Familial adenomatous polyposis (FAP) is an autosomal dominant disorder that is associated with the development of numerous colorectal adenomas.
- Prevalence varies: 1 in 6000 to 1 in 35,000
- 2nd most common inherited colorectal cancer (CRC) syndrome
- Only 30% of patients with FAP have no family history.
- FAP has been described in all races.
- The average age at onset of polyposis in FAP is 16 years.
- The average age at onset of CRC is 39 years.
- Both sexes are equally affected.
Pathogenic mutations in the tumor suppressor gene adenomatous polyposis coli (APC) in chromosome 5 on band 5q21:
- Often nonsense or frameshift mutations
- Evolves into truncation of the APC protein, creating a nonfunctional protein
- The APC gene exerts a tumor-suppression function that induces apoptosis.
- Dysfunctional APC protein → prevents colonic cell apoptosis → allows β-catenin protein to accumulate intracellularly → stimulates cell growth → uncontrolled growth of cells → adenomatous polyps → enough genetic events occur to allow the polyps to become malignant
- Most patients are asymptomatic until cancer develops.
- Presymptomatic screening is key: 75%–80% have a family history of polyps and/or CRC by < 40 years of age.
- Nonspecific symptoms:
- Unexplained rectal bleeding (hematochezia)
- Abdominal pain
- Flat, localized pigmented lesions of the retina (no visual symptoms)
- Hypertrophy of the retinal pigment epithelium
- Highly specific for FAP
- Best seen by slit-lamp examination
- Often multiple and bilateral
- Head: osteomas in the mandible or skull
- Neck: thyroid nodules
- Skin and soft tissues:
- Epidermoid cysts on the scalp, face, and back (young patients)
- Fibromas on the trunk, back, and extremities
- Desmoid tumors: very large masses, abdominal cavity
- A palpable abdominal mass in someone < 40 years old is suggestive of FAP.
- A palpable mass on rectal exam in someone < 40 years old is suggestive of FAP.
There are 4 syndromes from the germline mutation in the APC gene:
- Gardner syndrome:
- Colonic polyposis typical of FAP
- Osteomas (bony growth most commonly on the skull and the mandible)
- Dental abnormalities
- Soft tissue tumors
- Turcot syndrome:
- Colonic polyposis typical of FAP
- CNS tumors (medulloblastoma).
- Attenuated adenomatous polyposis coli (AAPC):
- Fewer colonic polyps than FAP
- Polyps tend to develop at a later age (average age: 36 years).
- Involve the proximal colonic area
- Patients with known family history of FAP (with age at onset for relatives)
- Starting at 10–12 years of age
- Annual endoscopy evaluation with flexible sigmoidoscopy or colonoscopy
- Diagnosis is made by visualizing > 100 polyps on flexible sigmoidoscopy or colonoscopy.
- Serum studies:
- No positive results in the majority of patients
- CBC for iron deficiency anemia due to polyp bleeding
- Alpha-fetoprotein (AFP) blood test for children until age 5 years to screen for hepatoblastoma
- Genetic testing:
- Genetic counseling prior to the performance of these tests
- Performed in patients with clinical diagnosis
- Not recommended at an early age
- 3 genetic tests are available:
- In vitro protein synthesis assay:
- Test of choice
- Commercially available
- DNA from peripheral blood is analyzed for a truncated APC gene product.
- 100% accuracy in detecting gene carriers in a family
- Gene sequencing:
- Most accurate test
- Logistically difficult
- Reserved for research purposes
- Linkage testing:
- DNA markers near or in the APC locus are used to identify mutant gene carriers.
- Requires 2 affected family members to have an appropriate linkage relationship; therefore, it is not logistical.
- 90% accuracy
- In vitro protein synthesis assay:
- Flexible sigmoidoscopy/colonoscopy yearly
- Esophagogastroduodenoscopy recommended if sigmoidoscopy/colonoscopy establishes the diagnosis:
- Part of the surveillance program, as the duodenum is the 2nd most common area of involvement in FAP-related cancer.
- Recommended every 1–3 years
- Dental and skull X-ray films for Gardner variant
- Barium studies can visualize intestinal polyposis.
- Periodic abdominal ultrasonography (US) or CT scans are used to check desmoid tumors and pancreatic cancer.
- Periodic thyroid US: because of the ↑ risk of thyroid cancer
- Prophylactic colectomy with or without proctectomy
- Indications in FAP:
- Suspected CRC
- Presence of colonic dysplasia or neoplasia
- Significant ↑ in polyps during surveillance endoscopy
- Lifetime risk of CRC (100%)
- Gastric polyps (90%)
- Ampulla of Vater adenocarcinoma (10%)
- Desmoid tumors (20%)
- Thyroid tumors (2%)
- Short life expectancy (desmoid tumors are the most aggressive)
- Survival improves with colectomy
- Risk of developing non-CRC increases with advancing age.
- Cowden disease: autosomal dominant disorder caused by mutations in the tumor-suppressor gene PTEN and characterized by the development of multiple benign hamartomas. Cowden disease is a genodermatosis characterized by multiple benign hamartomas in any location, mucocutaneous lesions, and macrocephaly. Management depends on the location of the hamartoma.
- Hereditary nonpolyposis colon cancer (HNPCC): also known as Lynch syndrome. Hereditary nonpolyposis colon cancer is an autosomal dominant disorder caused by mutations in the mismatch repair (MMR) genes that ultimately leads to the development of CRC in 1st-degree relatives. Management is with prophylactic colectomy and frequent endoscopy for surveillance.
- Juvenile polyposis: autosomal dominant condition characterized by the growth of hyperplastic, hamartomatous polyps in the colon. Juvenile polyposis is commonly associated with mutations in the SMAD4 and BMPR1A genes. Diagnosis is made by visualizing > 5 polyps on colonoscopy or on visualizing any number of polyps plus a positive family history. Management is surgical to reduce the likelihood of GI bleeding and obstruction.
- Colorectal cancer (CRC): 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease, arising from genetic and epigenetic abnormalities, with influence from environmental factors. Almost all cases of CRC are adenocarcinoma. Most cases are asymptomatic, so screening is important. Diagnosis is by colonoscopy. Management is primarily surgical.
- Thyroid cancer: malignancy of the thyroid gland cells that can arise from the thyroid follicular cells or the calcitonin-producing C cells. Papillary cancer is the most common type associated with FAP. Exposure to ionizing radiation and iodine deficiency are also considered risk factors. Diagnosis is with thyroid-stimulating hormone measurement, ultrasound, and biopsy. Management is mainly surgical.
- Chung, D., Rodgers, L., (2021). Clinical manifestations and diagnosis of familial adenomatous polyposis. UpToDate. Retrieved June 12, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-familial-adenomatous-polyposis
- Burt, R. (2021). Gardner syndrome. UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/gardner-syndrome
- Wehbi, M. (2019). Familial adenomatous polyposis workup. Medscape. Retrieved June 13, 2021, from https://emedicine.medscape.com/article/175377-workup#c6