Hirschsprung disease is the main genetic cause of functional intestinal obstruction in infants and children, with an incidence of 1 in 5000 births. It is associated with congenital absence of parasympathetic ganglia in
the bowel. The majority of patients with HSCR (80%) have a short aganglionic segment (S-HSCR) affecting the region beneath the upper sigmoid. Patients with long-segment HSCR (L-HSCR), representing 20% of cases, have aganglionosis extending to or beyond the splenic flexure. HSCR presents as an isolated finding in ~70% of patients, while ~30% of cases are considered syndromic (associated with either a chromosome abnormality or multiple congenital anomalies). RET is the primary gene underlying HSCR, particularly in families with multiple cases of L-HSCR; however, evidence shows that the phenotype can result from mutations in several other genes with both recessive and dominant inheritance patterns (acting alone or in combination). Notably, RET mutations show incomplete, sex-dependent penetrance and do not always result in the Hirschsprung phenotype.