Approach

Familial adenomatous polyposis (FAP) typically does not present with any sign​s or symptoms. Most patients present for evaluation due to having a relative with FAP.[2][8]​​​​​​ The diagnostic work-up should include a thorough family history, referral to genetic counselling, and genetic testing.[9][28]

History

Approximately 70% of patients have a family history of FAP; however, up to 30% of FAP probands have no family history of polyposis or colorectal cancer; these cases may be explained by somatic mosaicism in the adenomatous polyposis coli (APC) gene.[2][3] The absence of a family history of polyposis should, therefore, not preclude consideration of the diagnosis in a patient with colonic adenomas.[24]​

The presence and type of any cancer diagnoses in first- or second-degree relatives; age at diagnosis; and presence of polyps in first-degree relatives should be established.[9][29]

Physical examination

In general, the majority of patients with FAP do not exhibit any physical signs indicating that they might have the condition.

Patients may present with iron deficiency anaemia, altered bowel habit or haematochezia that leads to a gastrointestinal tract evaluation and discovery of multiple colonic adenomas.[2][8]​​[24]

Extraintestinal manifestations of FAP may be evident and prompt genetic testing.[24][28]​​​ These include skin cysts, lipomas and fibromas, supernumerary teeth, thyroid nodules, osteomas, desmoid tumours, adrenal adenomas, and congenital hypertrophy of the retinal pigment epithelium.[10]

Genetic testing

Predictive genetic testing for at-risk patients (i.e., patients with a family history of FAP) and patients with suspected FAP is required for diagnosis.[9][12][24][28][30]

Most cases of FAP are caused by a germline mutation in the tumour-suppressor gene APC, but some cases result from germline mutations in POLD1, POLE, or GREM1.[16][17][18][19]​ If the pathogenic variant is already known, patients should undergo genetic testing for the identified familial pathogenic variant.[9] Where there are no known pathogenic variants in any polyposis genes, the National Comprehensive Cancer Network (NCCN) recommends germline multigene panel testing.[9] Germline testing is important to differentiate between other aetiologies of adenomatous polyposis (e.g., MUTYH-associated polyposis) for the consideration of extracolonic screening, as well as counselling, risk assessment, and testing of family members.[9] While the identification of a pathogenic variant confirms the diagnosis, FAP should not be excluded even where a pathogenic variant cannot be identified.[24]

For at-risk patients, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommends that predictive genetic testing for FAP should be offered to children aged 12-14 years.[24] The American Society for Gastrointestinal Endoscopy recommend a slightly earlier range of 10-12 years for FAP, extending this to 18-20 years in cases of attenuated FAP (AFAP).[12] However, any child with a family history of FAP/AFAP presenting with rectal bleeding should be considered for earlier testing.[24]

There is currently no international consensus regarding criteria for genetic testing in FAP.[9][12][24]​​​​​​​[28][29]

The American College of Gastroenterology recommend testing in individuals who have one of the following criteria:[29]

  • A personal history of >10 cumulative colorectal adenomas

  • A family history of one of the adenomatous polyposis syndromes

  • A history of adenomas and FAP-type extracolonic manifestations (duodenal/periampullary adenomas, desmoid tumours [abdominal>peripheral], papillary thyroid cancer, congenital hypertrophy of the retinal pigment epithelium [CHRPE], epidermal cysts, osteomas)

The American Society for Gastrointestinal Endoscopy recommends genetic testing in the following situations:[12]

  • When 10 or more cumulative adenomatous polyps are noted on a single colonoscopy

  • If the patient has 10 or more adenomas and a personal history of colorectal cancer

  • If the patient has 20 or more adenomatous polyps in his or her lifetime.

NCCN criteria recommend genetic testing be offered in the following instances:[9]

  • Personal history of ≥20 cumulative adenomas

  • Known pathogenic variant in adenomatous polyposis gene in family

  • Multi-focal/bilateral congenital hypertrophy of retinal pigment epithelium (CHRPE)

Genetic testing should be considered if the patient has a personal history of between 10 and 19 cumulative adenomas; desmoid tumour; hepatoblastoma; cribriform-morular variant of papillary thyroid cancer; unilateral CHRPE; or patient meets criteria for serrated polyposis syndrome with at least some adenomas.[9]

The American Society of Colon and Rectal Surgeons advise that the diagnosis of polyposis syndromes should be considered in patients with:[28]

  • >10 lifetime adenomas

  • Colorectal cancer diagnosed at <50 years of age

  • A personal history of desmoid disease or other extraintestinal manifestations of FAP

  • Family members with known FAP

​​​Genetic counselling is recommended for all patients with diagnosed or suspected FAP.[9][12][24]​​​​​ ​​​

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