Cancer risk in individuals with polydactyly: a Swedish population-based cohort study.

BACKGROUND: Polydactyly is a feature of several cancer predisposition syndromes (CPS), however, cancer risk in individuals with polydactyly is largely unknown. METHODS: We performed a matched cohort study using data from Swedish national registers. We included 6694 individuals with polydactyly, born in Sweden between 1970-2017. Polydactyly was categorised as thumb polydactyly, finger polydactyly, polydactyly+ (additional birth defects and/or intellectual disability) or isolated polydactyly. Each exposed individual was matched to 50 comparisons by sex, birth year and birth county. Associations were estimated through Cox proportional hazard models. FINDINGS: An increased childhood cancer risk was found in males (HR 4.24, 95% CI 2.03-8.84) and females (HR 3.32, 95% CI 1.44-7.63) with polydactyly+. Isolated polydactyly was associated with cancer in childhood (HR 1.87, 95% CI 1.05-3.33) and young adulthood (HR 2.30, 95% CI 1.17-4.50) in males but not in females. The increased cancer risk remained after exclusion of two known CPS: Down syndrome and neurofibromatosis. The highest site-specific cancer risk was observed for kidney cancer and leukaemia. CONCLUSIONS: An increased cancer risk was found in individuals with polydactyly, especially in males and in individuals with polydactyly+. We encourage future research about polydactyly and cancer associations and emphasise the importance of clinical phenotyping.

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.

Carriers of a Classic CYP21A2 Mutation Have Reduced Mortality: A Population-Based National Cohort Study.

CONTEXT: Congenital adrenal hyperplasia (CAH) is a common monogenic recessive disorder. It has been suggested that CYP21A2 deficiency is common because carriers may have a survival advantage, 1 in 15,000 in most populations. Carriers of CYP21A2 mutations typically do not have clinical symptoms but have a defined phenotype with a more prompt cortisol response to ACTH. OBJECTIVE: We investigated whether the mortality was lower, and determined the cause of death in carriers and population controls. DESIGN: A total of 1143 obligate carriers of a CYP21A2 mutation (561 men) were identified from the Swedish National CAH Registry, encompassing >700 patients and the Multi-Generation Registry to identify their parents. The mortality and cause of death were identified through the Swedish Cause of Death Registry. The hazard ratios (HRs) and 95% CIs were calculated. The results were compared with controls from the general population, matched for sex and age. RESULTS: The overall mortality was lower in carriers of a CYP21A2 mutation compared with the controls (HR 0.79; 95% CI, 0.678 to 0.917; P = 0.002). The difference was more marked among carriers of a more severe mutation. Infection as the cause of death was significantly lower (HR 0.65; 95% CI, 0.48 to 0.87; P < 0.01), particularly for death in pneumonia (HR 0.22; 95% CI, 0.06 to 0.88; P = 0.03). The lower overall mortality among women compared with men in the general population was confirmed among both carriers and controls. CONCLUSION: Obligate CYP21A2 carriers of a classic mutation had a reduced mortality. Specifically, a possible reduced mortality due to pneumonia was seen.

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.

Reduced Frequency of Biological and Increased Frequency of Adopted Children in Males With 21-Hydroxylase Deficiency: A Swedish Population-Based National Cohort Study.

Context: Fertility in males with 21-hydroxylase deficiency (21OHD) is unclear. Objective: Study fertility outcome in males with congenital adrenal hyperplasia. Design, Setting, and Participants: Males ≥15 years old with 21OHD (n = 221) were compared with controls matched for sex and year and place of birth (n = 22,024). Data were derived by linking national population-based registers. Subgroup analyses were performed regarding phenotype [salt-wasting (SW), simple virilizing (SV), and nonclassic (NC)] and CYP21A2 genotype (null, I2 splice, I172N, and P30L) and stratified by the introduction of neonatal screening. Main Outcome Measures: Number of biological and adopted children. Results: Males with 21OHD were less likely to be fathers of biological children [odds ratio (OR), 0.5; 95% confidence interval (CI), 0.4 to 0.7; after adjusting for socioeconomic characteristics: OR, 0.4; 95% CI, 0.2 to 0.5]. This was true for SW, SV, I2 splice, and I172N, but not for NC, null, and P30L groups (all adjusted). Among patients born before the neonatal screening introduction, fewer were fathers (adjusted OR, 0.3; 95% CI, 0.2 to 0.5), but this normalized in those born afterward. Adoption was more common in the 21OHD males (OR, 2.9; 95% CI, 1.0 to 7.9) and the SV and I172N subgroups. Age at becoming a father, marriage, region of residence, and education were similar, but fewer patients had high incomes. NC and I172N groups had, however, higher academic degrees and NC patients were more often married, whereas SW and I2 splice patients were more often divorced. Conclusions: 21OHD was associated with a reduced frequency of biological children and an increased frequency of adopted children, suggesting impaired fertility, although some subgroups had normal fertility.

