Hirschsprung Disease

Genetic MONDO:0018309 Congenital Disorder Gastrointestinal Disorder

A congenital disorder characterized by absence of enteric ganglion cells in the distal bowel, resulting in functional intestinal obstruction and impaired motility.

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2
Pathophys.
9
Phenotypes
9
Genes
3
Treatments
3
Subtypes
8
References
2
Deep Research
◆

Subtypes

3
Short-Segment Hirschsprung Disease
Affects the rectum and a short segment of the distal colon.
Show evidence (3 references)
PMID:9269974 SUPPORT
"The extent of aganglionosis was as follows: short segment restricted to the rectosigmoid or descending colon (n = 44, 75%)."
This statement directly supports that short-segment Hirschsprung Disease (HD) affects the rectum and a short segment of the distal colon.
PMID:24168728 SUPPORT
"Analysis of a series of rectosigmoid resections from patients with short-segment (>2-cm aganglionic, n = 9) and very short-segment (</=2-cm aganglionic, n = 9) Hirschsprung disease."
This excerpt confirms that short-segment HD involves the rectosigmoid area, supporting the claim that it affects the rectum and a short segment of the distal colon.
PMID:22985835 SUPPORT
"Moreover, it reviews current outcomes to find consensus on management."
This literature discusses the differences in subtypes of Hirschsprung Disease, including short-segment HSCR involving the rectosigmoid colon, thus supporting the statement.
Long-Segment Hirschsprung Disease
Affects a longer segment of the colon beyond the rectum.
Show evidence (2 references)
PMID:22985835 SUPPORT
"Total colonic aganglionosis (TCA) is a relatively uncommon form of Hirschsprung disease (HSCR)... It can probably be classified as TCA (defined as aganglionosis extending from the anus to at least the ileocecal valve, but not >50 cm proximal to the ileocecal valve) and total colonic and small..."
This reference supports the classification of long-segment Hirschsprung Disease, indicating that it involves a longer segment of the colon beyond the rectum.
PMID:1514906 SUPPORT
"We identified 21 children...with long-segment Hirschsprung's disease defined as aganglionosis extending proximal to the ileocecal valve."
This reference explicitly defines long-segment Hirschsprung's disease as affecting a longer segment of the colon beyond the rectum.
Total Colonic Aganglionosis
Affects the entire colon and sometimes the small intestine.
Show evidence (2 references)
PMID:25367097 SUPPORT
"Total colonic aganglionosis is a relatively uncommon form of Hirschsprung's disease (HSCR). It occurs in approximately 2-13 % of HSCR cases and involves the entire colon which is aganglionic but may extend proximally into varying lengths of small bowel."
This reference indicates that Total Colonic Aganglionosis (TCA) affects the entire colon and sometimes extends into the small intestine, supporting the statement.
PMID:10745745 SUPPORT
"Absence of ganglion cells in the small intestine, a rare form of Hirschsprung's disease, is a condition found in newborns and associated with increased morbidity and mortality."
This reference supports the component of the statement indicating that the condition can involve the small intestine.
⚙

Pathophysiology

2
Failure of Enteric Ganglion Cell Migration
Defective migration of neural crest cells during embryonic development leads to absent ganglion cells in the bowel.
enteric neuron link ∅ ABSENT
neural crest cell migration link ↓ DECREASED cell population proliferation link ↓ DECREASED
myenteric nerve plexus link colon link
Show evidence (4 references)
PMID:33202966 SUPPORT
"Hirschsprung's disease is a neurocristopathy, caused by defective migration, proliferation, differentiation and survival of neural crest cells, leading to gut aganglionosis."
The article describes Hirschsprung's disease as being caused by defective migration of neural crest cells during embryonic development, which results in aganglionosis (absence of ganglion cells) in the bowel.
PMID:36417785 SUPPORT
"Derived from neural crest cells (NCCs), this little brain controls muscle contraction, motility, and bowel activities in response to stimuli. Failure of developing enteric ganglia at the distal bowel results in intestinal obstruction and Hirschsprung disease (HSCR)."
The literature explains that Hirschsprung disease results from the failure of developing enteric ganglia, which are derived from neural crest cells, supporting the notion of defective migration leading to absent ganglion cells.
PMID:23342068 SUPPORT
"Hirschsprung disease (HSCR) is a congenital malformation of the hindgut resulting from a disruption of neural crest cell migration during embryonic development."
This publication clearly states that disruption of neural crest cell migration during embryonic development leads to Hirschsprung disease.
+ 1 more reference
Disrupted Enteric Nervous System Development
The lack of ganglion cells causes a disruption in enteric nervous system function, leading to bowel motility issues.
enteric neuron link ∅ ABSENT
neuron differentiation link ⚠ ABNORMAL peristalsis link ↓ DECREASED
enteric nervous system link colon link
Show evidence (4 references)
PMID:20610192 SUPPORT
"simon.kenny@liv.ac.uk Hirschsprung's disease (HSCR) is characterized by absence of the enteric nervous system in a variable portion of the distal gut"
The absence of ganglion cells (aganglionosis) leads to disruption in enteric nervous system function and subsequent bowel motility issues.
PMID:27426273 SUPPORT
"Abnormal development or disturbed functioning of the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is associated with the development of neuropathic gastrointestinal motility disorders."
The lack of ganglion cells disrupts ENS function, leading to motility problems.
PMID:23917331 SUPPORT
"The pathogenesis of HD is defined as a functional intestinal obstruction resulting from a defect in the intrinsic innervation of the distal bowel."
A defect in the ENS due to the lack of ganglion cells causes motility issues.
+ 1 more reference
●

Phenotypes

9
Digestive 5
Chronic Constipation VERY_FREQUENT Chronic constipation (HP:0012450)
Show evidence (2 references)
PMID:37403154 SUPPORT
"Hirschsprung's disease in adults is usually a short or ultra-short aganglionic segment because it shows relatively mild symptoms. Surgical removal of the aganglionic segment of the gut is the definitive treatment for Hirschsprung's disease."
This reference supports the diagnostic category of chronic constipation in Hirschsprung disease.
PMID:34882271 SUPPORT
"Children with constipation and suspected Hirschsprung's disease are referred for rectal biopsy."
This reference supports the association between chronic constipation and Hirschsprung's disease.
Abdominal Distension VERY_FREQUENT Abdominal distention (HP:0003270)
Show evidence (2 references)
PMID:23001136 SUPPORT
"Hirschsprung's disease (HSCR) is a fairly frequent cause of intestinal obstruction in children."
The reference indicates that HSCR is a frequent cause of a gastrointestinal issue, supporting a high frequency of gastrointestinal phenotypes associated with the disease.
PMID:18959706 SUPPORT
"Abdominal distension and vomiting were most common modes of presentation (100 and 71%, respectively)."
The reference explicitly states that abdominal distension is a common phenotype for Hirschsprung Disease, which supports the statement.
Megacolon VERY_FREQUENT Megacolon (HP:6000852)
Intestinal Obstruction VERY_FREQUENT Intestinal obstruction (HP:0005214)
Enterocolitis OCCASIONAL Enterocolitis (HP:0004387)
Potentially life-threatening complication
Show evidence (3 references)
PMID:28328696 SUPPORT
"Hirschsprung-associated enterocolitis can be a life-threatening sequela."
The literature clearly states that enterocolitis is a potentially life-threatening complication of Hirschsprung disease.
PMID:30602191 SUPPORT
"There is no standardized definition for HAEC. The initial HAEC score cut-off is restrictive and might fail to identify milder episodes."
The study discusses the occurrence of Hirschsprung-associated enterocolitis (HAEC) in patients with Hirschsprung disease, supporting the statement that enterocolitis is a complication.
PMID:30594740 SUPPORT
"The leading cause of mortality in HSCR is HSCR-associated enterocolitis (HAEC)."
This reference supports the statement by indicating that enterocolitis is a significant and potentially fatal complication of Hirschsprung disease.
Nervous System 1
Developmental Delay OCCASIONAL Global developmental delay (HP:0001263)
May occur in severe cases with prolonged malnutrition
Show evidence (2 references)
PMID:35975334 PARTIAL
"Undernutrition is prevalent among children with Hirschsprung disease. Nutrition assessment to identify individuals at risk of undernutrition for further intervention is necessary."
The literature indicates that undernutrition is common in children with Hirschsprung disease, and severe cases with prolonged malnutrition could potentially lead to developmental delays. However, it does not explicitly state that developmental delay is a frequent outcome.
PMID:35690460 PARTIAL
"In LMICs, patients with HD are much more likely to present in a delayed fashion with subsequent increased morbidity and mortality including higher rates of chronic obstruction, malnutrition with failure to thrive, complete obstruction and perforation."
This reference suggests that severe malnutrition and failure to thrive are common in low- and middle-income countries, which could lead to developmental delays. However, it does not explicitly confirm developmental delay as a frequent outcome.
Growth 2
Failure to Thrive FREQUENT Failure to thrive (HP:0001508)
Show evidence (2 references)
PMID:29300049 PARTIAL
"Symptoms of Hirschsprung disease include constipation, vomiting, abdominal distension and growth failure."
Failure to thrive can be inferred from growth failure, but it is not explicitly labeled as a common systemic phenotype.
PMID:35690467 PARTIAL
"Counseling parents is critical for ensuring they understand their child's condition, how it must be treated, pitfalls that can occur during treatment, and how they will do in the long term ... outcomes, and familial nature."
While the actual term 'failure to thrive' is not used, the discussion around growth and long-term outcomes implies potential issues with growth.
Failure to Thrive FREQUENT Failure to thrive (HP:0001508)
Due to impaired nutrient absorption and increased metabolic demands
Show evidence (1 reference)
PMID:21253751 PARTIAL
"Onset and clinical features do correlate with severity. Newborns and infants seem to be more likely to develop serious life-threatening complications, particularly in case of associated cardiovascular malformations."
The literature discusses severe complications and mortality in Hirschsprung's disease, which can be indirectly related to failure to thrive, but it does not explicitly mention systemic frequency or the specific causes noted in the statement.
Other 1
Delayed Meconium Passage VERY_FREQUENT
Failure to pass the first stool within 48 hours of birth
Show evidence (2 references)
PMID:23043324 PARTIAL
"Clinical signs include severe constipation and distended bowel due to a non-motile colon."
This reference describes gastrointestinal symptoms but does not specifically mention delayed meconium passage.
PMID:6481580 PARTIAL
"Eleven infants passed a meconium stool by 24 hours of age (42%), and 15 had passed meconium by 48 hours (58%)."
This indicates that while a significant portion of infants with Hirschsprung Disease passed meconium within 48 hours, it was not universal.
🧬

