Hirschsprung's disease

Hirschsprung's disease
Classification and external resources
Histopathology of Hirschsprung disease. Enzyme histochemistry showing aberrant acetylcholine esterase (ACHE)-positive fibres (brown) in the lamina propria mucosae.
ICD-10	Q43.1
ICD-9	751.3
OMIM	142623
DiseasesDB	5901
MedlinePlus	001140
eMedicine	med/1016
MeSH	D006627

Hirschsprung's disease (HSCR), or congenital aganglionic megacolon is a serious medical problem where the enteric nervous system is missing from the end of the bowel. The enteric nervous system is a complex network of neurons (i.e., ganglion cells) and glia that controls most aspects of intestinal function. When the ENS is absent, the region of the bowel that is aganglionic fails to relax causing a blockage in the bowel^[1]. People with Hirschsprung disease always have aganglionosis (lack of neurons) at the end of the bowel, but the length of bowel that is aganglionic varies. Severe symptoms may occur with even short segments of aganglionosis and symptom severity does not correlate well with the extent of aganglionic bowel.

History and description

The first report of Hirschsprung disease dates back to 1691^[2], however, the disease is named after Harald Hirschsprung, the Danish physician who first described two infants who died of this disorder in 1888,^[3][4].

Hirschsprung’s disease is a congenital disorder of the colon in which certain nerve cells, known as ganglion cells, are absent, causing chronic constipation.^[5] The lack of ganglion cells is in the myenteric plexus, which is responsible for moving food in the intestine. A barium enema is the mainstay of diagnosis of Hirschsprung’s, though a rectal biopsy showing the lack of ganglion cells is the only certain method of diagnosis.

The usual treatment is "pull-through" surgery where the portion of the colon that does have nerve cells is pulled through and sewn over the part that lacks nerve cells (National Digestive Diseases Information Clearinghouse). For a long time, Hirschsprung’s was considered a multi-factorial disorder, where a combination of nature and nurture were considered to be the cause. However, in August 1993, two articles by independent groups in Nature Genetics said that Hirschsprung’s disease could be mapped to a stretch of chromosome 10.^[6][7]

This research also suggested that a single gene was responsible for the disorder. However, the researchers were unable to isolate it.

Epidemiology

According to a 1984 study, Hirshsprung's disease appears on 18.6 per 100,000 live births. It is more common in male rather than female (4.32:1) and in white rather than non-white^[8] 9% of the Hirschsprung cases were also diagnosed as having Down's Syndrome.^[9]

Genetic basis

Several genes and loci have been shown or suggested to be associated with Hirschsprung's disease:

Type	OMIM	Gene	Locus
HSCR1	142623	RET	10q11.2
HSCR2	600155	EDNRB	13q22
HSCR3	600837	GDNF	5p13.1-p12
HSCR4	131242	EDN3	20q13.2-q13.3
HSCR5	600156	?	21q22
HSCR6	606874	?	3p21
HSCR7	606875	?	19q12
HSCR8	608462	?	16q23
HSCR9	611644	?	4q31-32
-	602229	SOX10	22q13
-	600423	ECE1	1p36.1
-	602018	NRTN	19p13.3
-	602595	SIP1	14q13-q21

Hirschsprung's disease can also present as part of a syndrome in Waardenburg-Shah syndrome, Mowat-Wilson syndrome, Goldberg-Shpritzen megacolon syndrome, and congenital central hypoventilation syndrome.^[10]

In 2002, scientists thought they found the solution. According to this new research, Hirschsprung's is caused by the interaction between two proteins encoded by two variant genes. The RET proto-oncogene on chromosome 10 was identified as one of the genes involved. The protein with which RET has to interact in order for Hirschsprung’s disease to develop is termed EDNRB and is encoded by the gene EDNRB located on chromosome 13.

RET codes for proteins that assist cells of the neural crest (which later become ganglion cells) in their movement through the digestive tract during the development of the embryo. EDNRB codes for proteins that connect these nerve cells to the digestive tract. This means that the absence of certain nerve fibers in the colon could be directly related to these two genes mutating so the wrong proteins are produced. Research published in June 2004 suggests that there are several genes associated with Hirschsprung’s disease.^[11] Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously thought.

