Rab25 is involved in hypospadias via the ß1 integrin/EGFR pathway.

BACKGROUND: Hypospadias is a common congenital abnormality of the penile. Abnormal regulation of critical genes involved in urethral development leads to hypospadias. We used the Rab25-/- mice and foreskin fibroblasts transfected with lentivirus in vitro and in vivo to investigate the role of Rab25 in hypospadias. METHODS: The expression levels of various molecules in tissue samples and foreskin fibroblasts were confirmed using molecular biology methods (western blotting, PCR, immunohistochemistry, etc.). A scanning electron microscope (SEM) was used to visualize the external morphology of genital tubercles (GTs) of gestation day (GD) 18.5 male wild-type (WT) and Rab25-/- mice. RESULTS: An expanded distal cleft and V-shaped urethral opening were observed in GD 18.5 Rab25-/- mice. We demonstrated that Rab25 mediated hypospadias through the ß1 integrin/EGFR pathway. In addition, silencing Rab25 inhibited cell proliferation and migration and promoted apoptosis in the foreskin fibroblasts; Ki-67- and TUNEL-positive cells were mainly concentrated near the urethral seam. CONCLUSION: These findings suggest that Rab25 plays an essential role in hypospadias by activation of ß1 integrin/EGFR pathway, and Rab25 is a critical mediator of urethral seam formation in GD18.5 male fetal mice.

A Japanese patient with Teebi hypertelorism syndrome and a novel CDH11 EC1 domain variant.

The gene CDH11 encodes cadherin-11, a Type II cadherin superfamily member that contains five extracellular cadherin (EC) domains. Cadherin-11 undergoes trans-dimerization via the EC1 domain to generate cadherin complexes. Compound heterozygous and homozygous loss-of-function CDH11 variants are observed in Elsahy-Waters syndrome (EWS), which shows characteristic craniofacial features, vertebral abnormalities, cutaneous syndactyly in 2-3 digits, genitourinary anomalies, and intellectual disability. Heterozygous CDH11 variants can cause Teebi hypertelorism syndrome (THS), which features widely spaced eyes and hypospadias. We report a THS patient with a novel CDH11 variant involving the EC1 domain. The patient was a 10-month-old male with normal developmental milestones, but had widely spaced eyes, strabismus, hypospadias, shawl scrotum, broad thumbs (right bifid thumb in x-ray), polysyndactyly of the left fourth finger, and cutaneous syndactyly of left third/fourth fingers. Exome sequencing identified a de novo heterozygous CDH11 variant (NM_001797.4:c.229C > T [p.Leu77Phe] NC_000016.9:g.64998856G > A). Clinical features were consistent with previously reported THS patients, but polysyndactyly, broad thumb, and cutaneous syndactyly overlapped phenotypic features of EWS. THS and EWS may represent a spectrum of CDH11-related disorders. Residue Leu77 in this novel CDH11 variant lines a large hydrophobic pocket where side chains of the partner cadherin-11 insert to trans-dimerize, suggesting that the cadherin-11 structure might be altered in this variant.

Primary hypospadias repair outcomes: results from a retrospective cohort of 292 children.

PURPOSE: Hypospadias surgery is challenging. Numerous techniques have been described with variable complication rates. The main objectives of our study were to evaluate the urethroplasty complication rate of primary hypospadias repair and to identify risk factors for complications. METHODS: We retrospectively evaluated the outcomes of all patients who underwent primary hypospadias repair in our department between January 2012 and December 2020. Demographic, anatomical, operative, and postoperative data were reported. Univariate and multivariate logistic regression analyses were performed to identify variables associated with complications. Statistical significance was set at p < 0.05. RESULTS: Of 292 patients, 203 (69.5%) had distal hypospadias, 63 (21.6%) had mid-penile hypospadias, and 26 (8.9%) had proximal hypospadias. The mean age at the time of surgery was 22.8 months. Seventy-eight patients (26.7%) had urethroplasty complications. The rate of complications was higher for proximal hypospadias (57.7%), onlay island flap (44.4%), and Koyanagi (75%) procedures. The mean follow-up duration was 29 months. Two predictors of complications were identified by multivariate analysis: catheterization duration and urethroplasty technique. The reoperation rate was 30.5%. CONCLUSION: Urethroplasty complications frequently occur after primary hypospadias repair. The complication rate was higher in proximal hypospadias. Catheterization duration and surgical technique were significant predictors of complications. A longer and more standardized follow-up is needed for a better assessment of hypospadias repair outcomes.

