title: Clinical and etiological heterogeneity in patients with tracheo-esophageal malformations and associated anomalies.
abstract: Esophageal Atresia (EA) is a severe developmental defect of the foregut that presents with or without a Tracheo-Esophageal Fistula (TEF). The prevalence of EA/TEF over time and around the world has been relatively stable. EA/TEF is manifested in a broad spectrum of anomalies: in some patients it manifests as an isolated atresia or fistula, but in over half it affects several organ systems. While the associated malformations are often those of the VACTERL spectrum (Vertebral, Anorectal, Cardiac, Tracheo-Esophageal, Renal and Limb), many patients are affected by other malformations, such as microcephaly, micrognathia, pyloric stenosis, duodenal atresia, a single umbilical artery, and anomalies of the genitourinary, respiratory and gastrointestinal systems. Though EA/TEF is a genetically heterogeneous condition, recurrent genes and loci are sometimes affected. Tracheo-Esophageal (TE) defects are in fact a variable feature in several known single gene disorders and in patients with specific recurrent Copy Number Variations and structural chromosomal aberrations. At present, a causal genetic aberration can be identified in 11-12% of patients. In most, EA/TEF is a sporadic finding; the familial recurrence rate is low (1%). As this suggests that epigenetic and environmental factors also contribute to the disease, non-syndromic EA/TEF is generally believed to be a multifactorial condition. Several population-based studies and case reports describe a wide range of associated risks, including age, diabetes, drug use, herbicides, smoking and fetal alcohol exposure. The phenotypical and genetic heterogeneity seen in EA/TEF patients indicates not one underlying cause, but several. Unraveling the complex multifactorial and heterogeneous etiology of EA/TEF and associated features will require large cohorts of patients. Combined statistical analysis of component findings, genome sequencing, and genome wide association studies will elucidate new causal genetic defects and predisposing loci in the etiology within specific sub-populations. Improved knowledge of environmental risk factors, genetic predisposition and causal genetic syndromes may improve prediction and parental counseling, and prevent co-morbidity.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Pediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands. Electronic address: e.brosens@erasmusmc.nl.
authors.forename: Erwin
authors.initials: E
authors.lastname: Brosens
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Pediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Ploeg
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Yolande
authors.initials: Y
authors.lastname: van Bever
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Koopmans
authors.affiliation: Department of Pediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: IJsselstijn
authors.affiliation: Department of Pediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Rottier
authors.affiliation: Department of Pediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Wijnen
authors.affiliation: Department of Pediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
mesh_terms: D001003:Anal Canal / Q000002:abnormalities; D000818:Animals; D004195:Disease Models, Animal; D004933:Esophageal Atresia / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology / Q000628:therapy; D004947:Esophagus / Q000002:abnormalities / Q000196:embryology; D006330:Heart Defects, Congenital; D006801:Humans; D007668:Kidney / Q000002:abnormalities; D017880:Limb Deformities, Congenital; D015995:Prevalence; D013131:Spine / Q000002:abnormalities; D014132:Trachea / Q000002:abnormalities / Q000196:embryology; D014138:Tracheoesophageal Fistula / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology / Q000628:therapy
keywords: Esophageal atresia; Tracheo-esophageal fistula; VACTERL association