Increased Cardiovascular and Metabolic Morbidity in Patients With 21-Hydroxylase Deficiency: A Swedish Population-Based National Cohort Study.

CONTEXT: Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with glucocorticoids. However, glucocorticoids may increase the risk of cardiovascular and metabolic morbidity. OBJECTIVE: This study aimed to study cardiovascular and metabolic morbidity in CAH. DESIGN, SETTING, AND PARTICIPANTS: Patients with CAH due to 21-hydroxylase deficiency (n = 588; >80% with known CYP21A2 mutations) were compared with controls matched for sex, year, and place of birth (n = 58 800). Data were obtained by linking national population-based registers. Subgroup analyses were performed regarding sex, clinical severity (salt wasting, simple virilizing, nonclassic), CYP21A2 genotype (null, I2 splice, I172N, P30L), and stratified by the introduction of neonatal screening, age groups, and nonobesity. MAIN OUTCOME MEASURES: To study cardiovascular and metabolic morbidity in CAH. RESULTS: In CAH, both any cardiovascular and metabolic disorders (OR [odds ratio], 3.9; 95% CI [confidence interval], 3.1-5.0), and cardiovascular disease (OR, 2.7; 95% CI, 1.9-3.9) were increased. Separate analyses of the individual diseases showed higher frequencies in CAH of hypertension, hyperlipidemia, atrial fibrillation, venous thromboembolism, obesity, diabetes (mainly type 2), obstructive sleep disorder, thyrotoxicosis, and hypothyroidism. Similar results were seen in the stratified groups. On the subgroup level, females were generally more affected (especially I172N and the nonclassic group), as were males with the null genotype. CONCLUSIONS: CAH was associated with excess cardiovascular and metabolic morbidity but the mechanism is not certain as the glucocorticoids were not assessed. Hypothyroidism and obesity may be an effect of close observation. However, more severe conditions were presumably detected equally in patients and controls. Screening for diabetes and other metabolic disorders that increase cardiovascular risk is important.

Ocular, airway, and dermal symptoms related to building dampness and odors in dwellings.

The authors examined the relationship between symptoms of Sick Building Syndrome and reports of building dampness and odors. Two hundred thirty-one multifamily buildings built prior to 1961 in Stockholm, Sweden, contained a total of 4,815 dwellings. The authors selected these buildings for study by stratified random sampling. Occupants answered a postal questionnaire that assessed weekly symptoms, personal factors, population density in each apartment, water leakage in the preceding 5 yr, different types of odors, and signs of high indoor air humidity. The response rate was 77%. Independent information on building characteristics was gathered from the building owners and the central building register in Stockholm. Multiple logistic-regression analysis was applied and odds ratios were calculated, with adjustments for age, gender, current smoking, hay fever, population density, type of ventilation, and ownership of the building. In total, 22% reported at least 1 sign of dampness, and 32% reported odor in the dwelling. Condensation on windows, high air humidity in the bathroom, moldy odor, and water leakage were reported from 6.8%, 8.8%, 5.7%, and 13% of the dwellings, respectively. A combination of odor and signs of high humidity was related to an increased occurrence of all symptoms (odds ratios = 2.2-3.6). Similar findings were observed for a combination of odors and a history of water leakage in the past 5 yr (odds ratios = 1.2-4.4). Symptoms increased with the number of signs of dampness. The study indicated that dampness in dwellings, with emissions of odorous compounds, are associated with an increase in symptoms consistent with Sick Building Syndrome.

Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

CONTEXT: Reports on mortality in patients with congenital adrenal hyperplasia (CAH) are lacking. OBJECTIVE: This study sought to study mortality and causes of death in CAH. DESIGN, SETTING, AND PARTICIPANTS: We studied patients with CAH (21-hydroxylase deficiency, n = 588; CYP21A2 mutations known, >80%), and compared them with controls (n = 58 800). Data were derived through linkage of national population-based registers. MAIN OUTCOME MEASURES: Mortality and causes of death. RESULTS: Mean age of death was 41.2 ± 26.9 years in patients with CAH and 47.7 ± 27.7 years in controls (P < .001). Among patients with CAH, 23 (3.9%) had deceased compared with 942 (1.6%) of controls. The hazard ratio (and 95% confidence interval) of death was 2.3 (1.2-4.3) in CAH males and 3.5 (2.0-6.0) in CAH females. Including only patients born 1952-2009, gave similar total results but only patients with salt wasting (SW) or with unclear phenotype had an increased mortality. The causes of death in patients with CAH were adrenal crisis (42%), cardiovascular (32%), cancer (16%), and suicide (10%). There were seven additional deaths in CAH individuals with incomplete or reused personal identification number that could not be analyzed using linkage of registers. Of the latter, all except one were deceased before the introduction of neonatal screening in 1986, and most of them in the first weeks of life, probably in an adrenal crisis. CONCLUSIONS: CAH is a potentially lethal condition and was associated with excess mortality due to adrenal crisis. The SW phenotype also seemed to have worse outcome in children and adults due to adrenal crisis and not only before the introduction of neonatal screening.