The Genetic and Environmental Factors Underlying Hypospadias

Bouty, Aurore; Ayers, Katie; Pask, Andrew J; Héloury, Yves; Sinclair, Andrew H.

doi:10.1159/000441988

Cited by 170 publications

(161 citation statements)

References 196 publications

(254 reference statements)

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“…Given that conditions associated with a defect in the androgen receptor (AR) are more likely to be associated with multiple hypospadias surgery [Lucas-Herald et al, 2016], it is plausible that the increased rate of complications in cases of proximal hypospadias may be partly related to the effect that reduced androgen exposure may exert during critical periods of prenatal development. In cases of hypospadias, extra-genital anomalies may also be part of a constellation that points towards a specific genetic aetiology [van der Zanden et al, 2012;Bouty et al, 2015]. For instance, cases of XY DSD with normal gonadal function that are small for gestational age are less likely to have a mutation in the AR gene [Poyrazoglu et al, 2017].…”

Section: Discussionmentioning

confidence: 99%

“…Hypospadias is a common congenital anomaly affecting approximately 1 in 300 male births [Ahmed et al, 2004], and its underlying aetiology may be multifactorial [Bouty et al, 2015]. Several congenital conditions that are associated with a disorder of sex development (DSD), including a disorder of gonadal development, disorder of androgen synthesis, or disorder of androgen action, can be associated with hypospadias [Ahmed et al, 2016].…”

confidence: 99%

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Association Between Extra-Genital Congenital Anomalies and Hypospadias Outcome

Aljuraibah

Lucas‐Herald

Nixon

et al. 2019

Sex Dev

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Extra-genital congenital anomalies are often present in cases of hypospadias, but it is unclear whether they have an association with the outcome of hypospadias surgery. The aim of this study was to review all hypospadias cases that had surgery between 2009 and 2015 at a single centre and identify clinical determinants of the surgical outcome. An extra-genital congenital anomaly was reported in 139 (22%) boys and 62 (10%) had more than 1 anomaly. Of the 626 boys, 54 (9%), including 44 with proximal hypospadias, had endocrine as well as limited genetic evaluation. Of these, 10 (19%) had a biochemical evidence of hypogonadism and 5 (9%) had a molecular genetic abnormality. At least 1 complication was reported in 167 (27%) patients, with 20% of complications (most frequently fistula) occurring after 2 years of surgery. The severity of hypospadias and the existence of other anomalies were clinical factors that were independently associated with an increased risk of complications (p < 0.001). In conclusion, complications following surgery are more likely in those cases that are proximal or who have additional extra-genital anomalies. To understand the biological basis of these complications, there is a greater need to understand the aetiology of such cases.

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Section: Discussionmentioning

confidence: 99%

Association Between Extra-Genital Congenital Anomalies and Hypospadias Outcome

Aljuraibah

Lucas‐Herald

Nixon

et al. 2019

Sex Dev

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“…Recently WNT7B and WNT9B were found to be regulators of ureter development in a mouse model system [10] and WNT3 was shown to be involved in bladder exstrophy in zebrafish [11]. WNT signalling is also involved in the development of the genital tubercle and impairment of WNT signalling can result in malformations of the urethra and hypospadia [12]. …”

Section: Introductionmentioning

confidence: 99%

Impact of Altered WNT2B Expression on Bladder Wall Fibroblasts: Implications for Apoptosis Regulation in the Stroma of the Lower Urinary Tract

et al. 2017

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Background: Little is known about the role of WNT signalling in pathological processes involving the urinary tract stroma. Here the impact of WNT signalling on bladder wall fibroblasts (BWFs) was studied using integrated expression profiling. Material and Methods: WNT ligand and downstream WNT pathway component expression was profiled in human BWFs using qRT-PCR. Highly expressed WNT2B was knocked down using siRNA in BWFs. The expression of 730 mRNAs and 800 miRNAs was analyzed on the nCounter MAX platform in #WNT2B and control transfected BWFs. qRT-PCR was used for validation in vitro and in matched scar and healthy bladder wall tissue samples of 12 patients with vesico-urethral anastomotic stricture (VUAS). Results: Thirteen genes and 9 miRNAs showed differential expression in #WNT2B cells. Among these were TNFSF10, a key apoptosis inductor, (0.22fold, p = 0.011) and miR-1246 (36.2fold, p = 0.031). miRNA target prediction indicated TNFSF10 to be regulated by miR-1246. qRT-PCR analysis confirmed differential expression of miR-1246 and TNFSF10 in #WNT2B BWFs. Furthermore, TNFSF10 was significantly underexpressed in VUAS tissue (p = 0.009). Conclusion: Perturbation of WNT signalling results in an altered expression of the apoptosis inductor TNFSF10. Similar changes are observed in VUAS. Further studies investigating the crosslink between WNT signalling and apoptosis regulation in the urinary tract stroma are warranted.

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“…Among them, SRD5A2 (steroid 5 alpha-reductase 2), MAMLD1 (mastermind like domain containing 1), and AR (androgen receptor) have been studied in human cases of hypospadias [Bouty et al, 2015], while AR polymorphisms also showed an association with cryptorchidism [Docampo and Hadziselimovic, 2015]. Moreover, mutations of AR and SRD5A2 can be also responsible for penis underdevelopment [Cimador et al, 2015].…”

mentioning

confidence: 99%

Polymorphisms of MAMLD1, SRD5A2, and AR Candidate Genes in Seven Dogs (78,XY; SRY-Positive) Affected by Hypospadias or Cryptorchidism

Krzemińska¹,

D’Anza²,

Ciotola³

et al. 2019

Sex Dev

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Knowledge of the molecular background of disorders of sex development (DSD) in dogs with normal sets of XY chromosomes (XY DSD) is very scarce. However, extensive studies have been carried out in humans, showing that polymorphisms and mutations of numerous genes, including SRY, MAMLD1, SRD5A2, and AR, are associated with or responsible for XY DSD. In this study, we analyzed the entire coding sequence of these genes in 7 dogs (78,XY) with ambiguous external genitalia (hypospadias, cryptorchidism, bifid scrotum, or rudimentary penis). The most common disorder was hypospadias (6 cases), followed by cryptorchidism (4 cases). The co-occurrence of both abnormalities was observed in 3 dogs. Polymorphisms were found in MAMLD1 (3 SNPs), SRD5A2 (5 SNPs), and AR (2 STRs and 1 SNP), while SRY was monomorphic. However, the distribution of the polymorphic variants in the DSD dogs and 11 control XY dogs did not differ significantly. Our study suggests that an association between the polymorphisms of the studied candidate genes and hypospadias or cryptorchidism is unlikely in dogs. We thus support the recent suggestion that hypospadias is not rare in this species, and moreover, we show that co-occurrence of hypospadias and cryptorchidism can be quite frequent.

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The Genetic and Environmental Factors Underlying Hypospadias

Cited by 170 publications

References 196 publications

Association Between Extra-Genital Congenital Anomalies and Hypospadias Outcome

Association Between Extra-Genital Congenital Anomalies and Hypospadias Outcome

Impact of Altered WNT2B Expression on Bladder Wall Fibroblasts: Implications for Apoptosis Regulation in the Stroma of the Lower Urinary Tract

Polymorphisms of <b><i>MAMLD1, SRD5A2,</i></b> and <b><i>AR</i></b> Candidate Genes in Seven Dogs (78,XY; <b><i>SRY</i></b>-Positive) Affected by Hypospadias or Cryptorchidism

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