Clinical Manifestations of EA/TEF

Infants with congenital forms of EA/TEF usually present shortly after birth with copious oral secretions, coughing, gagging, cyanosis, vomiting, and/or respiratory distress.

Establishing the Diagnosis of EA/TEF

EA/TEF may be suspected prenatally if ultrasound examination reveals polyhydramnios, absence of a fluid-filled stomach, a small abdomen, lower-than-expected fetal weight, and a distended esophageal pouch [Kronemer & Snyder-Warwick 2008]. Fetal MRI may be used to confirm the presence of EA/TEF [Langer et al 2001].

EA may be detected postnatally by:

• Failure to pass a nasogastric (NG) tube and radiographs that demonstrate coiling of the NG tube in the pouch

• Tracheal compression and deviation on plain chest radiographs

• Absence of a gastric bubble on plain radiographs, which may suggest EA without a TEF or EA with a proximal TEF

• Three-dimensional CT scanning [Kronemer & Snyder-Warwick 2008]

Note: Administration of barium into the esophagus followed by chest radiographs can confirm the diagnosis but is seldom required.

Differential Diagnosis of EA/TEF

Laryngotracheoesophageal cleft. Midline defect between the posterior larynx and trachea and the anterior wall of the esophagus. This entity can present prenatally with polyhydramnios and a small or absent stomach bubble and postnatally with aspiration after feeding. Laryngotracheoesophageal clefts are commonly associated with other anomalies including TEF.

Esophageal webs/rings. Circumferential partial obstruction of the esophageal lumen caused by membranous or diaphragmatic tissue. These can be associated with TEF. Many cases are asymptomatic. When symptomic, esophageal webs/rings typically present with recurrent vomiting, dysphagia (solid>liquids) and sometimes aspiration later in life than EA.

Esophageal stricture. A narrowing of the esophageal lumen caused by a variety of intrinsic and extrinsic disease processes. Congenital esophageal strictures typically present after the newborn period in a manner similar to that seen in esophageal webs/rings.

Esophageal diverticulum. A sack or pouch arising from the esophagus. Esophageal diverticula can be present at birth but most often arise and/or become symptomatic in adulthood, presenting with a history of dysphagia, chest pain, vomiting, and sometimes aspiration pneumonia.

Tubular esophageal duplications. Tubular channels that lie parallel to the esophagus and often connect to the main esophageal lumen or the stomach. These lesions are often asymptomatic and are most commonly identified serendipitously at autopsy. Symptoms typically result from inflammation and/or distention secondary to food entrapment and typically involve intermittent dsyphagia.

Congenital short esophagus. An abnormally short esophagus accompanied by an intrathoracic location of part of the stomach. Symptoms are often present at birth and include gastroesophageal reflux and vomiting.

Tracheal agenesis/atresia. Lack of communication between the larynx and the alveoli of the lungs. This can be associated with other anomalies including TEF. Prenatal findings can include hyperechogenic lungs, flattened diaphragms, oligo- or polyhydramnios, and large breathing movements. Postnatal symptoms include severe respiratory distress, cyanosis, absent cry, and failure to ventilate despite tracheal intubation.

Prevalence of EA/TEF

The incidence of EA/TEF is approximately one in 3,500 [Shaw-Smith 2006].

Environmental (Acquired) Causes

Although exposure to certain medications and infections during pregnancy have been proposed as possible risk factors for development of esophageal atresia/tracheoesophageal fistula (EA/TEF), no external factor has been consistently linked to the development of EA/TEF [Felix et al 2007].

Exposure to methimazole during pregnancy has been postulated to cause a specific embryopathy, which includes EA/TEF, but data supporting this association remain anecdotal [Clementi et al 1999, Di Gianantonio et al 2001].

Maternal diabetes mellitus has been suggested as a possible risk factor for development of VACTERL association [Castori et al 2008].

Heritable Causes

Unknown Cause

It is not known in what proportion of individuals with EA/TEF the cause is unknown.

Mode of Inheritance

Esophageal atresia/tracheoesophageal fistula (EA/TEF) can occur as an isolated finding, as part of a genetic syndrome or as part of a non-isolated (but not syndromic) set of findings.

If an affected individual is found to have an inherited or de novo chromosome abnormality, or a specific syndrome or association with EA/TEF, genetic counseling for that condition is indicated.

Nonsyndromic EA/TEF is generally considered to be inherited in a multifactorial manner.

Empiric Risks to Family Members —TEF

Most individuals with EA/TEF are simplex cases (i.e., the only affected member of the family). A small subset of families are multiplex (i.e., two or more relatives have EA/TEF).

Sibs of a proband. For individuals with isolated EA/TEF without a clear etiology, recurrence risk for sibs is likely to be approximately 1% [Shaw-Smith 2006]. The twin concordance rate for EA/TEF is also low (~2.5%) [Robert et al 1993]. Note: No data for recurrence risks for isolated vs non-isolated EA/TEF are available.

