A role for sonic hedgehog signaling in the pathogenesis of human tracheoesophageal fistula.

Background/purpose: Many theories of the pathogenesis of esophageal atresia with tracheoesophageal fistula (EA/TEF) have been proposed, but no specific mechanism has been demonstrated. The authors previously reported data suggesting a respiratory origin of the fistula tract in the rat model and in humans. Sonic hedgehog (Shh) "knockout" mice have the VACTERL association, and thus it was hypothesized that defects in Shh signaling may exist in the human neonatal EA/TEF fistula tract.

Methods: With IRB approval, human proximal esophageal pouch and distal fistula samples were removed at the time of standard repair of EA/TEF in accordance with what the surgeons deemed appropriate in preparation for anastomosis. Tissues were processed for HE, reverse-transcriptase polymerase chain reaction (RT-PCR), and immunohistochemistry. Normal embryonic lung cDNA was used as a positive control for the RT-PCR reactions.

Results: As expected, Shh was present by immunohistochemistry in the proximal esophageal pouch, but was specifically absent in the distal fistula tract. Gli-1, -2, and -3 (all intracellular mediators of Shh signaling) were present in the proximal pouch and distal esophagus by RT-PCR.

Conclusions: The absence of Shh signaling in the developing fistula tract of the human neonate was surprising given that Shh normally is present in esophagus and other gut components. These results support the conclusion that the fistula tract is not an esophaguslike structure, despite both its histologic appearance and its use as an esophageal replacement. Also, like in Shh-null mutant mice, aberrant Shh signaling may play a critical role in the pathogenesis of EA/TEF in humans.