Autonomic dysfunction in children with Hirschsprung's disease

During embryogenesis, two different transmembrane receptors, Ret and Ednrb, together with their ligands, respective, GDNF and endothelin-3, are involved in the migration and differentiation of enteric ganglion cells, sympathetic neurons and melanocytes from the neural crest. Mutations in these genes have been found in a number of human and murine neurocristopathies, including Hirschsprung's disease. RET and GDNF knockouts suggest that they are involved in a correct autonomic nervous system formation. The aim of this study is the evaluation of the autonomic nervous system in patients with Hirschsprung's disease. Seventeen children (mean age: 8.6 years) with Hirschsprung's disease and 19 age- and sex-matched control children (mean age: 9.9 years) underwent pupillary and cardiovascular testing of sympathetic adrenergic and cholinergic function and cardiovagal cholinergic function. Seven of 17 patients with Hirschsprung's disease were affected by autonomic dysfunction. Three of seven patients had evidence of sympathetic denervation, two showed a parasympathetic dysfunction, whereas the remaining two had dysfunction of both sympathetic and parasympathetic tests. Our data in a small number of patients with Hirschsprung's disease show that a subset of these patients exhibits measurable autonomic dysfunction. A RET mutation has been found in one of them. As for the absence of the enteric ganglion cells, autonomic dysfunction in these subjects seems to be polygenic.