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The Genetics and Molecular Biology of Oesophageal Development

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Esophageal and Gastric Disorders in Infancy and Childhood

Abstract

The aetiology of esophageal atresia with or without tracheoesophageal fistula (EA/TEF) has been explored using both epidemiological and molecular methodologies [1, 2]. Three large population-based epidemiological studies have arrived at similar estimates of the incidence, familial aggregation and recurrence risk for this malformation [3–5]. The overall conclusion from these studies is that genetic factors are not strongly implicated in the etiopathogenesis of the EA/TEF malformation complex.

These indirect measures of the magnitude of the effect of potential genetic and environmental contributors to the causes of EA/TEF have been complemented by intensive study of the molecular underpinnings of Mendelian syndromes in which EA/TEF is a frequent manifestation of their phenotype. Whilst the evidence suggests that the contribution of genetic factors in causing EA/TEF at the population level is not large, the study of rare syndromes that feature the malformation has identified several genes that have been directly implicated in the biology of canalising and partitioning of the primitive foregut. It is plausible that the disruption of pathways defined by these genetic factors may lead to sporadic, non-syndromic instances of EA/TEF, although the mode by which these perturbations take place may not be inherently genetic.

Indications that genetic factors are not major etiological contributors to EA/TEF have focused attention on other potential causes. Epidemiological evidence that teratogenic or infectious contributors account for the comparatively low recurrence risk and lack of familial aggregation of this disorder is, at best, circumstantial; agents studied to date have little role in the aetiology of EA/TEF. Nevertheless, the possibility remains that unrecognised environmental agents could still play a causative role. This contention is distinctly plausible given that the most successful and well-characterised animal model for EA involves Adriamycin exposure of the foetal rat in utero: environmental exposure to this single agent results in a consistent and reproducible phenotype.

This chapter summarises the epidemiological, clinical and molecular evidence for the existence of genetic contributors to the genesis of EA and then proceeds to summarise our knowledge of the molecular and cell biology of the condition, as derived from studies in humans and animal models. For a more detailed discussion of the issues contained in this chapter, two recent reviews have also covered this subject in detail: Shaw-Smith (J Med Genet 43:545–54, 2006) and Genevieve et al. (Clin Genet 71:392–9, 2007).

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Authors and Affiliations

  1. University of Minnesota, 420 Delaware Street SE, Mayo Mail Code 495, Minneapolis, MN, 55455, USA

    Stephen P. Robertson

  2. Department of Paediatic Surgery, Christchurch Hospital, Second Floor Parkside East, Riccarton Avenue, Private Bay 4710, Christchurch, Canterbury, New Zealand

    Spencer W. Beasley

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  1. Stephen P. Robertson
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Correspondence to Spencer W. Beasley .

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Editors and Affiliations

  1. Medical University of Graz, Graz, Austria

    Holger Till

  2. Sheffield Children’s Hospital, Paediatric Gastroenterology Centre, Sheffield, United Kingdom

    Mike Thomson

  3. Division of Cardiothoracic Surgery, Department of Surgery, University of Minnesota Medical School, Minneapolis, Minnesota, USA

    John E. Foker

  4. Department Surgery, University of Missouri, Kansas City Children’s Mercy Hospital, Kansas City, Missouri, USA

    George W. Holcomb III

  5. University of Arizona, Tucson, Arizona, USA

    Khalid M. Khan

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Robertson, S.P., Beasley, S.W. (2017). The Genetics and Molecular Biology of Oesophageal Development. In: Till, H., Thomson, M., Foker, J., Holcomb III, G., Khan, K. (eds) Esophageal and Gastric Disorders in Infancy and Childhood. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-11202-7_2

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