Unaided visual assessment of ventral curvature during hypospadias repair is inferior to objective measurement using app goniometry.

OBJECTIVE: Failure to perform artificial erection or objectively assess ventral curvature (VC) during primary hypospadias repair is an important reason for residual/ recurrent chordee. The present study compares the accuracy of unaided visual inspection (UVI) with objective VC assessment using smartphone application (app) goniometry. METHODS: All patients who underwent primary hypospadias repair between January 2021 and September 2022 were included. Assistant surgeons were asked to grade the degree of VC on UVI (after degloving and an artificial erection test) into: none, mild (<30 degree), severe(>30 degree). Lateral profile photograph was taken and angle measurement was performed on an android mobile application (Angulus). Correlation was performed with both methods of assessment. RESULTS: During this period a total of 210 patients were analyzed; VC was noted in 40/138 (29%) cases of distal and in 62/72 (86%) cases of proximal hypospadias. Erroneous visual inspection was noted in 41/210 (20%; 95% CI 14-25%) on UVI (15 erroneously marked none while 26 marked mild). Among those found to have chordee, UVI assessed 39/82 (47%) as severe while app goniometry assessed 65/97 (67%) as severe. There was significant relative risk of labelling severe chordee as a mild one by UVI: 1.4 (95%CI 1-1.8; p=0.01). CONCLUSIONS: UVI was erroneous in 20% of cases. UVI was less accurate in differentiating severe chordee from mild one. In 60% patients UVI alone could have led to erroneous VC assessment and thus wrong selection of technique. Further studies are required to validate our findings and standardize VC measurement using an app goniometry.

Clinical, Hormonal, and Genetic Characteristics of 5α-Reductase Type 2 Deficiency in 103 Chinese Patients.

OBJECTIVE: 5α-Reductase type 2 (5α-RD2) deficiency causes variable degrees of undervirilization in patients. The correlation between its genotype and phenotype is unclear. METHODS: We retrospectively evaluated 103 patients with 46,XY disorders of sex development who were diagnosed with 5α-RD2 deficiency. RESULTS: The prevalence of female sex assignment (P = .008) and the incidences of cryptorchidism (P = .0003) and bifid scrotum (P = .0002) in the non-p.R227Q variant group were higher, but there were no significant differences in the incidences of hypospadias and isolated microphallus. The external masculinization score in the non-p.R227Q variant group was lower than that in the homozygous p.R227Q variant (P = .019) and compound heterozygous p.R227Q variant groups (P = .013). The level of anti-Mullerian hormone in the non-p.R227Q variant group was lower than that in the homozygous p.R227Q variant (P < .001) and compound heterozygous p.R227Q variant groups (P = .006). The testosterone-to-dihydrotestosterone ratio of the homozygous p.R227Q variant group was higher than that of the non-p.R227Q variant (P = .018) and compound heterozygous p.R227Q variant groups (P = .029). Twenty-three reportedly pathogenic variants and 11 novel steroid 5α-reductase 2 (SRD5A2) variants were identified. CONCLUSION: Compared with patients without p.R227Q, patients with p.R227Q exhibited higher external masculinization scores and anti-Mullerian hormone expression, a lower prevalence of female sex assignment, and lower incidences of cryptorchidism and bifid scrotum. We identified 23 reportedly pathogenic SRD5A2 variants and 11 novel SRD5A2 variants that led to 5α-RD2 deficiency. We established a genotype-phenotype correlation, and patients with p.R227Q showed a relatively mild phenotype.

Plate Objective Scoring Tool: A new preoperative indicator of penile curvature degree in children with distal hypospadias.

