Genetic Basis of Hirschsprung¿s Disease

Abstract

Hirschsprung disease (HSCR, OMIM: 142623), or aganglionic megacolon, is a developmental disorder characterised by the absence of intramural ganglion cells in the submucosal and myenteric plexuses (Meissner and Auerbach plexuses, respectively) along a variable length of the distal gastrointestinal tract, leading to the most common form of functional intestinal obstruction in neonates and children [1]. The disorder was first reported in 1888 by the Danish pediatrician Harald Hirschsprung in two unrelated boys treated until 7 and 11 month of age for severe constipation and abdominal distension resulting in congenital megacolon [2]. But was not till the 1940s, when histological studies revealed the absence of ganglion cells downstream of the dilated part of the colon [1]. HSCR is regarded as a failure of neural crest cells to migrate, proliferate, differentiate or survive in the wall of the gastrointestinal tract between the fifth and 12th week of gestation to form the enteric nervous system (ENS) [3]. The classification of HSCR is according to the length of the aganglionic segment [4]. While the internal anal sphincter is the constant inferior limit, patients could be classified as short-segment HSCR (S-HSCR: 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and long-segment HSCR (L-HSCR: 20% of cases) when aganglionosis extends proximal to the sigmoid. A less common HSCR variety is total colonic aganglionosis (TCA, 3–8% of cases) in which the entire colon and the terminal portion of the ileum is involved [5]. Three rare HSCR variants have also been reported: (1) total intestinal HSCR when the whole bowel is involved [5]; (2) ultra-short segment HSCR involving the distal rectum below the pelvic floor and the anus, proximal to the normal aganglionic zone [6]; (3) suspended HSCR, a controversial condition, where a portion of the colon is aganglionic above a normal distal segment. The incidence of HSCR is estimated at 1/5000 live births [7]. However, the incidence varies significantly among ethnic groups (1.0, 1.5, 2.1, and 2.8 per 10 000 live births in Hispanics, Caucasian-Americans, African-Americans, and Asians, respectively) [8]. S-HSCR is far more frequent than L-HSCR (80% and 20%, respectively) [9, 10]. There is a sex bias with a preponderance of affected males and a sex ratio of 4/1 [11]. Interestingly, the male: female ratio is significantly higher for S-HSCR (4.2–4.4) than for L-HSCR (1.2–1.9) [8, 11]. HSCR most commonly presents sporadically, although it can be familial and may be inherited as autosomal dominant or autosomal recessive, with reduced penetrance and male predominance [9, 11]. In 70% of cases, HSCR occurs as an isolated trait and in the other 30% HSCR is associated with other congenital malformation syndromes [12].