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Meeting Report on the NIDDK/AUA Workshop on Congenital Anomalies of External Genitalia: Challenges and Opportunities for Translational Research

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Meeting Report on the NIDDK/AUA Workshop on Congenital Anomalies of External Genitalia: Challenges and Opportunities for Translational Research UCLA UCLA Previously Published Works Title Meeting report on the NIDDK/AUA Workshop on Congenital Anomalies of External Genitalia: challenges and opportunities for translational research. Permalink https://escholarship.org/uc/item/1vk2c98g Journal Journal of pediatric urology, 16(6) ISSN 1477-5131 Authors Stadler, H Scott Peters, Craig A Sturm, Renea M et al. Publication Date 2020-12-01 DOI 10.1016/j.jpurol.2020.09.012 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Journal of Pediatric Urology (2020) 16, 791e804 Review Article Meeting report on the NIDDK/AUA Workshop on Congenital Anomalies of External Genitalia: challenges and opportunities for translational research* aDepartment of Skeletal Biology, Shriners Hospital for Children, a, ,1 b,c, ,1 d,1 3101 SW Sam Jackson Park Road, H. Scott Stadler *** , Craig A. Peters ** , Renea M. Sturm , b e f,g Portland, OR, Oregon Health & Linda A. Baker , Carolyn J.M. Best , Victoria Y. Bird , Science University, Department of h i j Orthopaedics and Rehabilitation, Frank Geller , Deborah K. Hoshizaki , Thomas B. Knudsen , i k l, ,1 Portland, 97239, OR, USA Jenna M. Norton , Rodrigo L.P. Romao , Martin J. Cohn * b Department of Urology, Summary parents, and short interviews to determine familial University of Texas Southwestern, 5323 Harry Hines Blvd., Dallas, Congenital anomalies of the external genitalia penetrance (small pedigrees), would accelerate 75390-9110, TX, USA (CAEG) are a prevalent and serious public health research in this field. Such a centralized datahub concern with lifelong impacts on the urinary func- will advance efforts to develop detailed multi- cPediatric Urology, Children’s tion, sexual health, fertility, tumor development, dimensional phenotyping and will enable access to Health System Texas, University of and psychosocial wellbeing of affected individuals. genome sequence analyses and associated metadata Texas Southwestern, Dallas, Complications of treatment are frequent, and data to define the genetic bases for these conditions. 75390, TX, USA reflecting long-term outcomes in adulthood are Inclusion of tissue samples and integration of clinical limited. To identify a path forward to improve studies with basic research using human cells and dDepartment of Urology, Division of treatments and realize the possibility of preventing animal models will advance efforts to identify the Pediatric Urology, University of CAEG, the National Institute of Diabetes and Diges- developmental mechanisms that are disrupted dur- California Los Angeles, 200 Medical Plaza #170, Los Angeles, 90095, CA, tive and Kidney Diseases and the American Urologi- ing development and will add cellular and molecular USA cal Association convened researchers from a range granularity to phenotyping CAEG. While the discus- of disciplines to coordinate research efforts to fully sion focuses heavily on hypospadias, this can be seen eAmerican Urological Association, understand the different etiologies of these common as a potential template for other conditions in the 1000 Corporate Boulevard, conditions, subsequent variation in clinical pheno- realm of CAEG, including cryptorchidism or the Linthicum, 21090, MD, USA types, and best practices for long term surgical exstrophyeepispadias complex. Taken together with success. Meeting participants concluded that a long-term clinical follow-up, these data could fDepartment of Urology, central data hub for clinical evaluations, including inform surgical choices and improve likelihood for University of Florida, Gainesville, collection of DNA samples from patients and their long-term success. 32610, FL, USA gNational Medical Association and Research Group, 5745 SW 75th Introduction outcomes in adulthood are limited [1e8]. Street, #507, Gainesville, 32608, Improving treatments and realizing the possi- FL, USA Congenital anomalies of the external genitalia bility of preventing CAEG will require the co- hDepartment of Epidemiology (CAEG) are a prevalent and serious public ordinated efforts of diverse research Research, Statens Serum Institut, health concern with lifelong impacts on the disciplines to fully understand the different 5 Artillerivej, Copenhagen S, DK- etiologies of these common conditions, sub- 2300, Denmark urinary function, sexual health, fertility, tumor development, and psychosocial well- sequent variation in clinical phenotypes, and best practices for long term surgical success. iNational Institute of Diabetes and being of affected individuals. CAEG include a Digestive and Kidney Diseases, broad set of conditions that present