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REVIEW |
Correspondence to:
Charles Shaw-Smith
Department of Medical Genetics, Box 134, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK;charles.shaw-smith{at}addenbrookes.nhs.uk]
Revised version received 7 November 2005
8 November 2005
 | ABSTRACT |
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Keywords: anophthalmia-oesophageal-genital; CHARGE syndrome; Feingold syndrome; oesophageal (esophageal) atresia; tracheo-oesophageal (-esophageal) fistula
Oesophageal atresia and tracheo-oesophageal fistula (OA/TOF) are common life-threatening malformations with an incidence of approximately 1 in 3500 births. The aetiology of OA/TOF is unknown in the majority of cases. In approximately half of the cases (syndromic oesophageal atresia), there are other associated anomalies, with cardiac malformations being the most common. These may occur as part of VATER or the VACTERL association (OMIM 192350). In the remaining cases, OA/TOF occur in isolation (non-syndromic oesophageal atresia).
The birth of a child with OA/TOF into a family without a previous history of the condition is associated with a low recurrence risk, of the order of 1%.1 The twin concordance rate for OA/TOF is likewise low, at around 2.5%.2 These data do not indicate a major role for genetic factors in the pathogenesis of OA/TOF, yet there are well-defined instances of the condition where genetic factors are clearly important. Trisomies of chromosomes 18 and 21 are a significant risk factor for OA/TOF, and there are other examples of specific chromosomal imbalances, discussed below, which also predispose to this malformation. Until recently, no genes had been associated with oesophageal atresia in humans. However, three separate genes associated with syndromic OA/TOF in humans have now been identified,3–5 making this an exciting time for those interested in the aetiology of this malformation.
This paper reviews current knowledge of the genetics, aetiology, and epidemiology of syndromic and non-syndromic OA/TOF, placing this new information in its overall context.
| EMBRYOLOGY |
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Although there are many references in the literature6–8 to the separation of the trachea from the foregut by means of a process of "pinching off" achieved by the existence of lateral tracheo-oesophageal ridges which grow and fuse in the midline, Williams et al9 have drawn attention to the lack of any direct imaging or reconstruction through histological sections of the tracheo-oesophageal ridges, and in addition have noted the presence of apoptotic bodies at the point of tracheo-oesophageal separation (originally described by Qi and Beasley10). Both groups of authors suggest that it is the process of apoptosis, with "collapse and fusion of the lateral walls of the foregut", rather than the growth and fusion of lateral ridges, which causes oesophagus and trachea to separate, although the existence of a tracheo-oesophageal septum arising from fusion of longitudinal ridges within the lumen of the foregut is still postulated by some authors.7
| ANATOMIC VARIANTS OF OA/TOF |
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is taken from Gross.12 The incidence of the various types of anomaly is derived from more than 2200 cases in six large series.11 A very detailed classification which corresponds broadly to other schemes but includes other rarer anatomic variants such as membranous atresia, oesophago-bronchial fistula, and oesophageal duplication, has been described.13
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| EPIDEMIOLOGY |
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. The incidence of OA/TOF is approximately 1 in 3500 births. There is little evidence to support significant geographical or secular variation in the incidence of OA/TOF. Robert et al2 reported a significantly lower birth frequency (1.82/10 000 births) in Norway, but the birth frequency in Sweden in the same study was 2.67/10 000, and other published data investigating this trend are lacking. No consistent secular trend was identified in the above studies, although Depaepe et al14 identified a downward trend in birth frequency over time in different regions of Europe. When chromosomal cases are excluded, there is no evidence for a link between OA/TOF and maternal age.
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Data on malformations associated with OA/TOF in these epidemiological studies are summarised in table 1
. The malformations most commonly found with OA/TOF are those present in the VACTERL association. These are discussed further in the section on the VACTERL association below.
The data suggest that the incidence of trisomies and other chromosomal imbalances is fairly consistent at between 6 and 10%. The lower figure of 6.3% in the Worldwide study2 is again likely to be explicable on the basis of cases excluded prior to 28 weeks’ gestation. The total number of cases in infants with trisomy 18 (127) exceeds the number of cases due to trisomy 21 (102) despite the fact that trisomy 18 is much rarer than trisomy 21. This appears to indicate that trisomy 18 may be a greater risk factor for OA/TOF than trisomy 21.
| OA/TOF AND TWINNING |
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The concordance rate in twins is low, suggesting that mechanisms other than genetics are responsible for the occurrence of OA/TOF in twins. In the series reported by Robert et al,2 80 twin pairs were identified, of which just two pairs (2.5%) were concordant, the remaining 78 being discordant. Of the 80 pairs, the sex of the co-twin was known in 50. Forty three were like-sexed (22 male, 21 female) and only seven unlike-sexed. These data may suggest an increased incidence of monozygosity in these twin pairs, although confirmatory data are lacking. Other studies have found similar results for twin pairs.18
| FAMILY STUDIES OF OA/TOF |
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McMullen et al20 studied first degree relatives of 140 index cases with OA/TOF, and obtained offspring and sibling recurrence risk figures for VACTERL-type malformations of 2–3% and 1.4%, respectively.
