Residency · Residency · Medical Genetics Genomics

Familial Adenomatous Polyposis and Polyposis Syndromes

Overview

Familial adenomatous polyposis (FAP) is characterized by the development of hundreds to thousands of adenomatous polyps throughout the colorectum, typically beginning in adolescence. Without prophylactic colectomy, virtually 100% of affected individuals develop colorectal cancer by age 40-50. FAP accounts for approximately 1% of all colorectal cancer cases, with an incidence of roughly 1 in 7,000-22,000 live births. The condition follows autosomal dominant inheritance with near-complete penetrance for polyposis.

APC Gene and Classic FAP

Molecular Biology of APC

The APC (adenomatous polyposis coli) gene is located on chromosome 5q21-q22 and functions as a tumor suppressor in the Wnt signaling pathway. The APC protein forms a "destruction complex" with axin, GSK3-beta, and CK1 that targets beta-catenin for proteasomal degradation. Loss of APC function leads to constitutive Wnt pathway activation and uncontrolled cell proliferation. Tumorigenesis follows the "two-hit" model: a germline mutation in one allele is followed by somatic loss of the second allele.

Mutation Spectrum

Over 1,500 different pathogenic variants have been identified in APC. Most are truncating mutations (nonsense or frameshift) that produce a shortened, nonfunctional protein. Approximately 25-30% of FAP cases arise from de novo mutations with no family history. Large deletions and whole-gene deletions account for 5-10% of cases and are not detected by sequencing alone, requiring MLPA or equivalent methods.

Genotype-Phenotype Correlations

The location of the APC mutation significantly influences the clinical phenotype. Mutations in the codon 1309 region produce severe polyposis with more than 5,000 polyps and early colorectal cancer onset. The mutation cluster region spanning codons 1250-1464 is associated with profuse polyposis, while mutations between codons 457-1309 produce the classic FAP phenotype. Mutations at the 5-prime end (before codon 157) or 3-prime end (after codon 1595) are associated with attenuated FAP. Congenital hypertrophy of retinal pigment epithelium (CHRPE) is associated with mutations between codons 311-1444.

<image>Diagram of APC gene with genotype-phenotype correlation map showing mutation cluster region, CHRPE region, and attenuated FAP regions at 5-prime and 3-prime ends</image>

Attenuated FAP (AFAP)

Attenuated FAP presents with fewer polyps (typically 10-100 adenomas), later onset (average age 55 for colorectal cancer), and a right-sided colonic predominance. It is associated with mutations in the 5-prime end (exons 1-4), the exon 9 alternative splicing region, or the 3-prime end of APC. The lifetime colorectal cancer risk remains significantly elevated at approximately 70% without surveillance, though management can often be achieved with colonoscopy rather than prophylactic colectomy. There is substantial phenotypic overlap with MUTYH-associated polyposis and Lynch syndrome.

Extracolonic Manifestations of FAP

Upper GI Involvement

Duodenal adenomas are present in 50-90% of FAP patients, with a lifetime risk of duodenal or periampullary cancer of 4-12%. The Spigelman classification (stages 0-IV) guides surveillance and intervention decisions. Gastric fundic gland polyps are found in over 80% of patients but generally carry low malignant potential. Gastric adenomas are less common but warrant surveillance.

Desmoid Tumors

Desmoid tumors occur in 10-20% of FAP patients. These locally aggressive fibromatoses, often intra-abdominal or mesenteric, represent a major cause of morbidity and mortality following colectomy. They are associated with mutations distal to codon 1444 and are frequently triggered by surgical trauma, which directly influences surgical decision-making. Management ranges from observation to NSAIDs (sulindac), anti-estrogens (tamoxifen), chemotherapy, or surgery for selected cases.

Other Extracolonic Features

Additional manifestations include mandibular and skull osteomas (part of the Gardner syndrome phenotype), dental anomalies such as supernumerary teeth and odontomas, and epidermoid cysts of the trunk and extremities. Hepatoblastoma carries approximately 1.6% risk in children under 5 years with FAP, warranting screening with alpha-fetoprotein and liver ultrasound every 6 months from birth to age 5. Thyroid cancer, particularly the cribriform-morular variant of papillary thyroid cancer, occurs predominantly in females. CNS tumors, specifically medulloblastoma, represent the Turcot syndrome variant.

<image>Clinical photographs showing extracolonic manifestations of FAP including desmoid tumor on CT scan, mandibular osteoma, and congenital hypertrophy of retinal pigment epithelium on fundoscopy</image>

MUTYH-Associated Polyposis (MAP)

MUTYH-associated polyposis follows autosomal recessive inheritance, requiring biallelic pathogenic variants. The MUTYH gene encodes a base excision repair glycosylase that corrects oxidative DNA damage, specifically 8-oxoguanine:adenine mispairs. The phenotype resembles attenuated FAP with typically 10-100 adenomas, though the range extends from a few polyps to over 1,000. Lifetime colorectal cancer risk is approximately 80% in biallelic carriers, with a debated approximately 2-fold increase in monoallelic carriers. Two common European founder mutations, Y179C and G396D, account for roughly 80% of pathogenic alleles in European populations. A somatic G>T transversion signature in tumors is a molecular hallmark. Colorectal cancers in MAP tend to be microsatellite stable with KRAS mutations. Duodenal adenoma and cancer risk is increased similarly to FAP. Management involves colonoscopic surveillance beginning at age 25-30, with colectomy when polyp burden becomes unmanageable.