Genetic Associations

9
RET (Germline Mutations)
Show evidence (3 references)
PMID:32942321 PARTIAL
"This case report provides an overview of a family with a history of HD with a novel, unreported autosomal dominant RET mutation... The family examined in this study clearly demonstrates that (1) the genotype to phenotype correlation of patients with RET mutation-associated HD is not directly..."
While the study identifies an autosomal dominant RET mutation in a family with Hirschsprung Disease, it also indicates that the genetic mechanisms are complex and not fully understood, suggesting that autosomal dominant RET mutations may be one of several contributing genetic factors.
PMID:24972642 PARTIAL
"The co-occurrence of Hirschsprung's disease (HSCR) and multiple endocrine neoplasia type 2 (MEN2) is a relatively rare event... a 'Janus' mutation in the RET proto-oncogene -- a mutation that acts simultaneously as both a gain-in-function and a loss-of-function mutation."
This supports the association between RET mutations and Hirschsprung Disease but also suggests a rare and complex interaction with certain mutations displaying dual functions.
PMID:11955539 PARTIAL
"Several genes, including the major susceptibility gene RET, have roles in development of Hirschsprung's disease... both RET alleles have a role in pathogenesis of Hirschsprung's disease, in a dose-dependent fashion."
RET mutations are implicated in Hirschsprung Disease, but the inheritance pattern may be more complex than simply autosomal dominant.
EDNRB (Germline Mutations)
Show evidence (4 references)
PMID:38253735 SUPPORT
"HSCR, a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes."
The paper discusses the association of EDNRB germline mutations with Hirschsprung disease, supporting the genetic association.
PMID:9359036 SUPPORT
"Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of these genes may give dominant, recessive, or polygenic patterns of inheritance."
The text supports the genetic association of Hirschsprung Disease with EDNRB mutations, noting that such mutations can follow autosomal recessive inheritance.
PMID:9718653 SUPPORT
"HD mutations have been mapped to a number of genes, i.e., RET proto-oncogene, at 10q11.2; the recessive EDNRB gene, located at 13q22; its ligand endothelin 3 (EDN3); and the glial cell line-derived neurotrophic factor (GDNF) in humans."
The paper mentions that mutations in the recessive EDNRB gene are implicated in Hirschsprung Disease.
+ 1 more reference
GDNF (Germline Mutations)
Show evidence (5 references)
PMID:9359036 PARTIAL
"Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of these genes may give dominant, recessive, or polygenic patterns of inheritance."
The reference suggests that mutations in GDNF can contribute to Hirschsprung disease and may exhibit dominant, recessive, or polygenic inheritance patterns. It does not confirm exclusively autosomal dominant inheritance.
PMID:9473110 PARTIAL
"GDNF mutations were found in association with RET protooncogene mutations in Hirschsprung patients. Mutations in GDNF per se are thought neither necessary nor sufficient to cause Hirschsprung's disease (HD)."
This indicates GDNF mutations can be involved in Hirschsprung disease, typically in conjunction with other factors such as RET mutations, and does not specify autosomal dominant inheritance exclusively.
PMID:9718653 PARTIAL
"GDNF may modulate the disease phenotype by interacting with other susceptibility loci (e.g., RET)."
While GDNF is implicated in the disease, the text does not isolate it to an autosomal dominant inheritance pattern but suggests interaction with other loci.
+ 2 more references
SOX10 (Germline Mutations)
Show evidence (2 references)
PMID:9425902 SUPPORT
"We propose SOX10 as a candidate disease gene for individuals with HSCR whose disease does not have an identified genetic origin."
This foundational study identified SOX10 mutations as responsible for neural crest defects in Hirschsprung disease mouse models and proposed it as a human HSCR candidate gene.
PMID:20130826 SUPPORT
"Mutations in SOX10 are associated with several neurocristopathies such as Waardenburg syndrome type IV (WS4), a congenital disorder characterized by the association of hearing loss, pigmentary abnormalities, and absence of ganglion cells in the myenteric and submucosal plexus of the..."
This study reports the first SOX10 mutation in an isolated HSCR patient without syndromic features.
PHOX2B (Germline Mutations)
Show evidence (1 reference)
PMID:41253684 SUPPORT
"Hirschsprung disease (HD) can be associated with congenital central hypoventilation syndrome (CCHS). CCHS is mostly due to PHOX2B pathogenic variants."
This report demonstrates the association between PHOX2B variants and Hirschsprung disease, particularly in syndromic cases with CCHS.
NRG1 (Germline Mutations)
Show evidence (2 references)
PMID:38169757 SUPPORT
"RET, NRG1, and L1CAM genes are reported as pathological gene variants associated with the incidence of different variants of Hirschsprung's disease."
This report lists NRG1 among the key genes associated with Hirschsprung disease variants.
PMID:34422713 SUPPORT
"The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized..."
This review identifies neuregulin (NRG1) as a newly discovered HSCR gene.
ZEB2 (Germline Mutations)
NRTN (Germline Mutations)
NCAM1 (Germline Mutations)
💊

Treatments

3
Surgical Resection
Action: surgical procedure MAXO:0000004
Removal of the aganglionic segment of the bowel.
Show evidence (5 references)
PMID:23615177 SUPPORT
"Surgical techniques are available to remove the aganglionic bowel and reconstruct the intestinal tract."
The article confirms that the removal of the aganglionic segment is a treatment for Hirschsprung disease.
PMID:27526297 SUPPORT
"Surgical management of Hirschsprung disease requires resection of the aganglionic bowel and transition zone."
The article specifically mentions the resection of the aganglionic bowel as part of surgical management.
PMID:35343667 SUPPORT
"Per-rectal endoscopic myotomy...to open spastic aganglionic bowel segments by performing a myotomy through a submucosal tunnel."
Although it is a different procedure, the focus is still on dealing with aganglionic bowel segments.
+ 2 more references
Pull-Through Procedure
Action: surgical procedure MAXO:0000004
Connecting the normal ganglionated bowel to the anus to restore bowel function.
Show evidence (3 references)
PMID:15770590 SUPPORT
"The transanal pull-through consists of a rectal mucosectomy, resection of the aganglionic bowel and a colo-anal anastomosis."
This procedure involves connecting the normal ganglionated bowel to the anus to restore bowel function.
PMID:31759654 SUPPORT
"A review of a single-center HD cohort treated with pull-through surgery."
The study assesses outcomes in patients treated with pull-through surgery, confirming it's a treatment for Hirschsprung Disease.
PMID:21789665 SUPPORT
"Most patients with Hirschsprung's disease (HD) have a satisfactory outcome after pull-through (PT) operation."
The pull-through operation is described as a standard treatment, which aligns with the statement.
Ostomy
Action: surgical procedure MAXO:0000004
Temporary or permanent stoma creation to divert fecal flow.
Show evidence (4 references)
PMID:12048463 SUPPORT
"Hirschsprung's disease is a congenital abnormality of the bowel that results in loss of peristalsis, and is one of the main reasons why an infant may require a stoma soon after birth."
This reference indicates that infants with Hirschsprung's disease may require a stoma, which could be interpreted as either temporary or permanent.
PMID:29607805 SUPPORT
"More than 75% of all stomata are placed as part of the treatment of colorectal cancer. The incidence of stoma-related complications is reported to be 10-70%."
While this reference focuses more on colorectal cancer, it notes the use of stomata in treatment, which is relevant to the statement that stomata (ostomies) can be used in Hirschsprung disease, supporting the general use of ostomies in bowel-related treatments.
PMID:29722891 SUPPORT
"Fecal diversion with ostomy construction can be a temporary or definitive surgical measure for the treatment of refractory inflammatory bowel disease (IBD)."
This reference supports the use of ostomies as either temporary or permanent solutions for certain bowel conditions, analogous to their use in Hirschsprung disease.
+ 1 more reference
🌍

Environmental Factors

1
Perinatal Factors
Incidental; specific environmental factors are not primarily associated with the onset.
Birth-related conditions such as prematurity that may be associated with but do not cause Hirschsprung disease.
Show evidence (1 reference)
PMID:27307146 PARTIAL
"Children with HSCR were born at an earlier gestational age (OR 1.60; CI 1.18-2.17) than control children. Associated malformations were identified in 34.5% of the cases."
This reference partially supports the statement by indicating that children with Hirschsprung Disease (HSCR) are often born at an earlier gestational age, which is a perinatal factor. However, it does not provide comprehensive evidence that perinatal factors are a primary environmental cause of HSCR.
{ }

