Hirschsprung Disease

Hirschsprung disease (HD), also known as congenital aganglionosis or congenital megacolon, is a congenital anomaly of the colon caused by the failure of neural crest-derived ganglion cells to migrate into the distal colon. The lack of innervation always involves the rectum and extends proximally and contiguously over variable distances. Most cases are diagnosed in the neonatal period, with a classic triad of symptoms including delayed passage of meconium, abdominal distension, and bilious vomiting. Individuals having less severe degrees of functional obstruction may not be diagnosed until later in infancy or childhood when they present with symptoms of chronic refractory constipation, abdominal distension, and failure to thrive. The diagnosis of HD is confirmed by the absence of ganglion cells on rectal biopsy after noninvasive testing such as anorectal manometry and the use of contrast enema. Surgical resection of the aganglionic segment is the standard treatment.

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Overview

Definition

Hirschsprung disease (HD), also known as congenital aganglionosis or congenital megacolon, is a congenital anomaly of the colon caused by the failure of neural crest-derived ganglion cells to migrate into the distal colon.

Classification

  • Sporadic:
    • Most common (70%)
    • ⅓ of cases have > 1 RET mutations.
  • Familial forms: Approximately half of the cases have > 1 receptor tyrosine kinase gene (RET) mutations.
  • As part of a genetic syndrome:
    • Down syndrome (DS)/trisomy 21: 
      • Approximately 10% of individuals with HD have DS.
      • < 1% of individuals with DS have HD.
    • Waardenburg syndrome: 
      • Autosomal dominant inherited pigment disorder
      • 100% of individuals with type 4 Waardenburg syndrome have HD.
    • Mowat-Wilson syndrome:
      • Intellectual disability, microcephaly
      • 41%–71% of cases have HD.
    • MEN type 2A (MEN2A): medullary thyroid cancer and pheochromocytoma with or without primary hyperparathyroidism

Epidemiology

  • Annual incidence is approximately 1 in 5,000 live births in the US.
  • The men:women ratio is 3–4:1, but is closer to 1:1 when the entire colon is involved.
  • More common in populations of Asian descent

Etiology

  • HD is associated with mutations in multiple genes that are important for the growth and differentiation of neural crest cells, most commonly in the RET gene.
  • Environmental factors and modifying genes (some sex-linked) are likely contributors.

Pathophysiology

The pathophysiology in HD is the complete absence of ganglion cells (aganglionosis) in the intrinsic nerve supply of the bowel due to the failure of neural crest-derived ganglion cells to migrate completely into the myenteric plexuses of the wall of the colon.

  • Extends proximally from the anal sphincter and involves varying lengths of the colon
  • Always involves the rectum 
  • Results in functional obstruction due to the arrest of peristalsis at the point of the arrest of the migration
  • Aganglionic segment also has abnormal alterations in the expression of receptors, channels, cytoskeletal proteins, and neurotrophic factors.
  • Gross pathology:
    • Rectosigmoid colon is most common (“short-segment disease”): 80%
    • Extension proximal to the sigmoid colon (“long-segment disease”): 15%–20% 
    • Total colonic aganglionosis: 5% of cases; rarely involves the ileum or entire small bowel
    • Muscular hypertrophy and dilatation of bowel proximal to obstruction, with possible progression to megacolon and rupture (usually in the cecum)
  • Microscopic pathology:
    • Absent enteric ganglion cells in the submucosal (Meissner) and myenteric (Auerbach) plexuses in the distal rectum and variable length of the proximal contiguous intestine
    • Hypertrophy of aganglionic myenteric nerves (variable)

Clinical Presentation

Most individuals with HD are diagnosed in the 1st month of life. Individuals with less severe disease may not present with symptoms until 3 years of age in approximately 10% of cases.

