FAP

**Genetics/Pathophysiology** - Autosomal dominant; germline mutation of the APC gene (5q21), a tumor suppressor. About 20–30% are de novo mutations. - APC normally degrades β-catenin (part of the Wnt signaling pathway). Loss of APC leads to β-catenin accumulation, increased transcription of proliferative genes (e.g., c-myc, cyclin D1), and polyp formation. - Follows Knudson's two-hit hypothesis: one inherited mutated allele, then somatic loss of the second allele ("second hit"). - Classic sequence (adenoma-carcinoma): APC loss → KRAS activation → p53 loss (also DCC/SMAD4 loss). Mnemonic: "APC, K-ras, p53." - Chromosomal instability pathway (unlike Lynch syndrome, which is a DNA mismatch repair defect with microsatellite instability).

**Clinical features** - Onset of polyps in the teens to 20s; >100 (often thousands) of adenomatous polyps, mainly in the rectosigmoid colon. - Presentation: often asymptomatic, or rectal bleeding, diarrhea, abdominal pain, and anemia. Many cases are found through family screening. - 100% lifetime risk of colorectal cancer if untreated (average age at cancer ~39 years).

**Extracolonic manifestations** - Duodenal/periampullary adenomas and carcinoma (the leading cause of cancer death after colectomy). - Gastric fundic gland polyps. - Congenital hypertrophy of the retinal pigment epithelium (CHRPE). - Desmoid tumors (fibromatosis; often after abdominal surgery). - Osteomas, dental abnormalities, and epidermoid cysts. - Thyroid papillary carcinoma and hepatoblastoma (in children). - Medulloblastoma (Turcot syndrome = FAP + CNS tumor, usually medulloblastoma; Lynch-associated Turcot is typically glioblastoma). - Gardner syndrome = FAP + osteomas, soft tissue tumors (desmoids, epidermoid cysts), and dental abnormalities. It is now considered a phenotypic variant of FAP.

**Variants** - Attenuated FAP: fewer than 100 polyps, later onset, and cancers that appear later (~50s); mutations in the 5' or 3' ends of APC. - MUTYH-associated polyposis (MAP): autosomal recessive, caused by a base excision repair defect, and similar in presentation to attenuated FAP.

**Diagnosis** - Colonoscopy/sigmoidoscopy showing >100 adenomas, plus APC genetic testing. - Screening of at-risk relatives: begin flexible sigmoidoscopy or colonoscopy at ages 10–12 and repeat every 1–2 years. Genetic testing of the affected proband first. - Upper endoscopy (including side-viewing duodenoscopy) beginning at ages 20–25 to monitor for duodenal disease.

**Management** - Prophylactic total proctocolectomy with ileal pouch-anal anastomosis (IPAA), or total abdominal colectomy with ileorectal anastomosis. Timing is usually in the late teens to 20s, or sooner if there are symptoms or advanced polyps. - Continue surveillance of the remaining rectum/pouch and the upper GI tract. - Chemoprevention (e.g., NSAIDs such as sulindac, celecoxib) may reduce polyp burden but does not replace surgery.

**Boards pearls** - A teenager with hundreds of colonic polyps and a family history → FAP → APC → colectomy. - CHRPE seen on fundoscopic exam is a marker of FAP. - A desmoid tumor after colectomy is a classic Gardner syndrome clue. - Distinguish from Peutz-Jeghers (hamartomatous polyps, mucocutaneous pigmentation, STK11), juvenile polyposis (SMAD4/BMPR1A), and Lynch (HNPCC, MSH2/MLH1, right-sided colon cancers, endometrial cancer).