Home  |   Archive  |   Online Submission  |   News & Events  |   Subscribe  |   APFA  |   Society  |   Contact Us  |   中文版

Ahead of print
Authors' Accepted
Current Issue
Special Issues
Browse by Category

Manuscript Submission

Online Submission
Online Review
Instruction for Authors
Instruction for Reviewers
English Corner new!

About AJA

About AJA
Editorial Board
Contact Us

Resources & Services

Email alert

Download area

Copyright licence
EndNote style file
Manuscript word template
Guidance for AJA figures
    preparation (in English)

Guidance for AJA figures
    preparation (in Chinese)

Proof-reading for the

AJA Club (in English)
AJA Club (in Chinese)


Volume 26, Issue 4 (July 2024) 26, 356–365; 10.4103/aja202377

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

Ding, Yu1,*; Chen, Zu-Quan1,*; Pan, Wen-Feng1; Chen, Hao-Jie1; Wu, Min1; Lyu, Yi-Qing1; Xie, Hua1; Huang, Yi-Chen1; Chen, Zhong-Zhong1,2; Chen, Fang1,3

1Department of Urology, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China
    2Urogenital Development Research Center, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China
    3Clinical Research Center for Hypospadias, Pediatric College, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, China

Correspondence: Dr. ZZ Chen (zhongzhongchen@sjtu.edu.cn) or Dr. F Chen (chenfang01@sjtu.edu.cn)

29 March 2024


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.

Full Text | PDF |

Browse:  29
Asian Journal of Andrology CN 31-1795/R ISSN 1008-682X  Copyright © 2023  Shanghai Materia Medica, Chinese Academy of Sciences.  All rights reserved.