A case of mild partial androgen insensitivity syndrome in a juvenile boy.

Androgen insensitivity syndrome (AIS) is a rare disorder with X-linked recessive inheritance in 46 XY patients. The clinical manifestations vary between patients, especially regarding external genitalia development. Herein, the case of AIS in a 13-year-old male, who was born with hypospadias and presented to the hospital with gynaecomastia that had developed from 8 years of age, is reported. No micropenis, cryptorchidism or bifid scrotum were found. Testis volume was 12 ml on both sides. His testosterone and luteinizing hormone levels were normal compared with sex- and age-adjusted reference range. His bone age was approximately 13 years according to Greulich-Pyle assessment. Sequence analysis of the androgen receptor (AR) gene revealed a mutation (c.2041A>G) in exon 4, a novel mutation site in the AR gene. Prediction analysis suggested this to be a disease-causing variant. A milder clinical presentation and normal hormone levels in cases of partial AIS might differ from the usually reported signs and symptoms. A diagnosis of AIS should not be ignored in teenage patients who present with gynaecomastia and hypospadias, but normal hormone levels.

Megameatus intact prepuce variant reconstruction: Long-term outcomes and comparison to post-circumcision hypospadias repair.

BACKGROUND: Megameatus intact prepuce (MIP) variant is considered a surgical challenge with associated high complication rates. It is usually diagnosed and corrected only after neonatal circumcision, which is discouraged in non-MIP hypospadias. OBJECTIVE: In order to determine whether the features of the MIP variant or the performance of a secondary reconstruction following circumcision comprise the cause of higher complication rates, we now compared the results of post-circumcision MIP hypospadias repair to the results of children who underwent repair of non-MIP hypospadias following neonatal circumcision. STUDY DESIGN: Reoperation rates of children operated for hypospadias repair following neonatal circumcision between 1999 and 2020 were compared between those with MIP and those with classic non-MIP hypospadias. RESULTS: In total, 139 patients who had undergone neonatal circumcision underwent surgical reconstruction at a mean age of 13 months. Sixty-nine had classic hypospadias and 70 had the MIP variant. The median follow-up was 10 years (interquartile range 6,13). The classic group had a higher rate of meatal location below the corona compared to the MIP variant group (53 % vs. 28 %, respectively, p = 0.002). The reoperation rate was comparable for the two groups (32 % vs. 27 %, p = 0.58, Table). Univariate analysis for the MIP hypospadias group showed no association between reoperation and the initial patient characteristics, while a higher probability of reoperation was demonstrated in the presence of ventral curvature (odds ratio 3.5, p = 0.02), and a higher grade of hypospadias (odds ratio 3.3, p = 0.03 for meatal location lower than the coronal sulcus) in the non-MIP group. DISCUSSION: The limitations of our work include its retrospective design wherein the patients' characteristics, including classification as MIP vs. non-MIP, are derived from medical records. More patients in the non-MIP group were documented to have penile curvature. The non-MIP group was composed of more patients with meatal location under the coronal sulcus, a factor which may increase the rates for reoperation in that group. Still, with the comparison of the largest reported cohort of circumcised MIP with circumcised non-MIP patients together with an extended follow-up period, we believe that we present strong evidence of the possible role of previous circumcision in the surgical challenge of reconstructing MIP hypospadias. CONCLUSIONS: Reoperation rates in MIP hypospadias are high but similar to those of classic hypospadias, both following circumcision, suggesting that circumcision, rather than the unique features of the variant, is the cause for complications.

Preimplantation genetic testing and prenatal diagnosis in a family with pseudovaginal perineoscrotal hypospadias: A case report.

RATIONALE: Pseudovaginal perineoscrotal hypospadias (PPSH) is a rare autosomal recessive disorder of sex development caused by biallelic mutations in SRD5A2. PPSH is characterized by a vaginal-like blind ending perineal opening, penoscrotal hypospadias, and impaired masculinization. PATIENT CONCERNS: We reported preimplantation genetic testing and prenatal diagnosis in a family with PPSH. DIAGNOSIS: Whole-exome sequencing of the family identified 2 SRD5A2 pathogenic variants (c.578A>G and c.607G>A). Haplotype analysis showed that the variants were inherited from the previous generation of this family. INTERVENTIONS: During subsequent in vitro fertilization, preimplantation genetic testing was performed on 9 embryos. One unaffected embryo was transferred, resulting in a singleton pregnancy. OUTCOMES: The prenatal diagnosis at 20 weeks' gestation confirmed the fetus was unaffected. A healthy female infant weighing 3100 g and measuring 50 cm was delivered vaginally at 39+5 weeks of gestation. LESSONS SUBSECTIONS: This case highlights the use of preimplantation genetic testing and prenatal diagnosis to prevent the transmission of PPSH in families at risk. Our approach provides an effective strategy for identification and management of families with autosomal recessive disorders like PPSH.