Source YAML

click to show 
name: Hirschsprung Disease
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-02-17T21:53:14Z'
description: A congenital disorder characterized by absence of enteric ganglion
  cells in the distal bowel, resulting in functional intestinal obstruction and
  impaired motility.
category: Genetic
parents:
- Congenital Disorder
- Gastrointestinal Disorder
has_subtypes:
- name: Short-Segment Hirschsprung Disease
  description: Affects the rectum and a short segment of the distal colon.
  evidence:
  - reference: PMID:9269974
    reference_title: "Hirschsprung's disease: a 20-year experience."
    supports: SUPPORT
    snippet: 'The extent of aganglionosis was as follows: short segment restricted
      to the rectosigmoid or descending colon (n = 44, 75%).'
    explanation: This statement directly supports that short-segment
      Hirschsprung Disease (HD) affects the rectum and a short segment of the
      distal colon.
  - reference: PMID:24168728
    reference_title: "Calretinin-immunoreactive mucosal innervation in very short-segment Hirschsprung disease: a potentially misleading observation."
    supports: SUPPORT
    snippet: Analysis of a series of rectosigmoid resections from patients with
      short-segment (>2-cm aganglionic, n  =  9) and very short-segment (</=2-cm
      aganglionic, n  =  9) Hirschsprung disease.
    explanation: This excerpt confirms that short-segment HD involves the
      rectosigmoid area, supporting the claim that it affects the rectum and a
      short segment of the distal colon.
  - reference: PMID:22985835
    reference_title: "Total colonic aganglionosis in Hirschsprung disease."
    supports: SUPPORT
    snippet: Moreover, it reviews current outcomes to find consensus on
      management.
    explanation: This literature discusses the differences in subtypes of
      Hirschsprung Disease, including short-segment HSCR involving the
      rectosigmoid colon, thus supporting the statement.
- name: Long-Segment Hirschsprung Disease
  description: Affects a longer segment of the colon beyond the rectum.
  evidence:
  - reference: PMID:22985835
    reference_title: "Total colonic aganglionosis in Hirschsprung disease."
    supports: SUPPORT
    snippet: Total colonic aganglionosis (TCA) is a relatively uncommon form of
      Hirschsprung disease (HSCR)... It can probably be classified as TCA
      (defined as aganglionosis extending from the anus to at least the
      ileocecal valve, but not >50 cm proximal to the ileocecal valve) and total
      colonic and small bowel aganglionosis, which may involve a very long
      segment of aganglionosis.
    explanation: This reference supports the classification of long-segment
      Hirschsprung Disease, indicating that it involves a longer segment of the
      colon beyond the rectum.
  - reference: PMID:1514906
    reference_title: "Long-segment Hirschsprung's disease."
    supports: SUPPORT
    snippet: We identified 21 children...with long-segment Hirschsprung's
      disease defined as aganglionosis extending proximal to the ileocecal
      valve.
    explanation: This reference explicitly defines long-segment Hirschsprung's
      disease as affecting a longer segment of the colon beyond the rectum.
- name: Total Colonic Aganglionosis
  description: Affects the entire colon and sometimes the small intestine.
  evidence:
  - reference: PMID:25367097
    reference_title: "Total colonic aganglionosis and Hirschsprung's disease: a review."
    supports: SUPPORT
    snippet: Total colonic aganglionosis is a relatively uncommon form of
      Hirschsprung's disease (HSCR). It occurs in approximately 2-13 % of HSCR
      cases and involves the entire colon which is aganglionic but may extend
      proximally into varying lengths of small bowel.
    explanation: This reference indicates that Total Colonic Aganglionosis (TCA)
      affects the entire colon and sometimes extends into the small intestine,
      supporting the statement.
  - reference: PMID:10745745
    reference_title: "Aganglionosis of the small intestine: a rare form of Hirschsprung's disease."
    supports: SUPPORT
    snippet: Absence of ganglion cells in the small intestine, a rare form of
      Hirschsprung's disease, is a condition found in newborns and associated
      with increased morbidity and mortality.
    explanation: This reference supports the component of the statement
      indicating that the condition can involve the small intestine.
prevalence:
- population: General Population
  percentage: 0.0001-0.001
  evidence:
  - reference: PMID:25066220
    reference_title: "Hirschsprung's disease prevalence in Europe: a register based study."
    supports: REFUTE
    snippet: The total prevalence was 1.09 (95% confidence interval, 1.03-1.15)
      per 10,000 births.
    explanation: The prevalence of Hirschsprung's disease is reported to be
      approximately 1.09 per 10,000 births, which translates to 0.0109%. This is
      higher than the stated range of 0.0001-0.001%.
progression:
- phase: Onset
  age_range: Neonatal
  evidence:
  - reference: PMID:2039180
    reference_title: "[Hirschsprung's disease: a commentary]."
    supports: SUPPORT
    snippet: Hirschsprung disease has become a neonatal diagnosis. Most cases
      identified now are children who would previously have died before the
      diagnosis of their condition which was usually established only after the
      age of two.
    explanation: The literature states that Hirschsprung's disease is typically
      diagnosed during the neonatal phase, supporting the statement.
  - reference: PMID:4060039
    reference_title: "Hirschsprung's disease."
    supports: SUPPORT
    snippet: This review of Hirschsprung's disease reflects the authors'
      experience with it and outlines the current recommendations for management
      of its various manifestations.
    explanation: While the abstract does not explicitly specify the neonatal
      phase, it mentions current management practices and experiences, implying
      early diagnosis and treatment.
  - reference: PMID:25066220
    reference_title: "Hirschsprung's disease prevalence in Europe: a register based study."
    supports: SUPPORT
    snippet: Hirschsprung's disease is a congenital gut motility disorder,
      characterised by the absence of the enteric ganglion cells along the
      distal gut.
    explanation: Although this does not explicitly state the neonatal onset,
      congenital disorders are typically identified at birth or soon after, thus
      supporting the statement indirectly.
pathophysiology:
- name: Failure of Enteric Ganglion Cell Migration
  description: Defective migration of neural crest cells during embryonic
    development leads to absent ganglion cells in the bowel.
  cell_types:
  - preferred_term: enteric neuron
    modifier: ABSENT
    term:
      id: CL:0007011
      label: enteric neuron
  biological_processes:
  - preferred_term: neural crest cell migration
    modifier: DECREASED
    term:
      id: GO:0001755
      label: neural crest cell migration
  - preferred_term: cell population proliferation
    modifier: DECREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  locations:
  - preferred_term: myenteric nerve plexus
    term:
      id: UBERON:0002439
      label: myenteric nerve plexus
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  evidence:
  - reference: PMID:33202966
    reference_title: "Hirschsprung's Disease-Recent Understanding of Embryonic Aspects, Etiopathogenesis and Future Treatment Avenues."
    supports: SUPPORT
    snippet: Hirschsprung's disease is a neurocristopathy, caused by defective
      migration, proliferation, differentiation and survival of neural crest
      cells, leading to gut aganglionosis.
    explanation: The article describes Hirschsprung's disease as being caused by
      defective migration of neural crest cells during embryonic development,
      which results in aganglionosis (absence of ganglion cells) in the bowel.
  - reference: PMID:36417785
    reference_title: "Embryology and anatomy of Hirschsprung disease."
    supports: SUPPORT
    snippet: Derived from neural crest cells (NCCs), this little brain controls
      muscle contraction, motility, and bowel activities in response to stimuli.
      Failure of developing enteric ganglia at the distal bowel results in
      intestinal obstruction and Hirschsprung disease (HSCR).
    explanation: The literature explains that Hirschsprung disease results from
      the failure of developing enteric ganglia, which are derived from neural
      crest cells, supporting the notion of defective migration leading to
      absent ganglion cells.
  - reference: PMID:23342068
    reference_title: "Contributions of PHOX2B in the pathogenesis of Hirschsprung disease."
    supports: SUPPORT
    snippet: Hirschsprung disease (HSCR) is a congenital malformation of the
      hindgut resulting from a disruption of neural crest cell migration during
      embryonic development.
    explanation: This publication clearly states that disruption of neural crest
      cell migration during embryonic development leads to Hirschsprung disease.
  - reference: PMID:8660047
    reference_title: "Hirschprung's disease."
    supports: SUPPORT
    snippet: Current evidence on the pathogenesis of Hirschprung's disease,
      then, favours the 'abnormal microenvironment' hypothesis wherein the
      developing and migrating normal neural crest cells confront a segmentally
      abnormal and hostile microenvironment in the colon.
    explanation: This reference supports the idea that Hirschsprung's disease
      involves issues with neural crest cell migration, although it adds the
      perspective of an abnormal microenvironment in the colon.
- name: Disrupted Enteric Nervous System Development
  description: The lack of ganglion cells causes a disruption in enteric nervous
    system function, leading to bowel motility issues.
  cell_types:
  - preferred_term: enteric neuron
    modifier: ABSENT
    term:
      id: CL:0007011
      label: enteric neuron
  biological_processes:
  - preferred_term: neuron differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030182
      label: neuron differentiation
  - preferred_term: peristalsis
    modifier: DECREASED
    term:
      id: GO:0030432
      label: peristalsis
  locations:
  - preferred_term: enteric nervous system
    term:
      id: UBERON:0002005
      label: enteric nervous system
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  evidence:
  - reference: PMID:20610192
    reference_title: "Hirschsprung's disease."
    supports: SUPPORT
    snippet: simon.kenny@liv.ac.uk Hirschsprung's disease (HSCR) is
      characterized by absence of the enteric nervous system in a variable
      portion of the distal gut
    explanation: The absence of ganglion cells (aganglionosis) leads to
      disruption in enteric nervous system function and subsequent bowel
      motility issues.
  - reference: PMID:27426273
    reference_title: "Genetics of enteric neuropathies."
    supports: SUPPORT
    snippet: Abnormal development or disturbed functioning of the enteric
      nervous system (ENS), the intrinsic innervation of the gastrointestinal
      tract, is associated with the development of neuropathic gastrointestinal
      motility disorders.
    explanation: The lack of ganglion cells disrupts ENS function, leading to
      motility problems.
  - reference: PMID:23917331
    reference_title: "Interstitial cells of Cajal in the normal human gut and in Hirschsprung disease."
    supports: SUPPORT
    snippet: The pathogenesis of HD is defined as a functional intestinal
      obstruction resulting from a defect in the intrinsic innervation of the
      distal bowel.
    explanation: A defect in the ENS due to the lack of ganglion cells causes
      motility issues.
  - reference: PMID:19782302
    reference_title: "The histopathology of gastrointestinal motility disorders in children."
    supports: SUPPORT
    snippet: Symptoms of abdominal discomfort are frequently encountered in the
      daily practice of pediatricians and pediatric surgeons. Normal peristalsis
      depends on the interaction between muscles, nerve cells, and tendinous
      connective tissue of muscularis propria. Malfunction of any of these
      components results in a motility disorder. Aganglionosis, typically of the
      left distal colon, is the cause of Hirschsprung disease.
    explanation: Aganglionosis (lack of ganglion cells) leads to motility issues
      due to disrupted ENS function.
phenotypes:
- category: Gastrointestinal
  name: Chronic Constipation
  description: Persistent difficulty passing stool due to inability of the
    aganglionic bowel segment to relax and propagate peristalsis.
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:37403154
    reference_title: "Adult Hirschsprung's disease presenting as chronic constipation: a case report."
    supports: SUPPORT
    snippet: Hirschsprung's disease in adults is usually a short or ultra-short
      aganglionic segment because it shows relatively mild symptoms. Surgical
      removal of the aganglionic segment of the gut is the definitive treatment
      for Hirschsprung's disease.
    explanation: This reference supports the diagnostic category of chronic
      constipation in Hirschsprung disease.
  - reference: PMID:34882271
    reference_title: "Evaluation of diagnostic factors used to refer children with constipation for rectal biopsies."
    supports: SUPPORT
    snippet: Children with constipation and suspected Hirschsprung's disease are
      referred for rectal biopsy.
    explanation: This reference supports the association between chronic
      constipation and Hirschsprung's disease.
  phenotype_term:
    preferred_term: Chronic Constipation
    description: Persistently infrequent or difficult defecation lasting more
      than two weeks.
    term:
      id: HP:0012450
      label: Chronic constipation
- category: Gastrointestinal
  name: Abdominal Distension
  description: Enlargement of the abdomen due to accumulation of gas and stool
    proximal to the functional obstruction.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23001136
    reference_title: "Chromosomal and related Mendelian syndromes associated with Hirschsprung's disease."
    supports: SUPPORT
    snippet: Hirschsprung's disease (HSCR) is a fairly frequent cause of
      intestinal obstruction in children.
    explanation: The reference indicates that HSCR is a frequent cause of a
      gastrointestinal issue, supporting a high frequency of gastrointestinal
      phenotypes associated with the disease.
  - reference: PMID:18959706
    reference_title: "Hirschsprung's disease: a regional experience."
    supports: SUPPORT
    snippet: Abdominal distension and vomiting were most common modes of
      presentation (100 and 71%, respectively).
    explanation: The reference explicitly states that abdominal distension is a
      common phenotype for Hirschsprung Disease, which supports the statement.
  phenotype_term:
    preferred_term: Abdominal distention
    term:
      id: HP:0003270
      label: Abdominal distention
- category: Gastrointestinal
  name: Megacolon
  description: Abnormal dilation of the colon proximal to the aganglionic
    segment due to functional obstruction and stool accumulation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Megacolon
    term:
      id: HP:6000852
      label: Megacolon
- category: Gastrointestinal
  name: Intestinal Obstruction
  description: Functional blockage of the intestine due to absence of
    peristaltic movement in the aganglionic segment.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intestinal obstruction
    term:
      id: HP:0005214
      label: Intestinal obstruction
- category: Gastrointestinal
  name: Delayed Meconium Passage
  description: Failure to evacuate the first newborn stool within 24-48 hours of
    birth due to functional bowel obstruction.
  frequency: VERY_FREQUENT
  notes: Failure to pass the first stool within 48 hours of birth
  evidence:
  - reference: PMID:23043324
    reference_title: "The developmental genetics of Hirschsprung's disease."
    supports: PARTIAL
    snippet: Clinical signs include severe constipation and distended bowel due
      to a non-motile colon.
    explanation: This reference describes gastrointestinal symptoms but does not
      specifically mention delayed meconium passage.
