Clinical Overview of Inherited Polyposis Syndromes

Colorectal polyps are common, but inherited polyposis syndromes (IPS) behave very differently from the sporadic adenomas found during routine colonoscopy. IPS conditions are:

• Genetically driven—usually autosomal-dominant or recessive gene mutations that run through families.
• High-penetrance for cancer—lifetime colorectal cancer (CRC) risk ranges from 40 % to nearly 100 % without surveillance.
• Often multi-organ—many syndromes boost the risk of gastric, duodenal, pancreatic, thyroid, breast, or uterine cancers.
• Actionable—with early genetic testing, colonoscopic surveillance, chemoprevention, or prophylactic surgery, clinicians can virtually eliminate CRC-related deaths.

Current NCCN 2024 guidelines list at least eight well-defined IPS entities, plus serrated polyposis of partly unknown inheritance.

*Data derived from affected kindreds; penetrance still being refined.

• Gene / Inheritance: APC, autosomal dominant.
• Phenotype: Classic FAP manifests in childhood with hundreds to thousands of colorectal adenomas; attenuated FAP (AFAP) may show <100 polyps and later cancer onset.

• Ten or more adenomas in a single colonoscopy <50 yr old
• CRP (congenital retinal pigment) on eye exam
• Osteomas, dental abnormalities, or epidermoid cysts

1. Colonoscopy every 12 mos starting age 10–12.
2. Prophylactic colectomy when polyp burden becomes unmanageable—often late teens.
3. Duodenoscopic surveillance (Spigelman staging) every 1–3 yrs.
4. Consider celecoxib 400 mg bid or sulindac + eicosapentaenoic acid as chemoprevention.

Biallelic MUTYH mutations lead to oxidative DNA-repair failure. Patients typically develop 10–100 adenomas by age 40–60. Half already harbor CRC at diagnosis, underscoring the value of predictive testing of siblings.

Surveillance: Colonoscopy every 1–2 yrs starting age 20–25; upper-GI scope every 3–5 yrs from age 30.

Surgery: Segmental colectomy if polyp number remains <20 and easily cleared; otherwise subtotal colectomy with ileorectal anastomosis.

Hallmarked by mucocutaneous lentigines (dark freckles on lips, nose, fingers) and multilobulated hamartomatous polyps, PJS carries aggregated cancer risk near 85 % across multiple organs.

*Adapted from NCCN v4.2024

Endoscopic polypectomy is preferred; laparotomy reserved for intussusception or uncontrollable bleeding.

Contrary to the name, “juvenile” refers to polyp histology, not age. These polyps can harbor dysplasia and carry a 40 % CRC risk by mid-40s.

Unique point: SMAD4 mutation carriers often present with hereditary hemorrhagic telangiectasia—look for recurrent nosebleeds and arteriovenous malformations.

Surveillance: Colonoscopy and EGD every 1–3 yrs from age 12; small-bowel imaging when symptoms dictate.

PTEN truncating variants provoke hamartomas throughout the GI tract plus macrocephaly, trichilemmomas, and elevated breast, thyroid, and endometrial cancer risks. Colonoscopy begins at age 35 (or 5 yrs younger than youngest case) and repeats every 5 yrs, increasing to 1–3 yrs with polyp burden.

SPS is defined phenotypically (>20 serrated polyps or ≥5 proximal serrated lesions >5 mm). Though many cases are apparently sporadic, germline RNF43 or gene-panel findings emerge in ~10 %. CRC risk reaches 70 % without surveillance; colonoscopic removal every 1 yr is the mainstay.

POLE and POLD1 exonuclease-domain mutations cripple DNA proofreading, causing hypermutated, microsatellite-stable cancers. Endometrial, brain, and CRC can manifest before 30.

Management: Annual colonoscopy from age 14 and endometrial transvaginal ultrasound or biopsy by age 25.

Biallelic NTHL1 mutations yield adenomatous mixed-type polyposis with CRC, breast, and endometrial cancers. Published families report 10–100 polyps and CRC onset in the 40 s.

Guidelines mirror MUTYH schedules until more penetrance data accumulate.

1. Who to test? Anyone meeting NCCN “adenomatous polyposis” criteria, plus relatives of mutation-positive patients.
2. Test type: Next-generation sequencing panels including APC, MUTYH, STK11, BMPR1A, SMAD4, PTEN, POLE, POLD1, NTHL1, RNF43.
3. Cascade testing: Positive first-degree relatives warrant tailored surveillance; negative relatives can often return to average-risk screening.
4. Variant interpretation: Use ACMG guidelines; uncertain variants deserve periodic re-review.

Colonoscopy frequency hinges on polyp burden: annual for dense fields, biennial when <10 adenomas, 3-yearly in post-colectomy rectal stump.

Upper-GI endoscopy every 1–3 yrs for FAP, MAP, JPS; every 1 yr for PJS duodenal polyp load or after ampullectomy.

Chemoprevention trials (e.g., celecoxib, sulindac, DFMO + sulindac) show 24–30 % polyp count reduction but are adjuncts—not replacements—for endoscopy.

Total proctocolectomy with ileal pouch–anal anastomosis (IPAA) remains curative for FAP patients with >1000 polyps or rectal involvement; subtotal colectomy may suffice in AFAP or MAP. Timing balances:

• Cancer risk trajectory—Spigelman stage IV duodenal polyps may trigger pancreas-sparing duodenectomy.
• Quality of life—pouch function, desmoid propensity, psychosocial impact.

Multidisciplinary discussion is crucial.

• Immune checkpoint inhibitors have produced durable responses in POLE-mutated tumors despite MSI-stability.
• mTOR inhibitors for PTEN hamartoma syndrome in trials.
• RNA-based APC read-through agents aim to postpone colectomy in FAP.
• Continued registry participation accelerates evidence for rare genotypes.

• Psychological burden—fear of cancer, body-image concerns post-surgery; early referral to counseling improves adherence.
• Diet & exercise—high-fiber, low-processed-meat diet and ≥150 min weekly activity correlate with lower polyp growth in observational data.
• Family planning—pre-implantation genetic testing allows mutation-free embryo selection for autosomal-dominant syndromes.

1. Think genetics when you see multiple polyps, young CRC, or suggestive extra-intestinal signs.
2. Panel testing beats single-gene testing; variant re-classification can change management.
3. Surveillance saves lives—annual colonoscopy or prophylactic surgery drives CRC mortality toward zero in IPS cohorts.
4. Extra-GI cancers are common; incorporate breast, thyroid, pancreas, and uterine screening where indicated.
5. Cascade testing is cost-effective cancer prevention for entire families.

Inherited polyposis syndromes are small in numbers but huge in impact; they turn what could be silent, early-onset malignancies into preventable diseases through gene discovery, tailored surveillance, and proactive surgery. Recognizing the pattern—and acting on it—protects not just the patient in front of you, but every future generation who shares their DNA.