Familial adenomatous polyposis syndromes

Familial adenomatous polyposis (FAP) syndrome is a hereditary colorectal cancer syndrome characterised by the development of hundreds to thousands of colorectal adenomas. The attenuated form leads to the formation of fewer than 100 polyps.

Median age of onset for polyps is 15 years.

Caused by germline mutations in the adenomatous polyposis coli gene.

In the absence of total colectomy or endoscopic polyp clearance, colorectal cancer arises in close to 100% of patients with FAP by 40 years of age and in 80% of patients with attenuated FAP by 60 years of age.

Prophylactic proctocolectomy is the mainstay preventive therapy for colorectal cancer in FAP.

Duodenal/periampullary polyps lead to an increased risk for duodenal/periampullary cancer, which is the most common cause of cancer death in patients with FAP who have had prophylactic colectomy.

FAP syndrome is an autosomal-dominant colorectal cancer syndrome caused by germline adenomatous polyposis coli (APC) gene mutations.[1]Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009 Oct 12;4:22. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-22 http://www.ncbi.nlm.nih.gov/pubmed/19822006?tool=bestpractice.com ​ Although most patients have a family history of FAP, up to 30% of probands have no family history of polyposis or colorectal cancer; these cases may be explained by somatic mosaicism in the APC gene.[2]Bisgaard ML, Fenger K, Bulow S, et al. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat. 1994;3:121-125. http://www.ncbi.nlm.nih.gov/pubmed/8199592?tool=bestpractice.com [3]Aretz S, Stienen D, Friedrichs N, et al. Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP). Hum Mutat. 2007 Oct;28(10):985-92. http://www.ncbi.nlm.nih.gov/pubmed/17486639?tool=bestpractice.com [4]Aretz S, Uhlhaas S, Caspari R, et al. Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis. Eur J Hum Genet. 2004 Jan;12(1):52-8. https://www.doi.org/10.1038/sj.ejhg.5201088 http://www.ncbi.nlm.nih.gov/pubmed/14523376?tool=bestpractice.com [5]Ripa R, Bisgaard ML, Bülow S, et al. De novo mutations in familial adenomatous polyposis (FAP). Eur J Hum Genet. 2002 Oct;10(10):631-7. https://www.doi.org/10.1038/sj.ejhg.5200853 http://www.ncbi.nlm.nih.gov/pubmed/12357334?tool=bestpractice.com

Patients with classical FAP have hundreds to thousands of colorectal adenomas and a nearly 100% risk for colorectal cancer by the age of 40 years if proctoprophylactic colectomy is not performed.[1]Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009 Oct 12;4:22. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-22 http://www.ncbi.nlm.nih.gov/pubmed/19822006?tool=bestpractice.com [6]Bjork J, Akerbrant H, Iselius L, et al. Epidemiology of familial adenomatous polyposis in Sweden: changes over time and differences in phenotype between males and females. Scand J Gastroenterol. 1999;34:1230-1235. http://www.ncbi.nlm.nih.gov/pubmed/10636071?tool=bestpractice.com ​​​ Attenuated FAP is also caused by APC mutations and is characterised by fewer than 100 adenomas and a later age of colorectal cancer onset.​[7]Knudsen AL, Bisgaard ML, Bulow S. Attenuated familial adenomatous polyposis (AFAP): a review of the literature. Fam Cancer. 2003;2:43-55. http://www.ncbi.nlm.nih.gov/pubmed/14574166?tool=bestpractice.com ​ The median age of onset for polyps is 15 years.[8]Giardiello FM, Brensinger JK, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology. 2001;121:198-213. http://www.ncbi.nlm.nih.gov/pubmed/11438509?tool=bestpractice.com

Individuals with FAP also have an increased lifetime risk for other cancers, including duodenal/periampullary cancer (1% to 10%), thyroid cancer (1% to 12%), gastric cancer (0.1% to 7.1%), and hepatoblastoma (0.4% to 2.5%, usually by age 5 years).[9]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: genetic/familial high-risk assessment: colorectal [internet publication]. https://www.nccn.org/guidelines/category_1 ​ Extraintestinal FAP features include skin cysts, lipomas and fibromas, supernumerary teeth, thyroid nodules, osteomas, desmoid tumours, adrenal adenomas, and congenital hypertrophy of the retinal pigment epithelium.[10]Dinarvand P, Davaro EP, Doan JV, et al. Familial adenomatous polyposis syndrome: an update and review of extraintestinal manifestations. Arch Pathol Lab Med. 2019 Nov;143(11):1382-98. https://meridian.allenpress.com/aplm/article/143/11/1382/433640/Familial-Adenomatous-Polyposis-Syndrome-An-Update http://www.ncbi.nlm.nih.gov/pubmed/31070935?tool=bestpractice.com

Historically, patients with FAP and extra-intestinal features were diagnosed with Gardner's syndrome and patients with FAP and primary central nervous system tumours were said to have Turcot's syndrome.[10]Dinarvand P, Davaro EP, Doan JV, et al. Familial adenomatous polyposis syndrome: an update and review of extraintestinal manifestations. Arch Pathol Lab Med. 2019 Nov;143(11):1382-98. https://meridian.allenpress.com/aplm/article/143/11/1382/433640/Familial-Adenomatous-Polyposis-Syndrome-An-Update http://www.ncbi.nlm.nih.gov/pubmed/31070935?tool=bestpractice.com ​ However, use of these terms should be avoided as they are FAP spectrum phenotypes and are part of APC-associated polyposis.