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.

A newborn with ectrodactyly, tetralogy of Fallot, esophageal atresia, hypospadias and TP63 gene mutation: A new type of EEC Syndrome?

EEC syndrome is an autosomal dominant genetic disease with incomplete penetrance characterized by ectrodactyly, ectodermal dysplasia, and cleft lip/palate; these manifestations can differently occur in the affected subjects and can also be associated with other anomalies, such as in the urogenital tract.We reported the case of a newborn with prenatal diagnosis of EEC type 3 associated with severe cardiac abnormalities (Tetralogy of Fallot), high esophageal atresia with fistula and penoscrotal hypospadias.

Surgical management of penoscrotal hypospadias in a child with Opitz G/BBB syndrome: a case report.

Opitz G/BBB syndrome is a rare condition characterized by three significant anomalies; hypertelorism, cleft lip and palate, and hypospadias. However, other anomalies may be associated. Herein, we report a 4-year-old child presented with penoscrotal hypospadias. On examination, hypertelorism and cleft lip and palate were noticed, suggesting a diagnosis of Opitz G/BBB syndrome. The cleft lip was corrected in the first year, and a two-staged surgical approach was implemented for penoscrotal hypospadias. In the first stage, the chordee was corrected and urethral plate was reconstructed using a tabularized incised plate urethroplasty and testicular tunica vaginalis flap. In the second stage, the remanent hypospadias was corrected, and the meatal opening reached its normal location. In conclusion, a two-staged surgical approach for the treatment of penoscrotal hypospadias associated with Opitz G/BBB syndrome may provide excellent outcomes in early-recognized cases. The urologist should pay attention to abnormal facial characteristics in patients with hypospadias.

What is the angle of a banana? The difficulty in reliable assessment of hypospadias chordee.

INTRODUCTION: The degree of chordee associated with hypospadias impacts operative management. Unfortunately, poor inter-observer reliability in assessing chordee by multiple methods in vitro has been demonstrated. This variability may be related to the fact that chordee is not a discrete angle, but rather an arc-like curvature similar to that of a banana. On an attempt to improve this variability, we assessed the inter-rater reliability of a novel method of chordee measurement and compared it to measurements with a goniometer both in vitro and in vivo. MATERIALS AND METHODS: In vitro assessment of curvature was performed using 5 bananas. In vivo chordee measurement was performed during 43 hypospadias repairs. On in vitro and in vivo cases, chordee was assessed independently by faculty and resident physicians. Angle assessment was performed in a standard manner with a goniometer and with a smartphone app using ruler measurements of the length and width of the arc (Summary Figure). The proximal and distal aspect of the arc to be measured was marked on the bananas, whereas the penile measurements were taken from the penoscrotal to the sub-coronal junctions. RESULTS: In vitro banana assessment demonstrated strong intra- and inter-rater reliability for length (0.89 and 0.88, respectively) and width measurements (0.97 and 0.96). The calculated angle demonstrated an intra- and inter-rater reliability of 0.67 and 0.67. The banana goniometer/protractor measurements were weak with an intra-rater and inter-rater reliability of 0.33 and 0.21. With hypospadias chordee, the inter-rater reliability was strong for length and width measurements (0.95 and 0.94) and 0.48 for calculated angle. The inter-rater reliability of the goniometer angle was 0.96. Further assessment of inter-rater goniometer reliability was performed relative to degree of chordee as characterized by faculty. The inter-rater reliability for ≤15°, 16-30, and ≥30° was 0.68 (n = 20), 0.34 (n = 14), and 0.90 (n = 9), respectively. When the goniometer angle was classified as ≤15, 16-30, or ≥30° by one physician, it was classified outside of this range by the other physician 23%, 47%, and 25% of the time, respectively. DISCUSSION: Our data demonstrate significant limitations of the goniometer for assessing chordee in vitro and in vivo. We were unable to demonstrate significant improvement in chordee assessment using arc length and width measurements to calculate radians. CONCLUSIONS: Reliable and precise techniques for measuring hypospadias chordee remain elusive and draw into question the validity and usability of management algorithms employing discrete values.

Utility of genetic work-up for 46, XY patients with severe hypospadias.

