Hirschsprung's disease pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
Hirschsprung’s disease is a [[congenital]] disorder of the colon | Hirschsprung’s disease is a [[congenital]] disorder of the colon in which certain [[nerve cells]], known as [[Ganglion cell|ganglion cells]], are absent. It may cause [[chronic constipation]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
===Genetics=== | ===Genetics=== | ||
* According to a | * According to a study in 2002 and more recent research, the interaction between two [[proteins]] [[genetic code|encoded]] by two variant [[genes]] may cause Hirschsprung’s disease. | ||
* The [[RET proto-oncogene]] on [[chromosome 10]] was identified as one of the involved [[gene]]s; it was determined that [[mutation|dominant mutation]]s may occur within this [[gene]] | * The [[RET proto-oncogene]] on [[chromosome 10]] was identified as one of the involved [[gene]]s; it was determined that [[mutation|dominant mutation]]s may occur within this [[gene]], leading to a loss of function in the [[genetic code|encoded]] protein.<ref name="urlThieme E-Journals - European Journal of Pediatric Surgery / Abstract">{{cite web |url=https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-2008-1066115 |title=Thieme E-Journals - European Journal of Pediatric Surgery / Abstract |format= |work= |accessdate=}}</ref> | ||
* The protein with which [[RET proto-oncogene|RET]] has to interact for Hirschsprung’s disease development is termed EDNRB, encoded by the [[gene]] ''EDNRB'' located on [[chromosome 13 (human)|chromosome 13]]. | * The protein with which [[RET proto-oncogene|RET]] has to interact for Hirschsprung’s disease development is termed EDNRB, encoded by the [[gene]] ''EDNRB'' located on [[chromosome 13 (human)|chromosome 13]]. | ||
* Six other genes were discovered to be associated with Hirschsprung’s disease. According to the study, these genes include: [[GDNF]] on [[chromosome 5 (human)|chromosome 5]], EDN3 on [[chromosome 20 (human)|chromosome 20]], [[SOX10]] on [[chromosome 22 (human)|chromosome 22]], ECE1 on [[chromosome 1 (human)|chromosome 1]], NTN on [[chromosome 19 (human)|chromosome 19]], and SIP1 on [[chromosome 2 (human)|chromosome 2]]. | * Six other genes were discovered to be associated with Hirschsprung’s disease. According to the study, these genes include: [[GDNF]] on [[chromosome 5 (human)|chromosome 5]], EDN3 on [[chromosome 20 (human)|chromosome 20]], [[SOX10]] on [[chromosome 22 (human)|chromosome 22]], ECE1 on [[chromosome 1 (human)|chromosome 1]], NTN on [[chromosome 19 (human)|chromosome 19]], and SIP1 on [[chromosome 2 (human)|chromosome 2]]. | ||
* Scientists concluded that the mode of inheritance in Hirschsprung’s disease is oligogenic inheritance. This means that two mutated [[genes]] interact to cause a disorder. Variations in [[RET proto-oncogene|RET]] and EDNRB have to coexist to involve a child with Hirschsprung’s disease.<ref name="urlA gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10 - Nature Genetics">{{cite web |url=https://www.nature.com/ng/journal/v4/n4/abs/ng0893-351.html |title=A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10 - Nature Genetics |format= |work= |accessdate=}}</ref> | * Scientists concluded that the mode of inheritance in Hirschsprung’s disease is oligogenic inheritance. This means that two mutated [[genes]] interact to cause a disorder. Variations in [[RET proto-oncogene|RET]] and EDNRB have to coexist to involve a child with Hirschsprung’s disease.<ref name="urlA gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10 - Nature Genetics">{{cite web |url=https://www.nature.com/ng/journal/v4/n4/abs/ng0893-351.html |title=A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10 - Nature Genetics |format= |work= |accessdate=}}</ref> | ||
* Although six other [[genes]] were shown to have an effect on Hirschsprung’s disease, the researchers were unable to determine how they interacted with [[RET proto-oncogene|RET]] and EDNRB. Thus, the specifics of the disease origin are still not completely known. | * Although six other [[genes]] were shown to have an effect on Hirschsprung’s disease, the researchers were unable to determine how they interacted with [[RET proto-oncogene|RET]] and EDNRB. Thus, the specifics of the disease origin are still not completely known. | ||
* More recently, syndromic cases of Hischprung's disease (i.e. | * More recently, syndromic cases of Hischprung's disease (i.e. cases associated with other defects of the [[autonomic nervous system]]) were shown to be caused by [[mutations]] in the [[homeobox gene]] [[PHOX2B]]. | ||
