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Chromosome Aberrations and Gene Mutations in Patients With Esophageal Atresia

Bednarczyk, Damian; Sasiadek, Maria M.; Smigiel, Robert

Journal of Pediatric Gastroenterology and Nutrition: December 2013 - Volume 57 - Issue 6 - p 688–693
doi: 10.1097/MPG.0b013e3182a373dc
Invited Review

ABSTRACT Esophageal atresia (EA) is one of the most frequent congenital malformations of the gastrointestinal tract. Many genetic alterations in patients with EA have been described in the literature. It is thought that the etiology of EA is heterogeneous. This review of the literature provides detailed information about chromosomal aberrations, gene mutations, and clinical features of neonates with EA, and serves as an excellent source to compare newly diagnosed patients with those described in the literature.

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Department of Genetics, Wroclaw Medical University, Wroclaw, Poland.

Address correspondence and reprint requests to Robert Smigiel, MD, PhD, Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland (e-mail:

Received 23 April, 2013

Accepted 27 June, 2013

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (

The authors report no conflicts of interest.

Esophageal atresia (EA; Online Mendelian Inheritance in Man [OMIM] no. 189960) is a congenital malformation, occurring approximately in 1/4000 births (1). This defect is characterized by a loss of continuity of the esophagus, which may be accompanied by a pathological connection to the trachea, resulting in a tracheoesophageal fistula (TEF). In the International Statistical Classification of Diseases-10, these defects are classified as Q39.0 (without a fistula) or Q39.1 (with a TEF).

Forty-five percent of patients with congenital EA present an isolated form without any additional associated defects. In the remaining 55% of patients, EA coexists with other defects (syndromic form), which together may form a genetic syndrome or association (1). In the group of syndromic patients, 9.6% have VACTERL (vertebral defects [Vertebral], defects of the rectum and anus [Anal], defects in the cardiovascular system [Cardiovascular], EA with or without a TEF [Tracheosophageal], kidney defects [Renal], and limb defects [Limb]) association, 1.0% CHARGE (malformations include defects in various structures of the eye [Coloboma], heart failure [Heart defects], choanal atresia [choanal Atresia], inhibition of growth and psychomotor development [Retardation of growth and development], defects of the genitourinary system [Genitourinary defects], and dysmorphia with deaf ears [Ear anomalies]) syndrome, 4.6% another nonchromosomal syndrome, 1.9% Down syndrome, 5.9% Edwards syndrome, and 0.8% another chromosomal syndrome. In patients with associated anomalies, the most frequently observed were congenital heart defects (29%), genitourinary tract defects (16%), other defects of the digestive tract (anal and duodenal atresia) (15%), and limb anomalies (13%) coinciding with EA (1).

EA is the most common congenital defect of the esophagus. It represents approximately 30% of all congenital atresias of the gastrointestinal tract and is present in various anatomical forms (2). Presently, the original Vogt classification (3), modified by Ladd (4) and Gross (5), is used. In 1976, Kluth published an extensive atlas of esophageal atresia that identified 10 basic types, each with many subtypes (6). In most cases (86%), EA exists together with distal TEF. An explanation for this overrepresentation of an anatomical subtype has not been found. Isolated EA occurs in 7% of patients. Four percent of the cases have H-type TEF with no EA. Two percent and 1% of patients have EA with proximal and distal TEF and EA with a proximal TEF, respectively (7). So far, no correlation between the clinical anatomic subtype and any specific genetic alteration has been found.

The availability of different imaging techniques allows both prenatal and postnatal diagnosis of birth defects. Progress in pediatric surgery in recent decades has reduced the mortality and the incidence of postoperative complications, but the treatment for congenital EA, particularly in the syndromic form, remains a challenge for many medical specialties (8). Anastomotic leakage, anastomotic stricture, recurrent fistula, gastroesophageal reflux, tracheomalacia, and dysmotility are possible postoperative complications (7).

