Genetic and environmental factors in the etiology of esophageal atresia and/or tracheoesophageal fistula: An overview of the current concepts

Abstract

Esophageal atresia and/or tracheoesophageal fistula (EA/TEF) are severe congenital anomalies. Although recent years have brought significant improvement in clinical treatment, our understanding of the etiology of these defects is lagging. Many genes and genetic pathways have been implicated in the development of EA/TEF, but only a few genes have been shown to be involved in humans, in animals, or in both. Extrapolating data from animal models to humans is not always straightforward. Environmental factors may also carry a risk, but the mechanisms are yet to be elucidated. This review gives an overview of the current state of knowledge about both genetic and environmental risk factors in the etiology of EA/TEF.

Prevalence of esophageal atresia among 18 international birth defects surveillance programs

“…Chromosomal anomalies have been reported to occur in 6 to 10% of EA cases (Garne et al, 2007;Genevieve et al, 2007;Pedersen et al, 2012); while greater than 50% and up to two thirds of infants with EA have additional anomalies (Genevieve et al, 2007;Spitz, 2007;de Jong et al, 2010a;Pedersen et al, 2012). Given that EA is more likely to be diagnosed in conjunction with other syndromes (particularly VACTERL: Vertebral anomalies, Anal atresia, Cardiovascular anomalies, Tracheo-Esophageal fistula, Renal and/or Radial anomalies, Limb defects) or chromosomal anomalies that may result in termination of pregnancy, it is important to include terminated cases in ascertainment (Shaw-Smith, 2006;Felix et al, 2009). For some anomalies, availability and reporting of ETOPFA may increase ascertainment of cases.…”

“…The underlying etiology of EA has been described as multifactorial and is likely to differ across settings (Robert et al, 1993;Felix et al, 2009;de Jong et al, 2010b). In addition to maternal ethnicity and geographic location, previous studies have reported EA to be associated with maternal age (Leck et al, 1968;Harris et al, 1995), multiple gestation (Harris et al, 1995;Riley et al, 1998), infant sex (Robert et al, 1993) and use of assisted reproductive technology (Reefhuis et al, 2009).…”

“…Underlying and still unknown (Genevieve et al, 2011) genetic susceptibility, biologic or physical differences may also modify risk of exposures. Although a number of genetic abnormalities have been associated with EA, no specific gene has been implicated (Felix et al, 2009). Further study with more detailed information to assess risk factors and underlying characteristics of cases with EA is required.…”

“…Diagnosis occurs prenatally or, in most cases, at birth and surgical repair is required in the first few days of life. Although the etiology of EA is largely unknown (Felix et al, 2009), geographic, temporal, and ethnic variations have been reported.…”

Abnormal Sonic hedgehog signaling in the lung of rats with esophageal atresia induced by adriamycin

“…Nevertheless, mutations/deletions affecting FOXF1, which is linked to Shh signaling, and mutation of HOXD13, a downstream target of Shh, result in a VACTERL-like phenotype (12); furthermore, several human syndromic esophageal atresias implicate deletions/mutations in genes that also seem to interact with the Shh pathway as MYCN (Feingold syndrome) (13,14), SOX2 (anophthalmia-esophageal-genital syndrome) (15,16), Mid1 (X-linked Opitz syndrome) (17,18), and Gli3 (Pallister-Hall syndrome) (19,20). These reported genetic disorders suggest that disturbances of Shh signaling due to interacting pathways may play a role in the EA-TEF/VACTERL association phenotype.…”