What should be next in lifelong posterior hypospadias: Conclusions from the 2023 ERN eUROGEN and EJP-RD networking meeting.

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.

Adult Hypospadias Outcomes for the Pediatric Urologist.

PURPOSE OF REVIEW: This review article will examine the current literature on hypospadias-related complications in adult patients. RECENT FINDINGS: In this article, we will review the most recent studies evaluating hypospadias-related stricture disease, erectile function, fertility, and psychosexual outcomes in adult men with history of hypospadias repair in childhood. Managing hypospadias-related complications in adult patients is challenging to reconstructive urologists due to the compounded complexity of innate tissue deficiency and history of prior surgical repairs. In this review, we explore overall functional outcomes of adults with history of hypospadias repair as well as repair strategies of hypospadias-related urethral stricture disease. We will review erectile function, fertility and psychosexual outcomes as well as potential complications, which often do not surface until late adolescence and adulthood. Although it is challenging to characterize and quantify hypospadias-related complications, further longitudinal study is needed to better care for this complex patient population.

Evaluation of postoperative complications of hypospadias using high-frequency ultrasound imaging.

PURPOSE: Various complications following hypospadias surgery present distinct manifestations when examined with ultrasound. Utilizing high-frequency ultrasound, clinicians can promptly identify these complications and initiate appropriate treatment. The aim of this study is to catalogue the ultrasonographic presentations of various postoperative complications following hypospadias surgery, thereby providing a reference for ultrasonographic diagnosis. METHODS: Ultrasonic images of post-hypospadias surgery from October 1, 2015, to June 30, 2023, recorded at the Plastic Surgery Hospital of the Chinese Academy of Medical Sciences, serve as the basis for this investigation. Drawing on patient clinical diagnoses, this study compiles and selects representative ultrasound images of diverse complications. RESULTS: The study encompassed a total of 121 subjects; 26 demonstrated urethral stricture on ultrasonic images, two presented local urethral dilation, six showed intraurethral hair-like structures, 17 revealed intraurethral septum, two exhibited intraurethral fold, one had urethral calculus, one displayed urethral calcification, 12 indicated intraurethral urine accumulation, and two showed urethral diverticulum. CONCLUSION: Ultrasound examination is helpful for postoperative diagnosis following hypospadias, detecting complications such as urethral stricture, urethral hair growth, and urethral diverticulum, which can help doctors choose appropriate clinical treatment strategies.

The potentiating effect of intravenous dexamethasone upon preemptive pudendal block analgesia for hypospadias surgery in children managed with Snodgrass technique: a randomized controlled study : Dexamethasone for pain management in children.

