The association and underlying mechanism of the digit ratio (2D:4D) in hypospadias.

ABSTRACT: The second-to-fourth digit (2D:4D) ratio is thought to be associated with prenatal androgen exposure. However, the relationship between the 2D:4D ratio and hypospadias is poorly understood, and its molecular mechanism is not clear. In this study, by analyzing the hand digit length of 142 boys with hypospadias (23 distal, 68 middle, and 51 proximal) and 196 controls enrolled in Shanghai Children's Hospital (Shanghai, China) from December 2020 to December 2021, we found that the 2D:4D ratio was significantly increased in boys with hypospadias (P < 0.001) and it was positively correlated with the severity of the hypospadias. This was further verified by the comparison of control mice and prenatal low testosterone mice model obtained by knocking out the risk gene (dynein axonemal heavy chain 8 [DNAH8]) associated with hypospadias. Furthermore, the discrepancy was mainly caused by a shift in 4D. Proteomic characterization of a mouse model validated that low testosterone levels during pregnancy can impair the growth and development of 4D. Comprehensive mechanistic explorations revealed that during the androgen-sensitive window, the downregulation of the androgen receptor (AR) caused by low testosterone levels, as well as the suppressed expression of chondrocyte proliferation-related genes such as Wnt family member 5a (Wnt5a), Wnt5b, Smad family member 2 (Smad2), and Smad3; mitochondrial function-related genes in cartilage such as AMP-activated protein kinase (AMPK) and nuclear respiratory factor 1 (Nrf-1); and vascular development-related genes such as myosin light chain (MLC), notch receptor 3 (Notch3), and sphingosine kinase 1 (Sphk1), are responsible for the limitation of 4D growth, which results in a higher 2D:4D ratio in boys with hypospadias via decreased endochondral ossification. This study indicates that the ratio of 2D:4D is a risk marker of hypospadias and provides a potential molecular mechanism.

For the penile length-how shall we choose the straightening procedures in hypospadias repair?

OBJECTIVE: To define the appropriate penile straightening procedures corresponding to the specific penile curvature by comparing the penile length resulting from various straightening procedures in hypospadias repair. METHODS: We retrospectively analyzed hypospadias patients between 2017 and 2019. Patients were divided into three groups based on the penile curvature after degloving: <30°, 30°-45°, and >45°. The penile straightening procedures include dorsal plication (DP), simple urethral plate (UP) transection, and UP transection with ventral lengthening (VL). The paired t-test was conducted for the penile length after fully straightening in each group, simultaneously calculating the length changes (∆T). In addition, the penile length changes among these procedures were compared using Spearman analysis to show the correlation between the penile curvature and the length. RESULTS: The penile length changed significantly after fully straightening in all groups. The length decreased mildly after DP, while increased in the other procedures. The penile curvature after degloving was positively correlated with the absolute change in the penile length (P < 0.001, r = 0.424) and the ratio of ∆T in the original length (P < 0.001, r = 0.433). CONCLUSION: For hypospadias, the 30° after degloving may serve as the cut-off for the selection of the straightening method from the perspective of the penile length. For those with < 30°, methods such as DP or UP transection can either be selected. In patients with > 30°, DP should be used with caution because of the potential risk to shorten the penis. In contrast, UP transection effectively corrects the penile curvature and increases the penile length concurrently, which should be primarily recommended in those patients.

Urethro-urethrostomy for urethral duplication (Type IIA1) in a 3-years-old boy: Surgical approach.

