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Hirschsprung disease, susceptibility to, 1(HSCR1; MGC; HSCR)

MedGen UID:
854827
Concept ID:
C3888239
Finding
Synonyms: Hirschsprung disease 1; HSCR 1; RET-Related Hirschsprung Disease
 
Gene (location): RET (10q11.21)
 
Monarch Initiative: MONDO:0007723
OMIM®: 142623

Definition

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.

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).

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.

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. [from MedlinePlus Genetics]

Clinical features

From HPO
Abdominal distention
MedGen UID:
34
Concept ID:
C0000731
Finding
Distention of the abdomen.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Enterocolitis
MedGen UID:
4966
Concept ID:
C0014356
Disease or Syndrome
An inflammation of the colon and small intestine. However, most conditions are either categorized as Enteritis (inflammation of the small intestine) or Colitis (inflammation of the large intestine).
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).
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Abnormal enteric ganglion morphology
MedGen UID:
927580
Concept ID:
C4293671
Anatomical Abnormality
An abnormality of the enteric nervous system, which comprises two types of ganglia, the myenteric (Auerbach's) and submucosal (Meissner's) plexuses. The enteric nervous system functions to control gut movement, fluid exchange between the gut and its lumen, and local blood flow.

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
Moore SW, Zaahl MG
J Pediatr Surg 2008 Feb;43(2):325-9. doi: 10.1016/j.jpedsurg.2007.10.021. PMID: 18280283

Recent clinical studies

Etiology

Yu XX, Chu X, Wu WJ, Wei ZL, Song HL, Bai MR, Lu YJ, Gu BL, Gong YM, Cai W
Pediatr Res 2021 Feb;89(3):694-700. Epub 2020 May 7 doi: 10.1038/s41390-020-0933-3. PMID: 32380506
Amooee A, Lookzadeh MH, Mirjalili SR, Miresmaeili SM, Aghili K, Zare-Shehneh M, Neamatzadeh H
Arq Bras Cir Dig 2019;32(3):e1448. Epub 2019 Oct 21 doi: 10.1590/0102-672020190001e1448. PMID: 31644668Free 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
Liang CM, Ji DM, Yuan X, Ren LL, Shen J, Zhang HY
PLoS One 2014;9(3):e90091. Epub 2014 Mar 20 doi: 10.1371/journal.pone.0090091. PMID: 24651702Free PMC Article
Moore SW, Zaahl MG
Pediatr Surg Int 2008 May;24(5):521-30. Epub 2008 Mar 26 doi: 10.1007/s00383-008-2137-5. PMID: 18365214

Diagnosis

Arora V, Khan S, El-Hattab AW, Dua Puri R, Rocha ME, Merdzanic R, Paknia O, Beetz C, Rolfs A, Bertoli-Avella AM, Bauer P, Verma IC
J Am Soc Nephrol 2021 Jan;32(1):223-228. Epub 2020 Oct 5 doi: 10.1681/ASN.2020040478. PMID: 33020172Free PMC Article
Amooee A, Lookzadeh MH, Mirjalili SR, Miresmaeili SM, Aghili K, Zare-Shehneh M, Neamatzadeh H
Arq Bras Cir Dig 2019;32(3):e1448. Epub 2019 Oct 21 doi: 10.1590/0102-672020190001e1448. PMID: 31644668Free PMC Article
Tam PK
J Pediatr Surg 2016 Jan;51(1):18-22. Epub 2015 Oct 21 doi: 10.1016/j.jpedsurg.2015.10.021. PMID: 26611330
Moore SW, Zaahl MG
Pediatr Surg Int 2008 May;24(5):521-30. Epub 2008 Mar 26 doi: 10.1007/s00383-008-2137-5. PMID: 18365214
Eng C
J Clin Oncol 1999 Jan;17(1):380-93. doi: 10.1200/JCO.1999.17.1.380. PMID: 10458257

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
Zhang Z, Li Q, Diao M, Liu N, Cheng W, Xiao P, Zou J, Su L, Yu K, Wu J, Li L, Jiang Q
Sci Rep 2017 Nov 1;7(1):14796. doi: 10.1038/s41598-017-14835-6. PMID: 29093530Free PMC Article
Cheng WW, Tang CS, Gui HS, So MT, Lui VC, Tam PK, Garcia-Barcelo MM
World J Gastroenterol 2015 Feb 21;21(7):2040-6. doi: 10.3748/wjg.v21.i7.2040. PMID: 25717236Free PMC Article

Prognosis

Zhang ZW, Guo X, Qi XP
Endocr Metab Immune Disord Drug Targets 2021;21(3):534-543. doi: 10.2174/1871530320666200910112230. PMID: 32914730
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 MG
Pediatr Surg Int 2008 May;24(5):521-30. Epub 2008 Mar 26 doi: 10.1007/s00383-008-2137-5. PMID: 18365214
Lantieri F, Griseri P, Ceccherini I
Ann Med 2006;38(1):11-9. doi: 10.1080/07853890500442758. PMID: 16448984
Eng C
J Clin Oncol 1999 Jan;17(1):380-93. doi: 10.1200/JCO.1999.17.1.380. PMID: 10458257

Clinical prediction guides

Zhang ZW, Guo X, Qi XP
Endocr Metab Immune Disord Drug Targets 2021;21(3):534-543. doi: 10.2174/1871530320666200910112230. PMID: 32914730
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
Fernández RM, Bleda M, Luzón-Toro B, García-Alonso L, Arnold S, Sribudiani Y, Besmond C, Lantieri F, Doan B, Ceccherini I, Lyonnet S, Hofstra RM, Chakravarti A, Antiñolo G, Dopazo J, Borrego S
Orphanet J Rare Dis 2013 Dec 2;8:187. doi: 10.1186/1750-1172-8-187. PMID: 24289864Free PMC Article
Moore SW, Zaahl MG
Pediatr Surg Int 2008 May;24(5):521-30. Epub 2008 Mar 26 doi: 10.1007/s00383-008-2137-5. PMID: 18365214

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
Amooee A, Lookzadeh MH, Mirjalili SR, Miresmaeili SM, Aghili K, Zare-Shehneh M, Neamatzadeh H
Arq Bras Cir Dig 2019;32(3):e1448. Epub 2019 Oct 21 doi: 10.1590/0102-672020190001e1448. PMID: 31644668Free PMC Article

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