The pathogenesis of EA is poorly understood, but it is thought that this defect arises because of errors in embryonic development. Both the trachea and the esophagus are formed during embryogenesis from the foregut. During the fourth week of fetal life, the foregut is divided into the ventral and dorsal parts. The exact mechanisms of this division are poorly understood, but several knockout murine models implicate the Hoxc4, Rara, Rarb, Sox2, Nog, Foxf1, Nkx2.1, Shh, Gli2, and Gli3 genes in the etiology of EA (9–18). Other studies try to describe alterations in gene expression in adriamycin-treated animal embryo during the embryogenesis of EA. The expression of the Shh, Hoxa3, Hoxb3, Hoxd3, Hoxc4, and Fgf10 genes was changed in organs derived from the foregut in these experimental models (19–21).

The etiology of EA and TEF is multifactorial. It is suggested that these defects result from a variety of genetic and/or environmental factors, and in most patients, it is extremely difficult to establish the real cause of the disease. Environmental factors in the etiology of EA were described by Oddsberg (22).

In recent years, a number of genetic alterations have been identified in patients with EA; however, all of the pathogenic mutations described so far occur in patients with the syndromic form of EA. There is no literature that reports disease-causing mutations in patients with isolated EA. Therefore, the specific risk factors for congenital EA remain unknown.

Genetic alterations that have been observed in patients with syndromic EA are both large-scale mutations (eg, chromosomal aberrations) and small-scale mutations (eg, gene/single nucleotide mutations).

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In 2007, Felix et al (23) and Lurie (24) published approximately 55 different chromosomal anomalies in patients with EA. Our work updates these conclusions with several new cases of chromosomal aberrations published in the last 7 years and provides a review of the most interesting cases for which the clinical features were available (Table 1).



Alterations in the number or structure of chromosomes occur in 6% to 10% of patients with EA, and trisomies are most frequent. EA is present in approximately 25% of patients with Edwards syndrome (trisomy 18), approximately 1% of patients with Down syndrome (trisomy 21), and occasionally in patients with Patau syndrome (trisomy 13) (23). The causes of EA in these aneuploidies are unknown. The malformations in trisomy 18 likely involve multiple mechanisms resulting from large-scale genomic imbalances; however the spectrum of defects related to the trisomy of chromosome 18 may be associated with decreased cholesterol synthesis, which is involved in the sonic hedgehog signaling pathway (25,26). Lam et al (26) reported a series of neonates and fetuses with trisomy 18 and abnormally low cholesterol levels, and proposed that downregulation of cholesterol synthesis in trisomy 18 is, in part, responsible for this phenotype. Trisomy 18, a multisystem malformation syndrome, has clinical features that overlap with disorders of cholesterol biosynthesis, and deregulation of this pathway may have a role in the development of the pathology. Cholesterol is involved in the proper functioning of the sonic hedgehog signaling pathway. The SHH gene encodes a protein that is instrumental in patterning the early embryo and is essential to foregut development. Litingtung et al (17) reported that homozygous Shh-null mutant mice show EA/stenosis, TEF, and tracheal and lung anomalies. The Shh protein is made as a precursor that is autocatalytically cleaved and then the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the developing embryo. Decreased synthesis of cholesterol can influence the sonic hedgehog signaling pathway and may be responsible for many developmental defects.

Among recurrent structural chromosomal abnormalities, EA may occur in deletion and microdeletion of 2q37.2-qter, 4q35-qter, 5p15-pter, 6q13-q15, 13q34-qter, 14q32.3-qter, and 22q11.2, as well as with duplications of 3p25-pter, 5q34-qter (23). Therefore, these regions may contain key genes, regulatory regions, or other genetic elements playing an important role in the etiology of EA.

Cases of 17q22-q23 interstitial deletion are particularly interesting (27). This region contains the NOG and RARα genes, the human orthologs of mouse genes that have been experimentally shown as being involved in the etiology of EA (14).

Stankiewicz et al (28) described a deletion of the 16q24.1 region in patients with EA. This chromosome region contains a number of neighboring genes that encode functionally related proteins. These include the FOXF1 gene, a transcription factor. It has been demonstrated that Foxf1 heterozygous gene deletion in mice results in EA (15).

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Congenital EA may coexist with at least 7 identified genetic disorders. These include associations such as VATER/VACTERL, as well as Feingold syndrome, CHARGE syndrome, anophthalmia-esophageal-genital (AEG) syndrome, Pallister-Hall syndrome, Opitz syndrome, and Fanconi anemia. In recent years, key genes for these diseases have been identified (Table 2).





