Defining the cellular origin of seminoma by transcriptional and epigenetic mapping to the normal human germline.

Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis.

Prenatal Presentation of a Covered Cloacal Exstrophy Variant; Early Diagnostic Challenges Within the Broad Spectrum of the Exstrophy-Epispadias Complex.

There is a broad range of variant phenotypes that can occur within the bladder exstrophy and epispadias complex spectrum. Accurate prenatal detection helps prepare families and to coordinate subspecialty resources. Here, we present the case of a patient with prenatally diagnosed patient with covered cloacal exstrophy variant along with four additional cases illustrating the nonlinear spectrum from isolated epispadias to cloacal exstrophy. Given the rarity of these variants overall and of each subtype within the spectrum, there is a need for long-term multi-institutional outcomes data to improve detection, characterization, and prognostication for these patients.

Utilizing RENAL nephrometry in pediatric patients undergoing nephron-sparing surgery for renal tumors: A single-institutional cohort.

INTRODUCTION: RENAL Nephrometry is a complexity score validated in adults with renal tumors and describes the likelihood of complication after partial nephrectomy (PN). Utilization in pediatrics has been limited. Thus, our goal is to quantify inter-rater agreement as well as determine how scores correlate with outcomes. We hypothesize that the RENAL Nephrometry Score is reproducible in children with renal tumors and is related to perioperative and post-operative complications. METHODS: All pediatric patients who underwent PN for a renal mass from 2006 to 2019 were identified. Patient data, operative details, and outcomes were aggregated. Pre-operative CT/MR imaging was anonymized and scored by 2 pediatric radiologists and 2 pediatric urologists using RENAL Nephrometry metrics. Statistical analysis utilized Fleiss' kappa and the intraclass correlation coefficient (ICC). Comparative analyses were performed based on Nephrometry Score <9 and ≥ 9. RESULTS: 28 patients undergoing 33 PN were identified. Median age at surgery was 3.2 years (IQR 1.8-4.0). There is moderate-good agreement across scorers on the domains of RENAL Nephrometry Score, with the lowest agreement noted for anterior vs posterior tumors. Comparing patients with scores <9 and ≥ 9, there was increased operative time (357 vs 267 min, p = 0.003) and LOS for those with a higher score, but no difference in the incidence of 30-day complications. CONCLUSION: RENAL Nephrometry Score is an easily reproducible complexity score for renal tumors in pediatric patients. Higher scores are associated with increased length of stay and estimated blood loss but not complications. Reporting of nephrometry scores in future publications on pediatric renal tumors should become standard in the literature.

Adverse Birth Experiences and Parent Adjustment Associated With Atypical Genital Appearance Due to Differences of Sex Development.

OBJECTIVE: Differences/disorders of sex development (DSDs) are rare, congenital conditions involving discordance between chromosomes, gonads, and phenotypic sex and are often diagnosed in infancy. A key subset of parents of children newly diagnosed with a DSD experience clinically elevated distress. The present study examines the relationship between perinatal factors (i.e., gestational age, delivery method) and trajectories of parental adjustment. METHODS: Parent participants (mothers = 37; fathers = 27) completed measures at baseline, 6- and 12-month follow-up. Multilevel linear regression controlled for clustering of the data at three levels (i.e., time point, parent, and family) and examined the relationship between perinatal factors and trajectories of depressive and anxious symptoms. Two-way interactions between perinatal factors and parent type were evaluated. RESULTS: Overall depressive and anxious symptoms decreased over time. There were significant interactions between gestational age and parent type for depressive and anxious symptoms, with younger gestational age having a stronger negative effect on mothers vs. fathers. There was a significant interaction between time and gestational age for depressive symptoms, with 36 weeks' gestational age demonstrating a higher overall trajectory of depressive symptoms across time compared to 38 and 40 weeks. Findings for the delivery method were not significant. CONCLUSIONS: Findings uniquely demonstrated younger gestational age was associated with increased depressive symptoms, particularly for mothers compared to fathers. Thus, a more premature birth may predispose parents of infants with DSD to distress. Psychosocial providers should contextualize early diagnosis-related discussions within stressful birth experiences when providing support.

Does Preoperative Testosterone Administration Decrease Complications in Distal Hypospadias Repair With Urethroplasty?

