Chromosomal anomalies in the aetiology of oesophageal atresia and tracheo-oesophageal fistula

doi:10.1016/j.ejmg.2006.12.004

European Journal of Medical Genetics

Volume 50, Issue 3, May–June 2007, Pages 163-175

https://doi.org/10.1016/j.ejmg.2006.12.004 Get rights and content

Abstract

Oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) are severe congenital anomalies of which the aetiology is largely unknown. Several chromosomal anomalies have been described in patients presenting with these anatomical malformations, but until now none of these has led to the identification of a single aetiological factor. This paper reviews the chromosomal abnormalities reported in cases of OA/TOF and serves as a starting point to identify chromosomal regions harbouring genes involved in the aetiology of OA/TOF.

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.

References (86)

M. Aramaki et al.
Phenotypic spectrum of CHARGE syndrome with CHD7 mutations
J. Pediatr.
(2006)
H.G. Brunner et al.
Genetic players in esophageal atresia and tracheoesophageal fistula
Curr. Opin. Genet. Dev.
(2005)
Y.F. Choong et al.
Goldenhar and cri-du-chat syndromes: a contiguous gene deletion syndrome?
J. Aapos.
(2003)
M.B. Forrester et al.
Epidemiology of oesophageal atresia and tracheo-oesophageal fistula in Hawaii, 1986–2000
Public Health
(2005)
Y. Kanamori et al.
A case of laryngeal atresia (congenital high airway obstruction syndrome) with chromosome 5p deletion syndrome rescued by ex utero intrapartum treatment
J. Pediatr. Surg.
(2004)
W.W. Lam et al.
Decreased cholesterol synthesis as a possible aetiological factor in malformations of Trisomy 18
Eur. J. Med. Genet.
(2006)
J. Luo et al.
Compound mutants for retinoic acid receptor (RAR) beta and RAR alpha 1 reveal developmental functions for multiple RAR beta isoforms
Mech. Dev.
(1996)
V. Marigo et al.
Cloning, expression, and chromosomal location of SHH and IHH: two human homologues of the Drosophila segment polarity gene hedgehog
Genomics
(1995)
R.M. McNeal et al.
Congenital anomalies including the VATER association in a patient with del(6)q deletion
J. Pediatr.
(1977)
J.E. Ming et al.
Human developmental disorders and the Sonic hedgehog pathway
Mol. Med. Today
(1998)

J. Que et al.

Morphogenesis of the trachea and esophagus: current players and new roles for noggin and Bmps

Differentiation

(2006)

E. Robert et al.

An international collaborative study of the epidemiology of esophageal atresia or stenosis

Reprod. Toxicol.

(1993)

C.H. Yi et al.

Virtual cloning and physical mapping of a human T-box gene, TBX4

Genomics

(2000)

S. Antonini et al.

Delimitation of duplicated segments and identification of their parental origin in two partial chromosome 3p duplications

Am. J. Med. Genet.

(2002)

C. Baccichetti et al.

Terminal deletion of the short arm of chromosome 5

Clin. Genet.

(1988)

S. Brown et al.

The 13q- syndrome: the molecular definition of a critical deletion region in band 13q32

Am. J. Hum. Genet.

(1995)

L. Bruni et al.

Lipid anomaly in a child with partial duplication 3p

Eur. Rev. Med. Pharmacol. Sci.

(1998)

H.G. Brunner et al.

Autosomal dominant inheritance of abnormalities of the hands and feet with short palpebral fissures, variable microcephaly with learning disability, and oesophageal/duodenal atresia

J. Med. Genet.

(1991)

P.J. Buchin et al.

Down's syndrome and the gastrointestinal tract

J. Clin. Gastroenterol.

(1986)

C.Y. Chen et al.

Esophageal atresia associated with tracheal stenosis and right lung agenesis: report of one case

Acta Paediatr. Taiwan

(2002)

S. Chittmittrapap et al.

Oesophageal atresia and associated anomalies

Arch. Dis. Child

(1989)

R. Ciccone et al.

Reciprocal translocations: a trap for cytogenetists?

Hum. Genet.

(2005)

M.K. Cooper et al.

A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis

Nat. Genet.

(2003)

K. Cottrall et al.

A case of proximal 14 trisomy with pathological findings

J. Ment. Defic. Res.

(1981)

A. Czeizel et al.

An aetiological study of the VACTERL-association

Eur. J. Pediatr.

(1985)

B. Dallapiccola et al.

Interstitial deletion del(17) (q21.3q23 or 24.2) syndrome

Clin. Genet.

(1993)

J.M. de Pina Neto et al.

Partial 3p trisomy and different rearrangements involving chromosome 3 in the proposita's family

Am. J. Med. Genet.

(1980)

A. Depaepe et al.

The epidemiology of tracheo-oesophageal fistula and oesophageal atresia in Europe. EUROCAT Working Group

Arch. Dis. Child

(1993)

E. Di Gianantonio et al.

Adverse effects of prenatal methimazole exposure

Teratology

(2001)

M.C. Digilio et al.

