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Introduction: There are currently no clinical criteria for obstructed urinary flow after hypospadias repair surgery. Previous studies have utilized adult and pediatric nomograms and flow shapes to define obstruction, however these methods are limited by a lack of standardization and lack of interrater reliability when determining flow shapes, respectively. The idealized voider derived flow indexes offer a way to track uroflowmetry results in a volume and age agnostic manner., Objective: We sought to evaluate all our hypospadias patients over a 10-year period and identify patients without complications and those with complications and determine their respective flow parameters. Our secondary objective is to identify which uroflowmetry parameters are the most significant predictors of urethral stricture and meatal stenosis at the time of the uroflowmetry study., Study Design: Retrospective chart review was used to compile demographic information, details of hypospadias repair surgeries, and uroflowmetry results from pediatric hypospadias repair patients. Subjects were divided into distal, midshaft, and proximal groups based on the initial location of their urethral meatus. Flows from the hypospadias repair groups were compared to flows from normal age matched controls from a previous study. We compared flows from hypospadias repair patients with no complications present with those who had urethral stricture or meatal stenosis present at the time of uroflowmetry. Binary logistic regression and ROC analysis was used to assess different uroflowmetry parameters' ability to detect the presence of obstructed urine flow., Results: 467 uroflowmetry studies from 200 hypospadias repair patients were included in the database. Compared to controls, the hypospadias repair groups tended to have significantly lower Qmax, Qavg, Qmax FI, Qavg FI, and longer ttQmax. Significant differences in flow parameters were observed when comparing hypospadias repair patients with and without flow obstructing complications at the time of uroflowmetry. Binary logistic regression including various uroflowmetry parameters showed Qmax FI had a significant effect on the odds of observing the absence of a stricture in proximal and distal hypospadias cases., Discussion: Of the uroflowmetry parameters analyzed, binary logistic regression and the likelihood ratio of a positive result all point to Qmax FI as the better parameter to use to detect the presence of complications in patients who have undergone distal or proximal hypospadias repair surgery., Conclusion: We have established normal parameters for post-operative hypospadias repair patients which can be used to follow patients over time and allow for the identification of complications by keeping track of flow indexes which are volume and age agnostic., Competing Interests: Conflicts of interest We have no conflicts of interest to report., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: A congenital disease is for life. Posterior hypospadias, the severe form of hypospadias with a penoscrotal, scrotal, or perineal meatus, is a challenging condition with a major impact on lifelong quality of life., Aim: Our network meeting is aimed to identify what is currently missing in the lifelong treatment of posterior hypospadias, to improve care, quality of life, and awareness for these patients., Methods: The network meeting "Lifelong Posterior Hypospadias" in Utrecht, The Netherlands was granted by the European Joint Programme on Rare Diseases-Networking Support Scheme. There was a combination of interactive sessions (hackathons) and lectures. This paper can be regarded as the last phase of the hackathon., Results: Surgery for hypospadias remains challenging and complications may occur until adulthood. Posterior hypospadias affects sexual function, fertility, and hormonal status. Transitional care from childhood into adulthood is currently insufficiently established. Patients should be more involved in defining desired treatment approach and outcome measures. For optimal outcome evaluation standardization of data collection and registration at European level is necessary. Tissue engineering may provide a solution to the shortage of healthy tissue in posterior hypospadias. For optimal results, cooperation between basic researchers from different centers, as well as involving clinicians and patients is necessary., Conclusions: To improve outcomes for patients with posterior hypospadias, patient voices should be included and lifelong care by dedicated healthcare professionals guaranteed. Other requirements are joining forces at European level in uniform registration of outcome data and cooperation in basic research., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background: Hypospadias is a relatively common genital anomaly in humans, usually followed by inelastic dartos that causes penile chordee. Vascular endothelial growth factor (VEGF) is strongly linked to the viscoelasticity of tissues and their elastic phase. This study aimed to evaluate VEGF expressions in (1) fascia dartos between hypospadias and controls and (2) chordee severity., Methods: This prospective cohort study involved 65 specimens from patients with hypospadias and ten specimens from controls. The samples were analyzed by quantitative real-time polymerase chain reaction (qPCR) for VEGF expression., Results: The expressions of VEGF were not different between proximal and distal hypospadias patients and controls (fold change: distal - 0.25; fold change: proximal - 0.2; p = 0.664). The scaled expressions related to chordee severity were mild - 0.1; moderate 0.1; severe - 0.25 (p = 0.660)., Conclusions: VEGF expressions might not affect the severity of hypospadias and chordee, implying the pathogenesis is complex involving many growth factors. Further study with a larger sample size is necessary to clarify and confirm our findings., (© 2021. The Author(s).)

Gonadal dysgenesis is a distinct variety of Disorders of Sexual Differentiation (DSD) characterised by incomplete or defective formation of the gonads due to either structural or numerical anomalies of the sex chromosomes or mutations in the genes involved in the development of the gland. Here we present two such rare cases that presented during childhood. Both patients presented with ambiguous genitalia with a 45XO/46XY mosaic chromosome pattern. First case, an infant underwent laparoscopic excision of streak gonad, and a single stage hypospadias repair later. Second case, an adolescent who underwent gonadectomy as a child, presented with a mass which was excised and found to contain uterine and ovarian tissue; second stage hypospadias repair is being planned. Mixed gonadal dysgenesis usually presents with a unilateral testis, a streak gonad on the contralateral side and persistent mullerian structures. The most common karyotype noted is 45XO/46XY. These cases are known to have ambiguous external genitalia. The streak gonads have an increased malignant potential and thus, these patients should be carefully screened and followed up for gonadoblastoma., Competing Interests: None

Background: Testicular germ cell tumour is a multifactorial disease in which various genetic and environmental factors play a role. Testicular germ cell tumour is part of the testicular dysgenesis syndrome which includes also cryptorchidism, hypospadias, oligo/azoospermia and short anogenital distance., Objectives: The primary objective was to examine anogenital distance in testicular germ cell tumour cases and healthy fertile controls. The secondary objective was to assess the (CAG)n polymorphism of the Androgen Receptor gene in relationship with anogenital distances and testicular germ cell tumour development., Material and Methods: 156 testicular germ cell tumour patients and 110 tumour-free normozoospermic controls of Spanish origin. All subjects underwent full andrological workup (including semen and hormone analysis) and genetic analysis (Androgen Receptor (CAG)n). The main outcome measures were the anopenile distance (AGDap), the anoscrotal distance (AGDas) and AR(CAG)n., Result: We observed significantly shorter anogenital distances in the group of testicular germ cell tumour patients in respect to controls (P < .001) independently from sperm count and testis histology. Threshold values, applicable only to our cohort, were calculated for anogenital distances with the best sensitivity and specificity. Subjects with AGDap and AGDas below threshold showed a significantly increased risk for testicular germ cell tumour (OR = 4.97, 95% CI = 2.01-12.33, P = .001 and OR = 4.11, 95% CI = 1.89-8.92, P ≤ .001, respectively). No significant correlation was observed between AR(CAG)n polymorphism and anogenital distances. The median values of the AR(CAG)n were similar between cases and controls, excluding a major role for this polymorphism in the etiopathogenesis of these testicular dysgenesis syndrome components., Conclusions: Ours is the first study focusing on anogenital distances in testicular germ cell tumour patients. We identified short anogenital distances (which is a surrogate biomarker of androgen action during foetal life) as a significant risk factor for this disease. After further validation of our preliminary data, anogenital distance measurement could become part of testicular germ cell tumour screening in order to better define those individuals who would benefit from long-term active follow-up., (© 2020 American Society of Andrology and European Academy of Andrology.)