INTRODUCTION: Evidence regarding the potentiating effects of intravenous dexamethasone on peripheral regional anesthesia in children is sparse. The objective of the current study was to investigate the potentiating effect of intravenous dexamethasone upon pudendal block during surgical correction of hypospadias using Snodgrass technique. METHODS: The study consisted of a monocentric, randomized controlled, double-blinded study. Patients were randomized to receive either intravenous dexamethasone 0.15 mg.kg- 1 (D group) or a control solution (C group). Both groups received standardized anesthesia including a preemptive pudendal block performed after the induction of anesthesia. The primary outcome was the proportion of patients needing rescue analgesia. Secondary outcomes were other pain outcomes over the first 24 postoperative hours. RESULTS: Overall, 70 patients were included in the study. Age were 24 [24; 36] and 26 [24; 38] months in the D and C groups, respectively (p = 0.4). Durations of surgery were similar in both groups (60 [30; 60], p = 1). The proportion of patients requiring rescue analgesia was decreased in the D group (23% versus 49%, in D and C groups respectively, p = 0.02). The first administration of rescue analgesia was significantly delayed in the D group. Postoperative pain was improved in the D group between 6 and 24 h after surgery. Opioid requirements and the incidence of vomiting did not significantly differ between groups. CONCLUSION: Associating intravenous dexamethasone (0.15 mg.kg- 1) to pudendal block during hypospadias surgery improves pain control over the first postoperative day. Further studies are needed in order to confirm these results. GOV IDENTIFIER: NCT03902249. A. WHAT IS ALREADY KNOWN: dexamethasone has been found to potentiate analgesia obtained with regional anesthesia in children. B. WHAT THIS ARTICLE ADDS: intravenous dexamethasone was found to improve analgesia with a preemptive pudendal block during hypospadias surgery. C. IMPLICATIONS FOR TRANSLATION: results of this study indicate that intravenous dexamethasone could be used as an adjunct to pudendal block.

The long-term consequences of the hypospadias salvage repair issue.

PURPOSE: To present the long-term results of redo-hypospadias at our tertiary referral center following a failed prior repair. METHODS: One hundred sixty-four individuals with a history of unsuccessful repairs qualified for our retrospective cohort study. Our inclusion criteria were as follows: pre-operative data that was accessible, redo-hypospadias that was successfully repaired, and at least three years of follow-up at the last hospital visit. RESULTS: The mean patient age was 91.3 ± 21.1 months. The mean follow-up after successful repair was 41.3 ± 3.1 months. Ninety-two (group A) had one prior repair, and 72 (group B) had 2 or 3 repairs. Group A underwent six primary techniques: 32 underwent Onlay Island Flap (OIF), 10 underwent Mathieu, 12 underwent Tubularized Incised Plate Urethroplasty (TIPU), 8 underwent Urethral Mobilization (UM), and 34 underwent Buccal Mucosal Graft (BMG) { dorsal inlay Graft Urethroplasty (DIGU) in 4 and staged BMG in 30 patients}. In group B, four procedures were used: TIPU in 4, UM in 6, and BMG in 62 (staged BMG in 50 cases and DIGU in 12). CONCLUSIONS: The selected type of repair will depend on many factors, like residual healthy local skin and expertise. Safe techniques for repair of redo hypospadias after its 1st failure include TIPU, Mathieu, UM, OIF, and DIGU for distal varieties. After 2nd or 3rd repair DIGU, UM, and TIPU can be performed in distal types, while staged BMG can be applied for proximal ones.

Intravenous dexamethasone does not prolong the duration of pudendal nerve block in infants and children undergoing hypospadias surgery: A randomized clinical trial.

BACKGROUND: The administration of intravenous dexamethasone increases the duration of neuraxial block and improves the quality of analgesia. However, little is known about these effects of dexamethasone on peripheral nerve blocks in children. AIMS: In this study, we aimed to investigate the benefit of intravenous dexamethasone for enhancing the effect of pudendal block on postoperative analgesia in children who underwent hypospadias surgery. METHODS: In total, 46 children aged 6-36 months who underwent hypospadias surgery were randomly allocated to either a control group (normal saline, group C) or dexamethasone group (0.5 mg/kg, group D). Pudendal block was performed before the surgery using 0.3 mL/kg of 0.225% ropivacaine on both sides. Parents were instructed to press the patient-controlled analgesia bolus button when their children's pain score was >4 points. The primary outcome measure was the time at which the first patient-controlled analgesia by proxy bolus dose was administered. The secondary outcome measures were pain score, number of patient-controlled analgesia administration by proxy bolus attempts, number of rescue analgesics required, total amount of fentanyl administered, and overall parental satisfaction. RESULTS: The time of first patient-controlled analgesia bolus administration by proxy was not different between the control and dexamethasone groups (5.6 [5.2, 8.8] h versus 6.5 [5.4, 8.1] h, hazard ratio 0.8, 95% confidence intervals 0.43 to 1.47, p = .46). There were no statistically significant differences among the secondary outcomes. CONCLUSIONS: Administration of intravenous dexamethasone did not enhance the duration of pudendal nerve block in infants and children aged 6-36 months who underwent hypospadias surgery.

