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Gastrointestinal (GI) polyposis syndromes are a group of conditions that are associated with an increased lifetime risk of colorectal adenocarcinoma and extraintestinal malignancies. The polyposis syndromes have traditionally been categorized according to polyp histology (adenomatous, hamartomatous, and serrated) and clinical phenotype. Criteria to be considered in differentiating the various polyposis conditions include polyp distribution throughout the GI tract, polyp number, the presence of extraintestinal manifestations or malignancy, and family history. Identification of relevant causative genes has improved our understanding of specific polyposis conditions, including phenotypic characteristics and associated cancer risks. The most common feature for when to consider a polyposis diagnosis and germline genetic testing is the finding of 10 or more colonic polyps, polyposis in other parts of the GI tract, and polyps in young individuals with a family history of a polyposis diagnosis. The clinical importance of these syndromes relates to their inheritance. Mutation-specific genetic testing offers the opportunity to test family members for the pathogenic mutation found in an index case, allowing a more personalized approach for cancer prevention with tailored screening and surveillance interventions.


Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is one of the most clearly defined polyposis syndromes. It is an autosomal dominant adenomatous polyposis condition caused by a germline mutation in the APC gene on chromosome 5q21, with nearly complete penetrance. APC is a tumor suppressor gene, and the loss of APC is among the earliest events in the chromosomal instability colorectal tumor pathway. Reported incidence varies from 1 in 7000 to 1 in 22,000 births.1 Up to one-third of newly diagnosed cases not belonging to previously identified families appear to represent either de novo germline mutations or mosaicism.

The classic form of FAP is characterized by hundreds to thousands of colonic adenomatous polyps that typically begin to emerge after the first decade of life. An attenuated version (AFAP), also caused by a mutation in APC, typically causes fewer than 100 polyps. The risk for colorectal cancer in FAP approaches 100% by age 50, and the recommended intervention is annual sigmoidoscopies or colonoscopies in adolescence and prophylactic colectomy in young adulthood or when the polyp burden becomes too high to be managed endoscopically.

In addition to a high risk of colon adenomas in FAP patients, various extracolonic manifestations have been described, including upper gastrointestinal tract adenomas and adenocarcinomas; fundic gland stomach polyps; nonepithelial benign tumors (osteomas, epidermal cysts, dental abnormalities); desmoid tumors; congenital hypertrophy of retinal pigment epithelium; and malignant tumors (thyroid, medulloblastoma, and hepatoblastoma) (Table 6.1). Gardner syndrome was previously the diagnosis for FAP patients who manifested with colorectal polyposis, osteomas, and soft tissue tumors. However, Gardner syndrome has been shown genetically to be a variant of FAP, and thus the term Gardner syndrome is essentially no longer used in clinical practice.1

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