source: GeneReviews

year: 2014

authors: Jasperson K W, Burt R W

CLINICAL CHARACTERISTICS : APC-associated polyposis conditions include: familial adenomatous polyposis (FAP), attenuated FAP, Gardner syndrome, and Turcot syndrome. FAP is a colon cancer predisposition syndrome in which hundreds to thousands of precancerous colonic polyps develop, beginning, on average, at age 16 years (range 7-36 years). By age 35 years, 95% of individuals with FAP have polyps; without colectomy, colon cancer is inevitable. The mean age of colon cancer diagnosis in untreated individuals is 39 years (range 34-43 years). Extracolonic manifestations are variably present and include: polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, and associated cancers. Attenuated FAP is characterized by a significant risk for colon cancer but fewer colonic polyps (average of 30), more proximally located polyps, and diagnosis of colon cancer at a later age; management may be substantially different. Gardner syndrome is characterized by colonic polyposis typical of FAP together with osteomas and soft tissue tumors. Turcot syndrome is the association of colonic polyposis and central nervous system (CNS) tumors. Differences in phenotype may relate to the location of the pathogenic variant within APC.

DIAGNOSIS/TESTING : APC is the only gene in which pathogenic variants cause APC-associated polyposis conditions. The diagnosis relies primarily on clinical findings. Molecular genetic testing of APC detects pathogenic variants in up to 90% of individuals with typical FAP. Molecular genetic testing is most often used in the early diagnosis of at-risk family members, as well as in confirming the diagnosis of FAP or attenuated FAP in individuals with equivocal findings (e.g.,

MANAGEMENT : Treatment of manifestations: Colectomy is advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have occurred. Nonsteroidal anti-inflammatory drugs (NSAIDs), especially sulindac, have caused regression of adenomas in FAP and decreased the number of polyps requiring ablation in the remaining rectum of persons with a subtotal colectomy. Endoscopic or surgical removal of duodenal adenomas is considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms. Osteomas may be removed for cosmetic reasons. Desmoid tumors may be surgically excised or treated with NSAIDs, anti-estrogens, cytotoxic chemotherapy, or radiation. Surveillance: Screening for hepatoblastoma by liver ultrasound and measurement of serum alpha-fetoprotein concentration (until age 5 years); sigmoidoscopy or colonoscopy beginning at age ten to 12 years; annual colonoscopy once polyps are detected until colectomy; esophagogastroduodenoscopy by age 25 years or prior to colon surgery; small bowel x-ray or CT when duodenal adenomas are detected; and regular physical examinations including thyroid palpation and possibly thyroid ultrasound imaging. Evaluation of relatives at risk: Molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant.

GENETIC COUNSELING : APC-associated polyposis conditions are inherited in an autosomal dominant manner. Approximately 75%-80% of individuals with APC-associated polyposis conditions have an affected parent. Offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant in APC. Prenatal testing and preimplantation genetic diagnosis may be an option if a pathogenic variant has been identified in an affected family member.