Maternal Diabetes and Risk of Hypospadias: A Systemic Review and Meta-Analysis.

INTRODUCTION: This study aimed to investigate the association between maternal diabetes and the risk of hypospadias in male infants, as the relationship between them remains uncertain. METHODS: To comprehensively evaluate the association between pregestational diabetes mellitus and gestational diabetes mellitus with hypospadias, we conducted a systematic review and meta-analysis. A thorough literature search was conducted, encompassing relevant publications published prior to January 2023. Crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Our meta-analysis comprised a total of 13 studies, 11 of which investigated the relationship between pregestational diabetes mellitus and hypospadias, while 9 studies explored the association between gestational diabetes mellitus and hypospadias. Notably, these investigations yielded compelling evidence of significant positive associations between pregestational diabetes mellitus and hypospadias (OR = 1.51, 95% CI = 1.13-2.03), as well as between gestational diabetes mellitus and hypospadias (OR = 1.18, 95% CI = 1.04-1.35). CONCLUSION: Our findings suggest that both pregestational diabetes mellitus and gestational diabetes mellitus are associated with an increased risk of hypospadias in offspring. Further investigations are needed to explore the optimal range of blood glucose during pregnancy that minimizes the risk of congenital malformation in the fetus, as well as to develop more effective measures for glycemic control in pregnant women.

Maternal exposure to dibutyl phthalate (DBP) impairs angiogenesis and AR signalling pathway through suppression of TGFB1I1 in hypospadias offspring.

Early exposure to dibutyl phthalate (DBP) can cause hypospadias in newborn foetuses. However, the underlying molecular mechanism is not well defined. Aberrant angiogenesis is associated with various dysplasias including urogenital deficits. In vivo and in vitro angiogenesis assays showed reduced angiogenesis in the hypospadias group and DBP exposed group. RNA-sequencing analysis of DBP-treated HUVECs revealed decreased expression of transforming growth factor beta 1-induced transcript 1 (TGFB1I1) and a significantly enriched angiogenesis-associated pathway. Further experiments revealed that decreased TGFB1I1 expression was associated with disrupted tube formation and migration, which resulted in decreased angiogenesis. Functional assays revealed that the overexpression of TGFB1I1 promoted tube formation and migration of HUVECs in the DBP-treated group. Moreover, we showed that the transcription factor AR was regulated by TGFB1I1 through inhibiting its translocation from the cytoplasm to the nucleus. Together, our results identified TGFB1I1 as a component of aberrant angiogenesis in hypospadias rats and its interaction with AR might be a potential target for hypospadias development.

Risk factors and timing of complication presentation following primary hypospadias repair in adolescents.

OBJECTIVES: To evaluate the risk factors for postoperative complications in adolescents who undergo primary hypospadias repair and determine the time required for complication detection. METHODS: Our study included patients classified as Tanner stages three to five who underwent primary hypospadias repairs at our hospital from January 2015 to August 2022. The patients' baseline information, clinical characteristics, postoperative complications, and time to complication detection were collected. Cox regression analysis, ROC curves, Kaplan-Meier survival analyses, and the Mann-Whitney U test were used. RESULTS: The study comprised 143 patients, with a median age of 12.58 years. Postoperative complications were experienced by 66 patients. The length of the urethral defect was identified as an independent risk factor for postoperative complications. The ROC curve analysis identified 3 cm as the optimal cutoff value for the length of the urethral defect. The median time to complication detection was 30.5 days (IQR 23 to 209.25). 89.4% of the complications were identified within the first year. Patients with a urethral defect of <3 cm experienced a significantly longer time for the detection of urethral fistula compared to those with a urethral defect of ≥3 cm (p = 0.047). CONCLUSIONS: Our data indicate that adolescents with a urethral defect ≥3 cm have a higher risk of postoperative complications. Although most complications were identified within the first year, conducting long-term follow-ups for adolescents is recommended to identify potential subsequent complications that may arise from persistent urethral alterations.

