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Genetic and environmental origins of hypospadias

Thorup, Jorgena,b; Nordenskjöld, Agnetac,d; Hutson, John M.e,f,g

Current Opinion in Endocrinology, Diabetes and Obesity: June 2014 - Volume 21 - Issue 3 - p 227–232
doi: 10.1097/MED.0000000000000063
ANDROGENS: Edited by David Handelsman

Purpose of review The purpose of this study was to review and comment on recent original presentations dealing with genetic and environmental factors in the cause of hypospadias.

Recent findings The heritability is definitely high and having an affected family member is the highest identified risk factor so far. Many candidate genes and polymorphisms have been suggested for hypospadias. Some associations with hypospadias were found, and many of these were replicated inconsistently as would be expected in a complex disorder affected by both genes and environment. The consistent association of hypospadias with low birth weight, maternal hypertension, and preeclampsia suggests that placental insufficiency is a major risk factor. Maternal exposure to chemical pollutants or endocrine disruptors in high concentrations related to selected occupations or geographic areas may be additional risk factors for hypospadias, especially in genetically predisposed individuals. So far, however, no environmental chemical pollutants or endocrine disruptor with a general common impact on the risk for hypospadias in most societies has been demonstrated.

Summary A major point that should be considered regarding the action of environmental toxicants in inducing hypospadias is the cumulative effects of multiple low-dose exposures. Furthermore, interactions between genetic and environmental factors may help to explain nonreplication in genetic studies of hypospadias.

aDepartment of Pediatric Surgery, Rigshospitalet

bFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

cDepartment of Women's and Children's Health, Pediatric Surgery Unit and Center for Molecular Medicine, Karolinska Institutet

dPediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden

eDepartment of Pediatric Urology, Royal Children's Hospital

fDouglas Stephens Surgical Research Laboratory, Murdoch Children's Research Institute, Melbourne

gDepartment of Paediatrics, University of Melbourne, Parkville, Victoria, Australia

Correspondence to Jorgen Thorup, MD, PhD, FEBPS, FEAPU, Professor and Chair, Head of Department, 4272 Department of Pediatric Surgery, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. Tel: +45 3545 4868; fax: +45 3545 3888; e-mail:

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