Objective: To identify the genetic etiology of recurrent disorders of sex development (DSDs) in a Taiwanese family with 46,XY sex reversal and hypospadias., Design: Genetic and functional studies., Setting: Academic hospital., Patient(s): A three-generation family consisting of 22 members, with eight cases of 46,XY DSD, of whom four have 46,XY male-to-female sex reversal and four are 46,XY males with hypospadias., Intervention(s): None., Main Outcome Measure(s): Results of exome sequencing and in vitro protein and RNA analyses., Result(s): All patients with DSDs were found to carry heterozygous missense mutations in the doublesex and mab-3-related transcription factor 3 (DMRT3; rs187176004, c.A815C, p.K272T) and 2',5'-oligoadenylate synthetase 3 (OAS3; rs16942374, c.G2606A, p.R869H) genes. The DMRT3 mutation increased estrogen receptor 1 (ESR1) expression. Upon binding with the OAS3-RNase L complex, wild-type DMRT3 promoted degradation of ESR1 mRNA. However, the DMRT3 A815C -OAS3 G2606A complex interacted less strongly with ESR1 mRNA and RNase L, ultimately preventing ESR1 mRNA degradation. The interactions between DMRT3, OAS3, and RNase L were confirmed in the patients' testis., Conclusion(s): Our results indicate that DMRT3 and OAS3 are involved in human DSDs by controlling ESR1 expression., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The paradigm for hypospadias repair is a straight penis with a vertical meatus at the tip of the glans that provides satisfactory urination and is cosmetically acceptable to the parents of the patient., Objective: To determine the cosmetic and functional outcomes of hypospadias repair in relation to the width of the urethral plate., Patients and Methods: This study was a prospective evaluation of patients operated for hypospadias. The urethral plate width (UPW) of the patients were measured preoperatively using vernier calipers. The patients were categorized into groups A and B. Group A patients have a UPW <8 mm, whereas group B patients have a UPW ≥8 mm. The width of the urethral plate was correlated to the cosmetic outcome (using hypospadias objective penile evaluation [HOPE]) and functional outcome (using the urinary stream) of hypospadias repair., Results: Overall, 47 patients had their hypospadias repaired during the study period. But, only 42 patients who had their distal hypospadias repaired using tubularized incised plate urethroplasty were evaluated. There were 20 patients (47.6%) in group A and 22 patients (52.4%) in group B, with a mean urethral plate of 7.3 mm ± 0.50 SD. The mean UPW in group A was 5.6 mm ± 1.22 SD and the mean UPW in group B was 8.8 mm ± 0.88 SD. Overall, mean HOPE score was 40.0 ± 6.83 SD. Group A patients had a mean HOPE score of 38.7 ± 7.49 SD, whereas Group B patients had a mean HOPE score of 41.2 ± 6.08 SD. P-value was 0.725, which is not statistically significant. Relating good urinary stream (15 in group A and 20 in group B) with the width of the urethral plate statistically (using Spearman correlation technique) gave a P-value of 0.03 (P < 0.05), which is statistically significant., Conclusion: Our findings indicate that the cosmetic outcome of hypospadias repair may not be determined by UPW, but the functional outcome may be predicted by the width of the urethral plate., (Copyright © 2019 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Pubertal development may be altered in boys with cryptorchidism and hypospadias, but existing knowledge is inconsistent. Therefore, we investigated the association between cryptorchidism and hypospadias and pubertal development in a large cohort study. Boys in the Puberty Cohort, a cohort nested within the Danish National Birth Cohort, were included in this study. Information on cryptorchidism and hypospadias was retrieved from the Danish National Patient Register. From 11 years until 18 years or full pubertal development, information on physical markers of pubertal development was provided biannually, including Tanner stages, axillary hair, acne, voice break, and first ejaculation. In multivariate regression models for interval censored data, the mean (95% confidence intervals [CIs]) differences in months in obtaining the pubertal markers between boys with and without the anomalies were estimated. Among 7698 boys, 196 (2.5%) had cryptorchidism and 60 (0.8%) had hypospadias. Boys with hypospadias experienced first ejaculation and voice break 7.7 (95% CI: 2.5-13.0) months and 4.5 (95% CI: 0.3-8.7) months later than boys without hypospadias. The age at attaining the Tanner stages for gonadal and pubic hair growth was also higher, though not statistically significant. Pubertal development seemed unaffected in boys with mild as well as severe cryptorchidism. In conclusion, hypospadias may be associated with delayed pubertal development, but pubertal development seems unaffected by cryptorchidism. The relation between hypospadias and later pubertal development may be due to the underlying shared in utero risk or genetic factors., Competing Interests: None

Background: Discordance between gonadal type and gender identity has often led to an assumption of infertility in patients with differences in sex development (DSD). However, there is now greater recognition of fertility being an important issue for this group of patients. Currently, gonadal tissue that may have fertility potential is not being stored for individuals with DSD and, where gonadectomy forms part of management, is often discarded. The area of fertility preservation has been predominantly driven by oncofertility which is a field dedicated to preserving the fertility of patients undergoing gonadotoxic cancer treatment. The use of fertility preservation techniques could be expanded to include individuals with DSD where functioning gonads are present., Methods: This is a systematic literature review evaluating original research articles and relevant reviews between 1974 and 2018 addressing DSD and fertility, in vitro maturation of sperm, and histological/ultrastructural assessment of gonadal tissue in complete and partial androgen insensitivity syndrome, 17β-hydroxysteroid dehydrogenase type 3 and 5α-reductase deficiency., Conclusion: Successful clinical outcomes of ovarian tissue cryopreservation are paving the way for similar research being conducted using testicular tissue and sperm. There have been promising results from both animal and human studies leading to cryopreservation of testicular tissue now being offered to boys prior to cancer treatment. Although data are limited, there is evidence to suggest the presence of reproductive potential in the gonads of some individuals with DSD. Larger, more detailed studies are required, but if these continue to be encouraging, individuals with DSD should be given the same information, opportunities and access to fertility preservation as other patient groups., (© 2019 John Wiley & Sons Ltd.)

The objective of our study was to use an established cohort of boys to investigate common patterns of malformations in those with hypospadias. We performed a retrospective review of the phenotype of participants in the Deciphering Developmental Disorders Study with neurodevelopmental delay and an 'Abnormality of the genital system'. This group was divided into two subgroups: those with hypospadias and without hypospadias. Associated phenotypes of the two subgroups were compared and analysed. Of the 166 Deciphering Developmental Disorders participants with hypospadias and neurodevelopmental delay, 47 (28%) had cardiovascular and 40 (24%) had structural brain abnormalities. The rate of cardiovascular abnormalities in those with neurodevelopmental delay and genital abnormalities other than hypospadias (N = 645) was lower at 19% (P = 0.001). In addition, structural brain malformations were higher at 24% in the hypospadias group versus 15% in the group without hypospadias (P = 0.002). The constellation of these features occured at a higher rate in the hypospadias group versus the no hypospadias group (P = 0.038). In summary, this is the first study to indicate that cardiovascular and brain abnormalities are frequently encountered in association with hypospadias in children with neurodevelopmental disorders. Not only do these associations provide insight into the underlying aetiology but also they highlight the multisystem involvement in conditions with hypospadias.

Hypospadias is among the most common congenital malformations in male neonates. It results from abnormal penile and urethral development, but is a multifactorial disorder that is highly heterogeneous, with several genetic and environmental determinants. Monogenic and chromosomal abnormalities are present in approximately 30% of cases, although the genetic factors contributing to hypospadias remain unknown in 70% of cases. While defects in androgen synthesis can lead to this malformation, mutational analyses have shown several genes, such as sonic hedgehog, fibroblast growth factors, bone morphogenetic proteins, homeobox genes, and the Wnt family, are involved in the normal development of male external genitalia. Mutations in the genes of penile development (e.g., HOX, FGF, Shh) and testicular determination (e.g., WT1, SRY), luteinizing hormone receptor, and androgen receptor have also been proposed to be implicated in hypospadias. Here we review the recent advances in this field and discuss the potential genes that could determine the risk of hypospadias., (© 2018 Wiley Periodicals, Inc.)