Offspring of a proband. In individuals with EA/TEF without a clear etiology, recurrence risk to offspring for EA/TEF and/or malformations in the VACTERL association is likely to be between 2% and 4% [Shaw-Smith 2006]. Note: Since these estimates were generated by studying the offspring of individuals with both isolated and non-isolated EA/TEF, it is possible that the risk to offspring in isolated cases may be lower.

Empiric Risks to Family Members — Non-Isolated EA/TEF

Recurrence risk counseling for individuals with non-isolated EA/TEF—in which additional anomalies have been identified—and for whom a specific genetic disorder is not recognized—is problematic.

• Some cases of non-isolated EA/TEF are probably caused by new dominant mutations, and therefore, pose a low recurrence risk to the sibs of the proband.

• Some are probably unrecognized or private autosomal recessive conditions.

• Some may be multifactorial disorders with a low recurrence risk.

• Non-genetic causes are possible as well, including stochastic events, epigenetic modifications, or teratogenic/environmental exposures.

Thus, counseling in this setting should be as for other multiple congenital anomaly disorders of unknown etiology. Specifically, the estimated recurrence risk to sibs is "low," but this estimate represents an averaging of a negligible, or very low, recurrence risk in the majority of families together with a higher recurrence risk (≤25%-50%) in the minority of families.

Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodologies and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories offering molecular genetic testing for prenatal diagnosis for EA/TEF are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering custom prenatal testing, see .

Ultrasound examination

• Prenatal ultrasound examination of a fetus affected by EA/TEF may reveal an absent or small fetal stomach bubble in combination with maternal polyhydramnios [Houben & Curry 2008]. The diagnostic accuracy is increased if an anechoic area is present in the middle of the fetal neck because it can help differentiate EA from diseases with possible swallowing impairments [Kronemer & Snyder-Warwick 2008]. In one study of 87 fetuses with a small (n = 53) or absent stomach bubble (n = 34), the positive predictive value of an absent stomach bubble and polyhydramnios was 56% and the sensitivity of prenatal sonography in the diagnosis of EA was 42% based on the outcome of all fetuses scanned during the same period [Stringer et al 1995]. The positive predictive value is likely to be even lower among fetuses with multiple anomalies [Choudhry et al 2007].

• The presence of a dilated blind-ending esophageal pouch on a sonogram is suggestive of EA; it is the most reliable sonographic sign indicative of EA and has been seen in cases with and without TEF [Kronemer & Snyder-Warwick 2008].

• Polyhydramnios can be seen in a wide variety of disorders and alone is a poor indicator of EA: only one in 12 fetuses with polyhydramnios have EA [Kronemer & Snyder-Warwick 2008].

• When EA/TEF is suspected on routine prenatal ultrasound examination:

  • A high-resolution ultrasound examination is indicated;

  • Fetal MRI should be considered to help confirm the diagnosis of EA/TEF and to evaluate for additional structural anomalies;

  • Chromosome analysis and/or array CGH studies of fetal cells obtained by amniocentesis should be considered.

• All fetuses suspected of having EA/TEF should be evaluated for the presence of additional major malformations that could be part of an underlying syndrome because such malformations and/or the underlying diagnosis may significantly affect the prognosis. Involvement of a medical geneticist in the evaluation of these families can be helpful.

Evaluations Following Initial Diagnosis

After an individual has been diagnosed with esophageal atresia/tracheoesophageal fistula (EA/TEF), the following evaluations should be considered as a means of identifying associated anomalies:

• X-ray evaluation for vertebral anomalies

• Echocardiogram

• Renal ultrasound examination

Treatment of Manifestations

Initial postnatal intervention, aimed at minimizing the risk of aspiration pneumonia, typically includes the elimination of oral feeds, placement of a suction catheter to allow continuous drainage of secretions, and elevation of the head of the bed to minimize reflux [Clark 1999]. Intravenous (IV) glucose and fluids should be provided; supplemental oxygen should be administered as needed. When intubation cannot be avoided, a possible complication is the collection of air in the stomach, which in severe cases can only be removed by gastrostomy.

Surgical repair consists of closure of the TEF and anastomosis of the esophageal segments [Sharma & Duerksen 2008]. Surgical repair may need to be delayed in infants with low birth weight, pneumonia, or other major congenital anomalies. When surgical repair is delayed, infants may be treated with parenteral nutrition, gastrostomy tube placement, and upper pouch suctioning until they become surgical candidates.

The most common complications after surgical repair include leakage at the site of the anastomosis, recurrent fistula, structure formation, and gastroesophageal reflux [Clark 1999, Kronemer & Snyder-Warwick 2008, Sharma & Duerksen 2008].

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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Author Notes

Author’s web page: www.bcm.edu/genetics/facultyaz/scott.html

Revision History

• 12 March 2009 (me) Review posted live

• 14 October 2008 (das) Original submission