OBJECTIVES: There is an unmet need for preoperative methods that surgeons can use to objectively quantify hypospadias anatomic variables and determine risk of penile curvature. We, therefore, assessed whether Plate Objective Scoring Tool measurements were correlated with degree of ventral curvature in affected children. METHODS: Patients undergoing distal hypospadias repair were enrolled into the study between January 2018 and December 2020 and were categorized independently by at least two surgeons using Plate Objective Scoring Tool. Scores were compared statistically to determine the degree of ventral curvature and requirement for correction. RESULTS: Sixty-five patients with a median age of 18 months (interquartile range 13-26) were enrolled into the study prior to surgery for primary distal hypospadias. Patient probability of significant postoperative curvature (>20°) was determined with moderate confidence using a cutoff Plate Objective Scoring Tool score of 1 (sensitivity 75%, specificity 60%). Presurgery Plate Objective Scoring Tool scores were negatively correlated with subsequent degree of curvature (r = -0.37, P = 0.003), with values <1.0 predicting >20° curvature. CONCLUSIONS: Plate Objective Scoring Tool scoring offers a succinct method of describing hypospadias severity and correlates well with postoperative outcomes. The Plate Objective Scoring Tool system can therefore be used to objectively predict the likelihood of penile curvature and aid communication between surgeons and researchers, as well as improving parental counseling.

Association of a GATA Binding Protein 4 Polymorphism with the Risk of Hypospadias in the Chinese Children.

PURPOSE: GATA binding protein 4 (GATA4) has been implicated in the etiology of congenital malformation of the urogenital system. The present study investigated the influence of GATA4 polymorphisms on susceptibility to hypospadias. METHODS: We genotyped 4 potentially functional polymorphisms (rs12458, rs12825, rs884662, and rs904018) in GATA4 in the hospital-based case-control study including 410 child patients and 520 nonmalformed individuals by the TaqMan MGB method. Risk associations were assessed using unconditional logistic regression, adjusted for potential confounding factors. RESULTS: A significant association was found between rs12458 (3'-UTR of GATA4) and susceptibility to hypospadias (p = 0.008). Compared with rs12458 AA genotype individuals, those harboring the variant allele (rs12458 AT/TT) were correlated with significantly higher risk of hypospadias (AT/TT vs. AA: OR = 1.42, 95% CI = 1.17-2.35, p = 0.036). Furthermore, the rs12458T allele showed significantly decreased activity in a luciferase reporter assay, indicating a possible role of rs12458 variant in regulating the combination of microRNAs with the GATA4 mRNA. CONCLUSIONS: The present results indicate that the functional GATA4 rs12458 variant confers individuals' susceptibility to hypospadias, possibly through regulating the GATA4 expression level.

[Diagnosis and surgical treatment of hypospadia in girls].

AIM: To suggest new method of surgical correction of hypospadias in girls. MATERIALS AND METHODS: For 50 years under our supervision there were 220 girls diagnosed with hypospadias of various forms. In the diagnosis used anamnesis, examination, catheterization and cystoscopy of the bladder, vaginoscopy, ultrasound and X-ray research methods. RESULTS AND DISCUSSION: Of 220 girls with a diagnosis of hypospadias, vestibular (partial) hypospadias occurred in 201 girls, vestibulovaginal (subtotal) in 16, and vaginal (total) in 3. Of 201 girls with vestibular hypospadias, 37 suffered from urinary incontinence, 16 had vesicoureteral reflux, 21 had doubling, 5 had renal hypoplasia, and 12 had renal dystopia. The vulvovaginal form was manifested not only by the dystopia of the external opening of the urethra, but also combined with the underdevelopment of the sphincteral apparatus of the bladder. All children had daytime and nighttime urinary incontinence, vulvovaginitis. Cystoscopy revealed hyperemia of the urethra and bladder neck. X-ray urological examination revealed VUR in 6 children, ureterohydronephrosis - in 2. All children suffered from chronic pyelonephritis, 8 - day and night urinary incontinence. There were 3 girls (14-16 years old) with vaginal (total) hypospadias. All suffered from constant urinary incontinence, vulvovaginitis, cystitis, chronic pyelonephritis, all had VUR. The new operation for the vaginal (total) form of hypospadias, proposed by us, restores the closure function of the bladder sphincter by suturing the defect in the posterior wall of the bladder neck. CONCLUSION: Hypospadias is rare in girls. There are vestibular, vestibulovaginal and vaginal forms of hypospadias. In most cases, the vestibular form does not require surgical treatment. With the vestibulovaginal and vaginal (total) form of hypospadias, surgical treatment is indicated.

Maternal rheumatoid arthritis and systemic lupus erythematosus and risk of cryptorchidism and hypospadias in boys: a Danish nationwide study.