Background: Hypospadias is a common malformation of the male external genitalia that results in urethral displacement with different levels of severity. Male genital development during the fetal period is dependent on androgen function, while the etiology of hypospadias differs and can be multifactorial. The psychosocial outcome is sometimes affected, but according to several studies acceptable. The question of whether hypospadias is associated with differences in psychosexual development has been investigated previously, with mixed results. There are no previous investigations of cognitive abilities in men with hypospadias., Objective: The aim of this study was to investigate whether hypospadias is associated with differences in performance on cognitive tests and/or gender role behavior., Participants: Eighty-six men with hypospadias were compared to male and female controls from the general population., Procedure: Cognitive tasks, previously shown to yield group level sex differences and questions regarding self-reported childhood gender role behavior, were administered either at an outpatient clinic visit or via online participation., Results: The cognitive performance of men and women in the control groups differed significantly in the expected directions. Men and women also differed on self-reported childhood gender role behavior questions. There were no significant differences between men with and without hypospadias on any of the measures. Men with proximal hypospadias performed slightly lower on many of the cognitive tasks in comparison to men with distal hypospadias and controls., Conclusion: In general, hypospadias is not associated with differences in performance on cognitive tests that typically yield sex differences or with altered gender role behavior in childhood. Further studies on cognitive abilities in boys and men with proximal hypospadias are warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The ventral aspect of the penis in boys with hypospadias is composed of dysplastic tissue of the skin and the urethra. The aim of this study was to assess the pre-operative size and biomechanical properties of urethrae in boys with and without hypospadias using a more objective catheter-based system., Materials & Methods: In this non-blinded clinical observation study, the study population consisted of 19 boys with hypospadias-the case group (median age 13.9 months [range: 12.2-21.3])-and seven boys without hypospadias-the control group (median age 8.5 months [range: 3.8-18.1]). Modified measurements of impedance were used to assess the size, compliance and viscoelasticity of the urethrae under stepwise increased pressures (between 0, 40 and 60 cmH 2 O) using a customised Endolumenal Functional Lumen Imaging probe (EndoFLIP®)., Results: The sizes of the urethrae in boys with hypospadias are variable but tend towards being narrower and less compliant than those of the control subjects i.e. median diameter for meatus urethra was 3.2 mm (range: 2.98-3.92) in the hypospadias group compared with 3.64 (range: 3.22-4.44) in the control group at 40 cmH 2 O, and the median change in diameter at meatus urethra was 0.08 mm (range: -0.02 to 0.52) in the hypospadias group compared with 0.23 mm (range: -0.02 to 0.34) when the pressure was increased from 40 to 60 cmH 2 O. This biomechanical analysis found that there was no significant viscoelasticity of the urethral meatus in both the groups, whereas the remainder of the urethral structure generally had viscoelastic properties in the control group, seen as a creep on the time/diameter curves (Figure). In the group of boys with hypospadias, evaluations of the urethrae revealed varying viscoelastic abilities, ranging from abilities that were comparable with those of the control subjects to no sign of viscoelasticity at all., Conclusions: This study is the first to measure the biomechanical properties of the urethra in children, which might help to provide an understanding as to the structural and functional changes associated with hypospadias. The urethrae in the subjects with hypospadias were variable in diameter but tended to be narrower overall, especially in the distal portion of the urethra. Furthermore, the urethrae in boys with hypospadias were frequently less viscoelastic than those of controls., Clinical Relevance: The EndoFLIP® system may be a future way of objectively estimating the severity of a urethral obstruction and could potentially be included in the postoperative assessment of patients with signs of hampered voiding., (Copyright © 2018 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

BACKGROUND We investigated the role of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway in finasteride-induced hypospadias rats and explored the mechanisms involved. MATERIAL AND METHODS The hypospadias model was established by intragastric administration of finasteride and confirmed by hematoxylin and eosin (HE) staining. The urethral plate fibroblasts (UPF) were obtained from normal and modeled rats and identified based upon vimentin expression. Thereafter, UPF were divided into a normal control group, a model group, a model + MAPK inhibitor group, and a model + ERK inhibitor group. Cell proliferation, apoptosis, and cell cycling of UPF were assessed. Quantitative real-time PCR and Western blot analysis were used to evaluate expression of the MAPK signaling pathway and apoptosis-related genes. RESULTS HE staining confirmed that 10 mg/kg finasteride caused severe hypospadias in rats. UPFs obtained from the 10 mg/kg finasteride group showed higher proliferation and cell cycling and lower apoptosis compared with those obtained from the normal control group (P<0.05). Interestingly, a MAPK inhibitor or an ERK inhibitor could attenuate the abnormalities of cell proliferation, cycling, and apoptosis of UPF induced by finasteride. Compared with controls, the relative expression of p-MEK1/MEK1, caspase 3, and P53 in the UPF of the model group were reduced, while the relative expression of p-MAPK14/MAPK14 was increased in the cells of the model group. By contrast, a MAPK inhibitor or an ERK inhibitor could alleviate the abnormalities of MAPK/ERK signaling pathway and apoptosis-related gene expression induced by finasteride. CONCLUSIONS Our study reveals that the MAPK/ERK signaling pathway is involved in the regulation of proliferation, apoptosis, and cell cycling of UPFs in finasteride-induced hypospadias.

Purpose: We evaluated psychosocial outcomes, psychosexual development and sexual function in adolescents who had undergone surgery for proximal hypospadias. We hypothesized that these outcomes would be impaired compared to peers., Materials and Methods: We identified 55 males age 14 years or older who underwent surgery for penoscrotal to perineal (intraoperatively defined) hypospadias between 1996 and 2005. A total of 33 patients with a median age of 17.5 years (range 14 to 25) answered a Web based questionnaire with self-constructed questions, completed the validated Psychological General Well-Being Index, Body-Esteem Scale for Adolescents and Adults and Penile Perception Score, and underwent clinical evaluation. A total of 31 patients with distal hypospadias (median age 19 years, range 14 to 35) and 25 age matched healthy men (17.5 years, range 14 to 25) served as controls., Results: Interest in sex, age at sexarche and satisfaction with sexual experiences were comparable between patients and controls. Three patients with proximal hypospadias (10%) and 1 control (4%) reported occasional erectile problems. Three patients with proximal hypospadias (11%), 1 patient with distal hypospadias (3%) and 1 control (4%) affirmed anejaculation. There were no differences in results between validated questionnaires. Patients with proximal hypospadias were more dissatisfied with penile length (39%) compared to controls (12%, p = 0.049). Concerning physical contact, 10 patients (38%) expressed uncertainty. Extra support in school was more frequent among patients with proximal hypospadias (p = 0.024 vs distal hypospadias, p = 0.068 vs control group)., Conclusions: Despite concerns regarding penile length, sexual experiences were comparable to those of other adolescents, although more than a third of patients with proximal hypospadias demonstrated uncertainty on questions relating to desire for physical contact. Specialized tutoring in school was more common in patients with proximal hypospadias. Continuous followup throughout childhood allowing extra time for age adequate information and support is warranted., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Disorders of sex development (DSD) are congenital conditions in which the typical genetic and hormonal profiles are affected and thereby the usual process of sexual differentiation. Most of these studies, however, have been conducted in Western countries. In the present study, preschool sex-typed activities of Iranian individuals with DSD and their age-matched non-affected male and female relatives were assessed using the Pre-School Activities Inventory (PSAI) modified for retrospective self-report. A total of 192 individuals participated in our study, including 33 46,XX individuals with congenital adrenal hyperplasia (CAH; M age = 10.36, SD = 5.52), 15 46,XY individuals with complete androgen insensitivity syndrome (CAIS; M age = 19.8, SD = 7.14), and 16 46,XY individuals with 5-alpha reductase deficiency type-2 (5α-RD-2; M age = 17.31, SD = 7.28), as well as one age-matched non-affected male and female relative for each patient. With regard to PSAI scores, male-identifying participants with 5α-RD-2 and male controls reported similar levels of male-typical childhood play. Female-identifying participants with 5α-RD-2 and CAH showed comparable scores: significantly less masculine and more feminine than male controls, but significantly more masculine and less feminine than females with CAIS and female controls. These findings support the role of androgens in the development of sex-typical childhood play behavior, with those being exposed to higher levels of fetal functional androgens expressing more masculine behavior at preschool ages.

Objective: To describe the surgical approach and outcomes in the treatment of adult patients with complications of childhood hypospadias surgery, as such patients present a significant reconstructive challenge due to the combination of anatomical and cosmetic deformity, which often results in major functional and psychosexual sequelae., Patients and Methods: We analysed prospectively collected data on 79 adults with complications of childhood hypospadias surgery, who were operated on between 2004 and 2016. Of the 79 patients, 48 underwent a two-stage urethroplasty using a buccal mucosa graft, and 31 underwent a one-stage distal urethroplasty., Results: Patients were followed up using flexible cystoscopy (every 6-9 months). The mean (range) follow-up was 48 (12-96) months. Of the 48 patients who underwent a two-stage repair, eight (16%) needed a revision of the first-stage graft. In total, nine of the 48 patients (16%) developed fistula requiring closure after the second stage; all but one was closed successfully on the first attempt, whilst one required two attempts before closure. Only two of the 48 patients that underwent a two-stage procedure required a re-do urethroplasty within 3 years. Of the 31 patients who underwent a one-stage repair, six (19%) needed fistula closure, all of which were successful. No patient required a further urethroplasty during follow-up., Conclusions: Despite the significant surgical challenges found in this patient group, excellent long-term functional outcomes can be achieved. As expected there is a need for additional intervention, either for revision of the first stage or to close fistulae and less commonly for further reconstruction for stricture recurrence., (© 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.)

