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Hirschsprung's Disease

Disease Details

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Description: Hirschsprung's disease is a congenital condition characterized by the absence of ganglion cells in the intestines, leading to severe constipation or intestinal obstruction.
Type: Hirschsprung's disease is a congenital disorder affecting the colon. The type of genetic transmission can vary, but it is often inherited in an autosomal dominant or autosomal recessive pattern, depending on the specific genetic mutation involved. In some cases, it can also occur sporadically with no clear inheritance pattern.
Signs And Symptoms: Typically, Hirschsprung disease is diagnosed shortly after birth, although it may develop well into adulthood, because of the presence of megacolon, or because the baby fails to pass the first stool (meconium) within 48 hours of delivery. Normally, 90% of babies pass their first meconium within 24 hours, and 99% within 48 hours.Some other signs and symptoms in newborns include a swollen belly, vomiting (green or brown vomit), and flatulence. In older children, some other signs and symptoms include chronic constipation, flatulence, swollen belly, fatigue, and failure to thrive.Other symptoms include symptoms of bowel perforation such as vomiting, constipation, poor feeding, lethargy, and diarrhea. Symptoms of bowel obstruction would include vomiting of bile and abdominal distension. Those who pass stools after 36 to 48 hours after birth should raise suspicion of Hirschsprung disease. Such suspicion can also be risen if there is only passage of stools after suppository, rectal exam, or enema. Children who do not respond to constipation treatment for six months should also raise suspicion of such disease. Enterocolitis, an acute complication of Hirschsprung disease, is characterised by sudden onset of fever, abdominal distension, vomiting, passage of bloody stools or release of explosive gas or stools after rectal examination.Some cases are diagnosed later, into childhood, but usually before age 10. The child may experience fecal retention, constipation, or abdominal distention.
Prognosis: Hirschsprung's disease is a congenital condition affecting the colon, where nerve cells are missing, leading to problems with passing stool. The prognosis largely depends on the severity and timing of diagnosis and treatment.

With early surgical intervention to remove the affected segment of the colon, most children experience significant improvement and lead relatively normal lives. However, long-term complications like constipation, enterocolitis, and fecal incontinence can occur, requiring ongoing medical management. Overall, the prognosis is generally good with appropriate treatment.
Onset: Hirschsprung's disease typically presents at birth or shortly after. The primary symptom is the failure to pass stool within the first 48 hours of life. Other symptoms may include abdominal swelling, vomiting, and constipation.
Prevalence: Hirschsprung's disease affects approximately 1 in 5,000 live births.
Epidemiology: According to a 1984 study conducted in Maryland, Hirschsprung's disease appears in 18.6 per 100,000 live births. In Japan, it occurs at a similar rate of about one in 5,000 births (20 per 100,000). It is more common in male than female (4.32:1) and in white rather than nonwhite. Nine percent of the Hirschsprung cases were also diagnosed as having Down syndrome. Most cases are diagnosed before the patient is 10 years of age.
Intractability: Hirschsprung's disease is not considered intractable because it can be effectively treated with surgery. The primary treatment involves removing the affected segment of the colon that lacks nerve cells and then connecting the remaining healthy parts of the intestine. With appropriate surgical intervention, most patients can achieve normal bowel function.
Disease Severity: Hirschsprung's disease is a congenital condition affecting the large intestine (colon) and causing problems with passing stool. The severity of Hirschsprung's disease can vary. Some children may have a short segment of the colon affected, leading to milder symptoms, while others may have long segments involved, resulting in more severe complications. Generally, the key symptom is chronic constipation or intestinal obstruction in newborns or young children. The condition can be severe if left untreated, potentially causing life-threatening complications like enterocolitis, which is an inflammation of the colon that can lead to severe infection and shock. Treatment usually involves surgery to remove the affected segment of the colon.
Healthcare Professionals: Disease Ontology ID - DOID:10487
Pathophysiology: During normal prenatal development, cells from the neural crest migrate into the large intestine (colon) to form the networks of nerves called the myenteric plexus (Auerbach plexus) (between the smooth muscle layers of the gastrointestinal tract wall) and the submucosal plexus (Meissner plexus) (within the submucosa of the gastrointestinal tract wall). In Hirschsprung disease, the migration is not complete and part of the colon lacks these nerve bodies that regulate the activity of the colon. The affected segment of the colon cannot relax and pass stool through the colon, creating an obstruction.The most accepted theory of the cause of Hirschsprung is a defect in the craniocaudal migration of neuroblasts originating from the neural crest that occurs during the first 12 weeks of gestation. Defects in the differentiation of neuroblasts into ganglion cells and accelerated ganglion cell destruction within the intestine may also contribute to the disorder.This lack of ganglion cells in the myenteric and submucosal plexus is well documented in Hirschsprung's disease. With Hirschsprung's disease, the segment lacking neurons (aganglionic) becomes constricted, causing the normal, proximal section of bowel to become distended with feces. This narrowing of the distal colon and the failure of relaxation in the aganglionic segment are thought to be caused by the lack of neurons containing nitric oxide synthase.The most cited feature is absence of ganglion cells: notably in males, 75% have none in the end of the colon (rectosigmoid) and 8% lack ganglion cells in the entire colon. The enlarged section of the bowel is found proximally, while the narrowed, aganglionic section is found distally, closer to the end of the bowel. The absence of ganglion cells results in a persistent overstimulation of nerves in the affected region, resulting in contraction.The equivalent disease in horses is lethal white syndrome.
Carrier Status: Hirschsprung's disease is typically passed down through families in an autosomal dominant or autosomal recessive manner, depending on the type of genetic mutation involved. However, the carrier status can vary. For autosomal recessive forms, carriers have one copy of the mutated gene but do not show symptoms. For autosomal dominant forms, carriers with one copy of the mutated gene may show symptoms, as the disease can exhibit incomplete penetrance or variable expressivity.
Mechanism: Hirschsprung's disease is a congenital disorder characterized by the absence of ganglion cells in the distal colon, resulting in a functional obstruction. The lack of these nerve cells impairs the muscle contractions needed to move stool through the colon, causing severe constipation or intestinal blockage.

