Etiology of esophageal atresia and tracheoesophageal fistula: "mind the gap".
ABSTRACT Esophageal atresia and tracheoesophageal fistula (EA/TEF) are major congenital malformations affecting 1:3500 live births. Current research efforts are focused on understanding the etiology of these defects. We describe well-known animal models, human syndromes, and associations involving EA/TEF, indicating its etiologically heterogeneous nature. Recent advances in genotyping technology and in knowledge of human genetic variation will improve clinical counseling on etiologic factors. This review provides a clinical summary of environmental and genetic factors involved in EA/TEF.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Biallelic mutations of the SLC25A13 gene result in citrin deficiency (CD) in humans. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is the major CD phenotype in pediatrics; however, knowledge on its genotypic and phenotypic characteristics remains limited. The present study aimed to explore novel molecular and clinical characteristics of CD. An infant suspected to have NICCD as well as her parents were enrolled as the research subjects. SLC25A13 mutations were investigated using various methods, including cDNA cloning and sequencing. The pathogenicity of a novel mutation was analyzed bioinformatically and functionally with a yeast model. Both the infant and her father were heterozygous for c.2T>C and c.790G>A, while the mother was only a c.2T>C carrier. The novel c.790G>A mutation proved bioinformatically and functionally pathogenic. The infant had esophageal atresia and an accessory hepatic duct, along with bile plug formation confirmed by laparoscopic surgery. However, the father seemed to be healthy thus far. The findings of the present study enrich the genotypic and phenotypic characteristics of CD patients, and provided clinical and molecular evidence suggesting the possible non-penetrance of SLC25A13 mutations and the likely involvement of this gene in primitive foregut development during early embryonic life.International Journal of Molecular Medicine 09/2014; · 1.88 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Esophageal atresia (EA) is defined as a discontinuity of the lumen of the esophagus repaired soon after birth. Dysphagia is a common symptom in these patients, usually related to stricture, dysmotility or peptic esophagitis. We present 4 cases of patients with EA who complained of dysphagia and the diagnosis of Eosinophilic esophagitis (EoE) was made, ages ranging from 9 to 16 years. Although our patients were on acid suppression years after their EA repair, they presented with acute worsening of dysphagia. Esophogastroduodenoscopy and/or barium swallow did not show stricture and biopsies revealed elevated eosinophil counts consistent with EoE. Two of 4 patients improved symptomatically with the topical steroids. It is important to note that all our patients have asthma and 3 out of 4 have tested positive for food allergies. One of our patients developed recurrent anastomotic strictures that improved with the treatment of the EoE. A previous case report linked the recurrence of esophageal strictures in patients with EA repair with EoE. Once the EoE was treated the strictures resolved. On the other hand, based on our observation, EoE could be present in patients without recurrent anastomotic strictures. There appears to be a spectrum in the disease process. We are suggesting that EoE is a frequent concomitant problem in patients with history of congenital esophageal deformities, and for this reason any of these patients with refractory reflux symptoms or dysphagia (with or without anastomotic stricture) may benefit from an endoscopic evaluation with biopsies to rule out EoE.World journal of gastroenterology : WJG. 12/2014; 20(47):18038-43.
- [Show abstract] [Hide abstract]
ABSTRACT: ABSTRACT H-type tracheoesophageal fistula (TEF) is a relatively uncommon congenital anomaly that can be difficult to identify and sometimes, challenging to repair. It is the Gross E type of esphageal atresia (EA) and constitutes 4% of all EA cases. Three infants with TEF were treated between 2003 and 2012. The diagnostic workup, surgical technique, and postoperative course of patients who underwent repair of H-TEF were reviewed. Conventional esophagram demonstrated the fistula in 2 of the patients and a cineradiographic procedure was performed to outline the H-TEF in the last patient. In all 3 cases the location of the fistula was confirmed by tracheoscopy. The closure of the fistula was made by cervical route in 2 cases and by thoracotomy in the remainig patient with distal located fistula. A high index of suspicion for an H-TEF should be maintained in the presence of neonatal respiratory symptoms. Since H-TEFs are known to be complicated with lower respiratory tract infection, early referral of these patients to pediatric surgeons and accurate and timely surgical treatment should be realized.İzmir Dr. Behçet Uz Çocuk Hast. Dergisi. 10/2013; 2014(4(1)):59-64.
Etiology of Esophageal Atresia and Tracheoesophageal
Fistula: “Mind the Gap”
Elisabeth M. de Jong & Janine F. Felix &
Annelies de Klein & Dick Tibboel
Published online: 28 April 2010
# The Author(s) 2010. This article is published with open access at Springerlink.com
Abstract Esophageal atresia and tracheoesophageal fistula
live births. Current research efforts are focused on understand-
ing the etiology of these defects. We describe well-known
animal models, human syndromes, and associations involving
EA/TEF, indicating its etiologically heterogeneous nature.