INTRODUCTION: To report a novel maneuver of end-to-side urethro-urethrostomy for managing Type IIA1 urethral duplication (UD). MATERIALS AND METHODS: A 3-years-old boy was referred to our institute for abnormal appearance of genitalia. Physical examination revealed an epispadiac meatus on the dorsum of the penile shaft, in addition to the orthotopic meatus at the tip of glans. He can void through both urethrae with continence (grade I). Voiding cystourethrography and the cystoscopy confirmed the Type IIA1 UD with two urethrae arising independently from the bladder neck. A novel maneuver of end-to-side urethro-urethrostomy transferring the dorsal urethra through the corpus cavernosa and anastomosing it to the posterior wall of the ventral urethra was successfully performed. RESULTS: The urethral catheter was removed 2 weeks postoperatively. Neither urethral stricture nor fistula was noticed. After 1 year of followed-up, the boy can void fluently with continence (grade I). The Qmax was 10.4 ml/s. CONCLUSION: Our maneuver of end-to-side urethro-urethrostomy for managing Type IIA1 UD was safe and effective, especially for the continent cases with the ectopic meatus on the penile shaft.

Molecular genetics and general management of androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is a rare genetic disorder that affects the development of the male reproductive system in individuals with a 46,XY karyotype. In addition to physical impacts, patients with AIS may face psychological distress and social challenges related to gender identity and acceptance. The major molecular etiology of AIS results from hormone resistance caused by mutations in the X-linked androgen receptor (AR) gene. Depending on the severity of androgen resistance, the wide spectrum of AIS can be divided into complete AIS (CAIS), partial AIS (PAIS), or mild AIS (MAIS). Open issues in the treatment and management of AIS include decisions about reconstructive surgery, genetic counseling, gender assignment, timing of gonadectomy, fertility and physiological outcomes. Although new genomic approaches have improved understanding of the molecular causes of AIS, identification of individuals with AIS can be challenging, and molecular genetic diagnosis is often not achievable. The relationship between AIS genotype and phenotype is not well established. Therefore, the optimal management remains uncertain. The objective of this review is to outline the recent progress and promote understanding of AIS related to the clinical manifestation, molecular genetics and expert multidisciplinary approach, with an emphasis on genetic etiology.

Urogenital sinus malformation: From development to management.

Urogenital sinus (UGS) malformation, also known as persistent urogenital sinus (PUGS), is a rare congenital malformation of the urogenital system. It arises when the urethra and vaginal opening fail to form properly in the vulva and fuse incorrectly. PUGS can occur as an isolated abnormality or as part of a complex syndrome, and is frequently associated with congenital adrenal hyperplasia (CAH). The management of PUGS is not well-established, and there are no standardized guidelines on when to perform surgery or how to follow up with patients over the long term. In this review, we discuss the embryonic development, clinical evaluation, diagnosis, and management of PUGS. We also review case reports and research findings to explore best practices for surgery and follow-up care, in hopes of increasing awareness of PUGS and improving patient outcomes.

One-stage repair of proximal hypospadias by in situ tubularization of the transverse preputial island flap.

PURPOSE: This study aimed to compare the efficacy of modified transverse preputial island flap (TPIF) repair with the traditional TPIF procedure and Byar's two-stage procedure in proximal hypospadias repair, especially in the postoperative urethral stricture incidence rates. MATERIALS AND METHODS: Patients admitted for proximal hypospadias treated with modified TPIF repair, the traditional TPIF procedure, or Byar's two-stage procedure at our institution from 2017 to 2021 were identified, and the incidence of postoperative complications among them was compared. RESULTS: In total, 142 patients were included (modified TPIF group, 43; traditional TPIF group, 37; and Byar's two-stage group, 62). The length of the neourethra was 4.21 ± 0.63 cm in the modified TPIF group, 4.18 ± 0.71 cm in the traditional TPIF group, and 4.20 ± 0.68 cm in the Byar's two-stage group. The rate of urethral stricture in the modified TPIF group (two cases, 4.65%) was significantly lower than that in the traditional TPIF group (four cases, 10.81%) (P = 0.008). Seven (16.28%) cases of urethrocutaneous fistula occurred in the modified TPIF group, six (16.22%) in the traditional TPIF group, and eight (12.90%) in the two-stage group. Additionally, one case (2.33%) of urethral diverticulum occurred in the modified TPIF group, one (2.70%) in the traditional TPIF group, and three (4.84%) in Byar's two-stage group. CONCLUSIONS: Modified TPIF repair can ensure a wedge anastomosis between the proximal urethral meatus and the neourethra, provide support and blood supply for the neourethra. Furthermore, it extended the urethral plate width at the anastomosis and urethral meatus, effectively reducing the incidence of urethral strictures.