* [[RET proto-oncogene|RET]] codes for the proteins that help [[neural crest cells]] (which become [[ganglion cells]]) move through the digestive tract | * [[RET proto-oncogene|RET]] codes for the proteins that help [[neural crest cells]] (which become [[ganglion cells]]) move through the digestive tract during the development of the [[embryo]]. | ||
* EDNRB codes for [[proteins]] | * 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 mutation of these two [[genes]], which would lead to the wrong proteins being produced. | ||
* | * Research in June 2004 suggested that there are actually ten [[genes]] associated with Hirschsprung’s disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously thought genes. | ||
* Dr. Bob Sawin | * Dr. Bob Sawin of the Seattle’s Children's Hospital notes that when looking for the genetic cause of Hirschsprung’s disease in the scientific community, it is generally accepted that [[RET proto-oncogene|RET]] is the most important gene. [[RET proto-oncogene|RET]] mutate in many ways and is associated with [[Down syndrome]]. Since [[Down Syndrome]] is co-morbid with two percent of Hirschsprung’s disease cases, it is assumed that [[RET proto-oncogene|RET]] is involved strongly in both Hirschsprung's disease and [[Down syndrome|Down Syndrome]].<ref name="pmid7472925">{{cite journal |vauthors=Elhalaby EA, Teitelbaum DH, Coran AG, Heidelberger KP |title=Enterocolitis associated with Hirschsprung's disease: a clinical histopathological correlative study |journal=J. Pediatr. Surg. |volume=30 |issue=7 |pages=1023–6; discussion 1026–7 |year=1995 |pmid=7472925 |doi= |url=}}</ref> | ||
* [[RET proto-oncogene|RET]] is also associated with [[thyroid cancer]] and [[neuroblastoma]]. | * [[RET proto-oncogene|RET]] is also associated with [[thyroid cancer]] and [[neuroblastoma]]. Both of these disorders have also been seen among Hirschsprung’s disease patients with greater frequency than general population. | ||
* In the developing [[fetus]], one function that [[RET proto-oncogene|RET]] controls is the travel of the [[neural crest cell]]s through the [[intestine]]s. When [[RET proto-oncogene|RET]] mutations | * In the developing [[fetus]], one function that [[RET proto-oncogene|RET]] controls is the travel of the [[neural crest cell]]s through the [[intestine]]s. When [[RET proto-oncogene|RET]] mutations occur, the cells that started traveling through the [[colon]] stop, causing Hirschsprung’s disease. The earlier the [[RET proto-oncogene|RET]] mutation occurs in Hirschsprung’s disease, the more severe the disorder becomes. | ||
* While researchers remain uncertain of the exact genetic cause of Hirschsprung’s disease, Dr. Sawin notes that in familial cases (in which families have multiple affected members), Hirschsprung’s disease exhibits [[Autosomal dominant|autosomal dominant transmission]], with dominance of the [[RET proto-oncogene|RET]]. However, in sporadic cases, Sawin notes that there is no identified inheritance pattern. | * While researchers remain uncertain of the exact genetic cause of Hirschsprung’s disease, Dr. Sawin notes that in familial cases (in which families have multiple affected members), Hirschsprung’s disease exhibits [[Autosomal dominant|autosomal dominant transmission]], with dominance of the [[RET proto-oncogene|RET]]. However, in sporadic cases, Sawin notes that there is no identified inheritance pattern. | ||
===Microscopic pathology=== | ===Microscopic pathology=== | ||
*[[Biopsy]] shows absence of [[Ganglion cells|ganglionic cells]]. | *[[Biopsy]] shows absence of [[Ganglion cells|ganglionic cells]]. | ||
*Presence of [[hypertrophy|hypertrophied]] nerve trunks in the [[lamina propria]] | *Presence of [[hypertrophy|hypertrophied]] nerve trunks in the [[lamina propria]] demonstrated by [[Acetylcholinesterase|acetylcholinesterase staining]].<ref>Worman and Ganiats 1995, Am Fam Physician 51, 487-494 [http://www.ncbi.nlm.nih.gov/pubmed/7840044]</ref> | ||
*[[Calretinin]] staining shows decreased [[immunofluorescence]]. | *[[Calretinin]] staining shows decreased [[immunofluorescence]]. | ||
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Revision as of 14:20, 4 August 2017
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Ahmed Younes M.B.B.CH [3], Aditya Ganti M.B.B.S. [4]
Overview
Hirschsprung’s disease is a congenital disorder of the colon in which certain nerve cells, known as ganglion cells, are absent. It may cause chronic constipation.