Recent advances in genotyping technology and in knowledge
of human genetic variation will improve clinical counseling on
etiologic factors. This review provides a clinical summary of
environmental and genetic factors involved in EA/TEF.
Keywords Congenital anomaly.Foregut.VACTERL.
Feingold syndrome.CHARGE syndrome.
Esophageal atresia (EA) and tracheoesophageal fistula (TEF)
are congenital malformations that occur approximately in
1:3500 live-born infants . Five subtypes are described,
based on the location of the atresia and the type of
connection between trachea and esophagus . Associated
anomalies occur in 50% of patients and include vertebral,
anal, cardiovascular, tracheoesophageal, renal, and limb
abnormalities (occurring together in the VACTERL
association). Better surgical techniques and pre- and
postoperative care have improved the prognosis of EA/
TEF over the past decades, but patients still have
significant short- and long-term morbidity [3•]. As with other
congenital malformations, EA/TEF occurs at an increased
rate in twins, but usually affects only one twin . Once a
couple has one child with EA/TEF, the risk of having a
second child with this anomaly is increased to 1% .
The pathologic mechanism leading to EA/TEF is
unknown. The trachea, esophagus, and lungs are foregut-
derived structures. During the fourth week of embryonic
life, the foregut divides into a ventral respiratory part and a
dorsal esophageal part. The underlying mechanism of
separation is not known.
EA/TEF is thought to be a multifactorial complex
disease, with involvement of genetic and environmental
factors. In 6% to 10% of patients a defined genetic
syndrome can be diagnosed, leaving 90% of patients of
unknown etiology . This paper aims to give an overview
of current knowledge and gaps in knowledge on the
etiology of EA/TEF. In this review we distinguish between
complex genetic syndromes and associations to facilitate
targeted genetic follow-up and counseling.
Various environmental factors have been suggested as risk
factors for the development of tracheoesophageal anomalies,
E. M. de Jong:J. F. Felix:D. Tibboel (*)
Department of Pediatric Surgery,
Erasmus MC—Sophia Children’s Hospital,
PO Box 2060, 3000 CB Rotterdam, The Netherlands
E. M. de Jong
J. F. Felix
E. M. de Jong:A. de Klein
Department of Clinical Genetics, Erasmus MC,
Rotterdam, The Netherlands
A. de Klein
Curr Gastroenterol Rep (2010) 12:215–222
including maternal exposure to methimazole , exogenous
sex hormones , maternal alcohol and smoking ,
infectious diseases , and working in agriculture or
horticulture . Previous studies from our group impli-
cate a possible role for maternal in utero exposure to
diethylstilbestrol (DES) . Observations in insulin-
dependent diabetic mothers suggest that first trimester
exposure to maternal diabetes is associated with the
development of congenital anomalies, including EA/TEF
and VACTERL-associated anomalies . Very recently,
studies from the European Surveillance of Congenital
Anomalies (EUROCAT) birth registry network found that
older mothers are at significantly greater risk of having a
child with EA [13•].
Administration of the anthracycline antibiotic adria-
mycin to pregnant rats causes EA/TEF and other major
congenital anomalies in the offspring . However, no
such association has been reported for humans . A role
for vitamin A deficiency in the development of EA/TEF
has also been suggested. A vitamin A–deficient diet given
to pregnant rats caused severe congenital anomalies in the
offspring, including agenesis of the lung and TEF .
Ethylnitrosourea (ENU), an alkylating and mutagenic
agent, induced a recessive mouse mutation with a
phenotype that includes abnormal tracheoesophageal
septation and VACTERL-associated anomalies . So
far, no specific environmental risk factor has consistently
Human Syndromes and Associations Involving EA/TEF
More than 50% of EA/TEF patients have associated
anomalies. Certain anomalies, such as cardiovascular
defects, renal agenesis, microcephaly, duodenal atresia,
limb reduction defects, and polycystic kidney are especially
prevalent in patients with EA/TEF [18, 19]. EA/TEF may
be present in several syndromes and associations, as
described in Table 1.
The department of Pediatric Surgery at the Erasmus
MC—Sophia Children’s Hospital admitted more than
300 EA/TEF patients from 1988 to 2009. In 29 patients,
a chromosomal abnormality or a single gene disorder
was causative to the EA/TEF phenotype. One in every
10 patients had a defined syndrome, which is in line with
the literature. Many of the known genetic syndromes
were seen in this cohort, including all full trisomies
(Down syndrome, Edwards syndrome, Patau syndrome),
single gene disorders (eg, CHARGE syndrome, Feingold
syndrome, Opitz syndrome, and Fanconi anemia), and
some less frequent syndromes (eg, Holt-Oram syndrome
and Townes Brocks syndrome). The distribution of
syndromes is according to the literature [5, 20].
