The molecular genetics of hirschsprung's disease

Abstract

Hirschsprung's disease (HSCR), or aganglionic megacolon, is a classic example of a complex genetic disease, characterized by the lack of enteric ganglia in the submucosal and myenteric plexuses, along variable portions of the distal gut. Since it is caused by a premature arrest of the migration of neural crest cells along the hindgut, it is defined also as a neurocristopathy. The variable extent of aganglionosis correlates with severity of the disease, leading to a classification of HSCR into short- and long-segment phenotypes [1, 2]. S-forms include aganglionosis confined below the rectosigmoid junction (80% of patients), while L-forms (20% of patients) can extend below the splenic flexure (colonic forms, 9%), to the whole colon (total colonic aganglionosis, TCA, 5-10%), or up to the whole bowel (total intestinal). The disease is a congenital malformation occurring in 1 in 5,000 live births, with the highest incidence in Asian populations (2.8 in 10,000), intermediate in Afro-Americans (2.1 in 10,000) and Caucasians (1.5 in 10,000) and lowest in Hispanics (1 in 10,000). The male to female ratio is 4:1, and the sex imbalance is particularly evident for S-forms (ranging from 4.2 to 5.5 in S-form and from 1.2 to 1.9 in L-form aganglionosis) [1-3] (Table 5.1). © 2008 Springer-Verlag.