Introduction: One of the goals of hypospadias repair is to create a neourethra with normal urinary stream and normal growth. Several studies have reported that dorsal inlay graft urethroplasty (DIG) has wide indications for various clinical phenotypes of hypospadias, with good short-term outcomes and few complications. However, there have been no reports that evaluated both short-term and long-term functional outcomes using uroflowmetry in patients with DIG., Objective: The aim was to investigate whether uroflowmetry parameters change with time following DIG for hypospadias in early childhood., Materials and Methods: Uroflowmetry parameters after DIG for hypospadias in childhood were retrospectively evaluated and compared between two defined ages at follow-up: 4-6 years and 11-13 years. Maximum urinary flow (Q max ) under the 25th percentile on the Miskolc nomogram was defined as obstruction. To evaluate the shapes of uroflow quantitatively, the flow index (FI) was used. The FI cut-offs for the flow shapes were defined as tower >1.253, plateaus <0.659; bells were between these two values., Results: Thirty-four patients met the inclusion criteria. The median operative age was 1.8 years (range 1.0-4.9 years). The median follow-up time was 10.3 years (range 7.2-12.3 years). The mean ± SD Q max at the two follow-up times increased with time, from 9.2 ± 3.7 to 18.8 ± 7.8. The mean ± SD FI changed from 0.53 ± 0.19 to 0.85 ± 0.31. Both Q max and the FI were significantly improved (p < 0.001, p < 0.001, respectively). There were significantly fewer patients with obstruction evaluated by the Miskolc nomogram at 11-13 years of age (n = 11, 32.4%) than at 4-6 years (n = 31, 91.2%) (p < 0.001). Plateau shapes assessed by the FI were seen in 24 (70.6%) patients at 4-6 years and 10 (29.4%) patients at 11-13 years (Table). The number of patients with plateau shapes was significantly decreased (p = 0.001)., Discussion: Only one report noted long-term outcomes and spontaneous uroflowmetry resolution after tubularized incised plate urethroplasty. The current report is the first to present the short-term and long-term uroflowmetry outcomes after DIG. In addition, the FI was used for the first time to evaluate uroflowmetry after hypospadias repair. It was found that the uroflowmetry parameters improved spontaneously over 11 years of age following DIG for hypospadias in early childhood., Conclusion: Uroflowmetry parameters improved spontaneously over 11 years of age following DIG for hypospadias in early childhood., (Copyright © 2018 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: Inhibin B is a hormone produced by the Sertoli cells that can provide important information for the investigation of disorders of sex development (DSD) with 46,XY karyotype. The aim of this study is to compare two enzyme-linked immunosorbent assay (ELISA) assays for dosage of serum inhibin B in patients with 46,XY DSD with normal testosterone secretion., Methods: Twenty-nine patients with 46,XY DSD and normal testosterone secretion (partial androgen insensitivity syndrome [PAIS] [n=8]; 5α-reductase deficiency [n=7] and idiopathic 46,XY DSD [n=14]) were included. Molecular analysis of the AR and SRD5A2 genes were performed in all patients and the NR5A1 gene analysis in the idiopathic group. Measurements of inhibin B were performed by two second-generation ELISA assays (Beckman-Coulter and AnshLabs). Assays were compared using the interclass correlation coefficient (ICC) and the Bland-Altman method., Results: ICC was 0.915 [95% confidence interval (CI): 0.828-0.959], however, a discrepancy was observed between trials, which is more evident among higher values when analyzed by the Bland-Altman method., Conclusions: It is recommended to perform the inhibin B measurement always using the same ELISA kit when several evaluations are required for a specific patient.

Background: : Tubularized incised plate (TIP) urethroplasty is the most common technique noted to correct hypospadias. However, urethrocutaneous fistula (UCF) is still one of the most common complications of this technique. Several techniques of providing vascularized flaps to the neourethra have been recommended to decrease this complication rate. The aim of the study was to assess the outcome of primary repair of hypospadias using tunica vaginalis (TV) flap with those using preputial dartos (PD) fascia., Patients and Methods: : Children diagnosed with hypospadias between the age group of 9 months to 18 years, who fulfilled the criteria were randomly divided into two groups by computerized randomization technique. Initially, TIP urethroplasty was done. Children with PD vascular cover were included in Group A and those with TV vascular cover were included in Group B. All the patients were followed up for a minimum of 6 months after surgery., Results: : Two (10%) patients in Group A developed UCF and one (5%) patient developed stricture urethra in the follow-up period. None of the patients developed UCF in the Group B. One (5%) patient had stricture urethra in Group B. Two (10%) patient developed meatal stenosis in Group A. Two (10%) patient in Group B developed meatal stenosis., Conclusions: TV flap could be an alternative to PD flap as a vascular cover of neourethra in patients undergoing primary hypospadias repair by TIP urethroplasty., Competing Interests: None

Objectives: The study aimed to evaluate the new modification of the Duckett technique in decreasing the incidence of urethral strictures for urethral plate transected hypospadias and also explored its clinical application., Methods: Thirty-three patients (aged 7 months to 12 years, mean age 2.8 years) who underwent repair of primary hypospadias using the new one-stage urethroplasty were enrolled. Clinical data, including cosmetic and its complications, and uroflowmetry data were documented. Uroflowmetry data of 19 patients who underwent Duckett urethroplasty were used as a comparison., Results: The length of the urethral defect ranged from 2.5 to 5.0 cm. The postoperative follow-up was 14-30 months. Ten patients (30.3%) had fistulas; no patients had strictures or diverticula. All ten fistulas were small (<0.5 cm) and repaired with fistula repairing operation. The appearance of the penis remained satisfactory, and the meatus was located in the normal anatomic position. Among 17 patients who underwent uroflowmetry, all patients were bell-shaped or platforms, and Q max was 7.37 ± 2.45 ml/s. Compared with 14 of 19 patients who underwent Duckett urethroplasty, the urethral function achieved with new one-stage urethroplasty was significantly better (p < 0.05)., Conclusions: The incidence of strictures was dramatically lowered in patients with proximal hypospadias. Small fistulas are common complications and can be repaired easily. Based on the uroflow pattern results, the quality of neourethra and function of it were better than Duckett urethroplasty. These preliminary results suggested that the modified procedure seems to be reliable and can be a suitable option for proximal hypospadias.

Background: We examined the association of hypospadias risk with maternal smoking and consumption of alcohol and caffeine., Methods: We analyzed data from mothers of 2437 moderate/severe cases and 5472 nonmalformed controls born from 1997 to 2011 who participated in the National Birth Defects Prevention Study (NBDPS). Exposures were assessed by maternal telephone interviews. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for mother's age, parity, race-ethnicity, education, vitamin/mineral supplement intake, obesity, and study center., Results: Active smoking during the first month of pregnancy was associated with reduced risk, with smaller ORs for increasing quantity smoked; the OR for smoking >1/2 pack/day was 0.7 (95% CI, 0.5-0.9). Among nonsmokers, the OR for any secondhand smoke exposure was 0.8 (95% CI, 0.7-0.9). ORs for alcohol and caffeine consumption were near one and CIs included 1.0. In an analysis of joint exposures to smoking and alcohol and caffeine consumption, the only OR for which the 95% CI excluded 1.0 was for women who smoked, drank, and had low caffeine consumption (OR, 0.6; 95% CI, 0.4-0.8)., Conclusion: Maternal exposure to cigarette smoke was associated with reduced risk, and women who smoked, drank, and had low caffeine intake were at lowest risk. We do not interpret these results to suggest that these exposures have overall benefit to a pregnant woman or developing fetus. They may, however, offer clues to help us understand mechanisms that lead to hypospadias. Birth Defects Research 109:1127-1133, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Sex assignment at birth remains one of the most clinically challenging and controversial topics in 46,XY disorders of sexual development (DSD). This is particularly challenging in deficiency of 5-alpha reductase type 2 given that external genitalia are typically undervirilized at birth but typically virilize at puberty to a variable degree. Historically, most individuals with 5-alpha reductase deficiency were raised females. However, reports that over half of patients who underwent a virilizing puberty adopted an adult male gender identity have challenged this practice. Consensus guidelines on assignment of sex of rearing at birth are equivocal or favor male assignment in the most virilized cases. While a male sex of rearing assignment may avoid lifelong hormonal therapy and/or allow the potential for fertility, female sex assignment may be more consistent with external anatomy in the most severely undervirilized cases. Herein, we describe five patients with 46,XY DSD due 5-alpha-reductase type 2 deficiency, all with a severe phenotype. An inter-disciplinary DSD medical team at one of two academic centers evaluated each patient. This case series illustrates the complicated decision-making process of assignment of sex of rearing at birth in 5-alpha reductase type 2 deficiency and the challenges that arise when the interests of the child, parental wishes, recommendations of the medical team, and state law collide., (© 2017 Wiley Periodicals, Inc.)