More than 30% of EA/TEF cases in our cohort
(syndromal cases excluded) were defined as VACTERL-
associated. EA/TEF is a component of the VACTERL
association, which includes vertebral, anal, cardiovascular,
tracheoesophageal, renal, and limb anomalies, and is seen
in 10% to 30% of EA/TEF patients [1, 19]. The use of this
acronym as a clinical entity is still being debated, as is the
minimum number of defects that must be present.
Of the VACTERL components, the vertebrae/ribs and
the cardiovascular system are most commonly affected in
combination with EA/TEF . EA/TEF occasionally
occurs in combinations with hemifacial microsomia, cardiac,
vertebral, and/or central nervous system anomalies
(Goldenhar syndrome), but no genetic basis has been
described for this syndrome .
VACTERL associated patients are of interest in the
search for new genetic factors underlying foregut-related
and associated anomalies. However, the combinations of
EA/TEF and its associated anomalies resemble and/or
overlap phenotypically with defined syndromes, such as
CHARGE syndrome, Feingold syndrome, and 22q11
deletion syndrome (discussed below). It is not easy,
therefore, to discriminate between the causal syndromes,
the more so as the etiology of VACTERL association is still
unclear. Specific phenotypes, such as VACTERL-associated
anomalies combined with hydrocephalus, did reveal
causative mutations in the genes FANCB and PTEN [22,
23]. A recent study found deletions in the FOX gene
cluster on chromosome 16q24, and mutations in the
FOXF1 gene, in patients with alveolar capillary dysplasia
combined with VACTERL-associated anomalies, includ-
ing EA/TEF [24••].
Single Gene Disorders Involving EA/TEF
Feingold syndrome is caused by germline mutations in,
or deletions of, the MYCN gene on chromosome 2p24.1.
It is the most frequent cause of familial syndromic
gastrointestinal atresias. About 30% to 40% of patients
diagnosed with Feingold syndrome have EA/TEF .
Marcelis et al. [26••] reviewed the clinical features of
Feingold syndrome in relation to the genotype; 23
different mutations of the MYCN gene and five deletions
encompassing MYCN have been described over the years.
The authors suggest that the presence of digital anomalies
in combination with microcephaly is enough to justify
MYCN analysis [26••]. Such analysis should also be
considered in patients with EA/TEF in combination with
216 Curr Gastroenterol Rep (2010) 12:215–222
About 10% of patients with CHARGE syndrome display EA/
TEF. This well-defined syndrome—involving coloboma,
heart anomalies, choanal atresia, growth and/or mental
retardation, genital and ear anomalies—is caused by muta-
tions in the chromodomain helicase DNA-binding (CHD7)
gene, present in about 60% of CHARGE patients . This
gene is thought to have a role in early embryonic
development affecting epigenetic regulation by chromatin
Table 1 Genetic syndromes and associations involving esophageal atresia and tracheoesophageal fistula
Locus Major defectsa
Single gene disorders
Feingold syndrome 164280 MYCN 2p24.1 Intestinal atresias, microcephaly, learning disability, CHD, limb defects,
Coloboma, CHD, choanal atresia, GR, genitourinary and ear anomalies/
Clinical anophthalmia, GD, mesial temporal abnormalities of the brain
Laryngotracheoesophageal cleft, hypothalamic hamartoblastoma,
pituitary dysfunction, AA, limb defects
Laryngotracheoesophageal cleft, hypertelorism, hypospadias, cleft lip/
palate, CHD, AA, developmental delay
Anemia, abnormal skin pigmentation, short stature, microphthalmia,
microcephaly, susceptibility to cancer, CHD, limb and renal defects
VACTERL-associated defects, hydrocephalus, Arnold-Chiari malfor-
mation, cleft palate, incomplete lung lobation
CHARGE syndrome214800 CHD78q12
Opitz G syndrome300000 MID1Xp22
Fanconi anemia607139 FANCA 16q24.3
605724 FANCD1 13q12.3
227646 FANCD2 3p25.3
VACTERL-associated defects, macrocephaly, ventriculomegaly
Major congenital anomalies, including MR, CHD, gastrointestinal
atresias, Hirschsprung disease, dysmorphic features
CHD, cleft palate, facial dysmorphism, hypocalcaemia, hypertelorism,
hypospadias, thymic hypoplasia, and midline defects
Hypertelorism, laryngotracheoesophageal cleft, cleft lip/palate, GD,
Central nervous system malformations, intestinal atresias, GR,
coloboma, genitourinary, midline and VACTERL-associated defects
MR, conductive hearing loss, impaired vision, craniofacial and skeletal
22q11 deletion (DiGeorge)
16q24.1ACD, VACTERL-associated defects, urinary tract obstruction
Vertebral, anal, cardiovascular, renal and limb defects
VACTERL-associated defects, hydrocephalus
Hemifacial microsomia, CHD, vertebral and central nervous system
Neonatal diabetes mellitus, intestinal atresias, hypoplastic pancreas and
gallbladder, biliary atresia, hypospadias
aOther defects in combination with esophageal atresia and tracheoesophageal fistula
bGene(s) of interest on chromosomal locus
AA anal atresia/imperforate anus; ACD alveolar capillary dysplasia; AEG anophthalmia-esophageal-genital; CHARGE syndrome coloboma, heart
anomalies, choanal atresia, growth and/or mental retardation, genital and ear anomalies; CHD congenital heart defects; GD genital defects,
including cryptorchidism, hypospadias, genital hypoplasia; GR growth retardation; MR mental retardation; VACTERL vertebral, anal,
cardiovascular, tracheoesophageal, renal, and limb abnormalities
Curr Gastroenterol Rep (2010) 12:215–222217
organization and euchromatic gene expression. Still, its
regulatory function and involvement in CHARGE syndrome
and foregut development should be clarified in functional
studies in humans and animal models.