PURPOSE: Testosterone administration prior to hypospadias repair is common practice among pediatric urologists; however, its impact on surgical outcomes remains controversial. We hypothesize that testosterone administration prior to distal hypospadias repair with urethroplasty significantly decreases postoperative complications. MATERIALS AND METHODS: We queried our hypospadias database for primary distal hypospadias repairs with urethroplasty from 2015 to 2021. Patients undergoing repair without urethroplasty were excluded. We collected information on patient age, procedure type, testosterone administration status, initial visit and intraoperative glans width, urethroplasty length, and postoperative complications. To determine the role of testosterone administration on incidence of complications, a logistic regression adjusting for initial visit glans width, urethroplasty length, and age was performed. RESULTS: A total of 368 patients underwent distal hypospadias repair with urethroplasty. One hundred thirty-three patients received testosterone and 235 did not. Initial visit glans width was significantly larger in the no-testosterone vs testosterone group (14.5 mm vs 13.1 mm, P = .001). Testosterone patients had significantly larger glans width at the time of surgery (17.1 mm vs 14.6 mm [no-testosterone group], P = .001). On multivariable logistic regression analysis after controlling for age at surgery, preoperative glans width, testosterone status, and urethroplasty length, testosterone administration did show significant association with reduced odds of postoperative complications (OR 0.4, P = .039). CONCLUSIONS: This retrospective review of patients shows that on multivariable analysis there is significant association between testosterone administration and decreased incidence of complications in patients undergoing distal hypospadias repair with urethroplasty. Future studies on testosterone administration should focus on specific cohorts of patients with hypospadias as benefits of testosterone may be more evident in some subgroups than others.

Caudal anesthesia is not associated with post-operative complications following distal hypospadias repair.

INTRODUCTION: The use of caudal anesthesia at the time of hypospadias repair remains controversial as some prior studies have reported increased postoperative complication rates associated with caudal nerve block. However, these results have been called into question due to confounding factors and heterogeneous study groups. OBJECTIVE: Given the importance of identifying true risk factors associated with increased hypospadias complication rate, we examined our experience with caudal anesthesia limiting our analysis to distal repairs. We hypothesized that caudal anesthesia would not be associated with increased postoperative complications. STUDY DESIGN: We retrospectively reviewed our institutional hypospadias database from June 2007 to January 2021. All boys who underwent single-stage distal hypospadias repair with either caudal or penile block with minimum 1 month follow up were included. Records were reviewed to determine the type of local anesthesia, type of hypospadias repair, all complications, and time to complication. Association between any complication and local anesthesia type was evaluated by univariate and multivariate logistic regression analysis controlling for age at surgery and type of repair. A sub-analysis was performed for complications occurring ≤30 days. RESULTS: Overall, 1008 boys, 832 (82.5%) who received caudal and 176 (17.5%) penile block, were included. Median age at surgery was 8.1 months and median follow up was 13 months. Overall complication rate was 16.4% with 13.8% of patients requiring repeat operation. Median time to complication was 10.59 months and was significantly shorter in the caudal group (8.45 vs. 25.2 months). Caudal anesthesia was associated with higher likelihood of complication on univariate analysis; however, this was not true on multivariate analysis when controlling for age and type of repair. Caudal anesthesia was not associated with increased likelihood of complication within 30 days. DISCUSSION: Since the association between caudal anesthesia and hypospadias complications was first suggested, several studies have tried to answer this question with variable results. Our findings add to the evidence that there is no association between caudal anesthesia and increased hypospadias complications in either the short or long term. The major strengths of our study are a large, homogenous study population, robust follow up and inclusion of data from 14 surgeons over 14 years. Limitations include the study's retrospective nature as well as lack of standardized follow up protocol throughout the study period. CONCLUSIONS: After controlling for possible confounders, caudal nerve block was not associated with increased risk of postoperative complications following distal hypospadias repair.

Deferring gonadectomy in patients with turner syndrome with a genetic Y component is not a safe practice.