Brown et al21 compared the incidence of VACTERL-type malformations in the first degree relatives of OA/TOF cases versus controls. They found that 5.8% of case families versus 3.1% of control families contained at least one first degree relative with one or more of the extended VACTERL components (p<0.01).
| HUMAN SINGLE GENE DISORDERS AND OESOPHAGEAL ATRESIA |
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. Inheritance is autosomal dominant, and the gene for the condition was previously mapped to chromosome 2p23.23
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CHARGE syndrome
OA/TOF is not a major criterion for CHARGE syndrome, which comprises Coloboma, Heart defect, Atresia choanae, Retarded growth, Genital hypoplasia and Ear anomalies, but it occurs in about 10% of cases of the syndrome.28 Heterozygous mutations (10) or whole gene deletions (two) of the chromodomain helicase DNA-binding family member CHD7 were recently identified in 12/19 individuals with CHARGE syndrome.4 In a more recent clinical survey, oesophageal atresia and/or tracheo-oesophageal fistula were found in 17% of individuals with CHD7 mutations.29
Chromodomain proteins have a role in the epigenetic regulation of heterochromatin function and euchromatic gene expression. One hypothesised role is that they serve to protect the chromatin fibre from changing its epigenetic state.30 Genotype-phenotype and functional studies in humans and model organisms will help to clarify the relationship between CHD7 and CHARGE syndrome.
Anophthalmia-oesophageal-genital syndrome (AEG syndrome)
The association of oesophageal atresia with anophthalmia and genital abnormalities is a rare though well-documented entity in the literature, with fewer than 20 cases reported.31,32 Loss of function mutations in SOX2 were previously reported in 4/102 patients with microphthalmia, anophthalmia, or coloboma.33 Recently, heterozygous SOX2 mutations have been demonstrated in patients with AEG syndrome.5 Little is known of the role of SOX2 in foregut and lung development. The chick homologue of SOX2, cSox2, is expressed in the developing foregut, though not more caudally in the gut tube. During morphogenesis, cSox2 expression levels fall in the developing lung primordium as it invades the surrounding mesenchyme.34 The precise role of SOX2 in relation to the pathogenesis of OA/TOF remains to be elucidated.
Fanconi anaemia and OA/TOF
OA/TOF, as well as other gastro-intestinal atresias (anal, duodenal) is a well-documented component of the malformation spectrum associated with Fanconi anaemia. Gastro-intestinal atresias have been reported in 14% of cases of Fanconi anaemia.35 Other malformations falling within the VACTERL spectrum also occur: skeletal (71%), cardiac (13%), and renal (34%).35 The birth frequency of OA/TOF is approximately 1 in 3000, that of Fanconi anaemia approximately 1 in 300 000, and that of Fanconi anaemia presenting with a gastro-intestinal atresia another order of magnitude lower. Clearly, therefore, the prior risk of FA in a child born with OA/TOF must be very small, and the contribution of FA to the aetiology of OA/TOF likewise small. Nonetheless, it is possible that mutations in one of the FANC genes are responsible for OA/TOF in a proportion of individuals with this malformation. Some of these individuals may not be penetrant for the haematological phenotype. Now that the majority of the FANC genes have been identified,36,37 this hypothesis is testable. The possible aetiological basis for the relationships between DNA repair disorders and human malformations has recently been discussed.38
Multiple gastro-intestinal atresias (MGIA)
There are several reports of a lethal syndrome of multiple gastro-intestinal atresias in the oesophagus, small intestine, and biliary system.39–41 Parental consanguinity and sibling recurrence in these families point to autosomal recessive inheritance. No mapping studies have been performed to date. This condition appears to be distinct from the syndrome of hereditary multiple intestinal atresias (HMIA), also considered to be autosomal recessive,42 which does not involve the oesophagus. In HMIA, septal atresias with incomplete separation of the atretic segments occur throughout the stomach and large bowel.
Oesophageal atresia and chromosomal abnormalities
The association between OA/TOF and trisomy for chromosomes 18 and 21 has already been discussed above in the section on epidemiology.
