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.

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.

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.