The majority of patients with DSD will be found to carry an XY karyotype and be assigned male gender. From a phenotypical standpoint, most will present with proximal hypospadias ± cryptorchidism. In this review article, the authors present the current status of reconstruction of the male genitalia in this setting. The report addresses the following topics: surgical input in the evaluation of the newborn with an undervirilized external genitalia, including gender assignment considerations; controversies surrounding timing and indication for hypospadias surgery in proximal cases as well as use of testosterone; surgical techniques and decision-making process for one- vs. two-stage repairs; complications of hypospadias surgery based on technique used for repair; and long-term follow-up. The high complication rates observed in the treatment of proximal hypospadias attest to its challenging nature. Concentration of experience, tracking carefully identified patient-centered outcomes and long-term follow-up of this patient population are recommended., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Male genital anomalies often require surgery in early life to address functional and cosmetic consequences. However, there has been little assessment of developmental outcomes of affected boys., Methods: We conducted a population-based cohort study of all boys born in New South Wales, Australia, and undergoing school-entry developmental assessment in 2009 or 2012. Health and developmental information was obtained by means of record-linkage of birth, hospital and Australian Early Development Census data. Boys with hypospadias or undescended testis (UDT) were compared with those without. Developmental outcomes were assessed in five domains (physical health, emotional maturity, communication, cognitive skills, and social competence), and boys were categorized as vulnerable (<10 th centile of national scores), developmentally high risk (DHR; vulnerable in 2+ domains), and special needs., Results: We included 420 boys with hypospadias, 873 with UDT, and 77,176 unaffected boys. There was no difference in the proportion of boys developmentally vulnerable in any domain or DHR between boys with hypospadias (DHR: n = 49; 13.1%; p = 0.9), UDT (n = 116; 15.2%; p = 0.06), and unaffected boys (n = 9278; 12.9%). Compared with unaffected boys (n = 4826; 6.3%), boys with hypospadias (n = 43; 10.2%; p < 0.001) or UDT (n = 105; 12.0%; p < 0.001) were more likely to have special needs. Stratified analyses revealed that only boys with UDT and coexisting anomalies had increased risk of being DHR (odds ratio: 2.65; 95% confidence interval, 1.61-4.36) or special needs (odds ratio: 2.91; 95% confidence interval, 2.00-4.22)., Conclusion: We found no increased risk of poor development among boys with hypospadias or UDT. However, boys with UDT and coexisting anomalies were more likely to have poorer development and special needs. Birth Defects Research 109:535-542, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Objective: To evaluate prevalence trends of hypospadias in South-America it is essential to perform multicenter and multinational studies with the same methodology. Herein we present systematic data as part of an international multicenter initiative evaluating congenital malformations in South America over a 24-year period., Materials and Methods: A nested case-control study was conducted using the Latin American Collaborative Study of Congenital Malformations (ECLAMC), between January 1989 and December 2012. Cases were stratified as isolated (IH) and non-isolated hypospadias (NIH). Global prevalence was calculated and discriminated by country. Associations between birth weight and gestational age, and NIH distribution by associated abnormality and severity of hypospadias, were analyzed., Results: A total of 159 hospitals from six countries participated, reporting surveillance on 4.020.384 newborns. A total of 4.537 hypospadias cases were detected, with a global prevalence of 11.3/10.000 newborns. Trend analyses showed in Chile, Brazil and Uruguay a statistically significant increase in prevalence. Analysis of severity and associated anomalies did not to find an association for distal cases, but did for proximal (RR=1.64 [95% CI=1.33-2.03])., Conclusion: This is one of only a few Latin American multicenter studies reporting on the epidemiology of hypospadias in South America in the last two decades. Our data adds to evidence suggesting an increase in some countries in the region at different times. There were also variations in prevalence according to severity. This study adds to literature describing associated anomalies at a hospital-based level., (Copyright® by the International Brazilian Journal of Urology.)

The aim of this study was to investigate sexual function and fertility in adult men born with hypospadias. Patients born with hypospadias, age-matched controls, and a group of circumcised men completed a questionnaire constructed to reflect their psychosexual situation and fertility. Core gender identity, sexual orientation, and gender role behavior was also assessed. 167 patients [63% distal, 24% mid shaft and 13% proximal, mean age 34 (19-54) years], 169 controls from the general population [mean age 33 (19-48) years] and 47 controls circumcised because of phimosis (mean age 26 [19-44]) participated and completed the questionnaire. There were no differences in having a partner, reported fertility, age at sexarche (mean age 17.8), number of sex partners or sexual interest between the patients and controls. More patients than controls reported anejaculation. Reported glanular sensitivity was lower in hypospadias patients and circumcised controls compared with non-circumcised controls. The odds of being satisfied with their sexual life increased with a higher penile perception score in patients (OR = 1.54, p = 0.01). There was no association with penile length. Sexual orientation, core gender identity and gender role behavior were sex-typical in both patients and controls. Patients with proximal hypospadias had a lower reported fertility, experienced anejaculation more often, and were less satisfied with their sexual life. Men born with hypospadias have a good long-term outcome concerning sexual function and fertility. Men born with proximal hypospadias have a more impaired outcome concerning both sexual function and fertility. As satisfaction with genital appearance is important for sexual life satisfaction, clinical, and psychological follow-up into adulthood is especially important in boys born with proximal hypospadias., (© 2016 American Society of Andrology and European Academy of Andrology.)

This paper provides the first detailed description of flutamide-induced hypospadias in the rat based upon wholemount, histologic, three-dimensional reconstruction, scanning electron microscopic, and immunocytochemical analysis. The penile malformations elicited by this potent anti-androgen include a substantial proximal shift in the urethral meatus that clearly conforms to the definition of hypospadias based upon specific morphological criteria for this malformation. Through examination of the normal penile development and flutamide-induced abnormal penile development observed in prenatally oil- and flutamide-treated rats, our analysis provides insights into the morphogenetic mechanism of development of hypospadias. In this regard, a common theme in normal penile development is midline fusion of epithelia followed by removal of the epithelial seam and establishment of midline mesenchymal confluence during development of the penile urethra and prepuce, processes which are impaired as a result of prenatal flutamide treatment. The developmental processes occurring in normal penile development, through comparison with development of female external genitalia and those impaired due to prenatal flutamide treatment, are consistent with critical role of androgen receptors in normal penile development in the rat, and the specific penile abnormalities embodied in flutamide-induced rat hypospadias., (Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

