0A-S7-2

NEW INSIGHTS INTO THE PATHOGENESIS AND PATHOPHYSIOLGY OF HIRSCHSPRUNG’S DISEASE

Tam PKH

Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong SAR, China

Hirschsprung's disease (HSCR) has emerged as a polygenic disease. The RET gene is most commonly involved, yet contrary to findings of earlier series, our population-based study reveals causative mutation in only 7% HSCR patients. One of the explanations is that HSCR could be caused by additive sub-clinical effects of more than one gene, including RET. This is supported by our recent comparative study of RET single nucleotide polymorphism (SNP) showing difference in the T allele frequency in Italian and Chinese populations. Expression studies of GFR, the receptors of the RET ligand GDNF-in HSCR bowel show that even in the absence of germline mutations the NET-GDNF-GFR pathway is involved in aganglionosis. SOX 10 is emerging as the key component in another signaling pathways, as evidenced by our findings of novel SOX10 mutations in Waardenberg Shan syndrome and SOX10 expression abnormalities in HSCR bowel. Discovery of new genes for HSCR can be anticipated.

The pathophysiology of HSGR is being unraveled. We have found decreased Trk C expression in both HSCR and slow transit constipation. Our findings of novel capsaicin (VR1) and purinergic (P2X₃) receptors in aganglionic HSCR bowel indicate that sensory nerves may form a significant proportion of its hypertrophic innervation. Most recently, we have provided evidence that deficiency of novel inhibitory neurotransmitter carbon monoxide may contribute to the failure of relaxation of aganglionic bowel in HSBR. Down regulation of caudal type homeobox genes CDX-1and-2provides a new clue to the occurrence of enterocolitis in HSCR.