Impact of corporate governance and CEO remuneration on bank capitalization strategies and payout decision in income shocks period.

The purpose of this research is to explore corporate governance and CEO remuneration with banks capitalization strategies and payout policy within the Pakistani banking context. Data were obtained from the financial statements of scheduled banks listed on the Pakistan stock exchange from 2005 to 2020. The findings of the research study revealed that corporate governance mechanisms that promote the bank's shareholders' interests are linked to low capitalization strategies. The size of the board of directors has a significant impact on the capitalization of banks. Banks' capitalization techniques are also adversely correlated with effective board size. The shareholder benefits from low capitalization. Corporate governance is positively related with banking sector instability, as seen by this negative correlation. Bank capitalization strategies have a significant impact on CEO remuneration. In the event of an income shock, dividend payout is essential. Banking sector payout policies are negatively related with corporate governance. In the event of a negative income shock, financial institutions reduce dividends. As a result, it has been argued that effective corporate governance benefits shareholders by reducing capitalization tactics and limiting financial institutions' aggressive payouts. JEL classification: G21, G30, G32, G35.

Exstrophy-Epispadias Complex With Isolated Ectopic Bowel Segment: A Case Series and Literature Review.

OBJECTIVE: To present a case series of the exstrophy-epispadias complex (EEC) with isolated ectopic bowel segment (IEBS) with the literature review, highlighting the clinical findings and treatments. MATERIALS AND METHODS: We present 3 cases of bladder exstrophy (BE) with IEBS in our institute and reviewed the literature in PubMed with the terms "("bladder exstrophy" OR "epispadias") AND ("visceral sequestration" OR "sequestered" OR "ectopic bowel")." RESULTS: There were 2 males and 1 female. The IEBS was detected by physical examination in 2 cases and by ultrasonography in another one. All cases were BE accompanying with lower abdominal mass which adhered to the bladder wall but was separated from the digestive system. All cases underwent the IEBS excision and BE repair simultaneously. Pathological result of IEBS suggested the histological structures of colon. There were totally 13 cases of EEC with IEBS reported in the literature, including 2 (15%) epispadias, 9 (69%) covered BE, 1 (8%) duplicate BE and 1 (8%) classic bladder exstrophy. Although their clinical manifestations were various, IEBS excision were safely conducted in all cases. CONCLUSION: EEC with IEBS is an extremely rare congenital malformation. Physical and imaging examinations are important for diagnoses. Surgical excision is safe and effective for managing IEBS.

Phenotypic modulation of vascular smooth muscle cells in the corpus spongiosum surrounding the urethral plate in hypospadias.

Hypospadias is an abnormal ventral development of the penis caused by incomplete virilization of the male genital tubercle. This study investigated the phenotypic modulation of vascular smooth muscle cells (VSMCs) in the corpus spongiosum surrounding the urethral plate in hypospadias. The urethral corpus spongiosum tissue was collected for HE, Masson and α-SMA immunohistochemical staining. Spongiosum VSMCs were cultured and identified by α-SMA fluorescence. qRT-PCR and Western blotting and fluorescence were performed. The results showed that the vascular lumen of the corpus spongiosum around the urethral plate was larger and that the vascular smooth muscle layer was thicker in hypospadias. The expression of the contractile markers α-SMA and Calponin 1 in VSMCs was decreased, the expression of the synthetic marker OPN was increased, and the transcription of the phenotypic switching factors SRF and MYOCD was decreased. The expression of Ki67, PCNA and BAX was increased, and the expression of Bcl-2 was decreased. The phenotype of corpus spongiosum VSMCs in hypospadias changed from the contractional type to the synthetic type. This phenotypic modulation was associated with increased proliferation and apoptosis rates. SRF and MYOCD may be the main factors mediating the phenotypic modulation of urethral corpus spongiosum VSMCs.