There is a weak association between OA/TOF and the 22q11 deletion syndrome. Digilio et al43 found a single case of 22q11 deletion syndrome in a series of 15 patients with syndromic oesophageal atresia, and there are other case reports in the literature.44
There appears to be a link between OA/TOF and deletions at chromosome 17q22q23.3. Marsh et al45 reported a single case and reviewed two others, in all three of whom OA/TOF and congenital heart defects were present. In addition, these patients had dysmorphic facial features and minor skeletal malformations. This chromosomal region contains the genes TBX2 and TBX4. Mice haploinsufficient for the Tbx2 gene have been shown to have atrioventricular septal defects, though not OA/TOF.46 A study in chick47 showed that ectopic expression of Tbx4 in foregut visceral mesoderm caused failure of formation of tracheo-oesophageal septum. Hitherto, haploinsufficiency of or mutations in these two genes have not been associated with OA/TOF in humans, except in the context of the large chromosomal deletions discussed above.
Patients with deletions at chromosome 13q32 have been reported to have multiple elements of the VACTERL association. This possible link is discussed further in the section below on the VACTERL association.
Disruption of the gene BPAG1 was recently reported in an individual with a 6;15 reciprocal translocation and oesophageal atresia.48
| OESOPHAGEAL ATRESIA AND TERATOGENS |
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| THE VACTERL ASSOCIATION |
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Earlier studies53–57 confirmed the non-random occurrence of the association but did not specifically address the question of which of the more peripheral elements of the association should be included within its definition. More recent studies58 have attempted to address this issue by taking, as far as possible, an approach free of ascertainment bias. The results58 indicated a distinct group of malformations corresponding with the VACTERL association, with an "upper" group associated with heart malformations and a "lower" group associated with renal malformations. The authors acknowledged the difficulty of controlling for possible bias in the way that patients are investigated which might tend to confirm some associations (oesophageal atresia, upper costo-vertebral defects, cardiac defects), but not others where the anatomic locations are more disparate.
There are very few published series of VACTERL patients in which the clinical phenotypes have been carefully delineated, perhaps unsurprisingly in view of the difficulties of definition, and the risk of inadvertent inclusion of cases with a syndromic diagnosis. Weaver et al59 reported a series of 46 patients.
One of the key difficulties in studies of this nature is the evolving nature of our knowledge of syndromes which may overlap with or resemble the VACTERL association. Feingold syndrome, CHARGE syndrome, 22q11 deletion syndrome, Townes-Brocks syndrome, and Pallister-Hall syndrome (all discussed further below) show some phenotypic overlap with the VACTERL association, and most series of patients ascertained by epidemiological means are not divided into subgroups according to confirmed or possible syndromic diagnoses.
Individuals with the VACTERL association do not typically have facial dysmorphic features, learning disability, or abnormalities of growth, including head circumference. For these individuals, sibling and offspring recurrence risks are low, and are usually quoted as being around 1%. There are very few instances of recurrence of the VACTERL association in the literature. However, two examples are Nezarati and McLeod60 and Auchterlonie and White.61
Where dysmorphic features, growth abnormalities, and/or learning disability are present, a syndromic diagnosis or chromosomal abnormality may be the underlying cause, as discussed in the following section.
| SINGLE GENE DISORDERS RESEMBLING THE VACTERL ASSOCIATION |
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.
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CHARGE syndrome
CHARGE syndrome may cause diagnostic difficulty, particularly where few features are present and the more characteristic features of the syndrome (coloboma, choanal atresia) are absent. Identification of the causative gene4 means that it will be possible to delineate the full phenotypic spectrum. It is likely that some cases previously classified clinically as the VACTERL association will prove to have CHD7 mutations, although this remains to be seen.
Fanconi anaemia and the VACTERL association
The apparently Mendelian segregation of VACTERL in association with hydrocephalus (VACTERL-H) is a rarely reported but distinct entity. X linked66–68 and recessive forms69 have been described.
Cox et al69 reported a dizygotic twin pair with features of VACTERL-H and no evidence of increased chromosome breakage on routine testing. Homozygous mutations in the FANCC gene were detected in both twins, providing the first molecular evidence of a link between VACTERL-H and Fanconi anaemia.
OA/TOF, as well as duodenal atresia, have been reported in several family members in pedigrees with VACTERL-H and apparently X linked inheritance. Some of these families have contained individuals with an increased incidence of chromosome breakages, diagnostic of Fanconi syndrome. The family reported by Wang et al66 contained three such individuals; but breakages were not found in a single case in a pedigree containing four affected individuals reported by Lomas et al.68 A gene responsible for X linked Fanconi anaemia has recently been identified;37 it will be interesting to test the possible role of this gene in X linked VACTERL-H families.
In one series, VACTERL-type clinical presentations accounted for 5% of all cases of Fanconi anaemia and there was over-representation of complementation groups D1, E, and F in this group.70 Faivre et al71 reported a series of 13 FA cases presenting with VACTERL-type malformations, all of whom had radial ray anomalies, and 12 out of 13 of whom had an additional FA feature (café au lait patches, microcephaly, growth retardation, or dysmorphism). They suggested that chromosome breakage studies should be performed in patients in this clinical group.
