U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Hirschsprung disease, susceptibility to, 4(HSCR4)

MedGen UID:
462325
Concept ID:
C3150975
Finding
Synonym: Hirschsprung disease 4
 
Gene (location): EDN3 (20q13.32)
 
Monarch Initiative: MONDO:0013384
OMIM®: 613712

Definition

The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid. Total colonic aganglionosis and total intestinal HSCR also occur (Amiel et al., 2008). Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance (Amiel et al., 2008). For a discussion of genetic heterogeneity of susceptibility to Hirschsprung disease, see 142623. [from OMIM]

Additional description

From MedlinePlus Genetics
Hirschsprung disease is an intestinal disorder characterized by the absence of nerves in parts of the intestine. This condition occurs when the nerves in the intestine (enteric nerves) do not form properly during development before birth (embryonic development). This condition is usually identified in the first two months of life, although less severe cases may be diagnosed later in childhood.

Hirschsprung disease can occur in combination with other conditions, such as Waardenburg syndrome, type IV; Mowat-Wilson syndrome; or congenital central hypoventilation syndrome. These cases are described as syndromic. Hirschsprung disease can also occur without other conditions, and these cases are referred to as isolated or nonsyndromic.

Enteric nerves trigger the muscle contractions that move stool through the intestine. Without these nerves in parts of the intestine, the material cannot be pushed through, causing severe constipation or complete blockage of the intestine in people with Hirschsprung disease. Other signs and symptoms of this condition include vomiting, abdominal pain or swelling, diarrhea, poor feeding, malnutrition, and slow growth. People with this disorder are at risk of developing more serious conditions such as inflammation of the intestine (enterocolitis) or a hole in the wall of the intestine (intestinal perforation), which can cause serious infection and may be fatal.

There are two main types of Hirschsprung disease, known as short-segment disease and long-segment disease, which are defined by the region of the intestine lacking nerve cells. In short-segment disease, nerve cells are missing from only the last segment of the large intestine (colon). This type is most common, occurring in approximately 80 percent of people with Hirschsprung disease. For unknown reasons, short-segment disease is four times more common in men than in women. Long-segment disease occurs when nerve cells are missing from most of the large intestine and is the more severe type. Long-segment disease is found in approximately 20 percent of people with Hirschsprung disease and affects men and women equally. Very rarely, nerve cells are missing from the entire large intestine and sometimes part of the small intestine (total colonic aganglionosis) or from all of the large and small intestine (total intestinal aganglionosis).  https://medlineplus.gov/genetics/condition/hirschsprung-disease

Clinical features

From HPO
Aganglionic megacolon
MedGen UID:
5559
Concept ID:
C0019569
Disease or Syndrome
The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid (Amiel et al., 2008). Total colonic aganglionosis and total intestinal HSCR also occur. Genetic Heterogeneity of Hirschsprung Disease Several additional loci for isolated Hirschsprung disease have been mapped. HSCR2 (600155) is associated with variation in the EDNRB gene (131244) on 13q22; HSCR3 (613711) is associated with variation in the GDNF gene (600837) on 5p13; HSCR4 (613712) is associated with variation in the EDN3 gene (131242) on 20q13; HSCR5 (600156) maps to 9q31; HSCR6 (606874) maps to 3p21; HSCR7 (606875) maps to 19q12; HSCR8 (608462) maps to 16q23; and HSCR9 (611644) maps to 4q31-q32. HSCR also occurs as a feature of several syndromes including the Waardenburg-Shah syndrome (277580), Mowat-Wilson syndrome (235730), Goldberg-Shprintzen syndrome (609460), and congenital central hypoventilation syndrome (CCHS; 209880). Whereas mendelian modes of inheritance have been described for syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance. The development of surgical procedures decreased mortality and morbidity, which allowed the emergence of familial cases. HSCR occurs as an isolated trait in 70% of patients, is associated with chromosomal anomaly in 12% of cases, and occurs with additional congenital anomalies in 18% of cases (summary by Amiel et al., 2008).

Professional guidelines

PubMed

Zhang ZW, Guo X, Qi XP
Endocr Metab Immune Disord Drug Targets 2021;21(3):534-543. doi: 10.2174/1871530320666200910112230. PMID: 32914730
Klemetti P, Valta H, Kostjukovits S, Taskinen M, Toiviainen-Salo S, Mäkitie O
Clin Genet 2017 Aug;92(2):204-207. Epub 2017 Mar 19 doi: 10.1111/cge.12969. PMID: 28094436
Borrego S, Ruiz A, Saez ME, Gimm O, Gao X, López-Alonso M, Hernández A, Wright FA, Antiñolo G, Eng C
J Med Genet 2000 Aug;37(8):572-8. doi: 10.1136/jmg.37.8.572. PMID: 10922382Free PMC Article

Recent clinical studies

Etiology

Lan C, Wu Y, Wang N, Luo Y, Zhao J, Zheng Y, Zhang Y, Huang L, Zhu Y, Lu L, Zhong W, Zeng J, Xia H
J Cell Mol Med 2021 Oct;25(20):9609-9616. Epub 2021 Sep 20 doi: 10.1111/jcmm.16905. PMID: 34545688Free PMC Article
Zhang H, Zhao JL, Zheng Y, Xie XL, Huang LH, Li L, Zhu Y, Lu LF, Hu TQ, Zhong W, He QM
BMC Med Genomics 2021 Jan 19;14(1):21. doi: 10.1186/s12920-020-00867-x. PMID: 33468134Free PMC Article
Tilghman JM, Ling AY, Turner TN, Sosa MX, Krumm N, Chatterjee S, Kapoor A, Coe BP, Nguyen KH, Gupta N, Gabriel S, Eichler EE, Berrios C, Chakravarti A
N Engl J Med 2019 Apr 11;380(15):1421-1432. doi: 10.1056/NEJMoa1706594. PMID: 30970187Free PMC Article
Austin KM
Semin Pediatr Surg 2012 Nov;21(4):319-27. doi: 10.1053/j.sempedsurg.2012.07.006. PMID: 22985837
Moore SW
Pediatr Surg Int 2011 Apr;27(4):347-52. Epub 2010 Dec 5 doi: 10.1007/s00383-010-2807-y. PMID: 21132502