Widening of narrow urethral plates with lateral skin in TIP hypospadias repair: single center series.

BACKGROUND: To compare the outcomes of hypospadias repair using tubularized incised plate (TIP) urethroplasty and modified TIP with lateral skin to widen the urethral plate (WTIP). MATERIALS AND METHODS: Data were obtained from pre-pubertal boys who underwent primary hypospadias repair between May 2018 and July 2023. The cases were divided into two groups; one group underwent TIP with urethral plate ≥ 6 mm width and the other group with urethral plate width < 6 mm underwent WTIP. WTIP urethroplasty was performed by widening incisions on the outer margins of the urethral plate to incorporate penile and glandular skin lateral to the urethral plate to facilitate tubularization. Complication rates and urinary functions were compared. RESULTS: A total of 157 patients were enrolled in this study. Eighty-eight cases with narrow urethral plate were subjected to WTIP urethroplasty, and the rest were subjected to TIP urethroplasty. The preoperative glans width in WTIP group was less than that in TIP group (P < 0.001), and 44.3% had midshaft meatus in WTIP group compared to 17.4% in TIP group (P < 0.001). However, the incidences of postoperative complications (17.6% vs. 21.6%, P = 0.550) were not statistically different between the TIP and WTIP groups. In addition, both groups did not differ significantly in postoperative uroflowmetry assessment. CONCLUSIONS: The described technique helps to create an adequately caliber aesthetic neomeatus and facilitates tubularization, especially in hypospadias with a narrow urethral plate. Our data suggest that augmentation of a narrow urethral plate with WTIP has a similar surgical outcome to that of the TIP procedure in patients with a wide urethral plate.

Preoperative topical estrogen application in the management of hypospadias: a systematic review.

Local estrogen therapy has been explored as an alternative to conventional testosterone therapy in children requiring urethroplasty for hypospadias. Our objective is to evaluate if preoperative estrogen stimulation reduces post-urethroplasty complications and enhances penile dimensions. A systematic search was conducted on various databases, selecting only randomized controlled trials (RCTs) that tested estrogen on hypospadias patients under 18 years. Articles underwent sorting following PRISMA guidelines and bias risk was assessed using the JBI clinical appraisal tool for RCTs. Out of 607 screened records, 10 underwent full-text review, and 4 randomized controlled trials (RCTs) were selected for analysis. The total patient cohort across studies was 387 with 174 in the estrogen group. All studies utilized topical estrogen, but in different formulations and timings. Prudence is necessary for interpreting results due to variations in formulation, timing, and hypospadias type across studies. Limited by a small number of studies and outcome presentation non-uniformity, the review suggests no change in penile dimensions or postoperative complications with topical estrogen. Further research is needed to explore wound-healing properties of estrogen in hypospadias through animal and human studies.Registration and protocol: Registered in Prospero CRD42024502183.

The median effective concentration of ropivacaine for ultrasound-guided caudal block in children: a dose-finding study.