In 10% to 30% of patients with EA, the VATER association (OMIM no. 192350) or VACTERL (OMIM 276950, 314390) can be diagnosed (46). VACTERL association can be diagnosed when a combination of ≥3 of the listed anomalies coexist. Sometimes hydrocephalus coexists with such a syndrome and then the acronym used is VACTERL-H. In patients diagnosed as having EA and 1 of the 3 forms of the above associations, mutations in the FANCB, PTEN, and ZIC3 genes have been identified (47–49).

Mutation of the first of these genes—FANCB (Xp22.2)—consists of a nucleotide substitution from G to A at a highly conserved donor site of intron 7, which is involved in splicing during the maturation process of mRNA (47).

Germline heterozygous, missense H61D mutations in the PTEN tumor suppressor gene (10q23.31), encoding a phosphatase involved in cell-signaling processes, have been described in patients with macrocephaly, ventriculomegaly, and features of the VATER association. This mutation is in exon 3, which encodes part of the tensin and auxilin homology domains. The H to D substitution, representing the replacement of a heterocyclic basic hydrophilic amino acid by an aliphatic, polar, acidic dicarboxylic amino acid, is a nonconservative change, and Reardon et al (48) suggest that this mutation is highly likely to be pathogenic and caused clinical features, including the VATER-hydrocephalus association, in their study patient.

Mutations in the ZIC3 gene cause X-linked visceral heterotaxy, which includes congenital heart disease and left-right axis defects in organs. In a male patient with an X-linked heterotaxy and features of VACTERL association, an insertion of 6 nucleotides within the GCC repeat sequence of the ZIC3 gene (Xq26.3) has been found. This mutation increases the number of alanines from 10 to 12 at the end of the protein chain. This novel mutation was not present in the mother, nor in 336 chromosomes from 192 ethnically matched controls. It is hypothesized that polyalanine expansion in the ZIC3 gene contributes to the features of VACTERL association observed in this male patient (49).

Several studies have attempted to describe DNA gains or losses, which may be connected with VATER/VACTERL association. Brosens et al (50) performed an analysis of copy number variations (CNVs) in 68 patients with VACTERL. In their results, they did not observe any clear de novo CNVs, but they identified 3 regions with recurrent duplications. Those regions inherited from a patient's mother or father were 10q25.3 containing the ABLIM1 gene, 22q11.2, and the SHOX gene (50). In a single patient with tetralogy of Fallot and VACTERL association, Arrington et al (51) described an approximate 451-kb loss in copy number on the distal long arm of chromosome 3 at band 3q28 (51; references 51–71 are available online only at This region of chromosome 3 includes a single known gene, LPP, which encodes the LIM domain containing a preferred translocation partner in lipoma, also known as the lipoma preferred partner: at least 5 of the 11 exons (exons 3–7) were deleted. Because the ABLIM1 and LPP genes encode a cytoskeletal protein that binds to actin filaments and proteins, which may be involved in cell–cell adhesion and cell motility, respectively, Brosens et al (50) conclude that the presence of mutations affecting these genes in some VACTERL association patients suggests that disturbances of the cytoskeleton may contribute to VACTERL phenotypes. Solomon et al (52) performed exome sequencing and high-density microarray testing in 2 sets of monozygotic twins who were discordant according to the features of VACTERL association. Neither microarray analysis nor exome sequencing revealed an obvious discordant genetic anomaly that would readily explain the presence of congenital anomalies in 1 just child in such a set of twins. Recently, in patients with VATER/VACTERL association, Hilger et al (53) identified 3 de novo CNVs involving chromosomal regions 1q41, 2q37.3, and 8q24.3 comprising 1 (SPATA17), 2 (CAPN10, GPR35), and 3 (EPPK1, PLEC, PARP10) genes, respectively, but sequencing analysis of the GPR35 gene in 192 patients with VATER/VACTERL association and a VATER/VACTERL-like phenotype revealed no disease-causing mutation.

The defects that together form the VACTERL-H association are often a component of Fanconi anemia. This rare, in most cases autosomal recessive, disease is highly heterogeneous. Among others, an increased susceptibility to DNA damaging agents such as mitomycin C and diepoxybutane results in a high rate of chromosomal breaks because of impairment in the DNA repair system. To date, at least 13 genes have been identified, whose mutations can cause Fanconi anemia. These genes are classified into complementary groups such as A to G and I, L, M, and N. Gastrointestinal atresias (including duodenal atresia and EA) are observed in approximately 14% of patients with FA (54).