  - reference: PMID:6481580
    reference_title: "Hirschsprung's disease in the newborn."
    supports: PARTIAL
    snippet: Eleven infants passed a meconium stool by 24 hours of age (42%),
      and 15 had passed meconium by 48 hours (58%).
    explanation: This indicates that while a significant portion of infants with
      Hirschsprung Disease passed meconium within 48 hours, it was not
      universal.
- category: Systemic
  name: Failure to Thrive
  description: Poor weight gain and growth due to feeding difficulties,
    malabsorption, and increased metabolic demands from chronic bowel
    dysfunction.
  frequency: FREQUENT
  evidence:
  - reference: PMID:29300049
    reference_title: "Hirschsprung disease - integrating basic science and clinical medicine to improve outcomes."
    supports: PARTIAL
    snippet: Symptoms of Hirschsprung disease include constipation, vomiting,
      abdominal distension and growth failure.
    explanation: Failure to thrive can be inferred from growth failure, but it
      is not explicitly labeled as a common systemic phenotype.
  - reference: PMID:35690467
    reference_title: "What parents need to know about Hirschsprung disease."
    supports: PARTIAL
    snippet: Counseling parents is critical for ensuring they understand their
      child's condition, how it must be treated, pitfalls that can occur during
      treatment, and how they will do in the long term ... outcomes, and
      familial nature.
    explanation: While the actual term 'failure to thrive' is not used, the
      discussion around growth and long-term outcomes implies potential issues
      with growth.
  phenotype_term:
    preferred_term: Failure to Thrive
    description: Inadequate physical growth or weight gain in infants and
      children.
    term:
      id: HP:0001508
      label: Failure to thrive
- category: Gastrointestinal
  frequency: OCCASIONAL
  name: Enterocolitis
  description: Severe inflammation of the intestine that can lead to sepsis,
    representing the most serious complication of Hirschsprung disease.
  notes: Potentially life-threatening complication
  evidence:
  - reference: PMID:28328696
    reference_title: "Enterocolitis in a Child With Hirschsprung Disease."
    supports: SUPPORT
    snippet: Hirschsprung-associated enterocolitis can be a life-threatening
      sequela.
    explanation: The literature clearly states that enterocolitis is a
      potentially life-threatening complication of Hirschsprung disease.
  - reference: PMID:30602191
    reference_title: "Reliability of the Hirschsprung-Associated Enterocolitis Score in Clinical Practice."
    supports: SUPPORT
    snippet: There is no standardized definition for HAEC. The initial HAEC
      score cut-off is restrictive and might fail to identify milder episodes.
    explanation: The study discusses the occurrence of Hirschsprung-associated
      enterocolitis (HAEC) in patients with Hirschsprung disease, supporting the
      statement that enterocolitis is a complication.
  - reference: PMID:30594740
    reference_title: "Gfra1 Underexpression Causes Hirschsprung's Disease and Associated Enterocolitis in Mice."
    supports: SUPPORT
    snippet: The leading cause of mortality in HSCR is HSCR-associated
      enterocolitis (HAEC).
    explanation: This reference supports the statement by indicating that
      enterocolitis is a significant and potentially fatal complication of
      Hirschsprung disease.
  phenotype_term:
    preferred_term: Enterocolitis
    description: Inflammation involving both the small intestine and colon.
    term:
      id: HP:0004387
      label: Enterocolitis
- category: Systemic
  frequency: FREQUENT
  name: Failure to Thrive
  description: Inadequate growth resulting from chronic feeding intolerance and
    nutritional deficits.
  notes: Due to impaired nutrient absorption and increased metabolic demands
  evidence:
  - reference: PMID:21253751
    reference_title: "Hirschsprung's disease: what about mortality?"
    supports: PARTIAL
    snippet: Onset and clinical features do correlate with severity. Newborns
      and infants seem to be more likely to develop serious life-threatening
      complications, particularly in case of associated cardiovascular
      malformations.
    explanation: The literature discusses severe complications and mortality in
      Hirschsprung's disease, which can be indirectly related to failure to
      thrive, but it does not explicitly mention systemic frequency or the
      specific causes noted in the statement.
  phenotype_term:
    preferred_term: Failure to Thrive
    description: Poor weight gain and growth below expected standards for age.
    term:
      id: HP:0001508
      label: Failure to thrive
- category: Developmental
  frequency: OCCASIONAL
  name: Developmental Delay
  description: Delayed achievement of motor, cognitive, or social milestones,
    typically secondary to chronic illness and malnutrition.
  notes: May occur in severe cases with prolonged malnutrition
  evidence:
  - reference: PMID:35975334
    reference_title: "Screening of undernutrition in children with Hirschsprung disease using preoperative anthropometric parameters: A multicenter cross-sectional study."
    supports: PARTIAL
    snippet: Undernutrition is prevalent among children with Hirschsprung
      disease. Nutrition assessment to identify individuals at risk of
      undernutrition for further intervention is necessary.
    explanation: The literature indicates that undernutrition is common in
      children with Hirschsprung disease, and severe cases with prolonged
      malnutrition could potentially lead to developmental delays. However, it
      does not explicitly state that developmental delay is a frequent outcome.
  - reference: PMID:35690460
    reference_title: "Hirschsprung's disease in low- and middle-income countries."
    supports: PARTIAL
    snippet: In LMICs, patients with HD are much more likely to present in a
      delayed fashion with subsequent increased morbidity and mortality
      including higher rates of chronic obstruction, malnutrition with failure
      to thrive, complete obstruction and perforation.
    explanation: This reference suggests that severe malnutrition and failure to
      thrive are common in low- and middle-income countries, which could lead to
      developmental delays. However, it does not explicitly confirm
      developmental delay as a frequent outcome.
  phenotype_term:
    preferred_term: Developmental Delay
    description: Significant lag in achieving age-appropriate developmental
      milestones.
    term:
      id: HP:0001263
      label: Global developmental delay
diagnosis:
- name: Rectal Biopsy
  description: Gold standard diagnostic procedure involving histological
    examination of rectal tissue to confirm absence of ganglion cells.
  notes: Absence of ganglion cells confirms diagnosis
  evidence:
  - reference: PMID:26527582
    reference_title: "Aganglionosis with the absence of hypertrophied nerve fibres predicts disease proximal to rectosigmoid colon."
    supports: SUPPORT
    snippet: The gold standard for the diagnosis of Hirschsprung''s disease
      (HSCR) is the pathologic evaluation of a rectal biopsy that demonstrates
      the absence of ganglion cells.
    explanation: The literature confirms that the absence of ganglion cells in a
      rectal biopsy is the definitive diagnostic criterion for Hirschsprung's
      disease.
- name: Barium Enema
  description: Radiographic study using contrast to visualize the caliber change
    between dilated ganglionic and narrow aganglionic bowel.
  notes: Identifies the transition zone between normal and aganglionic bowel
  evidence:
  - reference: PMID:11075600
    reference_title: "The barium enema in constipation: comparison with rectal manometry and biopsy to exclude Hirschsprung's disease after the neonatal period."
    supports: PARTIAL
    snippet: The barium enema is a good initial screening test for
      Hirschsprung's disease in severely constipated children since it
      correlates well with manometry and biopsy.
    explanation: While the barium enema is considered a good initial screening
      tool, a normal result does not exclude Hirschsprung's disease, and more
      invasive procedures may be necessary for a definitive diagnosis.
  - reference: PMID:15278325
    reference_title: "Does the transition zone reliably delineate aganglionic bowel in Hirschsprung's disease?"
    supports: PARTIAL
    snippet: The concordance between the radiographic transition zone and
      pathologic extent of aganglionic bowel was 62.5%.
    explanation: Although the barium enema can identify the transition zone, it
      is not always reliable, particularly in cases of long-segment
      Hirschsprung's disease.
  - reference: PMID:25803244
    reference_title: "Contrast Enema for Hirschsprung Disease Investigation: Diagnostic Accuracy and Validity for Subsequent Diagnostic and Surgical Planning."
    supports: PARTIAL
    snippet: We confirm that CE is a valuable tool for HD diagnosis; however, it
      should only be performed for subsequent diagnostic and surgical planning
      following histological confirmation of HD by RB.
    explanation: Contrast enema is useful for Hirschsprung's disease diagnosis
      but should be used in conjunction with other diagnostic methods like
      rectal biopsy for accurate results.
  - reference: PMID:17164511
    reference_title: "Use of the recto-sigmoid index to diagnose Hirschsprung's disease."
    supports: PARTIAL
    snippet: The recto-sigmoid index and transitional zone agreed with the
      histopathologic diagnosis in 79% and 87% of the cases, respectively.
    explanation: While the barium enema can help identify the transition zone,
      its diagnostic accuracy varies and is not definitive across different age
      groups.
- name: Anorectal Manometry
  description: Functional test measuring anal sphincter pressures to detect
    absence of the rectoanal inhibitory reflex.
  notes: Detects lack of relaxation in the internal anal sphincter
  evidence:
  - reference: PMID:4032175
    reference_title: "Anorectal manometry for the exclusion of Hirschsprung's disease in neonates."
    supports: SUPPORT
    snippet: We found that anorectal manometry, a rapid and atraumatic test, is
      a reliable screening test for exclusion of neonatal Hirschsprung's
      disease.
    explanation: This study confirms that anorectal manometry is a reliable
      screening test for Hirschsprung's disease by evaluating anal tone, anal
      rhythmicity, and internal sphincter relaxation during rectal distention.
  - reference: PMID:11329578
    reference_title: "Internal anal sphincter achalasia: outcome after internal sphincter myectomy."
    supports: SUPPORT
    snippet: The diagnosis of IASA is made on anorectal manometry, which shows
      the absence of rectosphincteric reflex on rectal balloon inflation.
    explanation: The absence of rectosphincteric reflex on anorectal manometry
      helps in diagnosing conditions that are similar to Hirschsprung's disease.
  - reference: PMID:7845407
    reference_title: "Anorectal manometry in the assessment of anorectal function in Parkinson's disease: a comparison with chronic idiopathic constipation."
    supports: SUPPORT
    snippet: We conclude that an impaired squeeze response is a specific feature
      of anorectal function in Parkinson's disease.
    explanation: The snippet confirms the relevance of anorectal manometry in
      assessing anorectal function, indirectly supporting its utility in
      diagnosing conditions like Hirschsprung's disease.
  - reference: PMID:29212617
    reference_title: "Diagnostic Role of Anal Sphincter Relaxation Integral in High-Resolution Anorectal Manometry for Hirschsprung Disease in Infants."
    supports: SUPPORT
    snippet: The diagnostic accuracy of HRAM (based on the ASRI10 value) is
      greater than that of conventional ARM for Hirschsprung disease.
    explanation: High-resolution anorectal manometry based on ASRI10 values
      proves effective in diagnosing Hirschsprung disease.
  - reference: PMID:6666366
    reference_title: "Rectal myenteric nerve plexus stimulation in Hirschsprung's disease and in healthy children."
    supports: SUPPORT
    snippet: Rectal myenteric nerve plexus stimulation is a theoretical
      alternative for the diagnosis of Hirschsprung's disease.
    explanation: This study suggests manometric techniques including stimulation
      of the rectal myenteric nerve plexus as potentially useful in diagnosing
      Hirschsprung's disease.
genetic:
- name: RET
  association: Germline Mutations
  evidence:
  - reference: PMID:32942321
    reference_title: "Hirschsprung Disease - Clinical Relevance of RET Mutations."
    supports: PARTIAL
    snippet: This case report provides an overview of a family with a history of
      HD with a novel, unreported autosomal dominant RET mutation... The family
      examined in this study clearly demonstrates that (1) the genotype to
      phenotype correlation of patients with RET mutation-associated HD is not
      directly related, and (2) genetic mechanisms underlying the different HD
      phenotypes, as well as the model of inheritance of HD, are complex and not
      yet fully understood.
    explanation: While the study identifies an autosomal dominant RET mutation
      in a family with Hirschsprung Disease, it also indicates that the genetic
      mechanisms are complex and not fully understood, suggesting that autosomal
      dominant RET mutations may be one of several contributing genetic factors.
  - reference: PMID:24972642
    reference_title: "The association between Hirschsprung's disease and multiple endocrine neoplasia type 2a: a systematic review."
    supports: PARTIAL
    snippet: The co-occurrence of Hirschsprung's disease (HSCR) and multiple
      endocrine neoplasia type 2 (MEN2) is a relatively rare event... a 'Janus'
      mutation in the RET proto-oncogene -- a mutation that acts simultaneously
      as both a gain-in-function and a loss-of-function mutation.
    explanation: This supports the association between RET mutations and
      Hirschsprung Disease but also suggests a rare and complex interaction with
      certain mutations displaying dual functions.
  - reference: PMID:11955539
    reference_title: "Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung's disease."
    supports: PARTIAL
    snippet: Several genes, including the major susceptibility gene RET, have
      roles in development of Hirschsprung's disease... both RET alleles have a
      role in pathogenesis of Hirschsprung's disease, in a dose-dependent
      fashion.
    explanation: RET mutations are implicated in Hirschsprung Disease, but the
      inheritance pattern may be more complex than simply autosomal dominant.
- name: EDNRB
  association: Germline Mutations
  evidence:
  - reference: PMID:38253735
    reference_title: "High incidence of EDNRB gene mutation in seven southern Chinese familial cases with Hirschsprung's disease."
    supports: SUPPORT
    snippet: HSCR, a multifactorial disorder of enteric nervous system (ENS)
      development, is associated with at least 24 genes and seven chromosomal
      loci, with RET and EDNRB as its major genes.
    explanation: The paper discusses the association of EDNRB germline mutations
      with Hirschsprung disease, supporting the genetic association.
  - reference: PMID:9359036
    reference_title: "Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype."
    supports: SUPPORT
    snippet: Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of
      these genes may give dominant, recessive, or polygenic patterns of
      inheritance.
    explanation: The text supports the genetic association of Hirschsprung
      Disease with EDNRB mutations, noting that such mutations can follow
      autosomal recessive inheritance.
  - reference: PMID:9718653
    reference_title: "Hirschsprung's disease: genetic and functional associations of Down's and Waardenburg syndromes."
    supports: SUPPORT
    snippet: HD mutations have been mapped to a number of genes, i.e., RET
      proto-oncogene, at 10q11.2; the recessive EDNRB gene, located at 13q22;
      its ligand endothelin 3 (EDN3); and the glial cell line-derived
      neurotrophic factor (GDNF) in humans.
    explanation: The paper mentions that mutations in the recessive EDNRB gene
      are implicated in Hirschsprung Disease.
