Chromosomal anomalies in the aetiology of oesophageal atresia and tracheo-oesophageal fistula
Introduction
Oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) are relatively frequently occurring malformations of the foregut, with a prevalence of around 1 in 3500 births. Associated anomalies occur in some 50% of cases [64]. The best known association of anomalies is the VACTERL (Vertebral, Anal, Cardiac, Tracheo-Oesophageal, Renal, Limb) association, found in around 10% of infants with OA/TOF [10].
The aetiology of these anomalies is as yet poorly understood, but it is generally considered to be multifactorial. Environmental factors, such as exposure to certain medications [19], [42] or infectious diseases [40] might be risk factors for isolated OA or VACTERL association, but no external factor has consistently been identified [15], [78], [79]. Chromosomal anomalies have been reported in 6–10% of patients with OA/TOF and are mostly trisomies [7], [18]. No single specific chromosomal defect has been described as a proven aetiological factor. Recently however, four genes, MYCN, CHD7, SOX2 and MID1, were reported to be involved in the aetiology of syndromic OA/TOF (for recent reviews: Brunner & Van Bokhoven and Shaw-Smith [6], [73]).
Knockout studies in mice implicate genes like Sonic hedgehog (Shh), Gli2, Gli3, TTF-1 and RARα and β in the development of OA/TOF (for review: Felix et al., 2004 [23]). As described below, deletions in or close to the regions of SHH (7q36) and RARα (17q21.1) have been reported in humans with OA/TOF. Nevertheless, the chromosomal defects in these patients have not been proven to be causes of the oesophageal anomalies.
Over 30 reports describing chromosomal anomalies in children with OA/TOF have been published. These reports could serve as a starting point in the search for genes involved in the development of OA/TOF.
This paper presents an overview of the findings from these reports in combination with data from our hospital-based database of cases with OA/TOF.
Section snippets
Hospital-database
Clinical characteristics, including karyotypes when available, of all 255 patients with OA/TOF treated in the Erasmus MC – Sophia Children's Hospital in Rotterdam, the Netherlands, since 1988 have been stored in a database. This hospital is the paediatric referral center for the South western part of the Netherlands, with a population of around four million people and approximately 35,000 births per year. It has the only specialized paediatric surgical intensive care unit in the Netherlands.
Chromosomal anomalies described in association with OA and/or TOF
The PubMed electronic database of the U.S. National Library of Medicine was searched using all possible combinations of: (o)esophageal atresia or tracheo(-)(o)esophageal fistula combined with: chromosome(s), chromosomal anomaly or anomalies and gene(s). In addition, the first two terms were combined with the word “chromosome” followed by numbers 1 to 22, X and Y (e.g. oesophageal atresia and chromosome 1, oesophageal atresia and chromosome 2 etc.).
There were no restrictions to year of
Discussion
OA/TOF may occur as an isolated anomaly, it may be part of a complex of congenital defects or it may develop within the context of a known syndrome or association. Genetic factors are most likely to play a role in the latter two groups. Detailed description and comparison of cases of OA/TOF, combined with (cyto)genetic testing may lead to the discovery of specific loci or genes with a possible causative role. Techniques such as Fluorescent In Situ Hybridisation (FISH), DNA-based Comparative
Acknowledgements
We thank J. Hagoort for his excellent editorial support.
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