Hirschsprung Disease

 

Etiology

Hirschsprung Disease is the congenital absence of ganglion cells in the mucosal and muscular layers of the bowel.  Failure of neural crest cells to migrate during development to the most distal part of the bowel results in a continuous absence of these cells at a variable distance from the internal anal sphincter. 

The myenteric and submucosal plexuses normally allow for adequate relaxation of the bowel; their absence at the distal end of the bowel results in a hypertonic segment of bowel, which causes obstruction

The rectum (30%), rectosigmoid (44%), or entire colon (8%) may be affected, but rarely the entire GI tract.  The affected segment may be normal or narrowed, but leads to dilation of the proximal bowel causing the mucosa to become thin and inflamed leading to diarrhea, bleeding and protein loss. 

hirschsprungs.JPG
 

hirschsprungs text.JPG

Figure from Enteric nervous system development and Hirschsprung disease: advances in genetic and stem cell studies. Nat Rev Neurosci. 2007 Jun;8(6):466-79.

 

Genetics

At least eight genes have been identified in patients with Hirschsprung disease with the predominant gene being the RET proto-oncogene, which is also implicated in multiple endocrine neoplasia (MEN).  The RET gene codes for a receptor tyrosine kinase which contributes to growth and differentiation in neural crest cells as well as in other tissues throughout the body.  It is necessary for the migration and survival of enteric neurons. 

Other genes that have been identified include endothelin 3, endothelin receptor B, endothelin converting enzyme, SOX10 and PHOX2B.

Hirschsprung disease is also associated with several syndromes including Down’s, Bardet-Biedl and Waardenburg syndromes.

 

Epidemiology

  • 1:5000 live births
  • Male:Female is 4:1 for short segment, but approaches 1:1 for longer segment disease
  • Family History exists in 7% cases
  • 15% have at least one other congenital anomaly including:
     
    • Cardiac
    • GU
    • CNS
    • Other GI
  • Down’s syndrome in 2 to 8% of individuals with Hirschsprung

 

Clinical Features

  • Newborn
    • Failure of newborn to pass meconium - 40% fail to pass in first 24 hours, but 60% will pass meconium in first 48 hours
    • Vomiting, abdominal distention, reluctance to feeding
    • 50% newborns will have enterocolitis manifesting as fever and explosive diarrhea
    • Dilation causes risk of perforation
  • Later Infancy
    • Alternating obstipation and diarrhea
  • Older Child
    • Constipation alone most likely, see below
    • Foul smelling, ribbon-like stool
    • Intestinal obstruction, hypochromic anemia, hypoproteinemia and failure to thrive are common

 

Exam

  • Anal canal and rectum devoid of stool
  • Sudden evacuation of stool on digital rectal exam

 


Special Case: Hirschsprung in the Older Child

 

A recent study (Maerzheuser et al., 2012) was published concerning diagnosis of Hirschsprung disease in older children between the ages of 14 months and 14 years.  Six of the 10 patients in the study had delayed diagnosis because contrast enema had nonspecific findings, in all cases the enema was performed in the first three weeks of life. 

The authors concluded that contrast enema was not a specific method for diagnosing HD and that rectal biopsy must be done. 

Common symptoms among the older diagnosed children were:

  • Intractable constipation since birth
  • Delayed passage of meconium
  • Onset of symptoms AFTER cessation of breast-feeding
  • Abdominal distention
  • Lack of symptom-free intervals
  • Need for constant laxatives or enemas
  • Fecal impaction in distal colon
  • Recurrent GI infection

 

Differential Diagnosis

  • Small left colon syndrome (seen in infants of diabetic mothers)
  • Retentive Constipation (in childhood)
  • Celiac disease (in childhood)
  • Mechanical obstruction
  • GI smooth muscle dysfunction
  • Adrenal insufficiency
  • Hypothyroidism
  • Electrolyte abnormalities (K, Ca, Mg)
  • Medications causing decreased motility
  • Neuronal intestinal dysplasias
  • VACTERL

 

Workup

  • Plain Film
             
    • Abdominal xray may reveal dilated colon proximal to affected segment with paucity of rectal air
  • Barium enema demonstrates a narrow segment with abrupt transition to dilated segment
  • Anorectal manometry – PPV 75-95% but less accurate in infants <1 month; Lack of relaxation of internal anal sphincter and distension of the bowel are suggestive of Hirschsprung Disease.
  • Full-thickness rectal biopsy (2-3 cm above anal verge) demonstrating absence of ganglion cells is diagnostic

 

Figure4.jpg
Biopsy from a normal colon. The black box is surrounding ganglion cells of the myenteric plexus that are absent in the figure below - http://www.med-ed.virginia.edu/courses/cell/resources/HirschsprungClinCor/

Figure3.jpg
Biopsy from a Hirschsprung colon. - http://www.med-ed.virginia.edu/courses/cell/resources/HirschsprungClinCor/

 

 

Treatment

Treatment for Hirschsprung disease is surgical.  Attempts to treat medically are unsafe as dilation of bowel can lead to perforation.  Frozen sections are used in surgery to remove the entirety of the aganglionic bowel.  Several surgical techniques, including laparoscopy, may be used to anastomose the ganglionated bowel to the rectum, within 1 cm of the anal verge.  The anal sphincter is left intact for control of defecation and continence.  Stricture and anastomotic leak are the most common surgical complications.

In children with ultra-short segment disease, internal anal sphincter myotomy or botulinum toxin injection may relieve symptoms.

 

References

  1. Brunicardi et al. Schwartz’s Principles of Surgery. Chapter 39. Pediatric Surgery. 9th Edition: http//www.accessmedicine.com.  Accessed 10/14/12.
  2. Gariepy, C. Developmental Disorders of the Enteric Nervous System: Genetic and Molecular Bases. Journal of Pediatric Gastroenterology and Nutrition. 2004;39:5-11.
  3. Heanue T, Pachnis V. Enteric nervous system development and Hirschsprung’s disease: advances in genetic and stem cell studies. Nat Rev Neurosci. 2007 Jun;8(6):466-79.
  4. Hirschsprung Disease. Pediatrics in Review. 1989;10;207. 
  5. Maerzheuser et al.  Hirschsprung Disease in the Older Child: Diagnostic Strategies. Clin Pediatr.  Online 30 August 2012.
  6. Papadakis et al.  CURRENT Medical Diagnosis and Treatment. Chapter 20. Gastrointestinal Tract. 52nd Edition: http//www.accessmedicine.com
  7. Rudolph C, Benaroch L.  Hirschsprung Disease. Pediatrics in Review 1995; 16;5
  8. Wesson, D. Congenital aganglionic megacolon (Hirschsprung Disease).  www.uptodate.com.  Accessed 11/1/2012.