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Hirschsprung disease

Other Names: Intestinal aganglionosis, congenital megacolon


Hirschsprung disease is a condition that involves the large intestine and causes severe constipation or blockage in the intestine. As a multigenic condition, it is thought to be caused by changes or variants in multiple genes.

Characteristics of Hirschsprung disease
Hirschsprung disease is the lack of a specific type of nerve cell, ganglion cells, from a portion of the colon. Ganglion cells play a role in creating the wave-like motion that pushes digested food through the intestinal tract. Without these nerve cells, food waste is not able to move through the colon and a functional obstruction or severe constipation occurs. Hirschsprung disease is often suspected in newborns who have not passed meconium (i.e., the earliest stools passed by a newborn) within the first 2 days of life. In the majority of cases, the lack of ganglion cells (called aganglionosis) occurs only in the distal part of the colon, affecting the rectum and a portion of the colon closest to it. However, the aganglionosis may extend further into the colon, affecting any distal portion of the colon, the entire colon, and in rare cases upper portions of the digestive tract as well. Hirschsprung disease is more common in males, showing a 4:1 male to female ratio. Additionally, it may occur alone, or with additional birth defects or as a part of a known syndrome (a group of congenital anomalies or traits that have a single underlying cause).

Diagnosis/Testing
Hirschsprung disease is diagnosed by a rectal biopsy. This is a procedure where a surgeon removes a small piece of tissue from the inside of the rectum or colon. A pathologist then examines the piece of tissue and if ganglion cells are not present then the diagnosis of Hirschsprung disease is made. Other tests may be done to see if Hirschsprung disease is a likely diagnosis before a rectal biopsy is done for a definitive diagnosis. Hirschsprung disease is most often diagnosed in the newborn period with the remainder of individuals being diagnosed within the first 2 years of life. In rare cases, Hirschsprung disease is diagnosed in older children or adults suffering from chronic severe constipation.
The genetics of Hirschsprung disease is a complex puzzle, for which much is still to be learned. Research has shown that Hirschsprung disease is a multigenic condition, meaning that multiple genes are involved in causing disease. The RET gene is considered to be the major gene in Hirschsprung disease. RET variants and variants in other Hirschsprung disease genes have shown reduced penetrance, meaning that not all individuals who have a risk variant will have Hirschsprung disease. Therefore, in most cases two or more variants, often in multiple genes, must be combined for Hirschsprung disease to occur.
Researchers suspect that most, if not all, individuals who have Hirschsprung disease have a risk increasing variant somewhere in the RET gene. However, there are many other genes that are implicated in Hirschsprung disease and research is continuing to identify new genes.

Management/Surveillance
Hirschsprung disease is treated by surgically removing the portion of the colon that does not have ganglion cells and attaching the remaining healthy portion of the colon to the anus. The majority of children do well after surgical treatment, having normal stooling or needing slight changes in diet or medications to promote normal stooling. However, some individuals have ongoing difficulties with constipation, soiling or other complications.

Mode of inheritance
As stated earlier, research suggests that multiple genes are involved in causing Hirschsprung disease. In most cases, tow or more variants, often in multiple genes, are needed for Hirschsprung disease to occur.
In instances where Hirschsprung disease occurs as part of a known syndrome, the chance that future individuals born into the family will be affected depends upon the specific syndrome and its inheritance pattern.

Risk to family members
Once an individual in a family is born with Hirschsprung disease, the chance for future children born into the family to have Hirschsprung disease is increased from that of the general population. An estimated chance for future children to be affected may be provided based on the family history, gender of the affected individual, and the length of colon that was affected. Genetic testing can also sometimes give additional information.

Special considerations
None

Resources
Genetics Home Reference: Hirschsprung disease
National Digestive Diseases Information Clearinghouse
American Pediatric Surgical Association
Hirschsprung Disease Genetics Study at Johns Hopkins University

References
Amiel, J. et al. (2008)."Hirschsprung disease, associated syndromes and genetics: a review." Journal of Medical Genetics 45(1): 1-14.
Badner, JA. et al. (1990)."A genetic study of Hirschsprung disease." American Journal of Human Genetics 46: 568-580.
Chakravarti A, Lyonnet S. (2001). Hirschsprung Disease (Scriver CR, Beaudet AL, Valle D, Sly WS, Childs B, Kinzler K, Vogelstein B, Eds.). In The Metabolic and Molecular Bases of Inherited Disease (pp.6231-6255). New York, NY: McGraw-Hill. Print.
Emison, ES. et al. (2010)."Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability." American Journal of Human Genetics 87(1): 60-74.

Created:09/2013

Updated:mm/yyyy

Created by:Courtney Berrios, ScM, CGC

Edited by:Seema Jamal, MSc, LCGC



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