- •Introduction
- •Epidemiology
- •Risk factors
- •Sex distribution
- •Maternal factors
- •Ethnicity
- •Intestinal segment length
- •Preterm infants
- •Associated syndromes
- •Family history
- •Associated congenital anomalies
- •Mechanisms/pathophysiology
- •Enteric nervous system development
- •Signalling pathways in HSCR
- •Role of extracellular matrix in HSCR
- •Genetic factors
- •Variants, partial penetrance and epigenetics
- •Disease models
- •Diagnosis, screening and prevention
- •Clinical presentation
- •Diagnosis
- •Rectal biopsy
- •Histopathological evaluation
- •Differential diagnosis
- •Management
- •Preoperative management
- •Surgical treatment
- •Optimal timing of surgery
- •Single-stage versus multistage surgery
- •Optimal surgical approach and technique
- •Determining the extent of aganglionosis
- •Levelling biopsies and intraoperative pathology
- •Postoperative surgical pathology
- •Postoperative complications
- •Postoperative HAEC
- •Quality of life
- •Outlook
- •Genetics and genomics
- •Diagnosis
- •Treatment
- •Patient-centred research
- •Acknowledgements
Primer
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1920s: Identi ication |
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1956: Retro-rectal pull-through |
1960: Sigmoid resection and colorectal |
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of aganglionosis |
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(Bernard Duhamel) |
anastomosis (Fritz Rehbein) |
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1880s |
1920s |
1930s |
1940s |
1950s |
1960s |
1990s |
2000s |
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1886: First description |
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1949: First pull-through |
1952–1964: Submucosal dissection |
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2000: Total transanal |
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by Harald Hirschsprung |
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(Orvar Swenson) |
(Asa Yancey–Franco Soave) |
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(Jacob Langer– |
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Luis De la Torre Mondragón) |
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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
Ethnic background |
Prevalence (per 10,000 births) |
Refs. |
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Hispanic |
1.0–2.0 |
23 |
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White American |
1.5–2.6 |
23,28 |
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African American |
2.1–4.0 |
23,28 |
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Paci ic Islander |
5.4 |
26 |
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Asian |
2.2–2.8 |
20,28 |
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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.
Nature Reviews Disease Primers | |
(2023) 9:54 |
4 |
Primer
Similarly, the signalling pathway between EDNRB (encoding endothe- |
which leads to distal aganglionosis due to diminished migration of |
lin receptor type B) and its ligand, EDN3, is important for maintaining |
enteric NCCs66. This finding suggests that the location of COL6A3 |
enteric NCCs in an undifferentiated, proliferative state56,57. Perturba- |
(encoding collagen VI) on chromosome 21 might be one of the rea- |
tions in this signalling pathway can lead to premature differentiation |
sons for the increased incidence of HSCR in patients with trisomy 21 |
and disruption of normal migration, resulting in HSCR. Mutations in |
(ref. 67). Some extracellular matrix components, such as collagen VI, |
EDNRB can cause Shah–Waardenburg syndrome, a condition char- |
collagen IX, laminin, agrin and versican, have been reported to impede |
acterized by congenital deafness, pigmentation abnormalities and |
normal NCC migration, whereas other components, such as collagen I, |
HSCR. In mice, homozygous loss of function of Ednrb leads to a com- |
collagen XVIII, tenascin, vitronectin and fibronectin, have been found |
mon model of HSCR called the piebald lethal mouse, whereas loss of |
to promote migration57,66,68–74. This composition of the extracellular |
function mutations in Edn3 results in another model called the lethal |
matrix also affects neuroglial differentiation75. In turn, enteric NCCs |
spotted mouse58. |
can influence their environment by secreting matrix metallopro- |
Studies have demonstrated a role for the transcription factors |
teinases that modify the extracellular matrix to promote migration. |
SOX10 and PHOX2B in HSCR development. SOX10, expressed by |
Thus, the normal development of the ENS is the result of a complex |