Deletions and mutations of the SOX2 gene are causative for
the phenotype of clinical anophthalmia/optic nerve hypo-
plasia, esophageal atresia, and/or genital anomalies in the
AEG syndrome . Studies in chickens and Xenopus
implicate a role for Sox2 in the developing foregut. Que et
al. [29••,30] demonstrated EA/TEF in Sox2 mutant mice
and thus provided evidence that down regulation of Sox2
plays a role in the etiology of EA. The proven relation
between murine models and the human phenotype was a
breakthrough in the knowledge about syndromic EA/TEF.
Pallister-Hall syndrome includes bifid epiglottis, hypo-
thalamic hamartoblastoma, postaxial polydactyly, anal
atresia, and occasionally laryngeal clefts. Mutations in
the GLI3 gene can cause Pallister-Hall syndrome .
The foregut-related anomalies, such as laryngeal clefts and
lobulation defects of the lungs, form a phenotypic link
between human Pallister-Hall patients and the combined
knockout mice for Gli2/Gli3. This provides evidence that
the Gli-genes and their pathways are important in foregut
Opitz G Syndrome
Opitz G syndrome is characterized by midline abnormalities
with mental retardation and agenesis of the corpus callosum.
Even though EA/TEF is rare in Opitz G syndrome, the
combination of EA/TEF with corpus callosum agenesis
warrants testing for mutations in the MID1 gene, causing
the X-linked form of Opitz syndrome. Laryngotracheoeso-
phageal defects in general are present in most MID1-mutated
males, but EA/TEF is rare . In addition, deletions on
chromosome 22q11.2 cause the autosomal-dominant form of
Opitz syndrome, which has the same size of the deletion as
observed in DiGeorge syndrome . Also, several cases of
EA/TEF have been described in patients with DiGeorge
syndrome (see below).
Fanconi anemia (FA) is a genetically and phenotypically
heterogeneous syndrome characterized by progressive bone
marrow failure and early occurrence of acute myeloid
leukemia, combined with several congenital malformations,
including gastrointestinal malformations. Thirteen genetic
subtypes have been described (A, B, C, D1, D2, E, F, G, I,
J, L, M, and N), of which FANCA, FANCC, and FANCG are
the three most common disease-causing genes .
Mutations in the FANCA, FANCB, FANCC, FANCD1
(BRCA2), FANCD2, and FANCG genes have been described
in patients with EA/TEF with various combinations of
defects, including microcephaly, short stature, pigment
changes, and several VACTERL-associated anomalies,
including heart, renal, and limb defects [22, 35–39]. EA/
TEF is not a common feature of FA, but gastrointestinal
malformations, including duodenal atresia, anorectal
malformations, and EA/TEF, are seen in 14% of all FA
patients . In addition, mutations in the FANCB gene,
on chromosome Xp22.31, were causes of X-linked
VACTERL with hydrocephalus in patients who also had
EA/TEF, lung lobulation defects, and confirmed central
nervous system anomalies . The diagnosis of Fanconi
anemia calls for early therapeutic interventions and
chromosome breakage studies. Faivre et al.  advised
performance of breakage studies in patients with common
VACTERL-associated anomalies, including EA/TEF, in
combination with skin pigmentation abnormalities, growth
retardation, microcephaly, and/or dysmorphism.
Many well-known chromosomal aberrations are observed
in EA/TEF patients, such as Down syndrome (trisomy 21),
Edwards syndrome (trisomy 18), and Patau syndrome
(trisomy 13) . Deletions on several chromosomal loci,
including 22q11 (DiGeorge syndrome), distal 13q,
17q21.3-q24.2, and 16q24.1 are found in some cases
[24••, 40–43]. The paper by Felix et al.  reviewed the
structural chromosomal anomalies reported in 30 patients.