  • Classic triad of symptoms:
    • Delayed passage of meconium (> 48 hours in a term infant)
    • Abdominal distension
    • Bilious vomiting
  • Additional signs and symptoms in the neonatal period:
    • Explosive expulsion of gas and stool after digital rectal examination, signifying temporary relief of obstruction
    • Enterocolitis (more common if the diagnosis is delayed): 
      • Sepsis with fever
      • Vomiting, diarrhea, and abdominal distension, which can lead to toxic megacolon
    • Sigmoid or other volvulus
    • Appendiceal perforation
  • Later presentations: 
    • Less severe degrees of functional obstruction
    • Some cases may have “ultrashort-segment HD” (< 4 cm from the internal anal sphincter).
    • Symptoms and signs:
      • Chronic refractory constipation
      • Abdominal distension
      • Failure to thrive
  • Associated congenital anomalies:
    • Present in 20%–25% of individuals with HD
    • Congenital heart disease in 50% of syndromic cases, especially in those with DS
    • Genitourinary anomalies:
      • Hydronephrosis
      • Renal hypoplasia
    • Visual anomalies: refractory and other visual defects
    • Hearing impairment
    • Anorectal malformations

Diagnosis and Management

Diagnosis

If HD is suspected based on the clinical presentations in the neonatal or postnatal periods, the following diagnostic tests are used:

  • Contrast enema: may show the pathognomonic sign of the “transition zone” (funnel-shaped segment between the aganglionic rectum and the proximal dilated colon)
  • Anorectal manometry:
    • Helpful in screening individuals with ultrashort-segment HD
    • Lack of relaxation of the internal anal sphincter with balloon rectal distension is suggestive of HD.
  • Abdominal X-ray: not usually necessary, but shows decreased or no air in the rectum
  • Rectal biopsy: necessary for confirmation of the diagnosis, and documents the absence of ganglion cells
Hirschsprung disease seen on contrast barium enema study

Hirschsprung disease as seen on contrast barium enema study, with the arrow showing the “transition zone” between the normal and aganglionic bowel

Image: “Contrast enema showing a CETZ at rectosigmoid, arrow” by Pratap, A., et al. License: CC BY 2.0, cropped by Lecturio.

Management

  • Assess for associated anomalies:
    • Genitourinary ultrasound to assess for urinary system malformations
    • Screening for hearing impairment
    • Screening for visual impairment
    • Clinical geneticist consultation, if needed, in case of possible MEN2A
  • Surgical resection of the aganglionic segment of the bowel
  • Ultrashort-segment HD (aganglionosis < 4 cm from the internal anal sphincter):
    • Medical management with diet, stool softeners, laxatives, or botulinum toxin injections
    • Surgical management with myomectomy may be needed.

Complications

  • Enterocolitis:
    • Potentially lethal complication
    • Common in the dilated segment due to stasis and bacterial overgrowth
  • Stercoral ulcers: sharply demarcated shallow ulcers with mucosal inflammation due to pressure of feces on an obstructed colon
  • Potential complications of surgery:
    • Bowel obstruction
    • Constipation
    • Mechanical obstruction (e.g., stricture)
    • Persistent or acquired aganglionosis → use rebiopsy to evaluate
    • Increased internal anal sphincter tone → botulinum toxin may help
    • Behavioral stool-withholding behavior
    • Enterocolitis (HD-associated enterocolitis):
      • Incidence rate: up to 45% postoperatively
      • Etiology: probably due to intestinal stasis
      • Signs and symptoms: abdominal pain, foul-smelling bloody diarrhea, fever, sepsis, intestinal necrosis, and perforation
      • Increased risk in long-segment disease, especially total colonic aganglionosis
      • Time course: usually occurs < 1 year after surgery
      • Treatment: IV fluids, antibiotics, repeated rectal irrigation
    • More common in long-segment disease:
      • Perianal excoriations
      • Electrolyte imbalance
      • Anastomotic leak
    • Volvulus
    • Incontinence and diarrhea:
      • Common in the early postoperative period
      • Usually improves with time
      • 12% of individuals have long-term issues.
    • Most individuals with DS/HD have long-term bowel disturbances:
      • Incontinence, diarrhea, soiling, enterocolitis
      • May need a permanent colostomy
    • Urologic and sexual complications may occur:
      • Urinary incontinence
      • Erectile dysfunction

Prognosis

  • Long-term outcomes:
    • Overall: > 90% of affected individuals with HD report satisfactory outcomes.
    • Many affected individuals have disturbances of bowel function for several years.
    • Approximately 1% of affected individuals have debilitating incontinence requiring a permanent colostomy.
  • Worse outcomes are seen in:
    • Affected individuals with total colonic aganglionosis:
      • 33% have persistent incontinence.
      • 14% require a permanent ileostomy.
    • Individuals with associated chromosomal abnormalities and syndromes

Differential Diagnosis

Causes of intestinal obstruction in the neonatal period can be distinguished from HD based on their clinical features and the presence of ganglia on a rectal biopsy.