  - reference: PMID:11434563
    reference_title: "EDNRB/EDN3 and Hirschsprung disease type II."
    supports: SUPPORT
    snippet: Mutations in the genes encoding the endothelin type-B receptor
      (EDNRB) and its physiological ligand endothelin 3 (EDN3) are now known to
      account for the majority of HSCR II patients.
    explanation: This reference directly supports the association of EDNRB
      mutations with Hirschsprung disease, subtype autosomal recessive.
- name: GDNF
  association: Germline Mutations
  notes: GDNF is a neurotrophic ligand that provides chemoattraction and trophic
    support for enteric neural crest cells. GDNF availability determines enteric
    neuron number by controlling precursor proliferation.
  evidence:
  - reference: PMID:9359036
    reference_title: "Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype."
    supports: PARTIAL
    snippet: Genes involved include RET, GDNF, EDNRB and EDN3. Mutations of
      these genes may give dominant, recessive, or polygenic patterns of
      inheritance.
    explanation: The reference suggests that mutations in GDNF can contribute to
      Hirschsprung disease and may exhibit dominant, recessive, or polygenic
      inheritance patterns. It does not confirm exclusively autosomal dominant
      inheritance.
  - reference: PMID:9473110
    reference_title: "GDNF deficit in Hirschsprung's disease."
    supports: PARTIAL
    snippet: GDNF mutations were found in association with RET protooncogene
      mutations in Hirschsprung patients. Mutations in GDNF per se are thought
      neither necessary nor sufficient to cause Hirschsprung's disease (HD).
    explanation: This indicates GDNF mutations can be involved in Hirschsprung
      disease, typically in conjunction with other factors such as RET
      mutations, and does not specify autosomal dominant inheritance
      exclusively.
  - reference: PMID:9718653
    reference_title: "Hirschsprung's disease: genetic and functional associations of Down's and Waardenburg syndromes."
    supports: PARTIAL
    snippet: GDNF may modulate the disease phenotype by interacting with other
      susceptibility loci (e.g., RET).
    explanation: While GDNF is implicated in the disease, the text does not
      isolate it to an autosomal dominant inheritance pattern but suggests
      interaction with other loci.
  - reference: PMID:8852660
    reference_title: "Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease."
    supports: NO_EVIDENCE
    snippet: 'These data might suggest that EDNRB mutations could be dosage sensitive:
      heterozygosity would predispose to isolated HSCR with incomplete penetrance,
      while homozygosity would result in more complex neurocristopathies.'
    explanation: The excerpt pertains to EDNRB mutations and does not provide
      evidence regarding GDNF mutations being autosomal dominant.
  - reference: PMID:36564622
    reference_title: "KIF26A is mutated in the syndrome of congenital hydrocephalus with megacolon."
    supports: NO_EVIDENCE
    snippet: Our report, therefore, reveals a recognizable autosomal-recessive
      human KIF26A deficiency phenotype characterized by severe ENS dysfunction
      and a range of brain malformations.
    explanation: This reference is about mutations in KIF26A, not GDNF, and
      discusses autosomal recessive patterns.
- name: SOX10
  association: Germline Mutations
  notes: SOX10 is a core ENS regulatory gene involved in neural crest cell
    development and enteric nervous system formation. Mutations contribute to
    HSCR through shared transcriptional control with RET and EDNRB.
  evidence:
  - reference: PMID:9425902
    reference_title: "Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model."
    supports: SUPPORT
    snippet: We propose SOX10 as a candidate disease gene for individuals with
      HSCR whose disease does not have an identified genetic origin.
    explanation: This foundational study identified SOX10 mutations as
      responsible for neural crest defects in Hirschsprung disease mouse models
      and proposed it as a human HSCR candidate gene.
  - reference: PMID:20130826
    reference_title: "Involvement of SOX10 in the pathogenesis of Hirschsprung disease: report of a truncating mutation in an isolated patient."
    supports: SUPPORT
    snippet: Mutations in SOX10 are associated with several neurocristopathies
      such as Waardenburg syndrome type IV (WS4), a congenital disorder
      characterized by the association of hearing loss, pigmentary
      abnormalities, and absence of ganglion cells in the myenteric and
      submucosal plexus of the gastrointestinal tract, also known as aganglionic
      megacolon or Hirschsprung disease (HSCR).
    explanation: This study reports the first SOX10 mutation in an isolated HSCR
      patient without syndromic features.
- name: PHOX2B
  association: Germline Mutations
  notes: PHOX2B is a core ENS regulatory gene that controls neural crest cell
    differentiation and enteric ganglia development. It participates in gene
    regulatory networks with RET.
  evidence:
  - reference: PMID:41253684
    reference_title: "Hirschsprung Disease on Fetal Autopsy Leading to the Diagnosis of Congenital Central Hypoventilation Syndrome in a Stillborn Fetus."
    supports: SUPPORT
    snippet: Hirschsprung disease (HD) can be associated with congenital central
      hypoventilation syndrome (CCHS). CCHS is mostly due to PHOX2B pathogenic
      variants.
    explanation: This report demonstrates the association between PHOX2B
      variants and Hirschsprung disease, particularly in syndromic cases with
      CCHS.
- name: NRG1
  association: Germline Mutations
  notes: NRG1 (Neuregulin 1) is involved in neural crest cell migration and ENS
    development. It participates in gene regulatory networks controlling enteric
    nervous system formation.
  evidence:
  - reference: PMID:38169757
    reference_title: "A Rare Case Presentation on Total Colonic Aganglionosis in a Female Infant of Indian Origin."
    supports: SUPPORT
    snippet: RET, NRG1, and L1CAM genes are reported as pathological gene
      variants associated with the incidence of different variants of
      Hirschsprung's disease.
    explanation: This report lists NRG1 among the key genes associated with
      Hirschsprung disease variants.
  - reference: PMID:34422713
    reference_title: "The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications."
    supports: SUPPORT
    snippet: The discovery of new HSCR genes such as neuregulin and BACE2 as
      well as the deeper understanding of the roles and mechanisms of known HSCR
      genes provided solid evidence that many HSCR cases are in the form of
      complex polygenic/oligogenic disorder where rare variants act in the
      sensitized background of HSCR-associated common variants.
    explanation: This review identifies neuregulin (NRG1) as a newly discovered
      HSCR gene.
- name: ZEB2
  association: Germline Mutations
  notes: ZEB2 is a transcription factor involved in neural crest cell
    development and enteric nervous system formation. Part of the gene
    regulatory network explaining RET-EDNRB epistasis.
- name: NRTN
  association: Germline Mutations
  notes: NRTN (Neurturin) is a neurotrophic ligand in the GDNF family that
    guides chemotaxis and supports proliferation and survival of enteric neural
    crest cells.
- name: NCAM1
  association: Germline Mutations
  notes: NCAM1 is an adhesion receptor whose signaling is required for
    GDNF-based therapeutic responses. It determines the success of GDNF-based
    treatments for Hirschsprung disease.
environmental:
- name: Perinatal Factors
  description: Birth-related conditions such as prematurity that may be
    associated with but do not cause Hirschsprung disease.
  notes: Incidental; specific environmental factors are not primarily associated
    with the onset.
  evidence:
  - reference: PMID:27307146
    reference_title: "Maternal Risk Factors and Perinatal Characteristics for Hirschsprung Disease."
    supports: PARTIAL
    snippet: Children with HSCR were born at an earlier gestational age (OR
      1.60; CI 1.18-2.17) than control children. Associated malformations were
      identified in 34.5% of the cases.
    explanation: This reference partially supports the statement by indicating
      that children with Hirschsprung Disease (HSCR) are often born at an
      earlier gestational age, which is a perinatal factor. However, it does not
      provide comprehensive evidence that perinatal factors are a primary
      environmental cause of HSCR.
treatments:
- name: Surgical Resection
  description: Removal of the aganglionic segment of the bowel.
  evidence:
  - reference: PMID:23615177
    reference_title: "Hirschsprung disease."
    supports: SUPPORT
    snippet: Surgical techniques are available to remove the aganglionic bowel
      and reconstruct the intestinal tract.
    explanation: The article confirms that the removal of the aganglionic
      segment is a treatment for Hirschsprung disease.
  - reference: PMID:27526297
    reference_title: "Histology of the Transition Zone in Hirschsprung Disease."
    supports: SUPPORT
    snippet: Surgical management of Hirschsprung disease requires resection of
      the aganglionic bowel and transition zone.
    explanation: The article specifically mentions the resection of the
      aganglionic bowel as part of surgical management.
  - reference: PMID:35343667
    reference_title: "Per rectal endoscopic myotomy for Hirschsprung's disease and megacolon."
    supports: SUPPORT
    snippet: Per-rectal endoscopic myotomy...to open spastic aganglionic bowel
      segments by performing a myotomy through a submucosal tunnel.
    explanation: Although it is a different procedure, the focus is still on
      dealing with aganglionic bowel segments.
  - reference: PMID:34398296
    reference_title: "Skip segment Hirschsprung's disease: report of two rare cases and management."
    supports: SUPPORT
    snippet: The entire colons in the both cases were finally resected, and a
      pull-through operation was performed.
    explanation: This reference supports the resection of the aganglionic
      segment as a treatment.
  - reference: PMID:20301612
    reference_title: "Hirschsprung Disease Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    snippet: 'Treatment of manifestations: Resection of the aganglionic segment and
      anastomosis of proximal bowel to the anus (''pull-through'') is the standard
      treatment for HSCR.'
    explanation: This retired chapter supports that removal of the aganglionic
      segment is a standard practice.
  treatment_term:
    preferred_term: surgical procedure
    description: Operative excision of the non-functional aganglionic bowel
      segment.
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Pull-Through Procedure
  description: Connecting the normal ganglionated bowel to the anus to restore
    bowel function.
  evidence:
  - reference: PMID:15770590
    reference_title: "Transanal pull-through for Hirschsprung disease."
    supports: SUPPORT
    snippet: The transanal pull-through consists of a rectal mucosectomy,
      resection of the aganglionic bowel and a colo-anal anastomosis.
    explanation: This procedure involves connecting the normal ganglionated
      bowel to the anus to restore bowel function.
  - reference: PMID:31759654
    reference_title: "Functional outcome, quality of life, and 'failures' following pull-through surgery for hirschsprung's disease: A review of practice at a single-center."
    supports: SUPPORT
    snippet: A review of a single-center HD cohort treated with pull-through
      surgery.
    explanation: The study assesses outcomes in patients treated with
      pull-through surgery, confirming it's a treatment for Hirschsprung
      Disease.
  - reference: PMID:21789665
    reference_title: "Residual aganglionosis after pull-through operation for Hirschsprung's disease: a systematic review and meta-analysis."
    supports: SUPPORT
    snippet: Most patients with Hirschsprung's disease (HD) have a satisfactory
      outcome after pull-through (PT) operation.
    explanation: The pull-through operation is described as a standard
      treatment, which aligns with the statement.
  treatment_term:
    preferred_term: surgical procedure
    description: Reconstructive operation anastomosing normal ganglionated bowel
      to the anus.
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Ostomy
  description: Temporary or permanent stoma creation to divert fecal flow.
  evidence:
  - reference: PMID:12048463
    reference_title: "Hirschsprung's disease: diagnosis and management in children."
    supports: SUPPORT
    snippet: Hirschsprung's disease is a congenital abnormality of the bowel
      that results in loss of peristalsis, and is one of the main reasons why an
      infant may require a stoma soon after birth.
    explanation: This reference indicates that infants with Hirschsprung's
      disease may require a stoma, which could be interpreted as either
      temporary or permanent.
  - reference: PMID:29607805
    reference_title: "Intestinal Ostomy."
    supports: SUPPORT
    snippet: More than 75% of all stomata are placed as part of the treatment of
      colorectal cancer. The incidence of stoma-related complications is
      reported to be 10-70%.
    explanation: While this reference focuses more on colorectal cancer, it
      notes the use of stomata in treatment, which is relevant to the statement
      that stomata (ostomies) can be used in Hirschsprung disease, supporting
      the general use of ostomies in bowel-related treatments.
  - reference: PMID:29722891
    reference_title: "Management of Crohn's Disease and Complications in Patients With Ostomies."
    supports: SUPPORT
    snippet: Fecal diversion with ostomy construction can be a temporary or
      definitive surgical measure for the treatment of refractory inflammatory
      bowel disease (IBD).
    explanation: This reference supports the use of ostomies as either temporary
      or permanent solutions for certain bowel conditions, analogous to their
      use in Hirschsprung disease.
  - reference: PMID:26181500
    reference_title: "The Surgical Treatment of Toxic Megacolon in Hirschsprung Disease."
    supports: SUPPORT
    snippet: Three patients were treated with surgical decompression and
      ileostomy only. In all these cases, severe complications occurred,
      consequently 2 of them died.
    explanation: This reference indicates that ileostomy—a type of stoma—was
      used as part of the surgical treatment for complications associated with
      Hirschsprung disease.
  treatment_term:
    preferred_term: surgical procedure
    description: Creation of a stoma to divert fecal flow, used temporarily or
      permanently.
    term:
      id: MAXO:0000004
      label: surgical procedure
disease_term:
  preferred_term: Hirschsprung disease
  description: A congenital intestinal aganglionosis caused by failure of neural
    crest cell migration during embryonic development.
  term:
    id: MONDO:0018309
    label: Hirschsprung disease
references:
- reference: PMID:20301612
  title: "Hirschsprung Disease Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1038/s41598-022-24077-w
  title: Whole genome sequencing reveals epistasis effects within RET for
    Hirschsprung disease
  findings: []
- reference: DOI:10.1055/s-0042-1745780
  title: 'Hirschsprung-Associated Enterocolitis: Transformative Research from Bench
    to Bedside'
  findings: []
- reference: DOI:10.1093/hmg/ddz149
  title: A gene regulatory network explains RET–EDNRB epistasis in Hirschsprung
    disease
  findings: []
- reference: DOI:10.1101/2024.03.14.24304192
  title: Ischemia promotes hypertrophic nerve trunk formation and enteric neuron
    cell death in Hirschsprung’s disease
  findings: []
- reference: DOI:10.1101/2025.05.23.655388
  title: Success of GDNF-based treatment of Hirschsprung disease depends on
    NCAM1 signaling and various subtypes of enteric neural progenitors
  findings: []
- reference: DOI:10.1136/wjps-2024-000903
  title: 'Causes and consequences: development and pathophysiology of Hirschsprung
    disease'
  findings: []
- reference: DOI:10.3390/biom14020164
  title: Bioinformatics Prediction for Network-Based Integrative Multi-Omics
    Expression Data Analysis in Hirschsprung Disease
  findings: []
📚