### Mechanism:
The primary mechanism of Hirschsprung's disease involves the failure of neural crest cells to migrate, proliferate, or differentiate properly during embryonic development. This results in an aganglionic segment of the bowel, which lacks the enteric nervous system components required for normal peristalsis.

### Molecular Mechanisms:
1. **RET Gene Mutations:**
- The RET proto-oncogene is crucial for the development of the enteric nervous system. Mutations in the RET gene are the most common cause, leading to disrupted signaling pathways vital for neural crest cell survival, migration, and differentiation.

2. **GDNF and NTN Signaling:**
- Glial cell line-derived neurotrophic factor (GDNF) and Neurturin (NTN) are important ligands for the RET receptor. Mutations or dysregulation in GDNF, NTN, or their receptors (GFRα1 for GDNF and GFRα2 for NTN) can impede neural crest cell development.

3. **EDNRB Pathway:**
- The endothelin receptor type B (EDNRB) and its ligand endothelin-3 (EDN3) are essential for neural crest cell migration. Mutations in EDNRB or EDN3 can also result in Hirschsprung's disease by disrupting this pathway.

4. **SOX10 Gene Mutations:**
- SOX10 is a transcription factor that regulates genes involved in neural crest cell development. Mutations in SOX10 can lead to a failure in the proper formation of enteric ganglia.

5. **PHOX2B and Other Genes:**
- Other genes such as PHOX2B, which is involved in autonomic nervous system development, can also contribute when mutated. These genetic mutations collectively interfere with the proper colonization and function of enteric ganglia.

Understanding these molecular mechanisms highlights the genetic and developmental complexity underlying Hirschsprung's disease and is essential for developing targeted therapies and diagnostics.
Treatment: Treatment of Hirschsprung's disease consists of surgical removal (resection) of the abnormal section of the colon, followed by reanastomosis.
Compassionate Use Treatment: Hirschsprung's disease, a congenital condition characterized by the absence of ganglion cells in the intestines, generally requires surgical intervention. However, for individuals who do not respond adequately to standard treatments or for whom surgery poses significant risks, compassionate use or experimental treatments might be considered.

