Hereditary Mixed Polyposis Syndrome

  • Huw Thomas
  • Ian Tomlinson


Hereditary mixed polyposis syndrome (HMPS) is an autosomal dominant inherited condition in which affected individuals develop colorectal polyps of multiple and mixed histological type including serrated lesions, Peutz-Jeghers polyps, juvenile polyps, conventional adenomas and colorectal carcinomas in the absence of any extra-colonic features. Most of the families described to date are Ashkenazi Jewish and have an ancestral founder mutation with a duplication of 40 kb upstream of the GREM1 gene. This leads to increased and ectopic expression of GREM1 in the colonic crypt. A smaller duplication of about 16 kb also upstream of GREM1 has been reported in a Swedish HMPS family. Presymptomatic genetic testing is now available in these families, and affected individuals require careful colonoscopic surveillance from an early age, with polypectomy to prevent the development of colorectal cancer.


Hereditary mixed polyposis syndrome HMPS GREM1 Colorectal cancer 


  1. 1.
    Whitelaw SC, Murday VA, Tomlinson IPM, Thomas HJW, Cottrell S, Ginsberg A, Bukofzer S, Hodgson SV, Skudowitz RB, Jass JR, Talbot IC, Northover JMA, Bodmer WF, Solomon E. Clinical and molecular features of hereditary mixed polyposis syndrome. Gastroenterology. 1997;112:327–34.CrossRefGoogle Scholar
  2. 2.
    Rosen P, Samual Z, Brazowski E. A prospective study of the clinical, genetic screening and pathologic features of a family with hereditary mixed polyposis syndrome. Am J Gastroenterol. 2003;98:2317–20.CrossRefGoogle Scholar
  3. 3.
    Tomlinson I, Rahman N, Frayling I, Mangion J, Barfoot R, Hamoudi R, Seal S, Northover J, Thomas HJ, Neale K, Hodgson S, Talbot I, Houlston R, Stratton MR. Inherited susceptibility to colorectal adenomas and carcinomas: evidence for a new predisposition gene on 15q14-q22. Gastroenterology. 1999;116:789–95.CrossRefGoogle Scholar
  4. 4.
    Rohlin A, Eiengard F, Lundstam U, Zagoras T, Nilsson S, Edsjo A, Pedersen J, Svensson J, Skullman S, Goran Karlsson B, Bjork J, Nordling M. GREM1 and POLE variants in hereditary colorectal cancer syndromes. Genes Chromosomes Cancer. 2016;55:95–106.CrossRefGoogle Scholar
  5. 5.
    Venkatachalam R, Verwiel ETP, Kamping EJ, Hoenselaar E, Gorgens H, Schackert HK, van Krieken HJM, Ligtenberg MJL, Hoorerbrugge N, van Kessel AG, Kuiper RP. Identification of candidate predisposing copy number variants in familial and early-onset colorectal cancer patients. Int J Cancer. 2011;129:1635–42.CrossRefGoogle Scholar
  6. 6.
    Tomlinson I, Jaeger E, Leedham S, Thomas H. The classification of intestinal polyposis. Nat Genet. 2013;45:2–3.CrossRefGoogle Scholar
  7. 7.
    Thomas HJW, Whitelaw SC, Cottrell SC, Murday VA, Tomlinson IPA, Markie D, Jones T, Bishop DT, Hodgson SV, Sheer D, Northover JMA, Talbot IC, Solomon E, Bodmer WF. Genetic mapping of the hereditary mixed polyposis syndrome to chromosome 6q. Am J Hum Genet. 1996;58:770–6.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Jaegers EEM, Woodford-Richens KL, Lockett M, Rowan AJ, Sawyer EJ, Heinimann K, Rozen P, Murday VA, Whitelaw SC, Ginsberg A, Atkin WS, Lynch HT, Southey MC, Eng C, Bodmer WF, Talbot IC, Hodgson SV, Thomas HJW, Tomlinson IPM. An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus is associated with hereditary mixed polyposis syndrome. Am J Hum Genet. 2003;72:1261–7.CrossRefGoogle Scholar
  9. 9.
    Jaeger E, Leedham S, Lewis A, Segditsas S, Becker M, Cuadrado PR, Davis H, Kaur K, Heinimann K, Howarth K, East J, Taylor J, Thomas H, Tomlinson I. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet. 2012;44:699–703.CrossRefGoogle Scholar
  10. 10.
    Lewis A, Freeman-Mills L, de la Calle-Mustienes E, Giráldez-Pérez RM, Davis H, Jaeger E, Becker M, Hubner NC, Nguyen LN, Zeron-Medina J, Bond G, Stunnenberg HG, Carvajal JJ, Gomez-Skarmeta JL, Leedham S, Tomlinson I. A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding. Cell Rep. 2014;8:983–90.CrossRefGoogle Scholar
  11. 11.
    Davis H, Irshad S, Bansal M, Rafferty H, Boitsova T, Bardella C, Jaeger E, Lewis A, Freeman-Mills L, Castro Giner F, Rodenas-Cuadrado P, Mallappa S, Clark S, Thomas H, Jeffrey R, Poulsom R, Rodriguez-Justo M, Novelli M, Chetty R, Silver A, Sansom O, Greten F, Wang LM, East J, Tomlinson I, Needham S. Subtypes of inherited and sporadic colorectal cancer result from GREM-1 induced acquisition of progenitor-like features by differentiated intestinal epithelial cells. Nat Med. 2015;21:62–70.CrossRefGoogle Scholar
  12. 12.
    Lieberman S, Walsh T, Schechter M, Adar T, Goldin E, Beeri R, Sharon N, Baris H, Ben Avi L, Half E, Lerer I, Shirts B, Pritcahrd C, Tomlinson I, King M, Levy-Lahad E, Peretz T, Goldberg Y. Features of patients with hereditary mixed polyposis syndrome caused by duplication of GREM1 and implications for screening and surveillance. Gastroenterology. 2017;156:1876–80.Google Scholar
  13. 13.
    Brazowski E, Misonzhnick-Bedny F, Rosen P. Immunohistochemical expression of COX-2 in polyps of hereditary mixed polyposis syndrome suggests the possibility of chemoprevention. Dig Dis Sci. 2004;49:1906–11.CrossRefGoogle Scholar
  14. 14.
    Burn J, Gerdes A-M, McCrea F, Mecklin J-P, Moeslein G, Olschwang S, Eccles D, Evans DG, Maher ER, Bertario L, Bisgaard M-L, Dunlop M, JWC H, Hodgson SV, Lindblom A, Lubinski J, Morrison PJ, Murday V, Ramesar R, Side L, Scott RJ, Thomas HJW, Vasen HF, Barker G, Crawford G, Elliott F, Movahedi M, Pylvanainen K, Wijnen JT, Fodde R, Lynch HT, Mathers JC, Bishop DT on behalf of the CAPP2 Investigators. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378:2081–7.CrossRefGoogle Scholar
  15. 15.
    Ballester-Vargas V, Tomlinson I. Hereditary mixed polyposis syndrome. In: Boardman LA, editor. Intestinal Polyposis Syndromes: Springer. ISBN 987-3-319-28101-8.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.St Mark’s Hospital, Imperial College LondonHarrowUK
  2. 2.Institute of Cancer and Genomic StudiesUniversity of BirminghamBirminghamUK

Personalised recommendations