  • Intestinal atresia: results in complete obstruction of the lumen in neonates, but is rare overall. About 50% of cases involve the duodenum and 20% of cases involve individuals with an associated chromosomal anomaly.
  • Duplication cyst: causes symptoms similar to that observed in an abdominal mass due to compression of the adjacent bowel; rare, usually in the small bowel.
  • Intestinal malrotation with volvulus: occurs due to arrest of the normal rotation of the embryonic gut. Bilious vomiting in an infant could indicate an obstructive lesion.
  • Meconium ileus (MI) due to cystic fibrosis (CF): obstruction at the terminal ileum with inspissated meconium. Approximately 80%–90% of infants with MI have CF. Prenatal carrier testing and prenatal ultrasound help with proactive management.
  • MEN2: MEN2A is associated with HD; MEN2B may be associated with ganglioneuromatosis, skeletal deformations, and Marfanoid habitus.
  • Intestinal neuronal dysplasia and other chronic or acute intestinal pseudo-obstructions: functional dysmotility disorders and not mechanical obstructions. Intestinal neuronal dysplasia and other chronic or acute intestinal pseudo-obstructions usually constitute neuropathic or myopathic causes in infants.
  • Meconium plug syndrome: a condition occurring in 1 among 500 newborns due to colonic dysmotility or abnormal consistency of the meconium. About 15% of cases have HD. A contrast enema is both diagnostic and therapeutic.

Causes of intestinal obstruction in older infants and children:

  • Internal anal sphincter achalasia: Diagnosis is made by anorectal manometry, revealing an absence of the rectosphincteric reflex on rectal balloon inflation.
  • Hypothyroidism: a condition associated with increased birth weight and macroglossia. Neonatal screening permits the early diagnosis of congenital hypothyroidism.
  • Chronic intestinal pseudo-obstruction: functional dysmotility disorders and not mechanical obstructions. Chronic intestinal pseudo-obstruction usually constitutes neuropathic or myopathic causes in infants.

References

  1. Kumar, V., Abbas, A.K., Aster, J.C. (Eds.). (2020). Hirschsprung Disease. In Robbins & Cotran Pathologic Basis of Disease. 10th ed. pp. 755–756.
  2. Wesson, D.E., Lopez, M.E. (2021). Congenital aganglionic megacolon (Hirschsprung disease). UpToDate. Retrieved July 14, 2021, from https://www.uptodate.com/contents/congenital-aganglionic-megacolon-hirschsprung-disease
  3. Wesson, D.E., Lopez, M.E. (2021). Emergency complications of Hirschsprung disease. UpToDate. Retrieved July 15, 2021, from https://www.uptodate.com/contents/emergency-complications-of-hirschsprung-disease
  4. Zhang, Z., et al. (2017). Sporadic Hirschsprung disease: Mutational spectrum and novel candidate genes revealed by next-generation sequencing. Scientific Reports. 7(1), 14796. https://doi.org/10.1038/s41598-017-14835-6
  5. Kapur, R.P., Smith, C., Ambartsumyan, L. (2020). Postoperative pull-through obstruction in Hirschsprung disease: Etiologies and diagnosis. Pediatric and Developmental Pathology. 23, 40–59. https://doi.org/10.1177/1093526619890735
  6. Wagner, J.P., Shekherdimian, S., Lee, S.L. (2020). Hirschsprung disease: Background, pathophysiology, epidemiology. Retrieved July 15, 2021, from https://emedicine.medscape.com/article/178493-overview#a2

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