early-migrating enteric NCCs, maintains NCCs in a proliferative pro- |
interplay between enteric progenitor cells and the extracellular |
genitor state. Homozygous loss of Sox10 results in total intestinal agan- |
environment. |
glionosis, whereas heterozygosity results in distal aganglionosis59,60. |
HSCR is primarily caused by the incomplete migration of vagal |
By contrast, PHOX2B, expressed by late-migrating enteric NCCs, pro- |
NCCs from cranial to caudal direction during development, although |
motes proliferation while driving NCCs towards a neuronal lineage61. |
other progenitor cell populations might also be involved. In addi- |
In humans, PHOX2B variants are associated with congenital central |
tion to vagal NCCs, the sacral neural crest also contributes to neu- |
hypoventilation syndrome, characterized by a loss of involuntary con- |
rons and glia of the pelvic plexus, and may also contribute to HSCR |
trol of respiration and an increased incidence of HSCR62,63. The pattern- |
pathogenesis48,76–79. However, the exact role of the sacral neural crest |
ing of the ENS in humans into two plexuses involves several pathways, |
in disease pathogenesis is still unknown. Schwann cell precursors may |
including sonic hedgehog, Indian hedgehog, bone morphogenetic |
also play a part in HSCR pathophysiology, as a proportion of neurons |
protein and netrin47,64. |
and glia in the colorectum seem to be derived from the population |
Role of extracellular matrix in HSCR. Environmental factors in |
of cells that migrate along extrinsic nerve fibres49,80. These findings |
suggest that ENS development and the pathogenesis of HSCR may be |
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the vicinity of migrating NCCs also have a crucial role in the normal |
more complex than previously postulated. A better understanding of |
development of the ENS65. For example, the Holstein mouse model |
the pathophysiological mechanisms of HSCR may uncover pathways |
carries a mutation that increases the expression of collagen VI, |
for future targeted therapy. |
Table 2 | Genetic syndromes with a strong association with Hirschsprung disease
Syndrome name |
Prevalence in the general |
Gene or chromosome involved |
Inheritance |
Orphanet code |
Refs. |
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population |
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Down syndrome |
1:400–3,000 |
Trisomy 21 |
Not applicable |
870 |
209 |
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Mowat–Wilson syndrome |
1:50,000–70,000 |
ZFHX1B |
Dominant |
261552 |
210 |
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Waardenburg–Shah syndrome (type 4A) |
<1:1,000,000 |
EDNRB |
Recessive |
897 |
211,212 |
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Waardenburg–Shah (type 4C) |
<1:1,000,000 |
SOX10 |
Dominant |
897 |
212 |
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MEN2A |
1:30,000 |
RET (RETMEN2A oncoprotein) |
Dominant |
247698 |
213 |
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Smith–Lemli–Opitz syndrome |
1:20,000–40,000 |
DHCR7 |
Recessive |
818 |
214 |
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L1 syndrome |
1:30,000 |
L1CAM |
Recessive (X-linked) |
275543 |
215 |
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Bardet–Biedl syndrome |
1:45,000–100,000 |
BBS1–BBS11 |
Recessive |
156183 |
216 |
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Congenital hypoventilation syndrome |
1:200,000 |
PHOX2B |
Dominant |
661 |
217 |
(Haddad) |
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Cartilage–hair hypoplasia |
1:23,000 (Finland, Amish |
RMRP |
Recessive |
175 |
218 |
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community in the USA) |
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Goldberg–Sphrintzen syndrome |
<1:1,000,000 |
KIAA1279 |
Recessive |
2462 |
219 |
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Pitt–Hopkins syndrome |
1:300,000 |
TCF4 |
Dominant |
2896 |
220 |
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BRESEK/BRESHECK syndrome |
<1:1,000,000 |
MBTPS2 |
Recessive (X-linked) |
85284 |
221 |
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Kaufman–McKusick syndrome |
Unknown |
MKKS |
Recessive |
2473 |
222 |
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Other (>30 syndromes) |
4% |
Deletions |
Dominant and/or |
Not applicable |
82 |
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Duplications |
recessive |
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Translocations |
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Data were obtained from refs. 33,90,223; for an extensive list, see ref. 82; for description of all diseases, see ref. 224.
Nature Reviews Disease Primers | |
(2023) 9:54 |
5 |