A.M. O'Donnell P. Puri A role for Pten in paediatric intestinal dysmotility disorders Pediatr Surg Int 27 5 2011 491 493

Abstract

The enteric nervous system (ENS) is a network of neurons and glia that lies within the gut wall. It is responsible for the normal regulation of gut motility and secretory activities. Hirschsprung disease (HD) is a congenital defect of the ENS characterized by an absence of ganglia in the distal colon. Intestinal neuronal dysplasia (IND) is a condition that clinically resembles HD, characterized by hyperganglionosis and giant and ectopic ganglia, resulting in intestinal dysmotility. Intestinal ganglioneuromatosis is characterized by hyperplasia and hypertrophy of enteric neuronal cells and causes chronic intestinal pseudoobstruction. Phosphatase and tensin homolog deleted on chromosome 10 (Pten) is a phosphatase that is critical for controlling cell growth, proliferation, and cell death. A recent study of Pten knockout mice showed evidence of ganglioneuromatosis in the ENS, suggesting a role for this protein in ENS development. Patients with ganglioneuromatosis have also been shown to have a decreased level of Pten expression in the colon. The aim of this study was to investigate Pten expression in the ENS of HD and patients with IND compared with healthy controls. Resected tissue from 10 patients with HD and 10 patients with IND type B was fixed and embedded in paraffin wax. Normal control colon tissue was obtained from 10 patients who underwent a colostomy closure for imperforate anus. Sections were cut, and immunohistochemistry was carried out using a Pten antibody. Results were analyzed by light microscopy. Staining showed that Pten was strongly expressed in ganglia of both the submucosal and myenteric plexus of normal and HD specimens from the ganglionic colon. Pten expression was significantly reduced in the giant ganglia in patients with IND in both the myenteric and submucosal plexuses compared with the healthy controls. Specimens from the aganglionic region of HD did not show Pten expression. This is the first study demonstrating a marked reduction of Pten expression in the myenteric and submucous plexuses of patients with IND. Neuronal Pten deficiency in IND may disrupt the chemical pathway associated with the proliferation and development of neuronal cells forming mature ganglia and thus cause motility dysfunction.