FaCD Online Syndrome Fact Sheet

Last updated: 30 Jan 2013

Name: Hereditary Mixed Polyposis Syndrome type 1

Synonym: HMPS1, Colorectal Adenoma Carcinoma syndrome, CRAC, CRAC1

Mode of Inheritance: AD

Genes

GREM1, mapped to 15q13.3
PTEN, mapped to 10q23.3

Tumor features

colorectal adenomas
colorectal cancer
colorectal hamartomatous polyps
intestinal hyperplastic polyps

Tumor features (possible)

pancreatic adenocarcinoma
renal cell cancer

Comment

Tomlinson et al.[1] reported an Ashkenazi family with colorectal adenomas (ages at diagnosis 22-63) and carcinomas (ages at diagnosis 31-67). Two relatives developed pancreatic cancer (ages 72 and 77) and one relative renal cell cancer at age 45. Linkage analysis and loss of heterozygosity studies in the colorectal tumors together suggested a putative colorectal cancer susceptibility gene (CRAC1 locus) on 15q14-q22. Morrison et al.[2] reported a non-Ashkenazi family from the U.K. with a similar tumor spectrum. Many years later, the mutation at 15q was identified as a duplication upstream of the GREM1 locus leading to increased expression of that gene[7].

Whitelaw et al.[3] reported a large Ashkenazi family with a tendency to develop colorectal polyps of the adenomatous, hyperplastic and atypical juvenile type (with mixed histological features, overlapping with adenomas and hyperplastic polyps). Typically, fewer than 15 polyps were found at colonoscopy. Malignant change was observed. The mean age at diagnosis of colorectal cancer was 47 years (range: 32 - 74). It was unclear whether the frequency of hyperplastic polyps seen in this family was increased above that in the general population. Follow up was reported by Rozen et al [4]. Types of polyps detected in this family were classified as juvenile polyps, mixed juvenile–adenomatous polyps, hyperplastic polyps, mixed hyperplastic–adenomatous polyps, serrated adenomas, and tubular adenomas. They observed that polyp numbers, size, and adenomatous elements increased with age of the patients. Other cases with mixed polyposis were considered to be rare[5].CRAC and HMPS are now considered to be identical disorders.
Sweet et al detected 2 patients with germline PTEN mutations in a series of 23 patients with hyperplastic/mixed polyposis[6].
Clinically, HMPS I should presently be considered part of the heterogenous spectrum of disorders which includes hyperplastic polyposis and hereditary mixed polyposis type type II.

References

[1] Tomlinson I, Rahman N, Frayling I, Mangion J, Barfoot R, Hamoudi R, Seal S, Northover J, Thomas HJW, 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 116[4], 789-795. 1999.
[2] Morrison PJ, Chu CE, Nevin NC. A second family with probable CRAC (colorectal adenomata and carcinoma) syndrome--a new familial cancer. Dis Markers 1999; 15(1-3):120-122.
[3] Whitelaw SC, Murday VA, Tomlinson IP, Thomas HJ, Cottrell S, Ginsberg A, Bukofzer S, Hodgson SV, Skudowitz RB, Jass JR, Talbot IC, Northover JM, Bodmer WF, Solomon E. Clinical and molecular features of the hereditary mixed polyposis syndrome. Gastroenterology 1997; 112(2):327-34.
[4] Rozen P, Samuel Z, Brazowski E. A prospective study of the clinical, genetic, screening, and pathologic features of a family with hereditary mixed polyposis syndrome. The American journal of gastroenterology 2003; 98(10):2317-20.
[5] Sarles JC, Consentino B, Léandri R, Dor AM, Navarro PH. Mixed familial polyposis syndromes. International journal of colorectal disease 1987; 2(2):96-9.
[6] Sweet K, Willis J, Zhou XP, Gallione C, Sawada T, Alhopuro P, Khoo SK, Patocs A, Martin C, Bridgeman S, Heinz J, Pilarski R, Lehtonen R, Prior TW, Frebourg T, Teh BT, Marchuk DA, Aaltonen LA, Eng C. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA : the journal of the American Medical Association 2005; 294(19):2465-73.
[7] Jaeger, E et al. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nature Genetics 2012; 44:699-703.