Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene

Although sufficient androgen receptor (AR) function is crucial for normal male sexual differentiation, single-point mutations in the AR gene are infrequent in the two most common male congenital malformations, hypospadias and cryptorchidism. Because polymorphic CAG and GGN segments regulate AR function, we investigated whether there was any association between these polymorphisms and mentioned malformations. Genotyping was performed by direct sequencing of DNA from patients diagnosed with hypospadias (n = 51) and cryptorchidism ( n = 23) and controls ( n = 210). The subjects with hypospadias were divided into subgroups of glanular, penile, and penoscrotal hypospadias. Median GGN lengths were significantly higher ( 24 vs. 23) among both subjects with cryptorchidism, compared with controls ( P = 0.001), and those with penile hypospadias, compared with either controls ( P = 0.003) or glanular and penoscrotal hypospadias combined ( P = 0.018). The frequency of cases with GGN 24 or more vs. GGN = 23, differed significantly among those with cryptorchidism (65/35%), compared with controls (31/54%) ( P = 0.012), and among subjects with penile hypospadias (69/31%), compared with either controls ( P = 0.035) or glanular or penoscrotal hypospadias combined (32/55%) ( P = 0.056). There were no significant differences in CAG lengths between the cases and controls. Our findings indicate an association between GGN length and the risk of cryptorchidism and penile hypospadias, both conditions considered consequences of low androgenicity

Organic Food Consumption during Pregnancy and Hypospadias and Cryptorchidism at Birth: The Norwegian Mother and Child Cohort Study (MoBa)

BACKGROUND: The etiologies of the male urogenital anomalies hypospadias and cryptorchidism remain unclear. It has been suggested that maternal diet and environmental contaminants may affect the risk of these anomalies via placental or hormonal disturbances. OBJECTIVES: We examined associations between organic food consumption during pregnancy and prevalence of hypospadias and cryptorchidism at birth. METHODS: Our study includes 35,107 women participating in the Norwegian Mother and Child Cohort Study (MoBa) who delivered a singleton male infant. Information about use of six groups of organically produced food (vegetables, fruit, bread/cereal, milk/dairy products, eggs, and meat) during pregnancy was collected by a food frequency questionnaire. Women who indicated that they sometimes, often, or mostly consumed organic foods in at least one of the six food groups were classified as organic food consumers in analyses. Hypospadias and cryptorchidism diagnoses were retrieved from the Medical Birth Registry of Norway. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multiple logistic regression. RESULTS: Seventy-four male newborns were diagnosed with hypospadias (0.2%), and 151 with cryptorchidism (0.4%). Women who consumed any organic food during pregnancy were less likely to give birth to a boy with hypospadias (OR = 0.42; 95% CI: 0.25, 0.70, based on 21 exposed cases) than women who reported they never or seldom consumed organic food. Associations with specific organic foods were strongest for vegetable (OR = 0.36; 95% CI: 0.15, 0.85; 10 exposed cases) and milk/dairy (OR = 0.43; 95% CI: 0.17, 1.07; 7 exposed cases) consumption. No substantial association was observed for consumption of organic food and cryptorchidism. CONCLUSIONS: Consumption of organically produced foods during pregnancy was associated with a lower prevalence of hypospadias in our study population. These findings were based on small numbers of cases and require replication in other study populations. CITATION: Brantsæter AL, Torjusen H, Meltzer HM, Papadopoulou E, Hoppin JA, Alexander J, Lieblein G, Roos G, Holten JM, Swartz J, Haugen M. 2016. Organic food consumption during pregnancy and hypospadias and cryptorchidism at birth: the Norwegian Mother and Child Cohort Study (MoBa). Environ Health Perspect 124:357–364; http://dx.doi.org/10.1289/ehp.140951

Aetiology of hypospadias: a systematic review of genes and environment.

Contains fulltext : 108791.pdf (postprint version ) (Open Access)BACKGROUND: Hypospadias is a common congenital malformation of the male external genitalia. Most cases have an unknown aetiology, which is probably a mix of monogenic and multifactorial forms, implicating both genes and environmental factors. This review summarizes current knowledge about the aetiology of hypospadias. METHODS: Pubmed was used to identify studies on hypospadias aetiology published between January 1995 and February 2011. Reference lists of the selected manuscripts were also searched to identify additional studies, including those published before 1995. RESULTS: The search provided 922 articles and 169 articles were selected for this review. Studies screening groups of patients with hypospadias for single gene defects found mutations in WT1, SF1, BMP4, BMP7, HOXA4, HOXB6, FGF8, FGFR2, AR, HSD3B2, SRD5A2, ATF3, MAMLD1, MID1 and BNC2. However, most investigators are convinced that single mutations do not cause the majority of isolated hypospadias cases. Indeed, associations were found with polymorphisms in FGF8, FGFR2, AR, HSD17B3, SRD5A2, ESR1, ESR2, ATF3, MAMLD1, DGKK, MID1, CYP1A1, GSTM1 and GSTT1. In addition, gene expression studies indentified CTGF, CYR61 and EGF as candidate genes. Environmental factors consistently implicated in hypospadias are low birthweight, maternal hypertension and pre-eclampsia, suggesting that placental insufficiency may play an important role in hypospadias aetiology. Exogenous endocrine-disrupting chemicals have the potential to induce hypospadias but it is unclear whether human exposure is high enough to exert this effect. Other environmental factors have also been associated with hypospadias but, for most, the results are inconsistent. CONCLUSIONS: Although a number of contributors to the aetiology of hypospadias have been identified, the majority of risk factors remain unknown

Common variants in DGKK are strongly associated with risk of hypospadias

Contains fulltext : 95737.pdf (publisher's version ) (Closed access) Contains fulltext : 95737a.pdf (postprint version ) (Open Access)Hypospadias is a common congenital malformation of the male external genitalia. We performed a genome-wide association study using pooled DNA from 436 individuals with hypospadias (cases) and 494 controls of European descent and selected the highest ranked SNPs for individual genotyping in the discovery sample, an additional Dutch sample of 133 cases and their parents, and a Swedish series of 266 cases and 402 controls. Individual genotyping of two SNPs (rs1934179 and rs7063116) in DGKK, encoding diacylglycerol kinase kappa, produced compelling evidence for association with hypospadias in the discovery sample (allele-specific odds ratio (OR) = 2.5, P = 2.5 x 10(1)(1) and OR = 2.3, P = 2.9 x 10, respectively) and in the Dutch (OR = 3.9, P = 2.4 x 10 and OR = 3.8, P = 3.4 x 10) and Swedish (OR = 2.5, P = 2.6 x 10 and OR = 2.2, P = 2.7 x 10) replication samples. Expression studies showed expression of DGKK in preputial tissue of cases and controls, which was lower in carriers of the risk allele of rs1934179 (P = 0.047). We propose DGKK as a major risk gene for hypospadias