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The association between Hirschsprung's disease and multiple endocrine neoplasia type 2a: a systematic review.
Pediatr Surg Int. 2014 Aug; 30(8):751-6.PS

Abstract

PURPOSE

The co-occurrence of Hirschsprung's disease (HSCR) and multiple endocrine neoplasia type 2 (MEN2) is a relatively rare event. The basis for this association is the presence of a "Janus" mutation in the RET proto-oncogene--a mutation that acts simultaneously as both a gain-in-function and a loss-of-function mutation. To date, four mutations in the exon 10 region of RET that are known to cause MEN2A have been implicated in this association: C620, C618, C611 and C609. We performed a systematic review of the published literature on this association to determine its incidence, the prevalence and phenotype of HSCR associated with the 4 RET mutations mentioned above.

METHODS

A systematic literature-based search for relevant articles was conducted using three online databases. After exclusion of ineligible publications, we recorded data on all patients with a diagnosis of HSCR or MEN2A with a "Janus" RET mutation, as well as those who carried the mutation but were unaffected. Statistical analysis was performed using SPSS.

RESULTS

The literature search yielded 885 publications, of which 36 articles, incorporating data on 341 individuals, were eligible for inclusion in the final analysis. Co-occurrence of HSCR and MEN2A was recorded in 84 cases (24.6 %). HSCR occurred alone in 64 carriers of a "Janus" mutation (18.8 %) and MEN2A occurred in isolation in 173 cases (50.7 %). Twenty individuals (5.9 %) were found to carry a "Janus" mutation after screening on the basis of family history but were unaffected by either MEN2A or HSCR. The most common mutation recorded was the C620 mutation [114 cases (48.1 %)]. There was a relatively high incidence of long-segment aganglionosis (29.3 %) and total colonic aganglionosis (17.3 %) in this cohort. This trend was particularly notable in those with C620 mutations, only 33 % of whom had short-segment disease.

CONCLUSION

While the overall incidence of HSCR co-occurring with MEN2A is low, both conditions occur with a relatively high frequency in families with a RET mutation at exon 10. The proportion of cases of long-segment HSCR and total colonic aganglionosis is higher than that in the general population with HSCR in those with C620 and C618 mutations. These findings reinforce the importance of RET mutation testing in HSCR when a family history of either HSCR or MEN2 is present. In families with MEN2A and known exon 10 RET mutations, the threshold for investigation for HSCR in those with gastrointestinal symptoms should be very low. High-quality prospective longitudinal studies of large HSCR populations are required to shed greater light on this rare but important phenomenon.

Authors+Show Affiliations

National Children's Research Centre, Our Lady's Children's Hospital, Crumlin Rd., Dublin 12, Ireland.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review
Systematic Review

Language

eng

PubMed ID

24972642

Citation

Coyle, David, et al. "The Association Between Hirschsprung's Disease and Multiple Endocrine Neoplasia Type 2a: a Systematic Review." Pediatric Surgery International, vol. 30, no. 8, 2014, pp. 751-6.
Coyle D, Friedmacher F, Puri P. The association between Hirschsprung's disease and multiple endocrine neoplasia type 2a: a systematic review. Pediatr Surg Int. 2014;30(8):751-6.
Coyle, D., Friedmacher, F., & Puri, P. (2014). The association between Hirschsprung's disease and multiple endocrine neoplasia type 2a: a systematic review. Pediatric Surgery International, 30(8), 751-6. https://doi.org/10.1007/s00383-014-3538-2
Coyle D, Friedmacher F, Puri P. The Association Between Hirschsprung's Disease and Multiple Endocrine Neoplasia Type 2a: a Systematic Review. Pediatr Surg Int. 2014;30(8):751-6. PubMed PMID: 24972642.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The association between Hirschsprung's disease and multiple endocrine neoplasia type 2a: a systematic review. AU - Coyle,David, AU - Friedmacher,Florian, AU - Puri,Prem, Y1 - 2014/06/28/ PY - 2014/06/18/accepted PY - 2014/6/29/entrez PY - 2014/6/29/pubmed PY - 2015/4/22/medline SP - 751 EP - 6 JF - Pediatric surgery international JO - Pediatr Surg Int VL - 30 IS - 8 N2 - PURPOSE: The co-occurrence of Hirschsprung's disease (HSCR) and multiple endocrine neoplasia type 2 (MEN2) is a relatively rare event. The basis for this association is the presence of a "Janus" mutation in the RET proto-oncogene--a mutation that acts simultaneously as both a gain-in-function and a loss-of-function mutation. To date, four mutations in the exon 10 region of RET that are known to cause MEN2A have been implicated in this association: C620, C618, C611 and C609. We performed a systematic review of the published literature on this association to determine its incidence, the prevalence and phenotype of HSCR associated with the 4 RET mutations mentioned above. METHODS: A systematic literature-based search for relevant articles was conducted using three online databases. After exclusion of ineligible publications, we recorded data on all patients with a diagnosis of HSCR or MEN2A with a "Janus" RET mutation, as well as those who carried the mutation but were unaffected. Statistical analysis was performed using SPSS. RESULTS: The literature search yielded 885 publications, of which 36 articles, incorporating data on 341 individuals, were eligible for inclusion in the final analysis. Co-occurrence of HSCR and MEN2A was recorded in 84 cases (24.6 %). HSCR occurred alone in 64 carriers of a "Janus" mutation (18.8 %) and MEN2A occurred in isolation in 173 cases (50.7 %). Twenty individuals (5.9 %) were found to carry a "Janus" mutation after screening on the basis of family history but were unaffected by either MEN2A or HSCR. The most common mutation recorded was the C620 mutation [114 cases (48.1 %)]. There was a relatively high incidence of long-segment aganglionosis (29.3 %) and total colonic aganglionosis (17.3 %) in this cohort. This trend was particularly notable in those with C620 mutations, only 33 % of whom had short-segment disease. CONCLUSION: While the overall incidence of HSCR co-occurring with MEN2A is low, both conditions occur with a relatively high frequency in families with a RET mutation at exon 10. The proportion of cases of long-segment HSCR and total colonic aganglionosis is higher than that in the general population with HSCR in those with C620 and C618 mutations. These findings reinforce the importance of RET mutation testing in HSCR when a family history of either HSCR or MEN2 is present. In families with MEN2A and known exon 10 RET mutations, the threshold for investigation for HSCR in those with gastrointestinal symptoms should be very low. High-quality prospective longitudinal studies of large HSCR populations are required to shed greater light on this rare but important phenomenon. SN - 1437-9813 UR - https://www.unboundmedicine.com/medline/citation/24972642/The_association_between_Hirschsprung's_disease_and_multiple_endocrine_neoplasia_type_2a:_a_systematic_review_ L2 - https://doi.org/10.1007/s00383-014-3538-2 DB - PRIME DP - Unbound Medicine ER -