Pelvic Floor Anatomical Variations in Children With Exstrophy-Epispadias Complex Using Magnetic Resonance Imaging.

OBJECTIVE: To quantitatively measure the anatomical variations of the pelvic floor in children with exstrophy-epispadias complex using magnetic resonance imaging. MATERIALS AND METHODS: Six cases of classic bladder exstrophy (CBE), 5 cases of penile epispadias (PE) and 11 cases of penopubic epispadias (PPE) were included. Another 8 cases with the testicular tumor were taken as the controls. A series of measurements obtained from the pelvic floor magnetic resonance imaging were analyzed, and the measurements with significant differences were obtained by ANOVA. RESULTS: The pelvic floor of the CBE was significantly different from that of controls in measurements including wider pubic diastasis (P <.001), greater posterior anal distance (P = .019), greater posterior bladder neck distance (P = .004), larger iliac wing angle (P <.001), diminutive ischial angle (P <.001), bigger puborectalis angle (P <.001), larger ileococcygeous angle (P = .002) and shortened anterior corporal length (P <.001). For the PE, the posterior bladder neck distance (P = .038) was greater than that of controls. In the PPE, the posterior bladder neck distance (P = .001) and puborectalis angle (P = .026) was greater than that of controls, respectively. CONCLUSION: CBE shows severe anatomical variations of the pelvic floor. The bladder neck moves more anteriorly both in PE and PPE than the control. The enlarged puborectalis angle resulting from wider pubic diastasis and more anterior position of the anorectal canal is also noticed in PPE.

Spongiosum-combined glanuloplasty reduces glans complications after proximal hypospadias repair.

We aim to design a new glanuloplasty procedure combined with spongiosum to reduce the incidence of glans dehiscence and coronal fistula after proximal hypospadias repair. Patients who underwent urethroplasty by dorsal preputial island flap for proximal hypospadias between January 2014 and December 2016 were reviewed in this retrospective cohort study. Those who underwent spongiosum-combined glanuloplasty comprised the new-maneuver group, whereas those who underwent conventional glanuloplasty comprised the control group. The incidence of complications was then compared. In the new-maneuver group, dysplastic corpus spongiosum alongside lateral Buck's fascia (0.3-0.4 cm wide) on both sides of the urethral plate was separated from the proximal normal spongy tissue, joining into the glans wings to increase tissue volume and covering the neourethra in the glans penis. In the control group, the neourethra was covered with superficial fascia under the coronal sulcus. As a result, the new-maneuver and control groups comprised 47 and 28 patients, respectively. In the new-maneuver group, no glans dehiscence was detected; however, two (4.3%) patients had coronal fistula, two (4.3%) had urethral stricture, and four (8.5%) had diverticulum. In the control group, two (7.1%) patients had glans dehiscence, eight (28.6%) had coronal fistula, four (14.3%) had urethral stricture, one (3.6%) had diverticulum, and one (3.6%) had penile curvature recurrence. The new-maneuver group had less incidences of coronal fistula (P < 0.001), glans dehiscence (P = 0.033), and urethral stricture (P = 0.008) but had a higher incidence of diverticulum than the control group (P = 0.040). It clearly demonstrates that spongiosum-combined glanuloplasty can significantly reduce the incidences of coronal fistula and glans dehisce.

A Histomorphological Study of the Divergent Corpus Spongiosum Surrounding the Urethral Plate in Hypospadias.

