Meeting report on the NIDDK/AUA Workshop on Congenital Anomalies of External Genitalia: challenges and opportunities for translational research

Abstract

Congenital anomalies of the external genitalia (CAEG) are a prevalent and serious public health concern with lifelong impacts on the urinary function, sexual health, fertility, tumor development, and psychosocial wellbeing of affected individuals. Complications of treatment are frequent, and data reflecting long-term outcomes in adulthood are limited. To identify a path forward to improve treatments and realize the possibility of preventing CAEG, the National Institute of Diabetes and Digestive and Kidney Diseases and the American Urological Association convened researchers from a range of disciplines to coordinate research efforts to fully understand the different etiologies of these common conditions, subsequent variation in clinical phenotypes, and best practices for long term surgical success. Meeting participants concluded that a central data hub for clinical evaluations, including collection of DNA samples from patients and their parents, and short interviews to determine familial penetrance (small pedigrees), would accelerate research in this field. Such a centralized datahub will advance efforts to develop detailed multidimensional phenotyping and will enable access to genome sequence analyses and associated metadata to define the genetic bases for these conditions. Inclusion of tissue samples and integration of clinical studies with basic research using human cells and animal models will advance efforts to identify the developmental mechanisms that are disrupted during development and will add cellular and molecular granularity to phenotyping CAEG. While the discussion focuses heavily on hypospadias, this can be seen as a potential template for other conditions in the realm of CAEG, including cryptorchidism or the exstrophyeepispadias complex. Taken together with long-term clinical follow-up, these data could inform surgical choices and improve likelihood for long-term success.

Whole-exome sequencing study of hypospadias

“… 28 In contrast to IDNAH genes or inner dynein arms (IDAs), the significant excess of rare damaging variants in ODNAH genes is indicative of their being a major factor in hypospadias causation. Hypospadias has lifelong effects on the urinary function and fertility, 3 which were mediated by testosterone signaling related genes, such as NR5A1 . 2 In the absence of testosterone, spermatogenesis rarely proceeds beyond meiosis.…”

“… 1 The androgen-dependent signals have fundamental roles in masculinization and are crucial for the developmental process of the external genitalia, 2 which has lifelong effects on the urinary function, fertility, and sexual health. 3 The development of hypospadias is influenced by androgens, specifically testosterone (T), and dihydrotestosterone (DHT). 2 Testosterone is the major androgen 4 and can be converted to DHT.…”

Advancements in Hypospadias Management: Trends, Techniques, Training, and Patient-Centric Outcomes

“…Additionally, epigenetic mechanisms, long noncoding RNAs, miRNAs, unfolded protein response (autophagy-apoptosis), and metabolome likely are important in the interplay with genetic susceptibility and require future elucidation. 2 Due to the range of associated genital development findings, phenotype/genotype correlation may be limited if meatal location is used as the main landmark to describe the phenotype. Proximal cases, for example, are more frequently associated with chordee, undescended testes, or genital ambiguity.…”