Congenital anorectal malformations (ARMs) are one of the most frequently observed birth defects of the digestive system. However, their etiology remains elusive. Therefore, we aim to summarize and critically appraise all existing literature on the genetic and nongenetic etiology of nonsyndromic ARM and to conclude with unifying hypotheses and directions for future research. A structured literature search on English language human studies was conducted in PubMed and Embase up to October 1, 2013, resulting in 112 included articles. Research on the identification of genes underlying nonsyndromic ARM is remarkably scarce. Most studies were focused on screening of candidate genes for mutations or single-nucleotide polymorphisms, which did not yield any substantial evidence. Nongenetic factors fairly consistently found to be associated with ARM are assisted reproductive techniques, multiple pregnancy, preterm delivery, low birth weight, maternal overweight or obesity, and preexisting diabetes. This review provides indications for the involvement of both genes and nongenetic risk factors in the etiology of ARM. In future studies, large cohorts of patients with ARM from national and international collaborations are needed to acquire new hypotheses and knowledge through hypothesis-generating approaches. Challenges for future studies may also lie in the investigation of gene-gene and gene-environment interactions.

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Birth Defects Research. Part C: Embryo Today Reviews
Department of Pediatric Surgery

Wijers, C., Rooij, I., Marcelis, C., Brunner, H. G., de Blaauw, I., & Roeleveld, N. (2014). Genetic and nongenetic etiology of nonsyndromic anorectal malformations: A systematic review. Birth Defects Research. Part C: Embryo Today Reviews, 102(4), 382–400. doi:10.1002/bdrc.21068