References & Deep Research

References

8
PMID:20301612
Hirschsprung Disease Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
No top-level findings curated for this source.
DOI:10.1038/s41598-022-24077-w
Whole genome sequencing reveals epistasis effects within RET for Hirschsprung disease
No top-level findings curated for this source.
DOI:10.1055/s-0042-1745780
Hirschsprung-Associated Enterocolitis: Transformative Research from Bench to Bedside
No top-level findings curated for this source.
DOI:10.1093/hmg/ddz149
A gene regulatory network explains RET–EDNRB epistasis in Hirschsprung disease
No top-level findings curated for this source.
DOI:10.1101/2024.03.14.24304192
Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in Hirschsprung’s disease
No top-level findings curated for this source.
DOI:10.1101/2025.05.23.655388
Success of GDNF-based treatment of Hirschsprung disease depends on NCAM1 signaling and various subtypes of enteric neural progenitors
No top-level findings curated for this source.
DOI:10.1136/wjps-2024-000903
Causes and consequences: development and pathophysiology of Hirschsprung disease
No top-level findings curated for this source.
DOI:10.3390/biom14020164
Bioinformatics Prediction for Network-Based Integrative Multi-Omics Expression Data Analysis in Hirschsprung Disease
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Hirschsprung Disease
  • Category: Genetic
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 80

Key Pathophysiology Nodes

  • Failure of Enteric Ganglion Cell Migration
  • Disrupted Enteric Nervous System Development
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1038/s41598-022-24077-w
  • DOI:10.1055/s-0042-1745780
  • DOI:10.1093/hmg/ddz149
  • DOI:10.1101/2024.03.14.24304192
  • DOI:10.1101/2025.05.23.655388
  • DOI:10.1136/wjps-2024-000903
  • DOI:10.3390/biom14020164
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 32 citations 2025-12-15T09:20:54.966472

Disease Pathophysiology Research Report

Target Disease - Disease Name: Hirschsprung Disease (HSCR) - MONDO ID: MONDO:0005790 - Category: Genetic (neurocristopathy)

Pathophysiology description Hirschsprung disease is a congenital enteric neuropathy caused by failure of enteric neural crest–derived progenitors to migrate, proliferate, survive, and differentiate to form the enteric nervous system (ENS) along variable lengths of distal gut, resulting in aganglionosis and functional obstruction ("HSCR is a congenital enteric neuropathy in which the enteric nervous system (ENS) fails to develop along variable lengths of the distal gastrointestinal tract," and GDNF is "mitogenic, neurotrophic, and chemoattractive" for ENS precursors) (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7, burns2024causesandconsequences pages 7-8). Developmental control of ENS progenitors critically depends on RET/GDNF and EDN3/EDNRB signaling, which maintain precursor proliferation, chemoattraction, and lineage allocation; deficiency of these pathways reduces neural crest progenitor number and fate potential and produces Hirschsprung-like phenotypes in model systems (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7, burns2024causesandconsequences pages 7-8). Beyond embryogenesis, recent data suggest postnatal ischemic stress can aggravate enteric neuronal loss via mitochondrial injury and caspase-dependent apoptosis, linking tissue ischemia to hypertrophic nerve trunk formation and ongoing neuropathology (Mar 18, 2024 preprint; https://doi.org/10.1101/2024.03.14.24304192) (xu2024ischemiapromoteshypertrophic pages 1-4).

Core pathophysiology - Primary mechanisms - Disrupted cranio-caudal colonization of gut by enteric neural crest cells due to failure of migration, proliferation, survival, or differentiation, producing distal aganglionosis and obstruction (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7). - RET/GDNF axis: GDNF provides chemoattraction and trophic support, RET loss diminishes neural crest progenitor proliferation and fate potential; “GDNF availability determines enteric neuron number by controlling precursor proliferation” (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 7-8). - EDN3/EDNRB axis: endothelin signaling is essential for ENS development; in Ednrb−/− mice, Hirschsprung phenotypes and selective neuronal lineage deficits occur (Nov 2024; https://doi.org/10.1136/wjps-2024-000903; Jun 2022; https://doi.org/10.1055/s-0042-1745780) (burns2024causesandconsequences pages 7-8, zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - Complex polygenic architecture and epistasis within RET regulatory elements modulate risk and penetrance (Nov 2022; https://doi.org/10.1038/s41598-022-24077-w) (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - Dysregulated molecular pathways - Neurotrophic signaling (GDNF/RET, NRTN/RET) and endothelin (EDN3/EDNRB) signaling (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 7-8). - Ischemia–NO–mitochondria–caspase axis in postnatal/complicating pathology, with NO donors preventing ischemia-induced ENC death (Mar 18, 2024 preprint; https://doi.org/10.1101/2024.03.14.24304192) (xu2024ischemiapromoteshypertrophic pages 1-4). - Network-level inflammatory, vascular-permeability, and epithelial ion-transport alterations implicated in HAEC (Jan 2024; https://doi.org/10.3390/biom14020164; Jun 2022; https://doi.org/10.1055/s-0042-1745780) (lucenapadros2024bioinformaticspredictionfor pages 27-28, zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - Affected cellular processes - Neural crest cell chemotaxis, proliferation, lineage specification and synaptic connectivity (e.g., altered nitrergic balance and interstitial cells of Cajal involvement in postoperative dysfunction) (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 7-8). - Mucosal barrier and immune functions predisposing to enterocolitis (Jun 2022; https://doi.org/10.1055/s-0042-1745780) (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7).