PURPOSE: To determine the 50% minimum effective concentration (MEC50) and the 95% effective concentration (MEC95) of ropivacaine for ultrasound-guided caudal block during hypospadias repair surgery of pediatric patients. METHODS: Children were enrolled with the American Society of Anesthesiologists (ASA) physical status I-II undergoing elective hypospadias repair surgery. Children were grouped into two age groups: toddlerhood (1-3 years old) and preschool (3-6 years old). We measured The MEC50 using Dixon's up-and-down method. The first children received the caudal block with 1.0 mL/kg of 0.15% ropivacaine. We determined each subsequent patient's concentration based on the previous patient's response and adjusted the concentration in intervals of 0.015%. Meanwhile, the probit regression analysis obtains 95% effective concentration (MEC95). In addition, we recorded the general condition, adverse events, and postoperative pain of each child. RESULTS: 46 children undergoing elective hypospadias repair surgery were included in this study, 22 in the toddlerhood group and 24 in the preschool group. Of the total number of patients, the caudal block was successful in 25 (54%) and failed in 21 (46%). The MEC50 of 1 ml/kg ropivacaine was 0.102% (95% CI 0.099%, 0.138%) in the toddlerhood group and 0.129% (95% CI 0.124%, 0.138%) in the preschool group. The MEC95 of 1 ml/kg ropivacaine was 0.148% (95% CI 0.131%, 0.149%) in the toddlerhood group and 0.162% (95% CI 0.134%, 0.164%) in the preschool group. Our results showed that ropivacaine concentration was statistically different between preschool children and toddlers (P < 0.001). None of the adverse events occurred. CONCLUSIONS: This study showed that children in the preschool group required higher concentrations of ropivacaine than children in the toddler group during ultrasound-guided sacral block combined with non-intubated general anesthesia. At the same time, this method of anesthesia is safe and effective for children undergoing surgery for hypospadias.

[Temporal analysis of the prevalence of congenital hypospadias in the municipality of Gela]. / Analisi temporale della prevalenza di ipospadia congenita nel comune di Gela.

OBJECTIVES: to evaluate the risk profile of hypospadias in Gela, an Italian National Priority Contaminated Site (NPCS) located in Sicily Region (Southern Italy), characterized by a significant excess of hypospadias in newborn residents compared to data from reference on regional, national, and international basis and, until 2014, by the presence of a petrochemical plant. DESIGN: geographical analyses were conducted by comparing the prevalence of the Gela municipality to prevalence found in Sicily, in a territorial area bordering Gela (ALG), and in the NPCSs of Milazzo and Priolo. The geographical comparisons were conducted for the period 2010-2020, the trend within the Gela NPCS was evaluated by comparing two subperiods (2010-2014 and 2015-2020). SETTING AND PARTICIPANTS: children up to 1 year of age with hypospadias resident in the municipality of Gela in the period 2010-2020. MAIN OUTCOMES MEASURES: crude odds ratios (OR) and respective 95% confidence intervals (95%CI) were used to compare the prevalence observed in Gela and that detected in the comparison areas. RESULTS: excess risk for hypospadias was highlighted in 2010-2020 in Gela vs Sicily (OR 4.45; 95%CI 3.45-5.75), vs ALG (OR 4.29; 95%CI 3.02-6.10), and vs the NPCSs of Milazzo (OR 2.32; 95%CI 1.32-4.07) and Priolo (OR 2.37; 95%CI 1.55-3.62). The between-period comparisons in Gela did not show an important difference between 2010-2014 and 2015-2020 (OR 1.37; 95%CI 0.83-2.24), with a prevalence of 98.9 and 72.4 per 10,000, respectively. CONCLUSIONS: the prevalence of hypospadias in 2015-2020 remains very high, although decreasing when compared to 2010-2014 period. The Gela data, despite the refinery being closed after 2014, suggest a complex situation in which multiple risk factors may play a role.

Penile Epithelioid Hemangioendothelioma in a Child.

An 8-year-old boy initially thought to have a penile arteriovenous malformation was later diagnosed with a rare vascular sarcoma, epithelioid hemangioendothelioma (EHE). Despite challenges in diagnosis, he underwent supraselective angioembolization and partial penectomy for oncological clearance. EHE, a low-grade malignancy, requires prompt identification and treatment due to potential systemic involvement.