Objective: To describe modification of the tubularized incised plate urethroplasty (TIP) for distal hypospadias, and assess its efficacy, and functional and cosmetic outcomes., Methods: A prospective evaluation of a consecutive series of patients operated for primary distal hypospadias was conducted at a tertiary reference center. A standardized modification of the TIP (mTIP) procedure was performed on a 10 French catheter. Clinical data were collected in a dedicated database. Intraoperative variables, postoperative complications and outcomes, by means of uroflowmetries and a validated (HOPE) questionnaire, were assessed. Efficacy was evaluated with the reported complications: functional outcome was evaluated with uroflowmetries and cosmetic assessment by a validated questionnaire (HOPE). A descriptive statistical analysis was performed., Results: Of the 112 boys operated between 30/09/2011 and 1/04/2014, 50 completed long-term follow-up with functional and esthetic evaluation, as required for inclusion. Median age at surgery was 25 months (range 14-156); median follow-up time was 21.5 months (range 6-48). Complications requiring re-intervention occurred in 2/50 boys. Uroflowmetry presented a bell-shaped curve in 47/50 boys, and the median HOPE score was 9.5 (range 7.6-10.0)., Conclusion: The mTIP procedure provided satisfactory long-term functional and cosmetic outcomes, as validated by uroflowmetries and standardized questionnaire., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Background: Several techniques have been used to repair mid-penile hypospadias; however, high failure rates and major complications have been reported. In this study, we describe a novel technique using a well-vascularized flap of the inner and outer preputial skin., Methods: A total of 110 male children with hypospadias underwent repair by our technique between 2008 and 2015. The inclusion criteria were children with mid-penile or slightly more proximal hypospadias, with or without ventral chordae, and an intact prepuce of the cobra eyes variety. Recurrent cases, patients with other preputial types, and circumcised children were excluded from this study. The prepared flap was sutured in its natural longitudinal orientation to the created urethral plate strip to form a neo-urethra over a urethral catheter. Outcome measures included surgical success without the formation of a urethra-cutaneous fistula, no ischaemia of the flaps, glans dehiscence or infection and functional outcome and cosmetic appearance., Results: The median follow-up duration was 3.3 years. There were 63 cases of mid-penile hypospadias (57.3 %), and in 47 cases (42.7 %), the meatus was slightly more proximal. The age of the patients ranged from 1.1 to 8.0 years, with a mean age of 4.6 ± 1.2 years. Surgery was successful in 106 (96.4 %) cases. Minor complications occurred in 11 patients (10 %) and included oedema of glans in ten patients and bluish discoloration on the ventral aspect of the glans close to the suture line in three patients. All patients improved within 2 weeks after surgery. Long-term follow-up revealed a properly functioning urethra with a forward, projectile, single, compact, and rifled urinary stream of adequate calibre and cosmetically acceptable repair. No cases of meatal retraction, meatal stenosis, urethral stricture, or acquired urethral diverticulum occurred., Discussion: Our technique is different from the split prepuce in situ technique. We create a narrow strip of the urethral plate that facilitates glanular closure, and we use the inner and adjacent outer skin in a vertical manner to preserve excess skin for penile coverage. Prepuce is split at midline to preserve more preputial skin with favourable dartos tissue for penile skin coverage. The glans is closed using a stitch-by-stitch method that has not been described previously., Conclusion: This study presents a novel technique for mid-penile hypospadias repair using a preputial skin flap with excellent results in terms of short- and long-term outcomes.

Hypospadias is a common malformation whose etiology is based upon perturbation of normal penile development. The mouse has been previously used as a model of hypospadias, despite an unacceptably wide range of definitions for this malformation. The current paper presents objective criteria and a definition of mouse hypospadias. Accordingly, diethylstilbestrol (DES) induced penile malformations were examined at 60 days postnatal (P60) in mice treated with DES over the age range of 12 days embryonic to 20 days postnatal (E12-P20). DES-induced hypospadias involves malformation of the urethral meatus, which is most severe in DES E12-P10, DES P0-P10 and DES P5-P15 groups, and less so or absent in the other treatment groups. A frenulum-like ventral tether between the penis and the prepuce was seen in the most severely affected DES-treated mice. Internal penile morphology was also altered in the DES E12-P10, DES P0-P10 and DES P5-P15 groups (with little effect in the other DES treatment groups). Thus, adverse effects of DES are a function of the period of DES treatment and most severe in the P0-P10 period. In "estrogen mutant mice" (NERKI, βERKO, αERKO and AROM+) hypospadias was only seen in AROM+ male mice having genetically-engineered elevation is serum estrogen. Significantly, mouse hypospadias was only seen distally at and near the urethral meatus where epithelial fusion events are known to take place and never in the penile midshaft, where urethral formation occurs via an entirely different morphogenetic process., (Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

Hypospadias is one of the most common birth defects in male infants. Maternal hypertension is a suspected risk factor; however, few previous studies have addressed the possibility of reporting bias, and several previous studies have not accounted for hypospadias severity. We analyzed data from the Texas Birth Defects Registry for 10,924 nonsyndromic cases and statewide vital records for deliveries during 1999-2009, using Poisson regression. After adjustment for potential confounders, hypospadias was associated with maternal hypertension (adjusted prevalence ratio: 1.5, 95% confidence interval: 1.4-1.7). Similar associations were observed with gestational and pregestational hypertension, including separate analyses restricted to the subset of cases with severe (second- or third-degree) hypospadias. All of these associations were also similar among the subset of cases with isolated hypospadias (without additional birth defects). To evaluate the potential for bias due to potential hypertension misclassification, we repeated our analyses using logistic regression, comparing the cases to controls with other birth defects. In these analyses, the associations with gestational hypertension were similar, but adjusted associations with pregestational hypertension were no longer observed. Our findings support an association between gestational hypertension and hypospadias in offspring, but also suggest that previously observed associations with pregestational hypertension may have been inflated due to differential misclassification of hypertension (e.g., reporting bias). As gestational hypertension is recognized after hypospadias development, more research is needed to determine if this association reflects an increase in gestational hypertension risk secondary to hypospadias or if both conditions have shared risk factors (e.g., precursors of gestational hypertension). © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Disorders of sexual development (DSD) encompass a broad spectrum of urogenital malformations and are amongst the most common congenital birth defects. Although key genetic factors such as the hedgehog (Hh) family have been identified, a unifying postnatally viable model displaying the spectrum of male and female urogenital malformations has not yet been reported. Since human cases are diagnosed and treated at various stages postnatally, equivalent mouse models enabling analysis at similar stages are of significant interest. Additionally, all non-Hh based genetic models investigating DSD display normal females, leaving female urogenital development largely unknown. Here, we generated compound mutant mice, Gli2+/-;Gli3Δ699/+, which exhibit a spectrum of urogenital malformations in both males and females upon birth, and also carried them well into adulthood. Analysis of embryonic day (E)18.5 and adult mice revealed shortened anogenital distance (AGD), open ventral urethral groove, incomplete fusion of scrotal sac, abnormal penile size and structure, and incomplete testicular descent with hypoplasia in male mice, whereas female mutant mice displayed reduced AGD, urinary incontinence, and a number of uterine anomalies such as vaginal duplication. Male and female fertility was also investigated via breeding cages, and it was identified that male mice were infertile while females were unable to deliver despite becoming impregnated. We propose that Gli2+/-;Gli3Δ699/+ mice can serve as a genetic mouse model for common DSD such as cryptorchidism, hypospadias, and incomplete fusion of the scrotal sac in males, and a spectrum of uterine and vaginal abnormalities along with urinary incontinence in females, which could prove essential in revealing new insights into their equivalent diseases in humans., Competing Interests: The authors have declared that no competing interests exist.