Key molecular players - Genes/Proteins (HGNC): - RET (HGNC:9967): receptor tyrosine kinase for GDNF family ligands; coding and noncoding variants confer major HSCR risk; epistatic enhancer interactions within the RET TAD modulate susceptibility (Nov 2022; https://doi.org/10.1038/s41598-022-24077-w; Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7, burns2024causesandconsequences pages 6-7). - GDNF (HGNC:4231) and NRTN (HGNC:7995): neurotrophic ligands guiding chemotaxis and supporting proliferation/survival; reduced availability lowers enteric neuron number (“GDNF availability determines enteric neuron number…”) (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 7-8). - EDNRB (HGNC:3189) and EDN3 (HGNC:3175): endothelin signaling required for ENS progenitor expansion/differentiation; EDNRB loss yields colonic aganglionosis and enterocolitis in models (Nov 2024; https://doi.org/10.1136/wjps-2024-000903; Jun 2022; https://doi.org/10.1055/s-0042-1745780) (burns2024causesandconsequences pages 7-8, zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - SOX10 (HGNC:11195), PHOX2B (HGNC:9140), NRG1 (HGNC:7997), ZEB2 (HGNC:11776): core ENS regulatory genes implicated by human genetics and GRNs; RET–EDNRB epistasis is explained by shared transcriptional control (“A gene regulatory network explains RET-EDNRB epistasis…”) (Jul 2019; https://doi.org/10.1093/hmg/ddz149; Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7, burns2024causesandconsequences pages 6-7). - NCAM1 (HGNC:7659): adhesion receptor whose signaling is required for GDNF-based therapeutic responses in experimental HSCR (May 2025 preprint; https://doi.org/10.1101/2025.05.23.655388) (gary2025successofgdnfbased pages 25-34). - Chemical entities (CHEBI) and modulators: - Nitric oxide donors (e.g., sodium nitroprusside; CHEBI:9306) attenuate ischemia-induced enteric neuron death via mitophagy induction (Mar 18, 2024 preprint; https://doi.org/10.1101/2024.03.14.24304192) (xu2024ischemiapromoteshypertrophic pages 1-4). - Cell types (CL): - Enteric neural crest–derived progenitors/ENCDCs (CL:0002563, progenitor-like): primary cells affected in colonization failure (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7). - Enteric neurons (CL:1001608) and enteric glia (CL:0002573): neuronal subtype imbalance (e.g., nitrergic) and glial alterations linked to dysfunction and HAEC (Nov 2024; https://doi.org/10.1136/wjps-2024-000903; Jun 2022; https://doi.org/10.1055/s-0042-1745780) (burns2024causesandconsequences pages 7-8, zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - Fibroblasts (CL:0000057): ischemia-associated CLDN1+ fibroblast wrapping of hypertrophic nerve trunks (Mar 18, 2024 preprint; https://doi.org/10.1101/2024.03.14.24304192) (xu2024ischemiapromoteshypertrophic pages 1-4). - Anatomical locations (UBERON): - Distal colon/rectosigmoid (UBERON:0001155/0001052) as the most commonly aganglionic segment; myenteric and submucosal plexuses (UBERON:8410064/0001271) are absent in affected bowel (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7).

Biological processes for GO annotation - ENS development and NCC biology: neural crest cell migration (GO:0014032), cell proliferation (GO:0008283), neuronal differentiation (GO:0030182), axon guidance/synaptogenesis (GO:0007411/GO:0007416); GDNF–RET signaling (GO:0048011) and endothelin signaling (GO:0007193) underpin these processes (“GDNF is a chemoattractant…”; “Interaction of endothelin-3 with endothelin-B receptor is essential…”) (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7, burns2024causesandconsequences pages 7-8). - Inflammatory and vascular responses relevant to HAEC: regulation of vascular permeability (GO:0043114), epithelial barrier maintenance (GO:0030277), immune response (GO:0006955), and NF-κB signaling/inflammatory transcriptional programs (surveyed in 2024 biomolecular network review of HSCR/HAEC) (Jan 2024; https://doi.org/10.3390/biom14020164) (lucenapadros2024bioinformaticspredictionfor pages 27-28). - Mitochondrial stress and apoptosis under ischemia: response to hypoxia (GO:0001666), mitochondrial membrane organization (GO:0007005), mitophagy (GO:0000422), and activation of cysteine-type endopeptidase activity involved in apoptotic process (GO:0006919) (Mar 18, 2024 preprint; https://doi.org/10.1101/2024.03.14.24304192) (xu2024ischemiapromoteshypertrophic pages 1-4).

Cellular components - Plasma membrane receptor complexes for RET and EDNRB signaling (GO:0005886; GO:0004930), growth cone/axon compartments during ENS wiring (GO:0030426), myenteric and submucosal plexus ganglia (UBERON:8410064/0001271), epithelial tight junctions pertinent to HAEC pathobiology (GO:0005923) (Nov 2024; https://doi.org/10.1136/wjps-2024-000903; Jan 2024; https://doi.org/10.3390/biom14020164) (burns2024causesandconsequences pages 6-7, lucenapadros2024bioinformaticspredictionfor pages 27-28).

Disease progression (sequence of events) - Embryonic initiation: reduced RET/EDNRB pathway dosage, plus polygenic modifiers, lower the pool and motility of ENCDCs at the wavefront (Nov 2022; https://doi.org/10.1038/s41598-022-24077-w; Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7, burns2024causesandconsequences pages 6-7). - Migration failure: incomplete caudal colonization leaves a distal aganglionic segment lacking myenteric and submucosal ganglia (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7). - Neonatal presentation: functional obstruction with megacolon; surgery removes aganglionic bowel but residual dysmotility can persist due to neuronal subtype imbalance and pan-enteric abnormalities (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 7-8). - Complications: HAEC arises from converging dysmotility, barrier dysfunction, immune dysregulation, and dysbiosis; postoperative vascular permeability and inflammatory pathways can heighten risk (Jan 2024; https://doi.org/10.3390/biom14020164; Jun 2022; https://doi.org/10.1055/s-0042-1745780) (lucenapadros2024bioinformaticspredictionfor pages 27-28, zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - Postnatal aggravating factors: intestinal ischemia can drive hypertrophic nerve trunk formation and enteric neuron apoptosis; nitric oxide signaling protects against this cascade (Mar 18, 2024 preprint; https://doi.org/10.1101/2024.03.14.24304192) (xu2024ischemiapromoteshypertrophic pages 1-4).

Phenotypic manifestations (HP terms) - Intestinal aganglionosis with distal colonic obstruction and delayed meconium passage (HP:0002251; HP:0004844), megacolon (HP:0002257), severe constipation (HP:0002019), abdominal distension (HP:0003270), and Hirschsprung-associated enterocolitis with fever, diarrhea, and sepsis risk (HP:0002014, HP:0002017) (Nov 2024; https://doi.org/10.1136/wjps-2024-000903; Jun 2022; https://doi.org/10.1055/s-0042-1745780) (burns2024causesandconsequences pages 6-7, zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7).

Recent developments and latest research (2023–2024 emphasis) - Integrative reviews and translational framing (2024): Comprehensive synthesis reaffirms that "critical numbers of neural crest cells are required" and that RET/GDNF and EDN3/EDNRB signaling orchestrate ENS colonization; it also highlights organoid/iPSC models and the trajectory toward cell replacement therapies (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7). - Polygenic and regulatory architecture: WGS in East Asian cohorts demonstrates epistatic interactions between RET enhancer variants within the RET TAD, suggesting synergistic cis-regulatory effects on RET transcription as a mechanism for variable penetrance (Nov 2022; https://doi.org/10.1038/s41598-022-24077-w) (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - Ischemia and neuronal death (2024): Spatial/single-cell transcriptomics in patient tissue, an ischemic mouse model, and cell assays show ischemia induces ENC zinc accumulation, mitochondrial injury, and caspase-dependent apoptosis; NO donor rescues by inducing mitophagy (Mar 18, 2024 preprint; https://doi.org/10.1101/2024.03.14.24304192) (xu2024ischemiapromoteshypertrophic pages 24-28, xu2024ischemiapromoteshypertrophic pages 1-4). - HAEC biology (2024): Network-based multi-omics review points to increased vascular permeability, inflammatory signaling, and epithelial transport/barrier perturbations as contributors, integrating miRNA and immune links with HSCR genetics (Jan 2024; https://doi.org/10.3390/biom14020164) (lucenapadros2024bioinformaticspredictionfor pages 27-28).

Current applications and real-world implementations - Surgical management remains standard (pull-through), but recognition of persistent pan-enteric dysfunction and neuronal subtype imbalance informs postoperative care and risk stratification (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 7-8). - Risk assessment: genetic architecture insights (RET regulatory epistasis) and GRN-driven models of RET–EDNRB interactions improve interpretation of variants and counseling (Nov 2022; https://doi.org/10.1038/s41598-022-24077-w; Jul 2019; https://doi.org/10.1093/hmg/ddz149) (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - HAEC mitigation: emerging evidence supports surveillance of vascular permeability/barrier function and inflammatory states in high-risk patients, consistent with network findings (Jan 2024; https://doi.org/10.3390/biom14020164) (lucenapadros2024bioinformaticspredictionfor pages 27-28).

Expert opinions and analysis - Burns & Goldstein (2024) emphasize the centrality of GDNF/RET and EDN3/EDNRB axes, critical cell-number thresholds for successful colonization, and the promise of organoid and regenerative strategies; they also note altered neuronal subtypes and interstitial cells of Cajal as contributors to long-term dysfunction (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7, burns2024causesandconsequences pages 7-8). - Zhang et al. (2022) synthesize HAEC pathogenesis across genetics, microbiome, barrier, and immune dimensions and underscore the clinical burden and mortality risk of HAEC, motivating translational work (Jun 2022; https://doi.org/10.1055/s-0042-1745780) (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7).

Relevant statistics and data - Genetic architecture: RET remains the major susceptibility locus, and epistatic enhancer interactions (65 variants within the RET TAD interacting with rs2435357) were identified in East Asian WGS, supporting polygenic regulatory control (Nov 2022; https://doi.org/10.1038/s41598-022-24077-w) (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - Ischemia model and patient data: ischemia induced ENC apoptosis with mitochondrial/mitophagy signatures, and NO donor treatment reduced neuronal death and inflammatory markers in experimental systems (Mar 18, 2024 preprint; https://doi.org/10.1101/2024.03.14.24304192) (xu2024ischemiapromoteshypertrophic pages 1-4).

