Association Between Hirschsprung’s Disease and Multiple Endocrine Neoplasia

  • David Coyle
  • Prem PuriEmail author


A “loss-of-function” mutation of the RET proto-oncogene is the most common genetic aberration implicated in the pathogenesis of Hirschsprung’s disease (HSCR). Some individuals with HSCR harbour RET mutations, which paradoxically also behave as “gain-of-function” mutations and lead to the co-occurrence of HSCR with multiple endocrine neoplasia 2 (MEN 2). The phenomenon appears to primarily occur in those with MEN 2A or familial medullary thyroid carcinoma (FMTC), while those with MEN 2B are susceptible to the development of multiple benign nerve cell tumours, known as ganglioneuromatosis, throughout the gastrointestinal tract.

The most common RET mutation to give rise to the co-occurrence of MEN 2 and HSCR is the C620 mutation, present in about 40% of such cases. C618, C611 and C609 mutations have also been implicated in this association. Long-segment aganglionosis is present in almost two thirds of HSCR patients with one of these mutations, with approximately 40% having total colonic aganglionosis. Such mutations are associated with a less aggressive phenotype of MTC than those with MEN 2A linked to a C634 mutation or in those with MEN 2B. The utility of RET genetic testing in cases of familial HSCR or in those with HSCR and a family history of MTC offers the opportunity to detect such mutations and screen patients and family members appropriately for MEN 2. Patients with MEN 2B almost invariably experience bowel symptoms due to ganglioneuromatosis, for which surgical management is only attempted for symptom management when obstructing lesions are present (approx. 30% of cases), unlike in HSCR where pull-through surgery is undertaken with “curative” intent.


Hirschsprung’s disease Aganglionosis Multiple endocrine neoplasia 2 Janus mutation RET Medullary thyroid cancer 



familial medullary thyroid cancer


Hirschsprung’s disease


Multiple endocrine neoplasia


Medullary thyroid cancer


Rearranged during transfection


  1. 1.
    Godbole K. Many faces of Hirschsprung’s disease. Indian Pediatr. 2004;41(11):1115–23.PubMedGoogle Scholar
  2. 2.
    Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med. 1961;31:163–6.CrossRefGoogle Scholar
  3. 3.
    Williams ED, Pollock DJ. Multiple mucosal neuromata with endocrine tumours: a syndrome allied to von Recklinghausen’s disease. J Pathol Bacteriol. 1966;91(1):71–80. Scholar
  4. 4.
    Verdy M, Weber AM, Roy CC, Morin CL, Cadotte M, Brochu P. Hirschsprung’s disease in a family with multiple endocrine neoplasia type 2. J Pediatr Gastroenterol Nutr. 1982;1(4):603–7.CrossRefGoogle Scholar
  5. 5.
    Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, Ploos Van Amstel HK, Lips CJM, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendy GN, Gharib H, Thibodeau SN, Lacroix A, Frilling A, Ponder BAJ, Mulligan LM. The relationship between specific ret proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: international RET mutation consortium analysis. J Am Med Assoc. 1996;276(19):1575–9.CrossRefGoogle Scholar
  6. 6.
    Edery P, Eng C, Munnich A, Lyonnet S. RET in human development and oncogenesis. BioEssays. 1997;19(5):389–95. Scholar
  7. 7.
    Moore SW, Zaahl M. The Hirschsprung’s-multiple endocrine neoplasia connection. Clinics. 2012;67(Suppl):63–7.CrossRefGoogle Scholar
  8. 8.
    Davis TK, Hoshi M, Jain S. To bud or not to bud: the RET perspective in CAKUT. Pediatr Nephrol. 2014;29(4):597–608. Scholar
  9. 9.
    Vega-Lopez GA, Cerrizuela S, Tribulo C, Aybar MJ. Neurocristopathies: new insights 150 years after the neural crest discovery. Dev Biol. 2018; Scholar
  10. 10.
    Butler Tjaden NE, Trainor PA. The developmental etiology and pathogenesis of Hirschsprung disease. Transl Res. 2013;162(1):1–15. Scholar
  11. 11.
    Read AP. Waardenburg syndrome. Adv Otorhinolaryngol. 2000;56:32–8.CrossRefGoogle Scholar
  12. 12.
    Coyle D, Puri P. Hirschsprung’s disease in children with Mowat-Wilson syndrome. Pediatr Surg Int. 2015;31(8):711–7. Scholar
  13. 13.
    Peczkowska M, Januszewicz A. Multiple endocrine neoplasia type 2. Familial Cancer. 2005;4(1):25–36. Scholar
  14. 14.
    Walls GV. Multiple endocrine neoplasia (MEN) syndromes. Semin Pediatr Surg. 2014;23(2):96–101. Scholar
  15. 15.
    Decker RA, Peacock ML. Occurrence of MEN 2a in familial Hirschsprung’s disease: a new indication for genetic testing of the RET proto-oncogene. J Pediatr Surg. 1998;33(2):207–14.CrossRefGoogle Scholar
  16. 16.
    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. Scholar
  17. 17.
    Moore SW, Zaahl M. Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 “Janus” genetic variation. J Pediatr Surg. 2010;45(2):393–6. Scholar
  18. 18.
    Arighi E, Popsueva A, Degl’innocenti D, Borrello MG, Carniti C, Perala NM, Pierotti MA, Sariola H. Biological effects of the dual phenotypic Janus mutation of ret cosegregating with both multiple endocrine neoplasia type 2 and hirschsprung’s disease. Mol Endocrinol. 2004;18(4):1004–17.CrossRefGoogle Scholar
  19. 19.
    Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG, American Thyroid Association Guidelines Task Force on Medullary Thyroid C. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567–610. Scholar
  20. 20.
    Cohen MS, Phay JE, Albinson C, DeBenedetti MK, Skinner MA, Lairmore TC, Doherty GM, Balfe DM, Wells SA Jr, Moley JF. Gastrointestinal manifestations of multiple endocrine neoplasia type 2. Ann Surg. 2002;235(5):648–54; discussion 654–645.CrossRefGoogle Scholar
  21. 21.
    Kenny SE, Tam PK, Garcia-Barcelo M. Hirschsprung’s disease. Semin Pediatr Surg. 2010;19(3):194–200. Scholar
  22. 22.
    Moore SW, Zaahl M. Clinical and genetic correlations of familial Hirschsprung’s disease. J Pediatr Surg. 2015;50(2):285–8. Scholar
  23. 23.
    Virtanen VB, Pukkala E, Kivisaari R, Salo PP, Koivusalo A, Arola J, Miettinen PJ, Rintala RJ, Perola M, Pakarinen MP. Thyroid cancer and co-occurring RET mutations in Hirschsprung disease. Endocr Relat Cancer. 2013;20(4):595–602.CrossRefGoogle Scholar
  24. 24.
    Wells SA Jr. Advances in the management of MEN2: from improved surgical and medical treatment to novel kinase inhibitors. Endocr Relat Cancer. 2018;25(2):T1–T13. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Temple Street Children’s University HospitalDublinIreland
  2. 2.National Children’s Research Centre, Our Lady’s Children’s Hospital, CrumlinDublinIreland

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