OBJECTIVES: RA and SLE are the most prevalent autoimmune rheumatic diseases affecting young women. Both diseases are characterized by systemic inflammation that may affect placental function and fetal development during pregnancy, and both diseases are associated with adverse pregnancy and child outcomes. We investigated the associations between maternal RA or SLE and the two genital malformations, cryptorchidism and hypospadias. METHODS: In this nationwide register-based study including all male singleton live births in Denmark from 1995 to 2016, we assessed the occurrence of cryptorchidism and hypospadias according to the prenatal disease-state of the mothers. Using Cox proportional hazards models we calculated adjusted hazard ratios, accounting for varying age at diagnosis. RESULTS: Among 690 240 boys, 1026 had a mother with RA and 352 had a mother with SLE. We found adjusted hazard ratios of 1.72 (95% CI: 1.15; 2.57) for cryptorchidism among boys born to mothers with RA and 1.46 (95% CI: 0.69; 3.06) for boys born to mothers with SLE, compared with the general population. As the number of hypospadias cases was low, multivariate analysis was not feasible. The crude hazard ratios were 0.51 (95% CI: 0.16; 1.58) and 1.00 (95% CI: 0.25; 4.03) for RA and SLE, respectively. CONCLUSION: Boys born to mothers with RA had higher risk of cryptorchidism, compared with unexposed boys. Boys born to mothers with SLE showed a similar tendency, however with less precision of the estimate. No conclusion could be reached on the risk of hypospadias, due to the low number of events.

Hydrothorax in fetal cases of Opitz G/BBB diagnosis: Extending the phenotype?

We report two fetal cases carrying a de novo MID1 mutation and presenting with severe hydrothorax, suggesting the expansion of the phenotype of Opitz GBBB syndrome.

Increased hand digit length ratio (2D:4D) is associated with increased severity of hypospadias in pre-pubertal boys.

INTRODUCTION: Hypospadias is a common congenital male disorder, with much research focusing on prenatal androgen exposure as a causative factor. Whilst digit length ratios were apparent in sexual dimorphism since the nineteenth century, their role in hypospadias remains unknown. The objective of our study was to determine the correlation between digit length (2D:4D) ratio, hypospadias severity, and anogenital distance. METHODS: Pre-pubertal boys (<3 years old) seen intra/postoperatively following hypospadias repair (June 2018-January 2019 inc.) were included. These were age-matched to non-hypospadias controls. Anthropomorphic measurements of digit lengths, penile/glans width, and anogenital distance were measured using digital calipers. RESULTS: Data measurements were collected for 105 boys with hypospadias (60 distal; 45 proximal) and 55 controls. There were significant differences in 2D:4D ratios in each hand (p < 0.001), as well as individual digits (p < 0.001), and a reduced anogenital distance (p < 0.001), when comparing the proximal group with distal or control groups. There were no significant differences in glans width, or between term- and preterm births. CONCLUSIONS: This study is the first to demonstrate increased 2D:4D ratios with proximal hypospadias, which also correlate with a shortened anogenital distance. This may provide a non-invasive, potentially antenatal, anthropomorphic measurement, as an indirect indicator of aberrant urogenital development.

The genetic factors contributing to hypospadias and their clinical utility in its diagnosis.

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.

Establishing reproductive potential and advances in fertility preservation techniques for XY individuals with differences in sex development.

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, 17ß-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.

Diagnostic accuracy of human chorionic gonadotropins (HCG) stimulation test in XY-disorders of sex development (XY-DSD) presented in Armed Forces Institute of Pathology.