Other genes that may be involved in the etiology of EA are the forkhead transcription factor genes, which are targets for sonic hedgehog signaling. In mice, Foxf1 haploinsufficiency causes a variable phenotype that includes lung immaturity and hypoplasia, fusion of right lung lobes, narrowing of the esophagus and trachea, EA, and TEF (15). In humans, point mutations in FOXF1 cause alveolar capillary dysplasia (ACD) with misalignment of the pulmonary veins (MPV). In a patient with ACD associated with EA and TEF, Stankiewicz et al (28) identified approximately 1.5-Mb microdeletions encompassing the FOX cluster of transcription factor genes. Stankiewicz et al also noted that, in contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, which they suggested was because of haploinsufficiency at the neighboring FOXC2 and FOXL1 genes.

Another gene that could play a role in the pathogenesis of congenital EA is the MYCN gene on chromosome 2q24.1. The protein product of this gene is located in the nucleus and is involved in transcriptional regulation, the cell cycle, differentiation, and morphogenesis, being under the control of the SHH, WNT, TGF, and FGF signaling pathways (55). Mutations in this gene result in Feingold syndrome (OMIM 164280). This disease is relatively rare and inherited in an autosomal dominant manner. It is characterized by dysmorphic facial features, microcephaly, abnormalities of fingers and toes, mild-to-moderate intellectual disability, and atresias of the intestinal tract located on different segments. Up until now, 23 different point mutations as well as 5 deletions in the MYCN gene have been identified (56). Approximately 30% to 40% of patients with Feingold syndrome have EA and TEF (57).

Mutations in the CHD7 gene, encoding the helicase enzyme, are present in 60% of patients with CHARGE syndrome (OMIM 214800) (58). In approximately 10% of patients with CHARGE syndrome, EA with or without TEF is observed. The CHD7 gene acts in early embryogenesis and is involved in gene expression regulation by epigenetic influence on chromatin formation.

Engelen et al (59) showed in mice that the Chd7 protein interacts with the protein encoded by the Sox2 gene in neural stem cells. Both proteins cooperate as cofactors in the activation of different genes. It seems, therefore, that mutations in the Chd7 and Sox2 genes could lead to birth defects in the same organs.

The clinical features of patients with SOX2 mutations consist of unilateral or bilateral anophthalmia, EA, and genital abnormalities (AEG syndrome, OMIM 206900). Mutations in the SOX2 gene are autosomal dominant (60).

EA occasionally appears in 2 other genetic syndromes: Pallister-Hall syndrome (OMIM 146510) and Opitz GBBB syndrome (OMIM 300000). Mutations in GLI3 are the cause of Pallister-Hall syndrome and they are inherited in an autosomal dominant manner. The contribution of this gene in the etiology of EA has been demonstrated by an animal model (18), but to date, no mutations in this gene in human with EA have been found (61). Opitz GBBB syndrome results from mutations in the MID1 gene, which is located on the X chromosome (62).

Recently, Gordon et al (63) showed that in patients with EA and mandibulofacial dysostosis, de novo 17q21.31 deletions encompassing EFTUD2 and neighboring genes or de novo heterozygous EFTUD2 loss-of-function mutations often occur.

The list of genes above constitutes our present knowledge of the molecular basis of syndromes associated with EA (Table 2). The causes of the isolated form of EA are still unknown.

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The dynamic development of modern embryology, molecular genetics, and other fundamental research fields allows the identification of mechanisms, including mutations of genes, which play a significant role in the pathogenesis of gastrointestinal malformations. Many of them are described in an animal model, but so far only a few of them have been linked to mutations in humans. It is considered that the etiology of the studied defect is heterogeneous. Despite this, it is suggested that in the etiology of EA there are ≥1 main factors initiating the abnormal development of the esophagus leading to atresia, so present research focuses on searching for the potentially most important factors.

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The authors thank David Ramsey for language editing and Professor Nicolaus Blin for helpful comments.

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      chromosome aberration; congenital malformations; esophageal atresia; gene mutation

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