Townes-Brocks syndrome
Townes-Brocks syndrome (reviewed in Powell and Michaelis64) is an autosomal dominant disorder, the main manifestations of which are external ear anomalies, preaxial polydactyly, imperforate anus, and renal malformations. Oesophageal atresia is not a reported feature; there may be an association with congenital heart disease but this is controversial.64 The most common limb defects are triphalangeal thumb and preaxial polydactyly. Hypoplasia of the thumb and radial bone are not features of this syndrome. Structural vertebral anomalies have not been reported. Mutations in the SALL1 gene at 16q12.1 are responsible for Townes-Brocks syndrome.72
Pallister-Hall syndrome
Anal atresia and limb malformations are features of this dominantly inherited syndrome,65 though in practice there should be little difficulty in distinguishing it from the VACTERL association as hypothalamic hamartoma and neurological complications are cardinal features, and the limb malformations are not of the VACTERL type. Pallister-Hall syndrome is due to mutations in the GLI3 gene,65 and, given the mouse knockout phenotypes discussed below, it is of interest that laryngeal clefts and atypical lung lobation are also features of this syndrome.
| OTHER CONDITIONS WITH PHENOTYPIC OVERLAP WITH THE VACTERL ASSOCIATION |
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There is a recognised overlap between the VACTERL association and hemifacial microsomia or oculo-auriculo-vertebral spectrum.73,74 Although ear and eye malformations are typical of hemifacial microsomia, vertebral anomalies, congenital heart defects, and oesophageal atresia are also described.74,75 The aetiology of hemifacial microsomia is poorly understood. Familial cases are described and linkage to chromosome 14q32 has been assigned on the basis of a large dominant pedigree.76
There are three reports in the literature of an association between VACTERL and tibial aplasia.77,78 All three cases had OA/TOF, but additional features (malformed ears, cleft lip/palate) were present in one case.
Reardon et al79 reported a mutation in the PTEN gene in a patient with macrocephaly, tracheo-oesphageal fistula, and bilateral thumb hypoplasia.
| TERATOGENS ASSOCIATED WITH THE VACTERL ASSOCIATION |
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| CHROMOSOMAL IMBALANCES IN THE VACTERL ASSOCIATION |
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Cinti et al88 reported a supernumerary ring chromosome 12 in a patient with an anorectal malformation, vertebral anomalies, and an absent kidney. There are very few other reports of chromosomal abnormalities in patients with the VACTERL association.89,90
| OA/TOF, VACTERL, AND ASSOCIATIONS |
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), and the term association is no longer applicable; or they may be due to environmental agents (teratogens), in which case they remain idiopathic. The underlying causes of the sporadic forms of the VACTERL association for the most part remain to be elucidated, with the exception of those instances due to maternal diabetes. According to the model proposed by Lubinsky, single malformations derived from teratologic events can be part of the same spectrum as associations.91 In this sense, oesophageal atresia with or without tracheo-oesophageal fistula, and sporadic forms of the VACTERL association can, for the purposes of hypothesis testing, be considered to be two different points on a spectrum constituting a single overarching entity. | KNOCK-OUT MICE FEATURING TRACHEO-OESOPHAGEAL MALFORMATIONS |
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The winged helix transcription factor foxf1 is activated by sonic hedgehog signalling and mice haploinsufficient for foxf1 display narrowing of the oesophagus and trachea, oesophageal atresia, and tracheo-oesophageal fistula.98
There is one report describing oesophageal abnormalities associated with the targeted disruption of a homeobox gene. Mice haploinsufficient for the homeobox gene hoxc4 had complete occlusion of the oesophageal lumen, with extensive disorganisation of the oesophageal musculature, although not oesophageal atresia.99
Mice homozygously deficient for the homeodomain transcription factor nkx2.1 show a severe tracheo-oesophageal phenotype with a common lumen that connects the pharynx to the stomach. In addition, the lungs are profoundly hypoplastic with absence of distal structures.100 Finally, failure of separation of the oesophagus and trachea is seen in mouse embryos doubly homozygous for mutations in the retinoic acid receptor genes RAR
and RARß2.101
| MOUSE MODELS OF THE VACTERL ASSOCIATION |
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In humans, mutations in SHH are associated with holoprosencephaly,105 and mutations in GLI3 with Pallister-Hall syndrome.65 There are no published data on the possible roles of these genes in patients with syndromic OA/TOF, to the author’s knowledge, although laryngeal clefts, which may be associated with tracheo-oesophageal fistula, are a feature of Pallister-Hall syndrome.65
| OTHER ANIMAL MODELS OF OESOPHAGEAL ATRESIA |
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| EVALUATION OF THE PATIENT WITH OA/TOF |
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 TOPABSTRACTEMBRYOLOGY |
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ABSTRACT
EMBRYOLOGY