OBJECTIVE: To determine diagnostic accuracy of human chorionic gonadotropins stimulation test in differentiating androgen insensitivity syndrome and 5-alpha reductase deficiency, keeping testosterone to dihydrotestosterone ratio as the gold standard. METHODS: The cross-sectional study was conducted at the Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from January to December, 2016, and comprised patients aged 01 day to 20 years having XY chromosomes on karyotyping and with a spectrum of phenotypes. Blood samples were collected from each subject for basal serum testosterone, serum luteinizing hormone and serum follicular stimulating hormone level. Human chorionic gonadotropins stimulation test was performed in every subject as per the protocol. Sandwich chemiluminescence immunoassay technique was used to analyse serum samples. Serum dihydrotestosterone level was also detected to determine testosterone and dihydrotestosterone ratio. Data was analysed using SPSS 24. . RESULTS: Of the 104 subjects with a mean age of 1.78}0.95 years,96(92.3%) were diagnosed as cases of androgen insensitivity syndrome on the basis of human chorionic gonadotropins stimulation response level, which was 2-9 times of basal serum testosterone level. Also, 8(7.7%) subjects were diagnosed to have 5-alpha reductase deficiency syndrome. In such subjects, post-human chorionic gonadotropins response level of serum testosterone was more than 10 times of the basal level. CONCLUSIONS: The human chorionic gonadotropins stimulation test was found to be comparable to testosterone-to dihydrotestosterone ratio in differentiating between case of androgen insensitivity syndrome and 5-alpha reductase deficiency.

Clinical and molecular characterization of 5α-reductase type 2 deficiency due to mutations (p.Q6X, p.R246Q) in SRD5A2 gene.

Early diagnosis and optimal management for steroid 5α-reductase type 2 deficiency (5α-RD2) patients are major challenges for clinicians and mutation analysis for the 5α-reductase type 2 (SRD5A2) gene is the golden standard for the diagnosis of the disease. In silico analysis of this enzyme has not been reported due to the lack of appropriate model. Moreover, the histological and pathological changes of the gonads are largely unknown. In the present study, a 5α-RD2 patient born with abnormal external genitalia was studied and mutation analysis for SRD5A2 gene was conducted. Moreover, we constructed the homology modeling of 5α-reductase using SWISS-MODEL, followed by the molecular docking study. Furthermore, immunohistochemical staining of Ki67 for the testes tissue was conducted to investigate the potential pathological characteristics. The patient had male (46, XY) chromosomes but presented female characteristics, and the mutation analysis identified a heterozygotes mutation (p.Q6X, p.R246Q) in SRD5A2 gene. In silico analysis elucidated the potential effect of the mutation on enzyme activity. Immunohistochemical staining for the excised testes showed that 30%-50% of the germ cells were Ki67 positive, which indicated the early neoplastic potential. In conclusion, we analyzed the genotype-phenotype correlations of 5α-RD2 caused by a heterozygotes mutation (p.Q6X, p.R246Q). Importantly, we conducted the homology modeling and molecular docking for the first time, which provided a homology model for further investigations. Immunohistochemical results suggested gonadectomy or testis descent should be performed early for 5α-RD2 patient, as delayed treatment would have maintained the testes in a tumorigenic condition.

Associations between hypospadias, cryptorchidism and anogenital distance: Systematic review and meta-analysis.

Hypospadias and cryptorchidism are potential manifestations of testicular dysgenesis syndrome (TDS) at birth. Anogenital distance (AGD) has been presumed as an indicator related to endocrine disruptors proposed as one of the pathogenetic mechanisms underlying male reproductive disorders. In humans, recent studies have correlated AGD in boys to testicular anomalies. However, the associations between hypospadias, cryptorchidism and AGD remain inconsistent and have not been combined. Hence, we conducted a meta-analysis to assess gradations in the severity of the endocrine disruption in cryptorchidism or hypospadias by using AGD. A total of 2,119 boys from five birth cohort studies and two cross-sectional studies were subjected to meta-analysis. Random-effect model was used to calculate the standardised mean difference (SMD) of AGD. Our results reveal that boys with hypospadias or cryptorchidism have shorter AGD ([SMD, -2.63; 95% CI, -4.65 to -0.62] and [SMD, -0.69; 95% CI, -1.36 to -0.02]) respectively. There was no indication of a publication bias either from the result of Egger's test or Begg's test for hypospadias and cryptorchidism.

The Staged Urethroplasty with Vascularised Scrotal Flap and Buccal Mucosa Graft after Failed Hypospadias Surgery: A Reliable Technique with a Novel Tool.

