-up times are needed to clarify the lifetime cancer risk in PWS. We have also described the second case of locus-specific loss-of-imprinting in a germ cell tumor in PWS, suggesting a possible mechanism of carcinogenesis.

Increased androgen-related comorbidity in adolescents and adults born with hypospadias: A population-based study.

BACKGROUND: Hypospadias is a common congenital malformation often related to the effect of androgens in utero. While hypogonadism is associated with many potential health risks including metabolic and cardiovascular disease, the risk of clinical hypogonadism and comorbidities in men with hypospadias later in life has not been studied. OBJECTIVES: Investigate the risk of hypogonadism and somatic comorbidities in adolescents and men born with hypospadias. MATERIALS AND METHODS: We conducted a population-based cohort study using Swedish registers. Associations between hypospadias and hypogonadism, delayed puberty, metabolic, and cardiovascular disease respectively were estimated using Cox proportional hazards regression. Body measurements from military conscription were analysed in a subpopulation as indicators of growth and cardiometabolic risk. We used sibling comparison analyses to control for familial confounding. RESULTS: Using register data, a total of 2,165,255 men including 9,714 men born with hypospadias were followed from the age of 10 to a maximum of 60 years. We found an association between hypospadias and hypogonadism (Hazard ratio (HR) 3.27, 95% confidence interval (CI) 2.33-4.59) which was more pronounced in proximal hypospadias. Men with hypospadias had shorter average height than their brothers and the general population. We further found an increased risk of delayed puberty (HR 1.49, 95% CI 1.08-2.07), diabetes mellitus type 2 (HR 1.57, 95% CI 1.18-2.09) and cardiovascular disease (HR 1.47, 95% CI 1.27-1.71). DISCUSSION: We found an increased risk of hypogonadism, metabolic and cardiovascular disease in men born with hypospadias, increasing with severity of phenotype, as well as impacted growth. These results indicate discruptions in androgen function past childhood, although some of the associations may be due to other underlying aetiologies. CONCLUSION: Hypospadias is associated with an increased risk of androgen-related comorbidity in adolescence and adulthood. We suggest that this can be considered clinically, while further research is needed, especially in older populations.

Fertility in men with hypospadias: A nationwide register-based study using dizygotic twinning rates as an indicator of semen quality.

BACKGROUND: It is not known if impaired fertility in men with hypospadias is caused by decreased semen quality or other factors. Semen quality in men born with hypospadias may be impaired due to effects of androgens or testicular dysgenesis but has been very little studied. OBJECTIVES: To study semen quality in men with hypospadias using dizygotic twinning rates as an epidemiological indicator. We further aimed to study men treated for cryptorchidism, given a hypothesized mutual etiology for decreased semen quality. MATERIALS AND METHODS: We conducted a population-based study using national Swedish registers. A total of 4,363,165 births between 1964 and 2013 were included. The association between hypospadias and cryptorchidism, and fathering dizygotic multiple births was estimated using logistic regression and presented as odds ratios. The main analyses excluded births conceived using assisted reproductive technology (ART). RESULTS: We identified a total of 5317 births with fathers with hypospadias, including 26 dizygotic births conceived unassisted. No significant association was found between hypospadias and dizygotic twinning (OR 1.10, 0.75-1.61). We estimated a significantly increased odds for dizygotic multiple births in men treated for cryptorchidism (OR 1.35, 1.01-1.81) which was decreased after exclusion of ART, but the estimate was not significant (OR 0.75, 0.48-1.18). DISCUSSION: Using dizygotic twinning rates as an indicator of semen quality, we did not find any difference between fathers with hypospadias and controls. Due to sample size, we could not analyze phenotypes separately and can therefore not exclude impaired semen quality in severe hypospadias. We could not demonstrate any association between dizygotic twinning and cryptorchidism. Men treated for cryptorchidism were more likely than controls to use ART to conceive. CONCLUSION: Men with hypospadias who conceived without ART were not shown to have impaired semen quality using dizygotic twinning as an epidemiological indicator.

Fertility in adult men born with hypospadias: A nationwide register-based cohort study on birthrates, the use of assisted reproductive technologies and infertility.

BACKGROUND: Fertility in men with hypospadias may be affected due to anatomical, surgical, or etiological factors and associated conditions. Fertility is further influenced by psychosocial and genetic factors, often shared within families. OBJECTIVE: To evaluate fertility in men born with hypospadias and assess confounding by familial factors. MATERIALS AND METHODS: A population-based cohort of 1.2 million men born in Sweden 1964-1998, identified through national demographic and healthcare registers. Associations between hypospadias and (a) being a biological father, (b) conceiving through ART, and (c) diagnosis of male infertility were investigated in the full cohort with logistic regression models and Cox proportional hazard models, expressed as odds ratios (ORs) and hazard ratios (HRs), respectively, with 95% confidence intervals (CIs). A stratified proportional hazard model, conditional on sibling group, was used to control for shared familial confounding. RESULTS: Men with hypospadias, as a whole group, had a lower probability of having biological children (adjusted HR 0.87, 95% CI 0.83-0.92). A significant association was present in both distal (adjusted HR 0.90, 95% CI 0.85-0.96) and proximal hypospadias (HR 0.59, 95% CI 0.42-0.81). Men with hypospadias more often became fathers through ART, regardless of concomitant cryptorchidism. The initial association between hypospadias and the diagnosis of infertility disappeared in sensitivity analyses excluding cryptorchidism. DISCUSSION: Men with hypospadias displayed lower birthrates as compared to their brothers and the general population. Mere birthrates may, however, be a questionable measure of fertility in a population using family planning. However, men with hypospadias were also at higher risk of reproducing through ART and did more often receive a diagnosis of male infertility. Altogether, these findings indicate impaired fertility in men with hypospadias. CONCLUSIONS: Fertility in men with hypospadias is impaired, as shown by lower birthrates, increased use of ART and higher risk of receiving a diagnosis of male infertility.

Psychosocial outcomes in adult men born with hypospadias: A register-based study.

In this nationwide matched cohort study, we have investigated whether being born with hypospadias affect subsequent psychosocial outcomes in adulthood. We analyzed prospectively collected data from national Swedish registers. Data on the diagnoses were collected from the National Patient Register and the Medical Birth Register. Data on psychosocial outcomes such as educational and income level, marital status and disability pension were collected from Statistics Sweden. The effects of covariates, such as age, county of birth, presence of other malformations and psychiatric illness, were taken into account. The associations between hypospadias and psychosocial outcomes were calculated using conditional logistic regression and expressed as odds ratios (OR) and 95% confidence intervals (CI). We included 4378 men diagnosed with hypospadias, born between 1969 and 1993 in Sweden. Patients with hypospadias were matched with unaffected men by year of birth and birth county. We did not detect any differences in educational or income level. The probability of entering marriage (OR 1.02, 95% CI 0.90-1.14) did not differ, regardless of phenotype. We did, however, detect a 40% increased probability of receiving a disability pension, (OR 1.39, 95% CI 1.20-1.61). In conclusion, men born with hypospadias in Sweden do not differ from unaffected men with respect to the majority of psychosocial outcomes studied. They are, however, at increased risk of receiving a disability pension, which motivates further investigations.