Pathophysiology
Genetics
- According to a study in 2002 and more recent research, the interaction between two proteins encoded by two variant genes may cause Hirschsprung’s disease.
- The RET proto-oncogene on chromosome 10 was identified as one of the involved genes; it was determined that dominant mutations may occur within this gene, leading to a loss of function in the encoded protein.[1]
- The protein with which RET has to interact for Hirschsprung’s disease development is termed EDNRB, encoded by the gene EDNRB located on chromosome 13.
- Six other genes were discovered to be associated with Hirschsprung’s disease. According to the study, these genes include: GDNF on chromosome 5, EDN3 on chromosome 20, SOX10 on chromosome 22, ECE1 on chromosome 1, NTN on chromosome 19, and SIP1 on chromosome 2.
- Scientists concluded that the mode of inheritance in Hirschsprung’s disease is oligogenic inheritance. This means that two mutated genes interact to cause a disorder. Variations in RET and EDNRB have to coexist to involve a child with Hirschsprung’s disease.[2]
- Although six other genes were shown to have an effect on Hirschsprung’s disease, the researchers were unable to determine how they interacted with RET and EDNRB. Thus, the specifics of the disease origin are still not completely known.
- More recently, syndromic cases of Hischprung's disease (i.e. cases associated with other defects of the autonomic nervous system) were shown to be caused by mutations in the homeobox gene PHOX2B.
- RET codes for the proteins that help neural crest cells (which become ganglion cells) move 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 mutation of these two genes, which would lead to the wrong proteins being produced.
- Research in June 2004 suggested that there are actually ten genes associated with Hirschsprung’s disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously thought genes.
- Dr. Bob Sawin of the Seattle’s Children's Hospital notes that when looking for the genetic cause of Hirschsprung’s disease in the scientific community, it is generally accepted that RET is the most important gene. RET mutate in many ways and is associated with Down syndrome. Since Down Syndrome is co-morbid with two percent of Hirschsprung’s disease cases, it is assumed that RET is involved strongly in both Hirschsprung's disease and Down Syndrome.[3]
- RET is also associated with thyroid cancer and neuroblastoma. Both of these disorders have also been seen among Hirschsprung’s disease patients with greater frequency than general population.
- In the developing fetus, one function that RET controls is the travel of the neural crest cells through the intestines. When RET mutations occur, the cells that started traveling through the colon stop, causing Hirschsprung’s disease. The earlier the RET mutation occurs in Hirschsprung’s disease, the more severe the disorder becomes.
- While researchers remain uncertain of the exact genetic cause of Hirschsprung’s disease, Dr. Sawin notes that in familial cases (in which families have multiple affected members), Hirschsprung’s disease exhibits autosomal dominant transmission, with dominance of the RET. However, in sporadic cases, Sawin notes that there is no identified inheritance pattern.
Microscopic pathology
- Biopsy shows absence of ganglionic cells.
- Presence of hypertrophied nerve trunks in the lamina propria demonstrated by acetylcholinesterase staining.[4]
- Calretinin staining shows decreased immunofluorescence.
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Video: Histopathological Findings
{{#ev:youtube|v3mfl0l6Tdo}}
References
- ↑ "Thieme E-Journals - European Journal of Pediatric Surgery / Abstract".
- ↑ "A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10 - Nature Genetics".
- ↑ Elhalaby EA, Teitelbaum DH, Coran AG, Heidelberger KP (1995). "Enterocolitis associated with Hirschsprung's disease: a clinical histopathological correlative study". J. Pediatr. Surg. 30 (7): 1023–6, discussion 1026–7. PMID 7472925.
- ↑ Worman and Ganiats 1995, Am Fam Physician 51, 487-494 [1]