Some of the above-mentioned deletions are of interest,
because the deleted loci include several candidate genes for
EA/TEF, for example, the 17q21.3-q24.2 region including
NOG and TBX4. Recently Stankiewicz et al. [24••]
described deletions on the16q24.1 locus, including the
forkhead genes FOXF1, FOXC2, and FOXL1. Of these
transcription factors, FOXF1 is of particular interest,
because heterozygote knockout mice for this protein have
large cohorts of patients with congenital anomalies; the copy
number variations in microarray studies yield additional
deletions and duplications. Such studies in EA/TEF patients
are expected to reveal new candidate regions. We confirmed
several chromosomal aberrations in patients with EA/TEF:
Triple-X syndrome, Xp duplications, 22q11 microduplication
syndrome, and a 5q11.2 deletion (unpublished data).
Microarray studies will also provide more insight into
218Curr Gastroenterol Rep (2010) 12:215–222
the polymorphic regions of the human genome in
relation to inherited aberrations in patients with congenital
Several murine models are described to cause tracheoesopha-
gealanomalies(Table2) [17, 30, 44]. Genes of developmental
pathways are involved, including vitamin A effectors (Rarα,
Rarβ), effectors of the sonic hedgehog (SHH) pathway (Shh,
Gli2, Gli3, Foxf1), other homeobox-containing transcription
factors and their regulators (Hoxc4, Ttf-1, Pcsk5), and
developmental transcriptional regulators (Tbx4, Sox2).
Research into the human homologues of these genes has
shed some light on the molecular basis underlying some
human cases of EA/TEF. For example, Que et al.  found
that 70% of null mutant mice for Noggin display EA/TEF. In
several human TEF cases there is a deletion of the 17q21.3-
24.2 locus, which includes the human orthologue NOG [30,
43]. Mice haploinsufficient for Foxf1 may show EA/TEF and
other foregut-derived anomalies, including lung hypoplasia
and lobulation defects . A patient with a heterozygote
deletion on chromosome 16q24, including the FOXF1 gene,
displayed lung anomalies, EA/TEF and other VACTERL-
associated features [24••]. The Gli2 and Gli3 genes are
essential for formation of the trachea and the esophagus.
Deletions of these genes are associated with congenital
defects that resemble the VACTERL association, at least in
mice [30, 32]. Szumska et al.  describe an ENU-induced
recessive mouse mutation in the Pcsk5 gene, a regulator of
Hox genes. Such mutations,in a heterozygote form, were also
present in two patients with EA/TEF and features of
were inherited from a phenotypically normal parent. The
etiologic role of these mutations remained unclear .
In conclusion, EA/TEF can be part of a spectrum of
anomalies in specific syndromes with a known cause or it
can be part of an association (Fig. 1). Clinicians should be
aware of specific combinations of anomalies, and should
these occur, consider counseling by a clinical geneticist.
Strategies and Future Prospects
Patients presenting with esophageal atresia receive treatment
by standardized clinical and surgical protocols. Adding
standardized genetic protocols for counseling and research
would provide a good opportunity to unravel the genetic
background of EA and other congenital abnormalities. The
clinical protocol for all patients with EA/TEF should include
an echocardiogram and vertebral and limb radiographs,
complemented with renal ultrasound evaluation if other
features of the VACTERL association are present.
Counseling by a clinical geneticist is advised, including
standard karyotyping and screening for subtelomeric
Table 2 Overview of genes essential for tracheoesophageal development and their human homologues
Gene Mutant phenotypeHuman
EA; TEF; lungs form rudimentary sacs
TEF; lung hypoplasia or agenesis
RARα: 17q21.1; RARβ: 3p24
EA; TEF; severe lung phenotype
No formation of esophagus, trachea, and lungs
Lethal before embryonic day 10; extra-embryonic defects
EA; TEF; lung immaturity/hypoplasia; lobulation defects
TEF; rudimentary peripheral lung primordial
EA; TEF; lung branching defects
EA; TEF; lung branching defects; abnormal notochord morphogenesis
Abnormal tracheoesophageal septation; hypoplastic lungs
GLI2; GLI3GLI2: 2q14; GLI3: 7p13
Partially or completely blocked esophageal lumen; disruption
of esophageal musculature
Tbx4 misexpressionTBX4 17q21-q22
aEthylnitrosourea (ENU)-induced mouse mutation
EA esophageal atresia; TEF tracheoesophageal fistula
(Adapted from Felix et al. , supplemented with findings from recent studies by Szumska et al.  and Que et al. [29••, 30])
Curr Gastroenterol Rep (2010) 12:215–222 219
aberrations with multiplex ligation-dependent probe amplifi-
cation. Clinical data should be reviewed and stored in
comprehensive databases, together with genetic information,
including pedigrees, DNA, tissue, and cell lines. With
improvements in microarray technologies, genome-wide
screening for copy number variations might replace standard
karyotyping in the near future.
Strategies that provide more insight into new etiologic factors
should be in place to find more evidence for gene-
environment interactions, to explore possible molecular
mechanisms, and to find new genetic pathways. Environmen-
explored by means of structured and validated questionnaires,
adding to the knowledge gained from case-control studies
. Such studies require large cohorts, as have been used in
population-based registries for surveillance of congenital
anomalies, such as EUROCAT, the International Clearing-
house for Birth Defects Surveillance and Research, and the
California Birth Defects Monitoring Program.