INTRODUCTION: Patients with Turner syndrome who harbor Y chromosome material are known to be at increased risk of developing germ cell neoplasms. The optimal timing to perform gonadectomy to reduce the risk of cancer development in these patients is not well defined. We present outcomes of Turner with a Y component (TSY) patients who underwent gonadectomy at our institution. HYPOTHESIS/OBJECTIVE: We hypothesized that tumors could occur in a significant portion of TSY patients at any age and gonadectomy can be safely performed at diagnosis rather than deferred. STUDY DESIGN: We performed an IRB-approved retrospective single center study in which we queried our institutions electronic health record to identify all patients with TSY who underwent gonadectomy at our institution from 2012 to 2021. RESULTS: In our series of 18 consecutive TSY patients, a tumor was identified in 6 patients (33.3%): 4 (22.2%) with dysgerminoma (DG) [Fig. 1] and 2 (11.1%) with gonadoblastoma (GB). DISCUSSION: Our cohort of 18 consecutive TSY who underwent gonadectomy over a 9-year period is the largest published single site cohort to date. Additionally, our patient who was found to have GB at 40 days is to our knowledge the youngest TSY patient to be diagnosed with GB in the literature. This patient's remarkably early incidence of tumor occurrence illustrates the urgency of protective gonadectomy. Given the high incidence of tumor formation in this population and the minimal morbidity associated with gonadectomy, we do not recommend delaying gonadectomy in this population for any reason. Our study is vulnerable to selection bias and confounding innate to any retrospective study. There was variation with respect to the frequency and timing of pre-operative imaging as a strict preoperative imaging protocol with sequential studies was not in place at our institution. Additionally, we do not have a comparison cohort of patients who are being followed without operative intervention as all TSY patients at our institution have undergone gonadectomy. CONCLUSION: TSY patients cannot be safely observed for tumor formation based on clinical factors such as imaging or age. Gonadectomy is safe with a low complication rate and without tumor recurrence during three-year follow-up. We continue to recommend bilateral gonadectomy in this patient population at the time of diagnosis.

Decisional Regret Among Caregivers of Infants with Differences of Sex Development Reared as Male.

OBJECTIVE: Differences of sex development (DSD) are congenital conditions in which individuals are discordant in their chromosomal, phenotypic, and/or gonadal sex. Treatment of DSD can involve surgical intervention to external genitalia to make anatomy seem male-typical (i.e., male genitoplasty). Caregiver-perceived decisional regret regarding young boys with DSD was explored quantitatively and qualitatively. METHOD: Participants (N = 39) were caregivers of infants (N = 23) diagnosed with DSD (mean age = 8.9 months, standard deviation = 5.9 months) reared male participating in a longitudinal investigation of psychosocial outcomes. Qualitative data were collected at 6 to 12 months after baseline enrollment to evaluate caregiver decision-making corresponding to levels of regret concerning their child's treatment. All but one infant received genital surgery before caregiver reporting on their decisional regret. Quantitative exploratory analyses evaluated longitudinal predictors of decisional regret at 6 to 12 months. RESULTS: When completing a write-in item inquiring about decision-making and potential regret, most caregivers (n = 16, 76%) reported that their child's genital surgery was their first medical decision. Two caregivers referenced gender assignment as a decision point. One-third of caregivers reported some level of decisional regret (33%), with 67% reporting no regret. No hypothesized predictors of decisional regret were statistically significant. CONCLUSION: Many caregivers of infants with DSD reared male view genital surgery as a first health care decision. Approximately one-third of caregivers reported some level of decisional regret. Further research is warranted to explore long-term decisional regret; it will be particularly important to investigate the decisional regret of patients with DSD.

Does ketorolac administration at the time of hypospadias surgery increase unplanned encounters in the immediate postoperative period?

INTRODUCTION & OBJECTIVE: The opioid crisis has raised concerns for long-term sequela of routine administration of opioids to patients, particularly in the pediatric population. Nonsteroidal anti-inflammatory drug use is limited in hypospadias surgery due to concerns for post-operative bleeding, particularly with ketorolac. We hypothesize that ketorolac administration at the time of hypospadias repair is not associated with increased bleeding or immediate adverse events. METHODS: A retrospective single institution study included all patients undergoing hypospadias surgery from 2018 to 2021. Outcomes measured include peri-operative ketorolac administration, opioid prescriptions, and unplanned encounters (i.e., emergency department or office visits). Comparative statistics using non-parametric and binary/categorical tests and a logistic regression were performed. RESULTS: 1044 patients were included, among whom there were 562 distal, 278 proximal and 204 hypospadias complication repairs. Ketorolac was administered to 396 (37.9%) patients and its utilization increased during the study period [Summary Figure]. Patients receiving ketorolac were older (p = 0.002) and were prescribed opioids less often after surgery (2.0% vs 5.2%, p = 0.009). There was no difference in unplanned encounters across repair types (p = 0.1). Multivariate logistic regression showed ketorolac use was not associated with an increased likelihood of an unplanned encounter. DISCUSSION: The use of NSAIDs post-operatively has traditionally been limited due to concerns about bleeding risks, however the present study displayed no significant increases in unplanned patient encounters either in the ED or outpatient clinic after ketorolac administration. Our study has several limitations including its retrospective and single-institutional design, difficulties of pain assessment in pediatric population, and possibility of under estimation of unplanned encounters due to limited access to patients' records outside of our institution. CONCLUSIONS: The use of ketorolac is not associated with an increase in unplanned encounters in children undergoing hypospadias repair. It should be considered a safe agent for perioperative analgesia to decrease opioid utilization. Further studies will evaluate long-term surgical outcomes in children receiving ketorolac after hypospadias repair.