RET can mutate in many ways and is associated with Down's syndrome. Since Down Syndrome is comorbid in two percent of Hirschsprung’s cases, there is a likelihood that RET is involved heavily in both Hirschprung's disease and Down Syndrome. RET is also associated with thyroid cancer and neuroblastoma. Both of these disorders have also been observed in Hirschsprung’s patients with greater frequency than in the general population. One function that RET controls is the travel of the neural crest cells through the intestines in the developing fetus. The earlier the mutation of RET occurs in Hirschsprung’s disease, the more severe the disorder becomes.

Hirschsprung's disease, hypoganglionosis, gut dysmotility, gut transit disorders and intussusception have been recorded with the dominantly inherited neurovisceral porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria). Children may require enzyme or DNA testing for these disorders as they may not produce or excrete porphyrins prepuberty.

Clinical features

A: Plain abdominal radiograph showing a PARTZ at rectosigmoid, arrow. B: Plain abdominal radiograph showing a PARTZ at midsigmoid, arrow. C: Plain abdominal radiograph showing a PARTZ at descending colon, arrow. D: Contrast enema showing a CETZ at rectosigmoid, arrow. E: Contrast enema showing a CETZ at midsigmoid, arrow. F: Contrast enema showing a CETZ at descending colon, arrow.

With an incidence of 1/5000 births, the most cited feature is absence of ganglion cells: notably in males, 75% have none in the recto-sigmoid and 8% with none in the entire colon. The enlarged section of the bowel is found proximally, while the narrowed, aganglionic section is found distally. The absence of ganglion cells results in a persistent over-stimulation of nerves in the affected region, resulting in contraction.

1. Delayed passage of meconium
2. Abdominal distension
3. Constipation

Diagnosis

Hirschsprung's disease is suspected in a baby who has not passed meconium within 48 hours of delivery. Normally, 90% of babies pass their first meconium within 24 hours, and 99% within 48 hours. Other symptoms include, green or brown vomit, explosive stools after a doctor inserts a finger into the rectum, swelling of the abdomen, lots of gas and bloody diarrhea. Definitive diagnosis is made by suction biopsy of the distally narrowed segment.^[12]

Diagnostic techniques involve anorectal manometry,^[13] barium enema, and rectal biopsy.

Radiologic findings may also assist with diagnosis.^[14]

Treatment

Treatment of Hirschsprung's disease consists of surgical removal (resection) of the abnormal section of the colon, followed by reanastomosis. There used to be two steps typically used to achieve this goal.

• The first stage used to be a colostomy. When a colostomy is performed, the large intestine is cut and an opening is made through the abdomen. This allows bowel contents to be discharged into a bag.
• Later, when the child’s weight, age, and condition is right, a pull-through procedure is performed.

Orvar Swenson, who discovered the cause of Hirschsprung’s, first performed it in 1948.^[15] The pull-through procedure repairs the colon by connecting the functioning portion of the bowel to the anus. The pull-through procedure is the typical method for treating Hirschsprung’s in younger patients. Swenson devised the original procedure, and the pull-through surgery has been modified many times.

The Swenson, Soave, Duhamel, and Boley procedures all vary slightly from each other:

• The Swenson procedure leaves a small portion of the diseased bowel.
• The Soave procedure leaves the outer wall of the colon unaltered. The Boley procedure is a small modification of the Soave procedure. The term "Soave-Boley" procedure is sometimes used.^[16][17]
• The Duhamel procedure uses a surgical stapler to connect the good and bad bowel.

Of those 15% of children who do not obtain full control, other treatments are available. If constipation is the problem then usually laxatives or a high fiber diet will overcome the problem. If lack of control is the problem then a stoma may be necessary. The Malone ACE is also an answer. This is where a tube goes through the abdominal wall to the appendix or, if available, to the colon. Then once a day the bowel is flushed. Children as young as 6 do fine with administering this on their own. Details of ostomical sugery and its results can be found in the book Unwanted Baggage by P. and E. Prosser.

If the affected portion of the lower intestine is restricted to the lower portion of the rectum, other surgical procedures, such as the posterior rectal myectomy, can be performed.