Studies in animal models implicate an essential role for sonic
embryogenesis of the foregut. Better understanding of normal
and abnormal development of the foregut could be achieved
by focusing on the overlapping effectors of Shh-signaling,
described in patients and animal models, for example, Gli2,
Gli3, FOXF1, MID1, Noggin, Bmp4, and TBX1 [30, 46•].
Advances in genotyping technology and in knowledge
of human genetic variation have enabled genome-wide
association studies to identify susceptibility for common
diseases, but also for congenital abnormalities, as proven in
neural tube defects . This approach requires large
cohorts so as to provide statistical and clinical significance.
Direct sequencing of candidate genes in patients and
controls will provide an alternative approach that could
reveal low-frequency alleles that influence disease suscep-
tibility . In addition, next generation sequencing will
soon be an excellent tool in the search for new pathogenic
mutations and copy number variations . Also, there is
increasing evidence that epigenetic modifications play an
important role in developmental defects through DNA
methylation and histone modifications . A unifying
approach seems to be the answer, therefore: analysis of
multiple candidate genes should be done in large groups of
well-genotyped individuals using next generation high-
throughput genomic technology. This will be of great help
in detecting possible gene-gene interactions as well as a
possible role for copy number variations and regulatory
mutations in patients with EA/TEF.
Many genetic pathways have been implicated in the
development of EA/TEF. Patients with distinct phenotypes
Fig. 1 Schematic representation of the commonest type of EA/TEF and
genetic syndromes and genes involved. The text boxes list the genetic
syndromes and genes most frequently found to be involved in EA/TEF.
EA —esophageal atresia; TEF —tracheoesophageal fistula; *—lung
phenotype present; **—deletion in a single case; L—lung; E—
esophagus; T—trachea; S—stomach; del—deletion; mut—mutation.
AEG syndrome—Anophthalmia/optic nerve hypoplasia, Esophageal
atresia, and/or Genital anomalies; CHARGE syndrome—Coloboma,
Heart anomalies, choanal Atresia, growth and/or mental Retardation,
Genital and Ear anomalies; VACTERL-H association—vertebral, anal,
cardiovascular, tracheal, esophageal, renal, and limb abnormalities
occurring together, with hydrocephaly
220Curr Gastroenterol Rep (2010) 12:215–222
may be diagnosed with genetic syndromes such as Feingold
syndrome, AEG syndrome, and CHARGE syndrome.
There is a substantial gap in our knowledge of how
environmental factors combined with genetic factors would
disrupt foregut development. We would do well to “mind
the gap” by performing clinical studies focusing on
phenotyping, combined with targeted molecular genetic
studies. In the near future, studies in large cohorts will lead
to the discovery of new genes, genetic pathways, and
perhaps environmental factors.
No potential conflict of interest relevant to this article
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
This article is distributed under the terms of the
Papers of particular interest, published recently, have been
• Of importance
•• Of major importance
1. Torfs CP, Curry CJ, Bateson TF: Population-based study of
tracheoesophageal fistula and esophageal atresia. Teratology 1995,
2. Gross RE: Surgery of Infancy and Childhood. Philadelphia: WB
3. • Spitz L: Oesophageal atresia. Orphanet J Rare Dis 2007, 2:24.
This article provides an overview of the history, epidemiology,
classification, and clinical description of esophageal atresia. In
addition, it discusses etiologic and pathophysiologic aspects and
the developments in management.
4. McMullen KP, Karnes PS, Moir CR, Michels VV: Familial
recurrence of tracheoesophageal fistula and associated malforma-
tions. Am J Med Genet 1996, 63:525–528.
5. Genevieve D, de Pontual L, Amiel J, et al.: An overview of isolated
and syndromic oesophageal atresia. Clin Genet 2007, 71:392–399.
of prenatal methimazole exposure. Teratology 2001, 64:262–266.
7. Nora JJ, Nora AH, Perinchief AG, et al.: Congenital abnormalities
and first-trimester exposure to progestagen/oestrogen [letter].
Lancet 1976, 1:313–314.
8. Wong-Gibbons DL, Romitti PA, Sun L, et al.: Maternal
periconceptional exposure to cigarette smoking and alcohol and
esophageal atresia +/−tracheo-esophageal fistula. Birth Defects
Res A Clin Mol Teratol 2008, 82:776–784.
9. Kyyronen P, Hemminki K: Gastro-intestinal atresias in Finland in
1970–79, indicating time-place clustering. J Epidemiol Community
Health 1988, 42:257–265.
10. Felix JF, van Dooren MF, Klaassens M, et al.: Environmental
factors in the etiology of esophageal atresia and congenital
diaphragmatic hernia: results of a case-control study. Birth Defects
Res A Clin Mol Teratol 2008, 82:98–105.