OBJECTIVE: Hypospadias is a common congenital abnormality that has been increasing in prevalence over the last decades. Historically, 46, XY patients with severe hypospadias and descended scrotal testes at birth have frequently lacked a genetic diagnosis. Platforms for molecular genetic testing have become more readily available and can offer an insight into underlying genetic causes of severe hypospadias. The goal of this study was to define the anatomical characteristics of severe hypospadias that can accurately define patients with 46, XY severe hypospadias and determine the practical utility of performing molecular genetic testing in this group of patients. METHODS: Patients who met the criteria for 46, XY severe hypospadias were offered a molecular genetic work-up in consultation with pediatric genetics. Patients were identified through chart review. Data extracted included karyotype, hypospadias phenotype including stretched penile length at diagnosis, age at genetic diagnosis, molecular genetic testing, pathogenic gene variant(s), gender identity, and clinical course. All patients underwent clinical genetic testing via 46, XY Disorders of Sexual Development (DSD) panels offered by Invitae®, GeneDx®, or Blueprint Genetics®. RESULTS: Of the 14 patients that underwent genetic testing, there were 5 previously published and 3 novel pathogenic or likely pathogenic variants in genes associated with 46, XY severe hypospadias (Table). Pathogenic variants were identified in AR (3), SRD5A2 [1], NR5A1 [2], WT1 [1], and ARTX [1]. Two patients had a variant of unknown significance, one in FREM2 and another in CEP41. Four had negative gene panels. The patient with the WT1 pathogenic variant was subsequently found to have developed a Wilms tumor and the patients with NR5A1 pathogenic variants are now undergoing adrenal insufficiency surveillance. DISCUSSION/CONCLUSION: Patients with 46,XY severe hypospadias and descended testes in the scrotum at birth can benefit from molecular genetic testing as their underlying disorders may reveal pathogenic variants that could have potentially life-altering consequences and change surveillance and monitoring.

Nerve stimulation guided bilateral pudendal nerve block versus landmark-based caudal block for hypospadias repair in young children: a prospective, randomized, pragmatic trial.

INTRODUCTION: Caudal block is frequently performed to provide analgesia for hypospadias repair. Literature suggests that pudendal block provides prolonged postoperative analgesia as compared with caudal block in children between 2 and 5 years. We compared the efficacy of pudendal and caudal blocks in children less than 2 years. METHODS: 60 children scheduled for hypospadias repair received standard general anesthesia along with either pudendal or caudal block (groups of 30 each). Variables collected were demographic data, block time, operating room time, intraoperative pain medication need, pain assessment score and medication need in the recovery room and pain assessment at home. RESULT: Groups were demographically similar. No differences were observed in the following recorded times (minutes): block procedure (caudal: 9.5±4.0, pudendal: 10.6±4.1, p=0.30), anesthesia (caudal: 17.3±5.3, pudendal: 17.7±4.3, p=0.75), total OR (caudal: 171±35, pudendal: 172±41; p=0.95) and postanesthesia care unit (PACU) stay (caudal: 88±37, pudendal: 86±42; p=0.80). Additionally, no differences were observed in rescue pain medication need in the operating room (caudal: 0, pudendal: 2 (p=0.49), in PACU (caudal: 4, pudendal: 4, p=0.99), pain assessed at home, time to pain level 2 (caudal: 13.93±8.9, pudendal: 15.17±8.7), average pain scores (p=0.67) and total pain free epochs (pain level of zero) (p=0.80) in the first 24 hours. DISCUSSION: In children less than 2 years, both blocks provide comparable intraoperative and postoperative pain relief in the first 24 hours after hypospadias surgery. TRIAL REGISTRATION NUMBER: NCT03145415.

Preliminary Reference Interval for 5-Alpha Reductase in Normal Male Children and Its Association with Hypospadias.

BACKGROUND: 5-alpha reductase (5-AR) enzyme is responsible for conversion of testosterone to dihydrotestosterone (DHT) in humans, which subserves various functions. The aim of the study was to establish a normal reference interval (RI) for blood levels of the enzyme 5-AR. METHODS: We conducted a prospective study on 150 boys, 75 of whom underwent circumcision for various benign conditions or for religious reasons (Group A/controls) and 75 suffering from hypospadias of variable severity (Group B/cases). The plasma levels of 5-AR were measured by enzyme-linked immunosorbent assay (ELISA) in all 150 boys and correlated with the severity of hypospadias. RESULTS: The 5-AR levels in Group A ranged from 14.6 to 17.3 ng/mL. The enzyme levels decreased in value with increasing severity of hypospadias in Group B (P-value <0.01 - statistically significant). The levels of the enzyme in this group ranged from 0.6 ng/mL (in the most severe variety of hypospadias) to 11.5 ng/mL (mild variety of hypospadias). CONCLUSIONS: There is no record of RI values of 5-AR in the literature. The RI of 5-AR needs to be determined by conducting more studies globally. Its levels falls considerably with clinical severity of hypospadias, reinforcing the importance of the enzyme in the development of male external genitalia.

Referral patterns, clinical features and management of uncorrected hypospadias in a series of adult men.