1. **Compassionate Use Treatments**:
- **Enzyme Therapy**: Targeting specific enzymes to aid the nervous system's function in the intestinal tract is being explored in some cases.
- **Stem Cell Therapy**: Early-stage research involves the transplantation of neural stem cells to potentially replace absent ganglion cells.

2. **Off-label or Experimental Treatments**:
- **Pharmacological Agents**: Use of drugs like neurotrophic factors or agents that modulate the enteric nervous system to enhance intestinal motility is being studied.
- **Gene Therapy**: Experimental approaches aiming to correct the genetic abnormalities associated with Hirschsprung's disease are under investigation.
- **Probiotic and Microbiome-based Therapies**: Manipulating gut flora to improve gastrointestinal function is an area of interest for researchers.

These treatments are in various stages of research and clinical trials, and their availability and success can vary. It is crucial for patients and caregivers to consult with healthcare professionals to discuss potential risks and benefits.
Lifestyle Recommendations: For Hirschsprung's disease, lifestyle recommendations include:

1. **Dietary Adjustments:**
- High-fiber diet to help prevent constipation.
- Increased fluid intake to aid digestion.
- Small, frequent meals to ease the digestive process.

2. **Regular Physical Activity:**
- Encourages bowel movements and overall digestive health.

3. **Bowel Management Routine:**
- Scheduled toilet times to establish regular bowel habits.
- Use of laxatives or stool softeners as advised by a healthcare provider.

4. **Monitoring and Care:**
- Regular follow-up with healthcare providers to monitor condition.
- Be aware of symptoms of enterocolitis, a serious complication, and seek prompt medical attention if symptoms arise.

Please consult with a healthcare professional for personalized medical advice and follow their recommendations closely.
Medication: Medications are generally not the primary treatment for Hirschsprung's disease. The primary treatment is surgical removal of the affected section of the colon. However, certain medications might be used to manage symptoms or complications. Stool softeners and laxatives can help manage constipation before surgery. Antibiotics may be used if there is any infection, such as enterocolitis, a potential complication. Consultation with a healthcare provider is necessary for appropriate management.
Repurposable Drugs: For Hirschsprung's disease, there aren't widely recognized repurposable drugs specifically for treating the underlying cause which is the absence of ganglion cells in the intestines. The primary treatment is surgical intervention to remove the affected portion of the intestine. However, some drugs could potentially help manage symptoms or complications:

1. **Botulinum toxin (Botox)**: In some cases, Botox can be used to relax the internal anal sphincter and help relieve obstructive symptoms in the short term.

2. **Acetylcholinesterase inhibitors**: Drugs like neostigmine may be used to improve intestinal motility temporarily.

It's essential to note that these are not cures but rather symptomatic treatments and should be prescribed by a healthcare professional. Ongoing research may identify more potential repurposable drugs in the future.
Metabolites: Hirschsprung's disease, also known as congenital aganglionic megacolon, primarily affects the gastrointestinal tract and does not have specific metabolites directly associated with its diagnosis or pathology. This condition is characterized by the absence of ganglion cells in the intestinal wall, leading to bowel obstruction and severe constipation. Diagnosis typically relies on clinical evaluation, rectal biopsy, and imaging studies rather than the assessment of metabolites.
Nutraceuticals: Nutraceuticals are not standard treatments for Hirschsprung’s disease. This condition typically requires surgical intervention to remove the affected portion of the colon. Nutraceuticals may help support overall health and recovery post-surgery but are not a substitute for medical treatment. Always consult with healthcare professionals for appropriate care plans.
Peptides: Hirschsprung's disease is not directly associated with specific peptides as its primary cause is a congenital absence of ganglion cells in the intestinal wall. The pathology results from a failure of neural crest cells to migrate completely during intestinal development, leading to a lack of enteric nervous system innervation in parts of the colon. This condition causes chronic constipation and intestinal obstruction. While peptides may play roles in various physiological processes, they are not central to the etiology or typical diagnosis of Hirschsprung's disease.