Background/Aims/Objectives: To report the outcome of staged urethroplasty with buccal mucosa and vascularised scrotal flap after failed hypospadias surgery. METHODS: n = 35. INCLUSION CRITERIA: destroyed urethral plate, deficient local skin, fistula and penile deviation. Five out of 35 patients also had a secondary proximal stricture. Stage 1: excision of scarred tissue and fistulae, correction of the penile deviation through dorsal plication and the ventral placement and quilting of buccal graft. Stage 2: tubularisation of the neourethral plate; in 20 patients with deficient penile skin a vascularised scrotal flap was developed and transferred on the tubularised urethra. In 5 patients, the proximal stricture was repaired during a separate operation by using buccal graft, the distal urethra was marsupialised. The repair of the distal urethra was performed later as described above. RESULTS: Thirty-three patients are recurrence-free without further interventions; successful reoperation was done in 2 cases. COMPLICATIONS: 1 graft necrosis; 1 coronary fistula; 1 scrotal flap necrosis and 1 case of hematoma. CONCLUSIONS: Complicated strictures after multiple failed hypospadias repair are well managed by using buccal graft. The vascularised scrotal flap is a very useful tool in case of deficient and scarred penile skin and could explain the low rate of fistula formation in our series.

Durham Smith Vest-Over-Pant Technique: Simple Procedure for a Complex Problem (Post-Hypospadias Repair Fistula).

OBJECTIVE: Urethrocutaneous fistula, which occurs after hypospadias surgery, is often a baffling problem and its treatment is challenging. The study aimed to evaluate the results of the simple procedure (Durham Smith vest-over-pant technique) for this complex problem (post-hypospadias repair fistula). METHODS: During the period from 2011 to 2015, 20 patients with post-hypospadias repair fistulas underwent Durham Smith repair. Common age group was between 5 and 12 years. Site wise distribution of fistula was coronal 2 (10%), distal penile 7 (35%), mid-penile 7 (35%), and proximal-penile 4 (20%). Out of 20 patients, 15 had fistula of size <5 mm (75%) and 5 patients had fistula of size >5 mm (25%). All cases were repaired with Durham Smith vest-over-pant technique by a single surgeon. In case of multiple fistulas adjacent to each other, all fistulas were joined to form single fistula and repaired. RESULTS: We have successfully repaired all post-hypospadias surgery urethrocutaneous fistulas using the technique described by Durham Smith with 100% success rate. CONCLUSION: Durham Smith vest-over-pant technique is a simple solution for a complex problem (post hypospadias surgery penile fistulas) in properly selected patients.

Risk Factors for Urethrocutaneous Fistula Repair After Hypospadias Surgery: A Retrospective Study.

OBJECTIVES: We review our experience in urethrocutaneous fistula (UCF) repair after hypospadias surgery to investigate the risk factors for unsuccessful outcome. METHODS: Two hundred eleven patients had undergone UCF repair in our department from January 2005 to December 2015. This study included 185 patients who were followed up for more than 6 months. The age of patients, size, site and number of UCFs, number of UCF repairs, urethral complications other than UCF, and postoperative infection were included as potential risk factors. Binary logistic regression analysis was used for multivariate analysis. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated. Stratified analysis and assessment of additive interaction were performed to have a better understanding of the relation between the risk factors. RESULTS: Urethrocutaneous fistula repairs failed in 38 patients (20.5%) at first attempt. In the univariate analysis, size of UCFs (P = 0.012), times of UCF repair (P = 0.008), and postoperative infection (P = 0.044) were statistically related with the outcome of surgery. In the multivariate analysis, only the size of UCFs (P = 0.030; adjusted OR, 2.42; 95% CI, 1.09-5.36) and times of repair (P = 0.008; adjusted OR, 3.09; 95% CI, 1.35-7.07) were identified as risk factors for unsuccessful outcome. We had consistent results in the stratified analysis. No additive or multiplicative interaction between the 2 risk factors was found. CONCLUSIONS: Our study suggested that UCF repairs after hypospadias surgery were easier to fail if one of the UCFs was larger than 2 mm or it had been repaired repeatedly. But when both factors existed, the increase of the risk was not statistically significant. The age of patients, site and number of UCFs, complications other than UCF, and postoperative infection were not significantly related to the success rate of UCF repair.