11. Felix JF, Steegers-Theunissen RP, de Walle HE, et al.: Esophageal
atresia and tracheoesophageal fistula in children of women
exposed to diethylstilbestrol in utero. Am J Obstet Gynecol
2007, 197:38 e31–e35.
12. Castori M, Rinaldi R, Capocaccia P, et al.: VACTERL association
and maternal diabetes: a possible causal relationship? Birth
Defects Res A Clin Mol Teratol 2008, 82:169–172.
13. • Loane M, Dolk H, Morris JK: Maternal age-specific risk of non-
chromosomal anomalies. Bjog 2009, 116:1111–1119.This
population-based prevalence study found that older mothers were
at a significantly greater risk of having a child with esophageal
atresia. The authors used data from EUROCAT congenital
anomaly registers in 23 regions of Europe, describing more than
1.75 million births from 2000 to 2004.
14. Diez-Pardo JA, Baoquan Q, Navarro C, Tovar JA: A new rodent
experimental model of esophageal atresia and tracheoesophageal
fistula: preliminary report. J Pediatr Surg 1996, 31:498–502.
15. Germann N, Goffinet F, Goldwasser F: Anthracyclines during
pregnancy: embryo-fetal outcome in 160 patients. Ann Oncol
16. Wilson JG, Roth CB, Warkany J: An analysis of the syndrome of
malformations induced by maternal vitamin A deficiency. Effects
of restoration of vitamin A at various times during gestation. Am J
Anat 1953, 92:189–217.
17. Szumska D, Pieles G, Essalmani R, et al.: VACTERL/caudal
regression/Currarino syndrome-like malformations in mice with
mutation in the proprotein convertase Pcsk5. Genes Dev 2008,
18. Stoll C, Alembik Y, Dott B, Roth MP: Associated malformations
in patients with esophageal atresia. Eur J Med Genet 2009,
19. de Jong EM, Felix JF, Deurloo JA, et al.: Non-VACTERL-type
anomalies are frequent in patients with esophageal atresia/tracheo-
esophageal fistula and full or partial VACTERL association. Birth
Defects Res A Clin Mol Teratol 2008, 82:92–97.
20. Shaw-Smith C: Oesophageal atresia, tracheo-oesophageal fistula,
the VACTERL association: review of genetics and epidemiology.
J Med Genet 2006, 43:545–554.
21. Mendelberg A, Ariel I, Mogle P, Arad I: Tracheo-oesophageal
22. Holden ST, Cox JJ, Kesterton I, et al.: Fanconi anaemia
complementation group B presenting as X linked VACTERL
with hydrocephalus syndrome. J Med Genet 2006, 43:750–754.
23. Reardon W, Zhou XP, Eng C: A novel germline mutation of the
PTEN gene in a patient with macrocephaly, ventricular dilatation,
and features of VATER association. J Med Genet 2001, 38:820–823.
of the FOX gene cluster on 16q24.1 and inactivating mutations of
FOXF1 cause alveolar capillary dysplasia and other malformations.
Am J Hum Genet 2009, 84:780–791. This study describes patients
with alveolar capillary dysplasia and VACTERL-associated anoma-
lies, including EA/TEF and a microdeletion on chromosome 16q24.
Thedeletedregionincludes thegenesFOXF1, FOXC2, and FOXL1.
Because haploinsufficiency of Foxf1 in mice causes EA/TEF and
other malformations, a genetic link between human and animal
studies was established.
25. van Bokhoven H, Celli J, van Reeuwijk J, et al.: MYCN
haploinsufficiency is associated with reduced brain size and intestinal
atresias in Feingold syndrome. Nat Genet 2005, 37:465–467.
26. •• Marcelis CL, Hol FA, Graham GE, et al.: Genotype-phenotype
29:1125–1132. The authors correlated genotype to phenotype
in patients with MYCN-related Feingold syndrome that causes
dominantly inherited esophageal atresia, microcephaly, and toes
syndactyly in humans
27. Vissers LE, van Ravenswaaij CM, Admiraal R, et al.: Mutations
in a new member of the chromodomain gene family cause
CHARGE syndrome. Nat Genet 2004, 36:955–957.
Curr Gastroenterol Rep (2010) 12:215–222 221
28. Williamson KA, Hever AM, Rainger J, et al.: Mutations in SOX2
cause anophthalmia-esophageal-genital (AEG) syndrome. Hum
Mol Genet 2006, 15:1413–1422.
29. •• Que J, Okubo T, Goldenring JR, et al.: Multiple dose-dependent
roles for Sox2 in the patterning and differentiation of anterior
foregut endoderm. Development 2007, 134:2521–2531. This
study investigated the importance of Sox2 in differentiation of
the foregut into esophagus. In humans, heterozygosity for SOX2 is
associated with AEG syndrome. This study provides evidence for
a relation between murine models and the human phenotype of
syndromic EA/TEF. Downregulation of Sox2 plays a role in the
etiology of EA/TEF and of columnar mucous cell metaplasia in
30. Que J, Choi M, Ziel JW, et al.: Morphogenesis of the trachea and
esophagus: current players and new roles for noggin and Bmps.