OBJECTIVE: To investigate the histomorphological changes of the divergent corpus spongiosum surrounding the urethral plate in hypospadias. METHODS: Seventy boys with hypospadias were divided into the distal (n = 44) and proximal (n = 26) groups by the location of the ectopic meatus. The morphology of the divergent corpus spongiosum was evaluated and the histopathological studies were carried out by HE staining, Masson staining, and immunohistochemical analyses of α-SMA, CD34, TGF-ß1 and androgen receptor. Western blotting was performed to measure the expression of TGF-ß1 and androgen receptor. RESULTS: The divergent corpus spongiosum was significantly thicker in the distal group than the proximal group (distal 3.14 ± 1.12 mm, proximal 1.74 ± 0.87 mm, P <.0001). Histological evaluation suggested the cavernous sinus in the hypospadias group had an abnormal structure, which was characterized by an increase in the width of the vascular lumen (control 7.20 ± 1.12 µm, hypospadias 13.75 ± 8.08 µm, P = .0068), an increased vascular wall thickness (control 5.40 ± 1.28 µm, hypospadias 14.11 ± 7.59 µm, P = .0006), a decreased vascular density (control 15.66 ± 1.17, hypospadias 7.24 ± 4.19, P <.0001) and a decreased trabecular density (control 9.80 ± 1.92, hypospadias 3.68 ± 2.87, P <.0001). The severity of the structural abnormalities was greater in the proximal group than the distal group. Immunohistochemical analysis and Western blotting showed decreased TGF-ß1 and androgen receptor expression in the hypospadias group (P <.0001). CONCLUSIONS: Histomorphological analysis showed that the divergent corpus spongiosum in hypospadias is abnormal. The structural variation is positively correlated with the severity of hypospadias.

Comparison of short-term complications between Onlay and Duckett urethroplasty and the analysis of risk factors.

AIMS: To compare the short-term complications between Onlay and Duckett urethroplasty and to analyze the various risk factors cause the complications. METHODS: The children with hypospadias who underwent treatment with Onlay or Duckett urethroplasty from November 2014 to June 2016 were followed up. The difference in complications between the two groups was analyzed. Moreover, a single-factor ANOVA was performed to analyze the length and curvature of the penis and the length of the urethral defect. RESULTS: 40 patients were treated by Duckett, while 54 by Onlay. In comparison to the Onlay group, the Duckett group showed the initial penile length was shorter (P = 0.044), the initial urethral defect (P = 0.024) and after the correction of chordee was longer (P < 0.001), and the initial penile curvature (P < 0.001) and after degloving (P < 0.001) was greater. Furthermore, the incidence of urethra percutaneous fistula (P = 0.041) and urethral stenosis (P < 0.001) in Duckett group was significantly higher. The analysis of risk factors showed that the age at the time of surgery, the initial penile curvature, the initial urethral defect, and the urethral defect after the correction of chordee were not correlated with the complications. The degree of penile curvature after skin degloving and urethra stenosis was significantly correlated (P = 0.019). CONCLUSION: The incidence of complications of urethra percutaneous fistula and urethral stenosis after 1 year of Duckett was higher than that by Onlay approach. The greater the curvature of the penis after skin degloving, the more likely the occurrence of urethral stenosis after surgery.

Association between diacylglycerol kinase kappa variants and hypospadias susceptibility in a Han Chinese population.

Previous genome-wide association studies have identified variants in the diacylglycerol kinase kappa (DGKK) gene associated with hypospadias in populations of European descent. However, no variants of DGKK were confirmed to be associated with hypospadias in a recent Han Chinese study population, likely due to the limited number of single-nucleotide polymorphisms (SNPs) included in the analysis. In this study, we aimed to address the inconsistent results and evaluate the association between DGKK and hypospadias in the Han Chinese population through a more comprehensive analysis of DGKK variants. We conducted association analyses for 17 SNPs in or downstream of DGKK with hypospadias among 322 cases (58 mild, 113 moderate, 128 severe, and 23 unknown) and 1008 controls. Five SNPs (rs2211122, rs4554617, rs7058226, rs7063116, and rs5915254) in DGKK were significantly associated with hypospadias (P < 0.05), with odds ratios (ORs) of 1.64-1.76. When only mild and moderate cases were compared to controls, 10 SNPs in DGKK were significant (P < 0.05), with ORs of 1.56-2.13. No significant SNP was observed when only severe cases were compared to controls. This study successfully implicated DGKK variants in hypospadias risk among a Han Chinese population, especially for mild/moderate cases. Severe forms of hypospadias are likely due to other genetic factors.