in a wide The National Institute of Diabetes and Diges- National Institutes of Health, 6707 spectrum, ranging from mild variants of tive and Kidney Diseases (NIDDK) and the Democracy Boulevard, Bethesda, American Urological Association (AUA) 20892, MD, USA normal to extreme anomalies that interfere with function (Table 1). Although many con- convened researchers from a range of disci- j plines, including pediatric urology, develop- US Environmental Protection ditions require surgical management, compli- Agency, Office of Research and cations are frequent and high-quality mental biology, genetics & genomics, Development, Center for epidemiological data reflecting long-term computational systems biology, toxicology, Computational Toxicology and endocrinology, and epidemiology at AUA Exposure, Research Triangle Park, 27711, NC, USA * The authors served as the Writing Group of the Workshop on Congenital Anomalies of the External Genitalia. https://doi.org/10.1016/j.jpurol.2020.09.012 1477-5131/ª 2020 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. 792 H.S. Stadler et al. kDepartments of Surgery and Headquarters in Linthicum, Maryland in May The external genitalia arise as paired gen- Urology, IWK Health Centre, 2018 to discuss the best way forward to ital swellings located on each side of the em- Dalhousie University, Halifax, Nova Scotia, Canada address this public health concern. bryonic cloaca [19]. During development Meeting participants discussed research (around embryonic day 28 in human and 10.5 lDepartment of Molecular needs relating to: 1) defining the molecular in mice) these genital swellings fuse to form Genetics and Microbiology, determinants of normal external genital the genital tubercle, the structure from which Department of Biology, And UF development to improve understanding of the external genitalia is derived. Genital tu- Genetics Institute, University of Florida, PO Box 103610, CAEG etiologies, 2) mapping molecular path- bercle development involves some of the same Gainesville, 32610, FL, USA ways to the cellular behaviors that drive processes as embryonic limb and digit devel- genitourinary development, 3) systems opment, including the specification and * Corresponding author. modeling to unravel complex tissue in- patterning of tissues along three spatial planes teractions that coordinate morphogenesis 4), or axes, namely proximodistal (base-to-tip), ** Corresponding author. improving the quality of epidemiological anteroposterior (cranial side, which will Department of Urology, University of Texas Southwestern, 5323 reporting in the era of “Big Data,” and 5) new become the dorsal aspect of the phallus, to Harry Hines Blvd., Dallas, 75390- approaches to clinical phenotyping. The caudal side, which will become ventral), and 9110, TX, USA. workshop resulted in development of a gen- mediolateral (midline to left and right sides) eral framework for advancing research and [20,21]. To achieve this differential *** Corresponding author. clinical care to improve outcomes for people patterning, the endodermal urethral plate [email protected] (H.S. Sta- dler) with CAEG, which we describe in this article epithelium grows out from the cloaca with the craig.peters@utsouth- (See Box 1). The goal was to provide a broad genital swellings and functions as the critical western.edu (C.A. Peters) and inclusive framework from varied per- organizing center of the genital tubercle. mjcohn@ufl.edu (M.J. Cohn) spectives, including basic scientists, epidemi- Signaling interactions between the urethral Keywords ologist, clinicians, environmental scientists plate and adjacent mesenchyme are mediated Hypospadias; Genitourinary and others. This framework is intended to by secreted proteins – including SHH, BMP4, development; Chordee; Epis- serve as a template for organizing current and BMP7, WNT5a, and FGF10 – that control many padias; Genetics; Endocrine future knowledge to better develop under- of the cellular processes required for genital disruption; Penis; Urethra standing of these conditions in order to facil- development [10,13,14,22,23]. itate possible prevention and clinical care. For the most part, the developmental pro- Abbreviations There was broad support for future workshops cesses regulated by these growth factors dur- ABM, agent-based models; AOP, that target specific needs, such as develop- ing genital development have been adverse outcome pathway; ment of more granular clinical phenotyping investigated through the use of genetically AUA, American Urological As- protocols that incorporate anatomic, molecu- engineered mice, which determined that the sociation; BMP, bone morpho- genic protein; CAEG, lar, and genetic data. formation of the urethral tube proceeds by Congenital anomalies of the central canalization of the urethral plate external genitalia; DNA, deox- Defining the molecular determinants [9,24]. While anatomical differences
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