Microdeletion 22q11 and oesophageal atresia

J. Med. Genet.

(1999)

B. Doray et al.

Esophageal and duodenal atresia in a girl with a 12q24.3-qter deletion

Clin. Genet.

(2002)

M. Entezami et al.

Combined partial trisomy 3p/monosomy 5p resulting in sonographic abnormalities

Clin. Genet.

(1997)

J.F. Felix et al.

Genetics and developmental biology of oesophageal atresia and tracheo-oesophageal fistula: lessons from mice relevant for paediatric surgeons

Pediatr. Surg. Int.

(2004)

B. Field et al.

Malformation syndrome of chromosome 10q duplication and the VATER association

Ann. Génét.

(1983)

J.J. Gibson-Brown et al.

Involvement of T-box genes Tbx2-Tbx5 in vertebrate limb specification and development

Development

(1998)

R. Giorda et al.

Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a 6;15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia

J. Med. Genet.

(2004)

S.M. Gribble et al.

The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes

J. Med. Genet.

(2005)

M. Hengstschlager et al.

Patient with partial trisomy 9q and learning disability but no pyloric stenosis

Dev. Med. Child Neurol.

(2004)

J.A. Hurst et al.

Balanced t(6;8)(6p8p;6q8q) and the CHARGE association

J. Med. Genet.

(1991)

R. Hutchinson et al.

Distal 8p deletion (8p23.1-8pter): a common deletion?

J. Med. Genet.

(1992)

J. Jackson et al.

How accurate does rapid fetal karyotyping need to be? Case of unbalanced t(13;18)

Prenat. Diagn.

(1993)

M.C. Jongmans et al.

CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene

J. Med. Genet.

(2006)

B. Kallen et al.

Major congenital malformations in Down syndrome

Am. J. Med. Genet.

(1996)

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Chromosomal anomalies in the aetiology of oesophageal atresia and tracheo-oesophageal fistula

Abstract

Introduction

Section snippets

Hospital-database

Chromosomal anomalies described in association with OA and/or TOF

Discussion

Acknowledgements

J. Pediatr.

Curr. Opin. Genet. Dev.

J. Aapos.

Public Health

J. Pediatr. Surg.

Eur. J. Med. Genet.

Mech. Dev.

Genomics

J. Pediatr.

Mol. Med. Today

Differentiation

Reprod. Toxicol.

Genomics

Delimitation of duplicated segments and identification of their parental origin in two partial chromosome 3p duplications

Am. J. Med. Genet.

Terminal deletion of the short arm of chromosome 5

Clin. Genet.

The 13q- syndrome: the molecular definition of a critical deletion region in band 13q32

Am. J. Hum. Genet.

Lipid anomaly in a child with partial duplication 3p

Eur. Rev. Med. Pharmacol. Sci.

Autosomal dominant inheritance of abnormalities of the hands and feet with short palpebral fissures, variable microcephaly with learning disability, and oesophageal/duodenal atresia

J. Med. Genet.

Down's syndrome and the gastrointestinal tract

J. Clin. Gastroenterol.

Esophageal atresia associated with tracheal stenosis and right lung agenesis: report of one case

Acta Paediatr. Taiwan

Oesophageal atresia and associated anomalies

Arch. Dis. Child

Reciprocal translocations: a trap for cytogenetists?

Hum. Genet.

A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis

Nat. Genet.

A case of proximal 14 trisomy with pathological findings

J. Ment. Defic. Res.

An aetiological study of the VACTERL-association

Eur. J. Pediatr.

Interstitial deletion del(17) (q21.3q23 or 24.2) syndrome

Clin. Genet.

Partial 3p trisomy and different rearrangements involving chromosome 3 in the proposita's family

Am. J. Med. Genet.

The epidemiology of tracheo-oesophageal fistula and oesophageal atresia in Europe. EUROCAT Working Group

Arch. Dis. Child

Adverse effects of prenatal methimazole exposure

Teratology

Microdeletion 22q11 and oesophageal atresia

J. Med. Genet.

Esophageal and duodenal atresia in a girl with a 12q24.3-qter deletion

Clin. Genet.

Combined partial trisomy 3p/monosomy 5p resulting in sonographic abnormalities

Clin. Genet.

Genetics and developmental biology of oesophageal atresia and tracheo-oesophageal fistula: lessons from mice relevant for paediatric surgeons

Pediatr. Surg. Int.

Malformation syndrome of chromosome 10q duplication and the VATER association

Ann. Génét.

Involvement of T-box genes Tbx2-Tbx5 in vertebrate limb specification and development

Development

Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a 6;15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia

J. Med. Genet.

The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes

J. Med. Genet.

Patient with partial trisomy 9q and learning disability but no pyloric stenosis

Dev. Med. Child Neurol.

Balanced t(6;8)(6p8p;6q8q) and the CHARGE association

J. Med. Genet.

Distal 8p deletion (8p23.1-8pter): a common deletion?

J. Med. Genet.

How accurate does rapid fetal karyotyping need to be? Case of unbalanced t(13;18)

Prenat. Diagn.

CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene

J. Med. Genet.

Major congenital malformations in Down syndrome