Differentiation 2006, 74:422–437.
31. Johnston JJ, Olivos-Glander I, Killoran C, et al.: Molecular and
clinical analyses of Greig cephalopolysyndactyly and Pallister-
Hall syndromes: robust phenotype prediction from the type and
position of GLI3 mutations. Am J Hum Genet 2005, 76:609–
32. Motoyama J, Liu J, Mo R, et al.: Essential function of Gli2 and
Gli3 in the formation of lung, trachea and oesophagus. Nat Genet
33. De Falco F, Cainarca S, Andolfi G, et al.: X-linked Opitz
syndrome: novel mutations in the MID1 gene and redefinition of
the clinical spectrum. Am J Med Genet A 2003, 120:222–228.
34. Robin NH, Feldman GJ, Aronson AL, et al.: Opitz syndrome is
genetically heterogeneous, with one locus on Xp22, and a second
locus on 22q11.2. Nat Genet 1995, 11:459–461.
35. Auerbach AD: Fanconi anemia and its diagnosis. Mutat Res 2009,
36. Faivre L, Portnoi MF, Pals G, et al.: Should chromosome
breakage studies be performed in patients with VACTERL
association? Am J Med Genet A 2005, 137:55–58.
37. Alter BP, Rosenberg PS, Brody LC: Clinical and molecular
features associated with biallelic mutations in FANCD1/BRCA2. J
Med Genet 2007, 44:1–9.
38. Levran O, Attwooll C, Henry RT, et al.: The BRCA1-interacting
helicase BRIP1 is deficient in Fanconi anemia. Nat Genet 2005,
39. Yamada T, Tachibana A, Shimizu T, et al.: Novel mutations of the
FANCG gene causing alternative splicing in Japanese Fanconi
anemia. J Hum Genet 2000, 45:159–166.
40. Digilio MC, Marino B, Bagolan P, et al.: Microdeletion 22q11 and
oesophageal atresia. J Med Genet 1999, 36:137–139.
41. Walsh LE, Vance GH, Weaver DD: Distal 13q Deletion Syndrome
and the VACTERL association: case report, literature review, and
possible implications. Am J Med Genet 2001, 98:137–144.
42. Felix JF, Tibboel D, de Klein A: Chromosomal anomalies in the
aetiology of oesophageal atresia and tracheo-oesophageal fistula.
Eur J Med Genet 2007, 50:163–175.
43. Puusepp H, Zilina O, Teek R, et al.: 5.9 Mb microdeletion in
chromosome band 17q22-q23.2 associated with tracheo-
esophageal fistula and conductive hearing loss. Eur J Med Genet
44. Felix JF, Keijzer R, van Dooren MF, et al.: Genetics and
developmental biology of oesophageal atresia and tracheo-
oesophageal fistula: lessons from mice relevant for paediatric
surgeons. Pediatr Surg Int 2004, 20:731–736.
45. Mahlapuu M, Enerback S, Carlsson P: Haploinsufficiency of the
forkhead gene Foxf1, a target for sonic hedgehog signaling,
causes lung and foregut malformations. Development 2001,
46. • Shaw-Smith C: Genetic factors in esophageal atresia, tracheo-
esophageal fistula and the VACTERL association: roles for
FOXF1 and the 16q24.1 FOX transcription factor gene cluster,
and review of the literature. Eur J Med Genet 2010, 53:6–13. This
article reviews the recent findings in patients with alveolar
capillary dysplasia combined with VACTERL associated anomalies,
including EA/TEF, and a microdeletion of the FOX gene cluster on
chromosome 16q24. Attention is paid to the relevant mouse models,
especially those for genes in the Sonic Hedgehog pathway, in
relation to this microdeletion and the etiology of VACTERL-
associated anomalies and EA/TEF
47. Martinez CA, Northrup H, Lin JI, et al.: Genetic association study
of putative functional single nucleotide polymorphisms of genes
in folate metabolism and spina bifida. Am J Obstet Gynecol 2009,
48. Furniss D, Kan SH, Taylor IB, et al.: Genetic screening of 202
individuals with congenital limb malformations and requiring
reconstructive surgery. J Med Genet 2009, 46:730–735.
49. Yoon S, Xuan Z, Makarov V, et al.: Sensitive and accurate
detection of copy number variants using read depth of coverage.
Genome Res 2009, 19:1586–1592.
50. Schnetz MP, Bartels CF, Shastri K, et al.: Genomic distribution of
CHD7 on chromatin tracks H3K4 methylation patterns. Genome
Res 2009, 19:590–601.
222Curr Gastroenterol Rep (2010) 12:215–222