Fig. 2 | Timeline of key advances in the history of Hirschsprung disease.

In 1886, Harald Hirschsprung first presented the cases of two infants who died of what we now identify as Hirschsprung-associated enterocolitis225. In the 1920s, Dalla Valle identified the absence of ganglion cells in the distal bowel and the presence of ganglion cells in the proximal bowel225. Orvar Swenson performed the first successful resection and pull-through for HSCR in 1949, which was

1994–1995: Laparoscopy-assisted pull-through (Thom Lobe–Keith Georgeson)

followed by technical variations of pull-through presented by Duhamel, Yancey, Soave and Rehbein7–9,11,12. Laparoscopic approaches were described by Lobe and Georgeson in the mid-1990s, followed by fully transanal approaches by

De la Torre Mondragón and Langer in 2000 (refs. 13–16). Notably, the earliest description of what we now refer to as Hirschsprung disease is found in the ancient Hindu text ‘Sushruta Samhita’, dating to 1200–600 bce226.

are found in RET or EDNRB or genes encoding transcription factors related to these genes (see below)38.

Family history. Families with a history of HSCR have an increased risk of recurrence, with affected families carrying a risk 200 times higher (estimated ~4%) than the general population33. This risk is even higher for long-segment HSCR, for which recurrence rates can be as high as 20–50%33. High-penetrance RET mutations — in coding sequence and enhancer regions — are involved in ~45–50% of cases of familial HSCR33,38. Loss-of-function RET mutations are found more often in familial HSCR than in sporadic HSCR. Non-affected parents can still be carriers of the mutations in families with a history of HSCR40.

Associated congenital anomalies. Associated congenital anomalies are often observed in children with HSCR, although they have been under-reportedinthepast.Theoverallincidenceofassociatedanomalies is estimated to be ~20–30%38,41,42. However, current studies have found increased incidence owing to active screening42. The most common anomalies are visual and ophthalmological (43%), such as hyperopia (29%) or astigmatism (26%), but their prevalence is also high in the generalpopulation42.Congenitalanomaliesofthekidneyandurinarytract are also commonly observed, affecting 14–21% of patients with HSCR, and routine screening for these conditions is now recommended43,44. Gastrointestinal tract anomalies such as malrotation, anorectal malformationsandintestinalatresiahavebeendetectedin2.8%ofpatients withHSCR42.Otherassociatedanomaliesincludecardiacdefectsin5%of patients(septaldefects),hearingimpairmentin5%andcentralnervous system anomalies in 2% (corpus callosum agenesis)42.

Table 1 | Prevalence of Hirschsprung disease according to ethnic background

Mechanisms/pathophysiology

Enteric nervous system development

The ENS is composed of >100 million enteric neurons (also known as ganglion cells) and glial cells, organized into two plexuses — the myenteric plexus between the longitudinal and circular muscle layers (Auerbach plexus) and the submucosal plexus between the mucosal and circular muscle layers (Meissner plexus). During embryonic development, the cells that form the ENS derive from the neural crest. The neural crest is a temporary structure that arises from the dorsal region of the neural tube and is located along the entire length of the body axis. In humans, vagal NCCs migrate from the oesophagus to the anal canal between the fourth and the seventh weeks of gestation45,46, forming the myenteric plexus outside the circular muscle layer by the 12th week of gestation and the submucosal plexus between the 12th and 16th weeks of gestation47 (Fig. 3). Although vagal NCCs are the primary source of enteric ganglion cells, studies have demonstrated additional sources and migrational routes for subsets of enteric neurons in animal models48,49.

Normal ENS development relies on a precise balance of migration, proliferation and differentiation of NCCs, which is controlled by intrinsic properties of the cells and extrinsic factors in the microenvironment45. The directional migration of NCCs from the vagal region of the dorsal neural tube is driven by extracellular signals such as retinoic acid and Hox transcription factors50–52. The migration of NCCs is complete by the seventh week of gestation in humans, embryonic day 14.5 (E14.5) in mice and 72 h after fertilization in zebrafish45,53. A critical number of enteric NCCs is needed to maintain cell-to-cell contact to drive migration. Diminished proliferation and premature differentiation of the enteric NCCs can lead to incomplete migration and consequently result in HSCR54. Owing to the complexity of this process, a number ofdifferent perturbations along the ENS developmental pathway can lead to the pathogenesis of HSCR55.

Signalling pathways in HSCR

Several signalling pathways that regulate the migration of NCCs are involved in the development of HSCR. RET and EDNRB are the two most common genes associated with HSCR development5. During development, signalling between RET (expressed in NCCs) and GDNF (ligand for RET produced in the gut mesenchyme) is important for the growth, survival and directional movement of enteric NCCs53.