Diagnosis

Zhang ZW, Guo X, Qi XP
Endocr Metab Immune Disord Drug Targets 2021;21(3):534-543. doi: 10.2174/1871530320666200910112230. PMID: 32914730
Gunadi, Budi NYP, Sethi R, Fauzi AR, Kalim AS, Indrawan T, Iskandar K, Makhmudi A, Adrianto I, San LP
BMC Pediatr 2018 Sep 4;18(1):292. doi: 10.1186/s12887-018-1265-x. PMID: 30180823Free PMC Article
Gosain A
Pediatr Surg Int 2016 Apr;32(4):313-20. Epub 2016 Jan 19 doi: 10.1007/s00383-016-3862-9. PMID: 26783087Free PMC Article
Moore SW
Semin Pediatr Surg 2012 Nov;21(4):302-9. doi: 10.1053/j.sempedsurg.2012.07.004. PMID: 22985835
Kapur RP
Semin Pediatr Surg 2009 Nov;18(4):212-23. doi: 10.1053/j.sempedsurg.2009.07.003. PMID: 19782303

Therapy

Nassar R, Hazan G, Leibovitz E, Ling G, Lazar I, Khalaila A, Fruchtman Y, Yerushalmi B
Eur J Clin Microbiol Infect Dis 2020 Mar;39(3):517-525. Epub 2019 Nov 25 doi: 10.1007/s10096-019-03753-2. PMID: 31768705
Wijesinha SS, Steer HW
Dis Colon Rectum 1982 May-Jun;25(4):312-20. doi: 10.1007/BF02553604. PMID: 7044725

Prognosis

Gunadi, Ryantono F, Sethi R, Marcellus, Kalim AS, Imelda P, Melati D, Simanjaya S, Widitjiarso W, Pitaka RT, Arfian N, Iskandar K, Makhmudi A, Lai PS
J Int Med Res 2021 Feb;49(2):300060520987789. doi: 10.1177/0300060520987789. PMID: 33557656Free PMC Article
Yang W, Chen SC, Lai JY, Ming YC, Chen JC, Chen PL
Neurogastroenterol Motil 2019 Nov;31(11):e13665. Epub 2019 Jun 25 doi: 10.1111/nmo.13665. PMID: 31240788
Kim JH, Jung SM, Shin JG, Cheong HS, Seo JM, Kim DY, Oh JT, Kim HY, Jung K, Shin HD
Mol Biol Rep 2017 Jul;44(3):307-313. Epub 2017 Jun 29 doi: 10.1007/s11033-017-4111-6. PMID: 28664405
Gunadi, Kapoor A, Ling AY, Rochadi, Makhmudi A, Herini ES, Sosa MX, Chatterjee S, Chakravarti A
J Pediatr Surg 2014 Nov;49(11):1614-8. Epub 2014 Aug 28 doi: 10.1016/j.jpedsurg.2014.04.011. PMID: 25475805Free PMC Article
Tam PK, Garcia-Barcelo M
Semin Pediatr Surg 2004 Nov;13(4):236-48. doi: 10.1053/j.sempedsurg.2004.10.011. PMID: 15660317

Clinical prediction guides

Gunadi, Ryantono F, Sethi R, Marcellus, Kalim AS, Imelda P, Melati D, Simanjaya S, Widitjiarso W, Pitaka RT, Arfian N, Iskandar K, Makhmudi A, Lai PS
J Int Med Res 2021 Feb;49(2):300060520987789. doi: 10.1177/0300060520987789. PMID: 33557656Free PMC Article
Yang W, Chen SC, Lai JY, Ming YC, Chen JC, Chen PL
Neurogastroenterol Motil 2019 Nov;31(11):e13665. Epub 2019 Jun 25 doi: 10.1111/nmo.13665. PMID: 31240788
Zhang Y, Xie X, Zeng J, Wu Q, Zhang R, Zhu D, Xia H
J Cell Mol Med 2018 Apr;22(4):2190-2199. Epub 2018 Jan 29 doi: 10.1111/jcmm.13498. PMID: 29377512Free PMC Article
Kim JH, Jung SM, Shin JG, Cheong HS, Seo JM, Kim DY, Oh JT, Kim HY, Jung K, Shin HD
Mol Biol Rep 2017 Jul;44(3):307-313. Epub 2017 Jun 29 doi: 10.1007/s11033-017-4111-6. PMID: 28664405
Moore SW, Zaahl M
J Pediatr Surg 2015 Feb;50(2):285-8. Epub 2014 Nov 7 doi: 10.1016/j.jpedsurg.2014.11.016. PMID: 25638620

Recent systematic reviews

Zhang ZW, Guo X, Qi XP
Endocr Metab Immune Disord Drug Targets 2021;21(3):534-543. doi: 10.2174/1871530320666200910112230. PMID: 32914730

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...