BACKGROUND: Hypospadias surgery undertaken in early life often continues to impose challenges as patients age. Little is known about the natural history of uncorrected hypospadias persisting into adulthood. OBJECTIVE: To describe presenting symptoms and management strategies in men with uncorrected hypospadias referred to our national tertiary transitional clinic for congenital urological conditions. MATERIALS AND METHODS: Patients with uncorrected hypospadias older than 16 years at the time of referral were identified by searching the electronic patient record system for ICD-10 hypospadias codes. Data were extracted over a 10-year period according to a predefined protocol. RESULTS: Among 201 referrals, 65 men with hypospadias (glanular n = 12, coronal n = 26, subcoronal n = 9, corporal n = 4, penoscrotal n = 2 and MIP n = 12) had never previously had reconstructive surgery undertaken. Obstructive symptoms predominated (n = 30) and the risk of symptoms increased with advancing age (Figure). Presenting complaints varied across the age span; cosmetic issues (n = 11) and coital pain (n = 5) were primarily seen in youth as opposed to urinary obstructive symptoms that were increasingly more frequent with age (p = 0.002) (Figure). Management included reconstructive surgery (n = 24), minor procedures (preputioplasty, circumcision, meatoplasty, dilatation/urethrotomy, total n = 28) as well as counselling (n = 12). The management strategies were independent of age and hypospadias type. DISCUSSION: The current cohort delineates the dynamic nature of hypospadias in itself. We speculate that the distinction in the primary complaint leading to referral between the extremes of age may relate to the vanity and insecurity of youth while older patients first come forward when other symptoms arise. Dissatisfaction with genital appearance is uncommon in previous smaller studies on men with uncorrected hypospadias unlike in our study, where 11 patients were assessed mainly for cosmetic concerns. Obstruction is the main symptom encountered in adult hypospadias patients operated in early life, and a similar picture was observed in our cohort of unoperated cases. Urethral dilatation and internal urethrotomy are temporizing procedures but were successful in immediate alleviation of obstructive symptoms in patients not willing to consign themselves to formal surgery. The study is limited by its retrospective design, and our symptomatic cohort may also represent the extreme end of the hypospadias spectrum. CONCLUSION: Medical issues vary across the age span in men with unrepaired hypospadias. Minor surgical procedures as well as counselling play an equally important role as reconstructive hypospadias surgery in the management of unrepaired hypospadias in adulthood.

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.

How accurate is eyeball measurement of curvature? A tool for hypospadias surgery.

INTRODUCTION: Correction of penile curvature or "chordee" is a major component in the management of hypospadias. Accurate assessment and management of penile curvature influence both short- and long-term outcomes of surgery. AIM OF THE STUDY: The objective of this study is to investigate the accuracy of eyeball measurement and how does it compare to objective measurement by standard goniometry (SG) and smartphone app goniometry (AG). MATERIALS AND METHODS: A Dropbox file request link was shared with paediatric urologists on various social media platforms requesting participants to upload a picture of their index finger showing what they thought 30 degrees of curvature look like using their proximal inter phalangeal joint as the point of maximal curvature., The images were assessed using SG to measure the angle of curvature. The images were also assessed using AG by the principal investigator, a physician, a scrub nurse and a paediatric urology consultant., Statistical analysis was performed using SPSS statistics software version 26 (Armonk, NY: IBM Corp). A one sample t-test and a one-way chi squared test were used to evaluate significant frequency differences. Pearson correlation was used to compare AG measurements to test intra- and inter-observer reliability and to compare AG measurements vs SG measurements. Assuming 5-degree variability in goniometer measurements and 2-degree difference between the sample and population, the number of participants needed was calculated to be 49. RESULTS: Fifty-two responses were received.32.7% of respondents simulated 30° accurately (17/52). A significant proportion (23/52, 44.2%) overrepresented the degree of curvature and 23.1% (12/52) underrepresented it (p = 0.01). Compared with objective measures, eyeball estimates differed by an average of 10° ± 1.5 SE. Measurements obtained by AG were comparable to measures obtained by SG and showed excellent intra-observer and inter-observer correlation (R = 0.983, P < 0.001). DISCUSSION: We demonstrated a significant discrepancy between eyeball assessment of curvature and objective measurements in a cohort of hypospadiologists. This can be very relevant to intraoperative decision making. The limitation of the study is the use of a simulated model rather than assessment of curvature in patients with hypospadias. Another limitation is the lack of standardization of the way the pictures were taken. CONCLUSION: We demonstrated a tendency among hypospadiologists to overestimate or underestimate curvature by an average of 10° on eyeball assessment. The use of App Goniometry shows excellent interobserver reliability and is comparable to standard goniometry in curvature assessment.

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.