Hypospadias with Intact Prepuce: A Spectrum of Anomalies and their Reconstruction.

Aims: The aim of the study was to perform a detailed analysis of the clinical characteristics of megameatus with intact prepuce (MIP) and to audit our results of reconstructive surgeries on MIP. Materials and Methods: Design: Retrospective analysis. Setting: Pediatric surgery department of tertiary level. Subjects, methods: Hospital records and pictures of MIP operated over a 9-year period. Age, size of penis, circumcised or not, shape of glans, external urethral meatus (EUM), urethral plate (UP), chordee, distal urethra, reconstructive surgery, and complications were analyzed. Postoperative result was objectively assessed by Hypospadias Objective Scoring Evaluation (HOSE). Results: Twelve of 254 hypospadias were MIP (incidence = 4.72%). The mean age at operation was 38.25 months (12-87 m). Patients sought circumcision or surgical correction of anomaly. Two patients were precircumcised. MIP was coronal 7, subcoronal 3, and glanular 2. Meatus was wide in 10 and normal in 2. Glans penis was wide in 9 and conical in 3. UP was wide (9), moderately wide (2), or narrow and shallow (1). In two cases of wide deep UP, distal septum was present. Distal urethra was nondilated in all but 1, which had megalourethra. Reconstructive surgery was Tubularized Urethral Plate Urethroplasty (7 cases) or classical Snodgrass (Tubularised incised plate urethroplasty (TIPU), with superimposed vascular dartos flap (5 cases). The megalourethra underwent partial excision and TIPU. Distal UP-septum was incised. Urethral injury (2 cases) and UP injury (1 case) were intraoperative complications. One postoperative complication (ventral glans necrosis) resulted. The mean follow-up period was 4.79 months (1-12 m). In the postoperative follow-up, 11 (92%) had HOSE score 14-16, whereas one had HOSE 13. Conclusion: Some hypospadias cases which have intact prepuce have no megameatus; hence, they cannot be termed MIP. All cases of hypospadias having intact prepuce can be covered by the umbrella term "Hypospadias with Intact Prepuce (HIP);" MIP is a large subgroup under HIP. HIP presents with a spectrum of anomalies of glans, EUM, and UP. Repair by tubularization of UP without or with midline incision gives excellent results.

Evaluation of USG-guided novel sacral erector spinae block for postoperative analgesia in pediatric patients undergoing hypospadias repair: A randomized controlled trial.

Background and Aims: Erector spinae plane block (ESPB) has been found to be simple, safe, and effective at thoracic and lumbar levels. There is no randomized controlled trial evaluating its effectiveness at sacral level. The present study was conducted to evaluate its effectiveness at sacral level for postoperative analgesia in pediatric patients undergoing hypospadias repair. Material and Methods: Forty children of 2-7 years with ASA grade I or II were included. They were randomly allocated to one of the two groups of 20 patients each. After induction of general anesthesia, patients of group I were given ultrasound-guided sacral ESPB with 1 ml/kg of 0.25% bupivacaine, and patients of group II were not given block. Postoperatively, pain was assessed using face, legs, activity, cry, consolability (FLACC) scale at 0 hour, every 15 min up to 1 hour, every half an hour up to 2 hours, 2 hourly up to 12 hours, and at 18th hour and 24th hour postoperatively. At FLACC score ≥4, rescue analgesia was given using 15 mg/kg paracetamol infusion. Primary objective was to compare postoperative analgesic (paracetamol) consumption, and secondary objective was time to first rescue analgesia. Results: Mean postoperative paracetamol consumption was 360 ± 156.60 mg in group I and 997.50 ± 310.87 mg in group II (P = 0.001). Time to first rescue analgesia was 906 ± 224.51 min in group I and 205.00 ± 254.92 min in group II (P = 0.001). Conclusion: Sacral ESPB has been found to be effective in reducing postoperative analgesic consumption in pediatric patients undergoing hypospadias repair.

Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations.

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.