See also

• Intestinal Neuronal Dysplasia
• Achalasia

References

1. ^ Parisi MA (2002). Pagon RA, Bird TC, Dolan CR, Stephens K. ed. "Hirschsprung Disease Overview". GeneReviews. PMID 20301612. http://www.ncbi.nlm.nih.gov/books/NBK1439/. 
2. ^ Hirschsprung's Disease and Allied Disorders. Berlin: Springer. 2007. ISBN 3-540-33934-5. 
3. ^ synd/1163 at Who Named It?
4. ^ Hirschsprung, H. (1888). "Stuhlträgheit Neugeborener in Folge von Dilatation und Hypertrophie des Colons". Jahrbuch für Kinderheilkunde und physische Erziehung (Berlin) 27: 1–7. 
5. ^ Worman S, Ganiats TG (February 1995). "Hirschsprung's disease: a cause of chronic constipation in children". Am Fam Physician 51 (2): 487–94. PMID 7840044. 
6. ^ Angrist M, Kauffman E, Slaugenhaupt SA, et al. (August 1993). "A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10". Nat. Genet. 4 (4): 351–6. doi:10.1038/ng0893-351. PMID 8401581. 
7. ^ Lyonnet S, Bolino A, Pelet A, et al. (August 1993). "A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10". Nat. Genet. 4 (4): 346–50. doi:10.1038/ng0893-346. PMID 8401580. 
8. ^ Colwell, Janice (2004). Fecal and Urinary Diversion Management. Mosby. pp. 264. ISBN 978-0-323-02248-4. 
9. ^ Goldberg EL (December 1984). "An epidemiological study of Hirschsprung's disease". Int J Epidemiol 13 (4): 479–85. doi:10.1093/ije/13.4.479. PMID 6240474. http://ije.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=6240474. 
10. ^ Online 'Mendelian Inheritance in Man' (OMIM) 142623
11. ^ Puri P, Shinkai T (February 2004). "Pathogenesis of Hirschsprung's disease and its variants: recent progress". Semin. Pediatr. Surg. 13 (1): 18–24. doi:10.1053/j.sempedsurg.2003.09.004. PMID 14765367. http://linkinghub.elsevier.com/retrieve/pii/S1055858603000623. 
12. ^ Dobbins, W. O.; Bill, A. H. (1965). "Diagnosis of Hirschsprung's Disease Excluded by Rectal Suction Biopsy". New England Journal of Medicine 272 (19): 990–993. doi:10.1056/NEJM196505132721903. PMID 14279253.  edit
13. ^ Eli Ehrenpreis (October 2003). Anal and rectal diseases explained. Remedica. pp. 15–. ISBN 9781901346671. http://books.google.com/books?id=nB-HLHPaxu0C&pg=PA15. Retrieved 10 November 2010. 
14. ^ Kim HJ, Kim AY, Lee CW, et al. (May 2008). "Hirschsprung disease and hypoganglionosis in adults: radiologic findings and differentiation". Radiology 247 (2): 428–34. doi:10.1148/radiol.2472070182. PMID 18430875. http://radiology.rsnajnls.org/cgi/pmidlookup?view=long&pmid=18430875. 
15. ^ Swenson O (August 1989). "My early experience with Hirschsprung's disease". J. Pediatr. Surg. 24 (8): 839–44; discussion 844–5. doi:10.1016/S0022-3468(89)80549-4. PMID 2671336. http://linkinghub.elsevier.com/retrieve/pii/S0022346889002721. 
16. ^ W. Allan Walker (1 July 2004). Pediatric gastrointestinal disease: pathophysiology, diagnosis, management. PMPH-USA. pp. 2120–. ISBN 9781550092400. http://books.google.com/books?id=dI5NhvRaWbkC&pg=PA2120. Retrieved 10 November 2010. 
17. ^ Timothy R. Koch (2003). Colonic diseases. Humana Press. pp. 387–. ISBN 9780896039612. http://books.google.com/books?id=OUDJ8Vr4ZrgC&pg=PA387. Retrieved 10 November 2010. 

External links

• Hirschsprung's disease at the Open Directory Project
• [1]