Other Polyposis Syndromes

Peutz-Jeghers Syndrome (PJS)

PJS is an autosomal dominant condition caused by pathogenic variants in STK11/LKB1 at 19p13.3. It is characterized by hamartomatous polyps (predominantly in the small bowel) and mucocutaneous melanin pigmentation of the lips, buccal mucosa, and digits. Cancer risks are substantial: colorectal (39%), breast (32-54%), pancreatic (11-36%), gastric, and ovarian (sex cord tumors with annular tubules). Cumulative cancer risk by age 70 reaches 80-90%. Surveillance includes upper and lower GI endoscopy, capsule endoscopy or MR enterography, breast MRI, and pancreatic screening.

Juvenile Polyposis Syndrome (JPS)

JPS is autosomal dominant, caused by mutations in SMAD4 (approximately 20%) or BMPR1A (approximately 20%), with no identifiable mutation in roughly 60% of cases. It is defined by five or more juvenile polyps in the colorectum, juvenile polyps throughout the GI tract, or any number of juvenile polyps with family history. Lifetime colorectal cancer risk ranges from 17-68%. Notably, SMAD4 mutations are associated with an overlap syndrome combining JPS with hereditary hemorrhagic telangiectasia (HHT), which carries risk of pulmonary arteriovenous malformations. Surveillance with colonoscopy and upper endoscopy begins at age 12-15.

PTEN Hamartoma Tumor Syndrome (Cowden Syndrome)

This autosomal dominant condition results from PTEN mutations at 10q23.3. Multiple hamartomatous polyps (ganglioneuromas, lipomas, inflammatory polyps) develop throughout the GI tract. Cancer risks include breast (85% lifetime), thyroid (35%), endometrial (28%), colorectal (9-16%), and renal. Pathognomonic features include trichilemmomas, acral keratoses, papillomatous papules, and mucosal neuromas. Macrocephaly is present in over 80% of affected individuals.

Serrated Polyposis Syndrome (SPS)

SPS is defined by WHO criteria: five or more serrated polyps proximal to the sigmoid (with at least two exceeding 10 mm), any serrated polyp proximal to the sigmoid with family history of SPS, or more than 20 serrated polyps of any size throughout the colon. Most cases have no identified single-gene cause and are likely polygenic or oligogenic, though RNF43 germline mutations have been identified in a subset. Lifetime colorectal cancer risk is 25-40%. Management involves annual colonoscopic surveillance with removal of all polyps 5 mm or larger.

<image>Histopathological comparison showing adenomatous polyp in FAP versus hamartomatous polyp in Peutz-Jeghers syndrome versus sessile serrated lesion, with characteristic features labeled</image>

Surgical Management of FAP

Timing and Indications

Genetic testing should be performed in at-risk children of FAP families by age 10-12. Colonoscopic surveillance begins at age 10-12 for classic FAP and 18-20 for attenuated FAP. Prophylactic surgery is recommended when polyp burden becomes unmanageable or high-grade dysplasia is detected, typically in the late teens to early twenties for classic FAP.

Surgical Options

Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) eliminates all colorectal mucosa but requires ongoing surveillance for pouch adenomas. Total colectomy with ileorectal anastomosis (IRA) preserves the rectum with better functional outcomes but necessitates lifelong rectal surveillance every 6-12 months. Total proctocolectomy with end ileostomy is reserved for low rectal cancers or failed IPAA. IRA is preferred when the rectal polyp burden is low and the patient is motivated for surveillance. Desmoid risk (family history, genotype) should influence surgical planning, as laparotomy can trigger mesenteric desmoids.

Chemoprevention

Sulindac reduces the number and size of colorectal adenomas but does not eliminate cancer risk and is not a substitute for surgery. Celecoxib is FDA-approved as an adjunct for FAP and reduces polyp burden, though cardiovascular risks limit long-term use. Aspirin showed benefit in Lynch syndrome in the CAPP2 trial, with ongoing studies in FAP. Chemoprevention may be useful for duodenal adenomas and rectal polyps post-IRA. No chemopreventive agent has been shown to replace the need for surgical intervention in classic FAP.

<image>Endoscopic images showing carpet of colorectal adenomatous polyps in classic FAP, sparse polyps in attenuated FAP, and duodenal adenomas with Spigelman staging examples</image>

Clinical Pearls

De novo APC mutations must always be considered, as 25-30% of FAP patients have no family history. Biallelic MUTYH testing is essential in patients with 10-100 adenomas and negative APC testing, since recessive inheritance means parents are typically unaffected. Hepatoblastoma screening (AFP plus liver ultrasound every 6 months until age 5) is recommended for children in FAP families, though supporting evidence remains limited. SMAD4-related juvenile polyposis requires screening for pulmonary arteriovenous malformations due to HHT overlap. Desmoid tumors are the leading cause of death in FAP patients who have undergone prophylactic colectomy. Genotype-phenotype correlations in APC guide surgical timing, surveillance intensity, and desmoid risk stratification. In patients with more than 10 adenomas and negative APC/MUTYH testing, a multigene panel including POLE, POLD1, NTHL1, MSH3, and AXIN2 should be considered.

References

• Kanth P, Grimmett J, Engel C, et al. "Hereditary colorectal polyposis and cancer syndromes: a primer on diagnosis and management." American Journal of Gastroenterology. 2021;116(11):2185-2198.
• NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 1.2025.
• Syngal S, Brand RE, Church JM, et al. "ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes." American Journal of Gastroenterology. 2015;110(2):223-262.
• Half E, Bercovich D, Rozen P. "Familial adenomatous polyposis." Orphanet Journal of Rare Diseases. 2009;4:22.
• Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews. University of Washington, Seattle. APC-Associated Polyposis Conditions. Updated 2023.

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