We recently described a two-step process of urethral plate canalization and urethral fold fusion to form the human penile urethra. Canalization ("opening zipper") opens the solid urethral plate into a groove, and fusion ("closing zipper") closes the urethral groove to form the penile urethra. We hypothesize that failure of canalization and/or fusion during human urethral formation can lead to hypospadias. Herein, we use scanning electron microscopy (SEM) and analysis of transverse serial sections to better characterize development of the human fetal penile urethra as contrasted to the development of the human fetal clitoris. Eighteen 7-13 week human fetal external genitalia specimens were analyzed by SEM, and fifteen additional human fetal specimens were sectioned for histologic analysis. SEM images demonstrate canalization of the urethral/vestibular plate in the developing male and female external genitalia, respectively, followed by proximal to distal fusion of the urethral folds in males only. The fusion process during penile development occurs sequentially in multiple layers and through the interlacing of epidermal "cords". Complex epithelial organization is also noted at the site of active canalization. The demarcation between the epidermis of the shaft and the glans becomes distinct during development, and the epithelial tag at the distal tip of the penile and clitoral glans regresses as development progresses. In summary, SEM analysis of human fetal specimens supports the two-zipper hypothesis of formation of the penile urethra. The opening zipper progresses from proximal to distal along the shaft of the penis and clitoris into the glans in identical fashion in both sexes. The closing zipper mechanism is active only in males and is not a single process but rather a series of layered fusion events, uniquely different from the simple fusion of two epithelial surfaces as occurs in formation of the palate and neural tube., (Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

Hypospadias, a congenital malformation of the penis characteristic of an abnormal urethral orifice, affects 1 in every 125 boys, and its incidence is rising. Herein we test the hypothesis that the basement membrane protein laminin α5 (LAMA5) plays a key role in the development of the mouse genital tubercle, the embryonic anlage of the external genitalia. Using standard histological analyses and electron microscopy, we characterized the morphology of the external genitalia in Lama5 knockout (LAMA5-KO) mouse embryos during both androgen-independent genital tubercle development and androgen-mediated sexual differentiation. We compared regulatory gene expression between control and LAMA5-KO by in situ hybridization. We also examined the epithelial structure of the mutant genital tubercle using immunofluorescence staining and histological analyses of semi-thin sections. We found that Lama5 was expressed in both ectodermal and endodermal epithelia of the cloaca. The LAMA5-KO displayed a profound external genital malformation in which the genital tubercle was underdeveloped with a large ectopic orifice at the proximal end. In older embryos, the urethra failed to form a tubular structure and was left completely exposed. These defects were not associated with a significant alteration in regulatory gene expression, but rather with a defective ectodermal epithelium and an abnormal disintegration of the cloacal membrane. We conclude that LAMA5 is required in the basement membrane to maintain normal architecture of the ventral ectoderm during genital tubercle development, which is essential for the formation of a tubular urethra. Perturbation of LAMA5, and possibly other basement membrane components, may cause hypospadias in humans., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose of Review: This article provides a subjective, concise review of contemporary advances in reconstructive urology as it pertains to adult hypospadias repair. Herein, we highlight the most important and interesting articles among the many published within the past 12 months., Recent Findings: The main themes in the recent literature covered herein, include management of postoperative complications, long-term follow-up, and penile cosmesis., Summary: Recent literature would suggest beauty is in the eye of the beholder when it comes to cosmesis after hypospadias repair. Long-term data are reassuring regarding uroflow improvement through puberty and into adulthood for common distal shaft hypospadias repairs.

Objective: To evaluate the role of subdartos fascial tissue as watertight layer in improving outcome for 2-stage proximal hypospadias surgery., Methods: The experimental study was conducted at the Department of Urology, Indus Hospital, Karachi, and comprised an audit of patients with proximal hypospadias who underwent surgery from July 1, 2007, to December 31, 2011. The initial two-stage repair of proximal hypospadias led to a high rate of urethrocutanous fistula formation (Group A), and, thus, a modification was introduced and subdartos facial double layer was applied over the urethral suture line (Group B). The results were compared regarding age, type of hypospadias, graft failure and urethrocutanous fistula in these patients., Results: There were 27 patients in Group A and 16(59.3%) of them ended up having urethrocutanous fistula. Group B had 25 patients and only 2(8%) had fistula formation., Conclusions: The application of dartos facial flap waterproofing layer reduced fistula rate.

Introduction: As there is only scarce information on the parents' view of the cosmetic outcome after hypospadias surgery we aimed to evaluate whether the results of the hypospadias objective penile evaluation (HOPE) score are transferable to parents satisfaction as measured by the pediatric penile perception score (PPPS)., Patients: 42 patients after hypospadias correction were included (2 (6.9%) glandular, 20 (68.9%) coronal, 6 (20.6%) penile and 1 (3.4%) scrotal hypospadias, median age 15.0 months). Two surgeons independently assessed HOPE score; the PPPS score as well as 4 questions specifically designed by a psychologist were completed by fathers and mothers. 29 (69.9%) full datasets were available for evaluation., Results: Parents' assessment of the cosmetic results was worse than surgeons' assessment (81.13% [PPPS] vs. 92.81% [HOPE] of the respectively possible highest score, P < 0.0001). All 58 parents (100%) were convinced that surgery led to a better cosmetic aspect of their sons' genitalia although both, mothers and fathers, perceived the operation as a major encumbrance (fathers 3.62 vs. mothers 3.97 on a scale from 0-6, P = 0.22)., Conclusion: Parents can be encouraged preoperatively that a hypospadias operation, seen from their point of view will be a major amendment to the cosmetic appearance of their sons' genitalia even if the operation itself is perceived as a major psychological burden. In direct comparison of the highest possible score of either tool (HOPE or PPPS), the cosmetic results were judged significantly more optimistic by surgeons as compared to parents using validated tools. HOPE score results therefore may not be transferred uncritically to the parents view on the cosmetic results., (Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Mutations in the NR5A1 gene, which encodes the steroidogenic factor 1 (SF1), are responsible for different phenotypes of disorders of sex development (DSD), such as bilateral anorchia and hypospadias. Furthermore, they can be associated with primary amenorrhea, premature ovarian failure, male infertility, adrenal tumors, and endometriosis. Direct sequencing of the 7 NR5A1 exons including ∼1,000 bp of the 5'-upstream and 3'-downstream regions and all intron-exon boundaries was performed in patients with DSD. Three different in silico tools were used to assess the consequences of a splice site mutation. As a result, 3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis: p.Lys38* and p.Leu80Trpfs*8 lead to premature translation termination codons within the SF1 DNA-binding domain, and the intronic nucleotide substitution c.1138+1G>T at the intron 6 donor splice site is considered to modify correct splicing. We assume that the anomalous mRNA produced as a result of p.Lys38* and p.Leu80Trpfs*8 will be degraded by nonsense-mediated mRNA decay even before translation, leading to SF1 haploinsufficiency. The c.1138+1G>T mutation is expected to produce a truncated protein. Heterozygous SF1 loss-of-function mutations in these cases resulted in mild DSD manifestations, such as dysgenetic testes, spontaneous puberty, and preserved adrenal function., (© 2016 S. Karger AG, Basel.)

This review presents published and novel results that define the programming window for diethylstilbestrol (DES)-induced abnormal development of the mouse penis. These data indicate that DES has its greatest effect during the period of most intense penile morphogenesis, namely postnatal days 0-15 (P0-P15). Pregnant mice and their neonatal pups were injected subcutaneously with 200 ng/gbw DES every other day from embryonic day 12-18 (DES E12-E18), postnatal day 0-10 (DES P0-P10), embryonic day 12 to postnatal day 10 (DES E12-P10), postnatal day 5-15 (DES P5-P15), and postnatal day 10-20 (DES P10-P20). Aged-matched controls received sesame oil vehicle. After euthanasia at 10, 15, 20 and 60 days, penises were analyzed by gross morphology, histology and morphometry. Penises of all 5 groups of DES-treated mice were reduced in size, which was confirmed by morphometric analysis of internal penile structures. The most profound effects were seen in the DES E12-P10, DES P0-P10, and DES P5-P15 groups, thus defining a DES "programming window". For all parameters, DES treatment from P10 to P20 showed the most mild of effects. Adverse effects of DES on the MUMP cartilage and erectile bodies observed shortly after the last DES injection reverted to normality in the DES P5-P15, but not in the E12-P10 and P0-P10 groups, in which MUMP cartilage and erectile body malformations persisted into adulthood, again emphasizing a "window of susceptibility" in the early neonatal period., (Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

A range of phenotypes that are associated with disorders of sex development (DSD) may also be encountered in patients with neurodevelopmental delay. In this study we have undertaken a collaborative retrospective review of anonymised phenotypic and genotypic data from the UK-wide Deciphering Developmental Disorders (DDD) study. Our objectives were to determine the frequency and range of DSD phenotypes observed in participants in the DDD study and to identify novel genetic associations. We found that of 7,439 DDD participants, 603 (8%) had at least one genital abnormality. In addition, we found that DSD occurs in 5% of patients with learning difficulties. Causative mutations were found in 13 developmental genes, of which, crucially, 6 had no previous reported association with DSD. Our findings indicate that recognition of these associations should not be overlooked in the management of patients with complex conditions and that exomic sequencing through projects like DDD increases diagnostic yield., (© 2016 S. Karger AG, Basel.)

