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Esophageal atresia

The research network great (genetic risk of esophageal atresia) investigates the genetic and non-genetic causes of esophageal atresia. The results of this research may facilitate the future generation of novel insights into the pathophysiology of this congenital malformation. Molecular genetic analyses for great are performed at the Center for Human Genetics at the University Hospital of Marburg, and at the Institute of Human Genetics and the Department of Neonatology at the University Hospital in Bonn. The website of the great consortium can be accessed under www.great-konsortium.de.

Clinical features of esophageal atresia

Esophageal atresia is a congenital malformation in which the continuity of connection of the esophagus to the stomach is partially or completely interrupted. Research suggests that the disorder occurs in approximately 1: 3,500 live births.

From an embryological perspective, esophageal atresia represents a disorder of arrested development. Physiologically, the esophagus and trachea develop together from the embryonic foregut, and then separate as embryonic development progresses. If this separation does not occur, a complete or partial interruption of the esophagus results, with or without a fistula to the trachea. Prenatal ultrasound reveals an excess of amniotic fluid on ultrasound, since the ability of the fetus to reabsorb this is either partially or completely impaired. After birth, the infant is unable to swallow saliva, and increased salivation is evident. This renders the infant at risk of fluid aspiration into the lungs.

Genetics of esophageal atresia

In most cases, esophageal atresia occurs as an isolated anomaly. The genetic cause of isolated esophageal atresia remains unknown. Researchers assume that isolated esophageal atresia has a spectrum of causes, and that both monogenic and multifactorial etiologies may occur.

Monogenic diseases arise secondary to mutations in a single gene. These mutations show high penetrance, i.e., mutation carriers are likely to develop the respective illness. Monogenic diseases can be further subdivided into autosomal recessive and autosomal dominant forms. In autosomal recessive diseases, the affected individual has two changes in one gene, one of which is inherited from the mother and the other from the father. The parents are healthy, since both carried only one mutation in the gene. In contrast, autosomal-dominant diseases arise when an individual has only one mutation in the respective gene. Since the parents are usually unaffected by esophageal atresia, it must be assumed that this is a so-called de novo mutation. In this case, the change first occurred in the parental germ cells (sperm or ovum).

In contrast, multifactorial diseases involve the effects of multiple genetic risk variants. Each individual risk variant has a relatively low penetrance, and is also common in the general population. The disease only manifests when the number of risk variants carried exceeds a certain threshold.

Since no genetic associations have yet been reported for isolated esophageal atresia, the proportion of monogenic versus multifactorial esophageal atresia cases remains unknown. In contrast, genes for syndromic forms of esophageal atresia have already been identified. In syndromic esophageal atresia patients, congenital abnormalities are also present in other organ systems. A particular focus of the work of the great Consortium is the elucidation of the genetics of isolated esophageal atresia. For this purpose, state-of-the-art molecular genetic approaches will be applied, including Next Generation Sequencing (NGS) and genome-wide association studies (GWAS). 

Contact person

Prof. Dr. Johannes Schumacher

The webpage of the great Consortium can be accessed under: www.great-konsortium.de.

Selected Publications

Hölscher AC, Laschat M, Choinitzki V, Zwink N, Jenetzky E, Münsterer O, Kurz R, Pauly M, Brokmeier U, Leutner A, Ure B, Lacher M, Schumacher J, Reutter H, Boemers TM. Quality of Life after Surgical Treatment for Esophageal Atresia: Long-Term Outcome of 154 Patients. Eur J Pediatr Surg 2017 27: 443-8.

Bogs T, Zwink N, Chonitzki V, Hölscher A, Boemers TM, Münsterer O, Kurz R, Heydweiller A, Pauly M, Leutner A, Ure BM, Lacher M, Deffaa OJ, Thiele H, Bagci S, Jenetzky E, Schumacher J, Reutter H. Esophageal Atresia with or without Tracheoesophageal Fistula (EA/TEF): Association of Different EA/TEF Subtypes with Specific Co-occurring Congenital Anomalies and Implications for Diagnostic Workup. Eur J Pediatr Surg 2018 28: 176-82.

Brosens E, Marsch F, de Jong EM, Zaveri HP, Hilger AC, Choinitzki VG, Hölscher A, Hoffmann P, Herms S, Boemers TM, Ure BM, Lacher M, Ludwig M, Eussen BH, van der Helm RM, Douben H, Van Opstal D, Wijnen RM, Beverloo HB, van Bever Y, Brooks AS, IJsselstijn H, Scott DA, Schumacher J, Tibboel D, Reutter H, de Klein A. Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula. Eur J Hum Genet 2016 24: 1715-23.

Zwink N, Choinitzki V, Baudisch F, Hölscher A, Boemers TM, Turial S, Kurz R, Heydweiller A, Keppler K, Müller A, Bagci S, Pauly M, Brokmeier U, Leutner A, Degenhardt P, Schmiedeke E, Märzheuser S, Grasshoff-Derr S, Holland-Cunz S, Palta M, Schäfer M, Ure BM, Lacher M, Nöthen MM, Schumacher J, Jenetzky E, Reutter H. Comparison of environmental risk factors for esophageal atresia, anorectal malformations, and the combined phenotype in 263 German families. Dis Esophagus 2016 29: 1032-42.

Choinitzki V, Zwink N, Bartels E, Baudisch F, Boemers TM, Hölscher A, Turial S, Bachour H, Heydweiller A, Kurz R, Bartmann P, Pauly M, Brokmeier U, Leutner A, Nöthen MM, Schumacher J, Jenetzky E, Reutter H. Second study on the recurrence risk of isolated esophageal atresia with or without trachea-esophageal fistula among first-degree relatives: no evidence for increased risk of recurrence of EA/TEF or for malformations of the VATER/VACTERL association spectrum. Birth Defects Res A Clin Mol Teratol 2013 97: 786-91.

Schulz AC, Bartels E, Stressig R, Ritgen J, Schmiedeke E, Mattheisen M, Draaken M, Ludwig M, Bagci S, Müller A, Gembruch U, Geipel A, Berg C, Heydweiller A, Bachour H, Schumacher J, Bartmann P, Nöthen MM, Reutter H. Nine new twin pairs with esophageal atresia: a review of the literature and performance of a twin study of the disorder. Birth Defects Res A Clin Mol Teratol 2012 94: 182-6.