Esophageal atresia (EA) and tracheoesophageal fistula (TEF) are congenital malformations that occur approximately in 1:3500 live-born infants [1
]. Five subtypes are described, based on the location of the atresia and the type of connection between trachea and esophagus [2
]. 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 [1
]. Once a couple has one child with EA/TEF, the risk of having a second child with this anomaly is increased to 1% [4
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 [5
]. 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.