Expanding the reproductive organ phenotype of CHD7-spectrum disorder.

CHD7 disorder is a multiple congenital anomaly syndrome with a highly variable phenotypic spectrum, and includes CHARGE syndrome. Internal and external genital phenotypes frequently seen in CHD7 disorder include cryptorchidism and micropenis in males, and vaginal hypoplasia in females, both thought to be secondary to hypogonadotropic hypogonadism. Here, we report 14 deeply phenotyped individuals with known CHD7 variants (9 pathogenic/likely pathogenic and 5 VOUS) and a range of reproductive and endocrine phenotypes. Reproductive organ anomalies were observed in 8 of 14 individuals and were more commonly noted in males (7/7), most of whom presented with micropenis and/or cryptorchidism. Kallmann syndrome was commonly observed among adolescents and adults with CHD7 variants. Remarkably, one 46,XY individual presented with ambiguous genitalia, cryptorchidism with Müllerian structures including uterus, vagina and fallopian tubes, and one 46,XX female patient presented with absent vagina, uterus and ovaries. These cases expand the genital and reproductive phenotype of CHD7 disorder to include two individuals with genital/gonadal atypia (ambiguous genitalia), and one with Müllerian aplasia.

Pediatric Genitourinary 3D Modeling and Printing Using Multiphase Postcontrast Imaging Segmentation.

OBJECTIVE: To describe the development and implementation of a process for creating accurate Pediatric genitourinary 3D modeling and printing with multiphase postcontrast imaging for surgical planning. MATERIALS AND METHODS: Additive manufacturing and 3D model present opportunities to support clinical planning, this manuscript's specific process and considerations for creating pediatric genitourinary 3D modeling to support urology. The process for creating the 3D models and prints covers 3 key aspects from image acquisition, imaging review and selection, and segmentation and modification (as needed). Each step is outlined with the key roles and procedures. RESULTS: The described case had digital and printed models prepared with references to the optimized imaging sequence for 3D modeling of Pediatric genitourinary. Case shared include complex genitourinary reconstruction and Kideny with Wilms tumors. CONCLUSION: The processes described have become a standard of practice for complex kidney tumors and exstrophy planning. The team continues to work on ever-changing improvements to make the best possible models to support clinical and surgical planning.

Precocious Puberty in a Boy With Bilateral Leydig Cell Tumors due to a Somatic Gain-of-Function LHCGR Variant.

Context: Autosomal dominant and rarely de novo gain-of-function variants in the LHCGR gene are associated with precocious male puberty, while somatic LHCGR variants have been found in isolated Leydig cell adenomas and Leydig cell hyperplasia. Bilateral diffuse Leydig cell tumor formation in peripheral precocious male puberty has not been reported. Case Description: We present a boy with gonadotropin-independent precocious puberty and rapid virilization beginning in infancy resistant to standard therapy. Treatment with abiraterone in addition to letrozole and bicalutamide proved effective. Bilateral diffuse Leydig cell tumors were identified at age 5 years. Results: Whole-genome sequencing of tumor and blood samples was performed. The patient was confirmed to have bilateral, diffuse Leydig cell tumors harboring the somatic, gain-of-function p.Asp578His variant in the LHCGR gene. Digital droplet polymerase chain reaction of the LHCGR variant performed in tumor and blood samples detected low levels of this same variant in the blood. Conclusion: We report a young boy with severe gonadotropin-independent precocious puberty beginning in infancy who developed bilateral diffuse Leydig cell tumors at age 5 years due to a somatic gain-of-function p.Asp578His variant in LHCGR. The gain-of-function nature of the LHCGR variant and the developmental timing of the somatic mutation likely play a role in the risk of tumor formation. Abiraterone (a CYP17A1 inhibitor), in combination with an antiandrogen, aromatase inhibitor, and glucocorticoid, appears to be an effective therapy for severe peripheral precocious puberty in boys.