Emerging therapies and models - GDNF-based strategies: preclinical findings indicate that the "success of GDNF-based treatment of Hirschsprung disease depends on NCAM1 signaling" and the presence of responsive enteric progenitor subtypes, aligning with known roles of GDNF in precursor proliferation (May 2025 preprint; https://doi.org/10.1101/2025.05.23.655388; Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (gary2025successofgdnfbased pages 25-34, burns2024causesandconsequences pages 7-8). - ENS progenitor transplantation: regenerative medicine reviews and translational discourse highlight “cell replacement and other regenerative therapies” as an emerging direction for HSCR management, supported by advancing organoid/iPSC platforms and progenitor isolation methods (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7).

Gene/protein annotations with ontology terms - RET (HGNC:9967): GO:0048011 (neurotrophin TRK receptor signaling via GDNF/RET); cellular component: plasma membrane (GO:0005886); process: neural crest cell migration (GO:0014032). Evidence: human genetics/functional studies summarized in 2024 review (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7). - GDNF (HGNC:4231): GO:0030935 (regulation of neuron differentiation); process: chemoattraction and proliferation of ENS progenitors; quote: “GDNF availability determines enteric neuron number by controlling precursor proliferation” (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 7-8). - EDNRB (HGNC:3189)/EDN3 (HGNC:3175): GO:0007193 (G protein-coupled receptor signaling); process: regulation of ENCDC proliferation/differentiation; essential for enteric neuron development (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7). - SOX10 (HGNC:11195), PHOX2B (HGNC:9140), NRG1 (HGNC:7997), ZEB2 (HGNC:11776): GO:0006355 (regulation of transcription); participate in ENS GRNs; RET–EDNRB epistasis via shared TF control (Jul 2019; https://doi.org/10.1093/hmg/ddz149) (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7).

Phenotype associations (HPO) - HP:0002251 (Intestinal aganglionosis), HP:0002257 (Megacolon), HP:0002019 (Constipation), HP:0002014 (Diarrhea), HP:0002017 (Enterocolitis) linked mechanistically to ENS absence and HAEC pathobiology (Nov 2024; https://doi.org/10.1136/wjps-2024-000903; Jun 2022; https://doi.org/10.1055/s-0042-1745780) (burns2024causesandconsequences pages 6-7, zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7).

Cell type involvement (CL) - ENCDCs (CL:0002563), enteric neurons (CL:1001608), enteric glia (CL:0002573), interstitial cells of Cajal (CL:0000632), fibroblasts (CL:0000057) in ischemia-associated HNTs (Nov 2024; https://doi.org/10.1136/wjps-2024-000903; Mar 18, 2024 preprint; https://doi.org/10.1101/2024.03.14.24304192) (burns2024causesandconsequences pages 7-8, xu2024ischemiapromoteshypertrophic pages 1-4).

Anatomical locations (UBERON) - Colon (UBERON:0001155), rectosigmoid (UBERON:0001052), myenteric plexus (UBERON:8410064), submucosal plexus (UBERON:0001271) (Nov 2024; https://doi.org/10.1136/wjps-2024-000903) (burns2024causesandconsequences pages 6-7).

Chemical entities (ChEBI) - Nitric oxide donor sodium nitroprusside (CHEBI:9306) as a modulator of ischemia-induced neuronal death pathways in ENS (Mar 18, 2024 preprint; https://doi.org/10.1101/2024.03.14.24304192) (xu2024ischemiapromoteshypertrophic pages 1-4).

Evidence items (selected with PMIDs/DOIs/URLs and dates) - Burns AJ, Goldstein AM. Causes and consequences: development and pathophysiology of Hirschsprung disease. World J Pediatr Surg. Nov 2024. DOI: 10.1136/wjps-2024-000903; URL: https://doi.org/10.1136/wjps-2024-000903. Key quotes: “GDNF is mitogenic, neurotrophic, and chemoattractive,” and “GDNF availability determines enteric neuron number by controlling precursor proliferation” (burns2024causesandconsequences pages 6-7, burns2024causesandconsequences pages 7-8). - Wang Y et al. Whole genome sequencing reveals epistasis effects within RET for Hirschsprung disease. Sci Rep. Nov 2022. DOI: 10.1038/s41598-022-24077-w; URL: https://doi.org/10.1038/s41598-022-24077-w. Summary: 65 epistatic variants within the RET TAD interact with lead enhancer rs2435357, consistent with synergistic cis-regulatory control (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - Xu D et al. Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in Hirschsprung's disease. medRxiv. Mar 18, 2024. DOI: 10.1101/2024.03.14.24304192; URL: https://doi.org/10.1101/2024.03.14.24304192. Key quote: ischemia triggers ENC mitochondrial injury/caspase-dependent apoptosis and NO donor “prevented enteric neuron cell death” by inducing mitophagy (xu2024ischemiapromoteshypertrophic pages 1-4). - Zhang Z et al. Hirschsprung-Associated Enterocolitis: Transformative Research from Bench to Bedside. Eur J Pediatr Surg. Jun 2022. DOI: 10.1055/s-0042-1745780; URL: https://doi.org/10.1055/s-0042-1745780. Synthesis: HAEC involves microbiome, mucus barrier, immune defects, and endothelin pathway susceptibility; Ednrb/Edn3-null models show lymphoid depletion and enterocolitis (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7). - Lucena-Padrós H et al. Bioinformatics prediction for network-based integrative multi-omics… in Hirschsprung Disease. Biomolecules. Jan 2024. DOI: 10.3390/biom14020164; URL: https://doi.org/10.3390/biom14020164. Highlights: increased vascular permeability in an HSCR murine model and integrative inflammatory/ion-transport pathways implicated in HAEC (lucenapadros2024bioinformaticspredictionfor pages 27-28). - Gary A et al. Success of GDNF-based treatment of Hirschsprung disease depends on NCAM1 signaling… bioRxiv. May 2025. DOI: 10.1101/2025.05.23.655388; URL: https://doi.org/10.1101/2025.05.23.655388. Implication: NCAM1 signaling as determinant of GDNF-based therapy responsiveness (gary2025successofgdnfbased pages 25-34).

Limitations and open questions - While foundational mechanisms (RET/GDNF, EDN3/EDNRB) are well supported, finer-grained single-cell human datasets, metabolic programs (e.g., oxidative phosphorylation in ENCDCs), and NF-κB-specific inflammatory circuits in HSCR/HAEC require additional primary evidence integration beyond the evidence included here; 2024–2025 preprints/reporting on ischemia and GDNF/NCAM1 provide plausible, but not yet fully peer-reviewed, mechanisms (Mar 18, 2024; May 2025) (xu2024ischemiapromoteshypertrophic pages 1-4, gary2025successofgdnfbased pages 25-34).

Conclusions HSCR pathophysiology centers on ENS colonization failure driven by dosage-sensitive RET/GDNF and EDN3/EDNRB signaling within a polygenic regulatory architecture, with downstream consequences for neuronal subtype balance and gut function; complications such as HAEC reflect converging dysmotility, barrier/immune dysfunction, and, as newly suggested, ischemia–mitochondrial injury cascades that may be mitigated by NO signaling. Advances in organoid/iPSC and regenerative strategies point to GDNF- and cell replacement–based interventions, with emerging evidence that NCAM1 signaling and progenitor subtype composition will influence therapeutic success (Nov 2024; https://doi.org/10.1136/wjps-2024-000903; Nov 2022; https://doi.org/10.1038/s41598-022-24077-w; Mar 18, 2024; https://doi.org/10.1101/2024.03.14.24304192; May 2025; https://doi.org/10.1101/2025.05.23.655388) (burns2024causesandconsequences pages 6-7, zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7, xu2024ischemiapromoteshypertrophic pages 1-4, gary2025successofgdnfbased pages 25-34).

References

  1. (burns2024causesandconsequences pages 6-7): Alan J. Burns and Allan M Goldstein. Causes and consequences: development and pathophysiology of hirschsprung disease. World Journal of Pediatric Surgery, 7:e000903, Nov 2024. URL: https://doi.org/10.1136/wjps-2024-000903, doi:10.1136/wjps-2024-000903. This article has 2 citations and is from a peer-reviewed journal.

  2. (burns2024causesandconsequences pages 7-8): Alan J. Burns and Allan M Goldstein. Causes and consequences: development and pathophysiology of hirschsprung disease. World Journal of Pediatric Surgery, 7:e000903, Nov 2024. URL: https://doi.org/10.1136/wjps-2024-000903, doi:10.1136/wjps-2024-000903. This article has 2 citations and is from a peer-reviewed journal.

  3. (xu2024ischemiapromoteshypertrophic pages 1-4): Deshu Xu, Weiwei Liang, Chaoting Lan, Lanying Li, Weiyong Zhong, Meng Yao, Xiaoyu Zuo, Jixiao Zeng, Wei Zhong, Qiang Wu, Andrew M Lew, Wenhao Zhou, Huimin Xia, Fan Bai, Yuxia Zhang, and Yan Zhang. Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in hirschsprung's disease. MedRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.14.24304192, doi:10.1101/2024.03.14.24304192. This article has 0 citations.

  4. (zhang2022hirschsprungassociatedenterocolitistransformative pages 7-7): Zhen Zhang, Bo Li, Qian Jiang, Qi Li, Agostino Pierro, and Long Li. Hirschsprung-associated enterocolitis: transformative research from bench to bedside. European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie, 32:383-390, Jun 2022. URL: https://doi.org/10.1055/s-0042-1745780, doi:10.1055/s-0042-1745780. This article has 7 citations.

  5. (lucenapadros2024bioinformaticspredictionfor pages 27-28): Helena Lucena-Padros, Nereida Bravo-Gil, Cristina Tous, Elena Rojano, Pedro Seoane-Zonjic, Raquel María Fernández, Juan A. G. Ranea, Guillermo Antiñolo, and Salud Borrego. Bioinformatics prediction for network-based integrative multi-omics expression data analysis in hirschsprung disease. Biomolecules, 14:164, Jan 2024. URL: https://doi.org/10.3390/biom14020164, doi:10.3390/biom14020164. This article has 2 citations and is from a poor quality or predatory journal.

  6. (gary2025successofgdnfbased pages 25-34): Alassane Gary, Rodolphe Soret, Marie A. Lefèvre, Nejia Lassoued, Ann Aspirot, Christophe Faure, and Nicolas Pilon. Success of gdnf-based treatment of hirschsprung disease depends on ncam1 signaling and various subtypes of enteric neural progenitors. bioRxiv, May 2025. URL: https://doi.org/10.1101/2025.05.23.655388, doi:10.1101/2025.05.23.655388. This article has 0 citations and is from a poor quality or predatory journal.

  7. (xu2024ischemiapromoteshypertrophic pages 24-28): Deshu Xu, Weiwei Liang, Chaoting Lan, Lanying Li, Weiyong Zhong, Meng Yao, Xiaoyu Zuo, Jixiao Zeng, Wei Zhong, Qiang Wu, Andrew M Lew, Wenhao Zhou, Huimin Xia, Fan Bai, Yuxia Zhang, and Yan Zhang. Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in hirschsprung's disease. MedRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.14.24304192, doi:10.1101/2024.03.14.24304192. This article has 0 citations.