Purpose: A standardized assessment for the optimal repair of hypospadias remains elusive. This study utilized validated questionnaires to assess the postoperative functional, cosmetic, and psychosocial outcomes of hypospadias repair., Materials and Methods: 172 patients who underwent hypospadias repair under the care of a single surgeon were identified. 25 agreed for follow-up using the validated questionnaires of Hypospadias Objective Scoring Evaluation (HOSE), Pediatric Penile Perception Scale (PPPS), and Pediatric Quality of Life Inventory (PedsQL™4.0)., Results: Mean follow-up was 59months postoperatively (range 7-113months). Techniques used included tubularized incised plate urethroplasty, meatal advancement and glanuloplasty, and a 2-stage repair. 23 of 25 patients achieved a HOSE score of 14 or more (maximum of 16). The PPPS scores correlated with severity of the hypospadias. Those with glanular hypospadias (mean score=10) scored higher than those with coronal (mean score=9) and penile/penoscrotal hypospadias (mean score=7). There was no correlation between PedsQL™4.0 scores and the severity of hypospadias or procedure used., Conclusion: Validated questionnaires revealed generally good functional, cosmetic, and early psychosocial outcomes after hypospadias repair. The use of validated questionnaires in routine follow-up sessions may facilitate objective assessment of both functional outcomes and patient satisfaction., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: An obstructive urinary flow pattern is frequently seen after tubularized incised plate urethroplasty for hypospadias. However, the significance of this finding has not been determined and long-term results are few. We describe postoperative long-term uroflowmetry results after puberty in males who underwent tubularized incised plate urethroplasty in childhood., Materials and Methods: A total of 126 boys underwent tubularized incised plate urethroplasty for distal penile to mid shaft hypospadias at Queen Silvia Children's Hospital in Gothenburg between 1999 and 2003. Of the patients 48 were toilet trained at surgery. We report on 40 patients who had data available at 2 and 12 months postoperatively, 7 years postoperatively and at puberty (median age 15.0 years, range 13.7 to 17.1). Of the patients 31 had distal and 9 had mid penile hypospadias. Clinical examination, urinary medical history, uroflowmetry and ultrasound measuring residual urine were performed. Maximum urinary flow was correlated to age and voided volume, using Miskolc nomograms for comparison of percentiles., Results: At 1 year postoperatively 15 boys (37.5%) had normal urinary flow (above 25th percentile), compared to 16 (40%) at 7 years and 38 (95%) at puberty (p <0.0001). Improvement was significant in patients with distal (p <0.0001) and mid penile hypospadias (p = 0.008), as well as in patients who did (p = 0.0078) and did not undergo intervention (p <0.0001). During followup 5 patients underwent meatotomy due to obstructive symptoms and 4 underwent dilation. Three of these 9 patients had lichen sclerosus., Conclusions: There is great potential for normalization of urinary flow at puberty for boys with hypospadias treated with tubularized incised plate urethroplasty. Unless symptoms occur, a conservative approach seems preferable., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Some men with corrected hypospadias perceive their penile appearance to be abnormal, although health professionals consider these results satisfactory., Aim: The aim of this study was to investigate how relevant women consider single aspects of penile appearance to be. Moreover, we studied whether women perceive hypospadias-affected surgically repaired genitals (HASRGs) to be as normal-looking as circumcised genitals and identified the most relevant predictors that influence whether a penis is perceived as normal., Methods: In this cross-sectional study, 105 women in different age groups (age range: 16-20, 25-30, and 40-45 years) completed a standardized questionnaire., Main Outcome Measures: Participants had to rate the importance of eight penile aspects and to indicate how normal they found the appearance of standardized photos of 10 HASRGs and of 10 circumcised genitals. Furthermore, they were asked about demographic characteristics and their sexuality., Results: Results showed that women considered the position and shape of the meatus as the least important penile aspect. Furthermore, results showed that HASRGs with distal hypospadias were perceived to be as normal-looking as circumcised genitals, whereas genitals with more proximal hypospadias were perceived as significantly less normal. However, the difference need not be considered clinically relevant, as the effect size was small. Observer-related predictors of a more positive perception of HASRGs were higher age, higher sexual interest, and perceiving the general cosmetic penile appearance as more important and penile length as less important., Conclusions: Overall, women were found to consider the "position and shape of the meatus" as the least important penile aspect. These findings may stimulate reflections regarding the relevance of surgical correction of the meatus in minor forms of hypospadias. In addition, this study indicates that women perceived genitals of men with distal operated hypospadias (which represents the majority of hypospadias) to be as normal as nonaffected, circumcised genitals., (© 2015 International Society for Sexual Medicine.)

Objective: To demonstrate surgical reconstruction of a megameatus variant of hypospadias by using a modified, patient-specific approach., Methods: An 8-month-old male had a megameatus, which was discovered after newborn circumcision. In repair of megameatus, it is important to recognize the full extent to which the distal urethra is widened, in order to avoid inadvertent urethrotomy during mobilization of the glans wings and skin immediately proximal to the glans. In this case, a small wedge of tissue was excised from the ventral aspect of the urethra, and a midline relaxing incision of the urethral plate was made. Standard principles of hypospadias repair should be followed, with tension-free urethral tubularization, coverage of the neourethra with well-vascularized tissue, and adequate mobilization of the glans wings to allow midline reconstruction without compression of the underlying neourethra., Results: There were no perioperative or postoperative complications in this case. The urethral meatus was positioned near the tip of the glans penis, and there was no evidence of meatal stenosis or urethrocutaneous fistula at 5-months follow-up., Conclusion: Each case of megameatus is unique, and a variety of surgical techniques can be used in formulating an approach that achieves optimal cosmetic and functional outcomes., (Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: Few studies of hypospadias repair in childhood have used validated questionnaires to investigate outcomes of cosmesis, urinary function, and sexual function in adulthood. We sought to investigate long-term outcomes in adult patients who had undergone severe hypospadias repair as children using an existing web-based application available to multiple institutions in order to develop an online patient survey of previously validated questionnaires., Materials and Methods: Patients aged 18 years or older who underwent severe hypospadias repair between 1992 and 1997 at our institution were contacted to complete an online survey. Through medical chart reviews, we analyzed the location of meatus, type of repair, and complications. The online survey included questions about penile appearance, and validated questionnaires to assess urinary and sexual function., Results: Of 58 patients who met the inclusion criteria, we contacted 19, and 13 completed the survey. Fifty-nine percent had complications, with an average of 2.2 procedures per patient. Most (85.0%) were satisfied with penile appearance, although 38.0% had residual penile curvature. Hypospadias patients had mean lower orgasmic function than normal controls. Mean scores for urinary function and other domains of sexual function were similar to normal controls., Conclusions: Although the majority of adult patients were satisfied with the outcomes of penile appearance, urinary function, and sexual function, our online survey suggests decreased lower orgasmic function as measured by validated questionnaire. An online survey accessible to multiple institutions with validated questionnaires may facilitate assessment of long-term hypospadias results., (Copyright © 2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: Outcome of urethral mobilization and advancement (Koff procedure) in hypospadias with a distal division of the corpus spongiosum and redo cases with distal urethral failure., Materials and Methods: From January 1999 to November 2012, 158 children with a distal hypospadias (115 primary cases and 43 redo cases) underwent surgical repair using the Koff technique with a median age at surgery of 21 months (range, 12-217 months)., Results: Mean follow-up was 19 months (median, 14 months). Thirty patients (19%) presented with a complication (13.9% in primary cases and 32.5% in redo surgery) mostly at the beginning of our experience. Meatal stenosis was the most common one (3.5% in primary case, 6% overall). Ventral curvature (>10°), which is considered as a possible long-term iatrogenic complication of the Koff procedure, was not found in patients with fully grown penis except in one redo patient who had, retrospectively, an inadequate indication for this type of repair. Of 158 patients, 33 reached the age of puberty (>14 years old) with a mean follow-up of 34 months, only one presented with a significant ventral curvature., Conclusion: Urethral mobilization and advancement is a reasonable alternative for anterior hypospadias and distal fistula repair in selected cases. It has two major advantages compared to other techniques: it avoids any urethroplasty with non-urethral tissue and eliminates dysplastic tissues located beyond the division of the corpus spongiosum, which may not grow at the same pace as the rest of the penis. Significant iatrogenic curvature in fully grown penis is not supported by this series., (Copyright © 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)