Exploring Factors Associated with Decisions about Feminizing Genitoplasty in Differences of Sex Development.

STUDY OBJECTIVE: Infants with genital development considered atypical for assigned female sex may undergo feminizing genitoplasty (clitoroplasty and/or vaginoplasty) in early life. We sought to identify factors associated with parent/caregiver decisions regarding genitoplasty for their children with genital virilization. DESIGN: Longitudinal, observational study SETTING: Twelve pediatric centers in the United States with multidisciplinary differences/disorders of sex development clinics, 2015-2020 PARTICIPANTS: Children under 2 years old with genital appearance atypical for female sex of rearing and their parents/caregivers INTERVENTIONS/OUTCOME MEASURES: Data on the child's diagnosis and anatomic characteristics before surgery were extracted from the medical record. Parents/caregivers completed questionnaires on psychosocial distress, experience of uncertainty, cosmetic appearance of their child's genitalia, and demographic characteristics. Urologists rated cosmetic appearance. For 58 patients from the study cohort with genital virilization being raised as girls or gender-neutral, we compared these data across 3 groups based on the child's subsequent surgical intervention: (i) no surgery (n = 5), (ii) vaginoplasty without clitoroplasty (V-only) (n = 15), and (iii) vaginoplasty and clitoroplasty (V+C) (n = 38). RESULTS: Fathers' and urologists' ratings of genital appearance were more favorable in the no-surgery group than in the V-only and V+C groups. Clitorophallic length was greater in the V+C group compared with the V-only group, with substantial overlap between groups. Mothers' depressive and anxious symptoms were lower in the no-surgery group compared with the V-only and V+C groups. CONCLUSIONS: Surgical decisions were associated with fathers' and urologists' ratings of genital appearance, the child's anatomic characteristics, and mothers' depressive and anxious symptoms. Further research on surgical decision-making is needed to inform counseling practices.

Trends in opioid and nonsteroidal anti-inflammatory (NSAID) usage in children undergoing common urinary tract reconstruction: A large, single-institutional analysis.

INTRODUCTION AND OBJECTIVE: Opioid stewardship is recognized as a critical clinical priority. We previously reported marked reductions in narcotic administration after implementation of an opioid reduction protocol for pediatric ambulatory urologic surgery. We hypothesize that a decrease in post-operative and discharge opioid administration will not increase short-term adverse events. STUDY DESIGN: All pediatric patients undergoing open or robot-assisted laparoscopic pyeloplasty or ureteral reimplantation between 2015 and 2019 were included. Patients' demographics, opioid and NSAID administration, urology or pain-related emergency department (ED) visits, readmissions, and reoperations within 30 days of surgery, were aggregated. RESULTS: 438 patients, with a median age of 3.5 years (IQR 1.5-8.3) at the time of surgery, met the inclusion criteria. Annual rates of inpatient opioid administration and prescriptions decreased significantly over the study period, while rates of intra-operative, inpatient, and prescribed NSAIDs significantly increased. There was no significant difference in the occurrence of ED visits, readmissions, or reoperations within 30 days of surgery between patients who received an opioid prescription and those who did not. Multivariate regression showed that patients who did not receive an opioid prescription at discharge were found to be at a lower risk for unplanned encounters including ED visits, readmissions, or reoperations (OR:0.5, 95%CI: 0.2-0.9, p = 0.04). DISCUSSION: The present study shows the decreasing trend in inpatient opioid administration and opioid prescription after discharge, when accompanied by an increase NSAID administration, does not result in a significant change in rates of unplanned encounters and complications, similar to results from previous studies on non-urological and ambulatory urological surgeries. CONCLUSIONS: Non-opioid pain control after major pediatric urologic reconstruction is safe and effective. We found that a reduction in opioid administration can be associated with a reduced risk of unplanned ED visits, readmissions, or reoperations. Further investigations are required to corroborate this finding.

Intrascrotal Lipoblastoma: A Rare Cause of Paratesticular Mass in a Pediatric Patient.

There is a broad differential diagnosis for a pre-pubertal child presenting with a scrotal mass including both benign and malignant etiologies. Lipoblastomas are rare benign neoplasms originating from fat cells that occur most commonly on the trunk or extremities of young children. There have been less than 20 cases of scrotal lipoblastomas reported in the literature, with the majority occurring in children less than 3 years of age. Here we present a unique case of an 18-month male presenting with a paratesticular mass found to be a lipoblastoma on final pathology.