Attenuated familial adenomatous polyposis

Attenuated familial adenomatous polyposis (AFAP) is a milder variant of classic familial adenomatous polyposis (FAP), a hereditary condition that predisposes individuals to the development of multiple colorectal adenomatous polyps and colorectal cancer. Unlike classic FAP, where hundreds to thousands of polyps develop, individuals with AFAP typically develop fewer polyps — usually between 10 and 100 — and the onset of polyp formation tends to occur later, often in the third to fourth decade of life. The polyps in AFAP frequently have a right-sided (proximal) colonic distribution, which can make them harder to detect with limited endoscopic examinations. Despite the reduced polyp burden, the lifetime risk of colorectal cancer remains significantly elevated, estimated at approximately 70% without appropriate surveillance and intervention. AFAP is most commonly caused by pathogenic variants in the APC gene, particularly mutations located at the 5' or 3' ends of the gene or in the alternatively spliced region of exon 9. In some cases, biallelic pathogenic variants in the MUTYH gene (associated with MUTYH-associated polyposis) can produce a similar clinical phenotype. Beyond colorectal involvement, individuals with AFAP may also develop upper gastrointestinal polyps, particularly duodenal adenomas, which carry a risk of duodenal cancer. Extraintestinal manifestations such as desmoid tumors, osteomas, and congenital hypertrophy of the retinal pigment epithelium (CHRPE) are less common in AFAP than in classic FAP but may still occur. Management of AFAP centers on regular endoscopic surveillance, typically beginning in the late teenage years or early twenties, with colonoscopy every one to two years. Upper endoscopy is also recommended to monitor for duodenal polyps. When the polyp burden becomes too great to manage endoscopically, surgical intervention — usually colectomy with ileorectal anastomosis — is recommended. Chemoprevention strategies, including the use of nonsteroidal anti-inflammatory drugs such as sulindac or celecoxib, have been studied as adjuncts but are not substitutes for surveillance or surgery. Genetic counseling and testing of at-risk family members are essential components of care.

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