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familial adenomatous polyposis

MIM.175100 5q21-q22

Thursday 20 November 2003

FAP is an autosomal dominant tumor predisposition syndrome characterized by numerous colorectal adenomas, which will eventually progress to adenocarcinoma. Without prophylactic colectomy, FAP will inevitably lead to colorectal cancer at a relatively young age.

Patients with FAP run the risk of developing extracolonic manifestations, and the duodenum is the main site for these (pre-) malignant developments (see duodenal FAP).

Despite its importance as a tumorigenic model, FAP accounts for @<@1% of colorectal cancers. This low figure reflects the rarity of the condition (occurs in approximately 1 in 8000 subjects) but is also due to cancer prevention in known affected subjects.

The presence of extra-colorectal features (sebaceous cysts, bone tumors, and fibromatosis) was first noted by Gardner.

The list of extra-colorectal features has gradually extended to include peri-ampullary adenoma and carcinoma, medulloblastoma, papillary carcinoma of thyroid, hepatoblastoma, fundic gland polyps and carcinoma of the stomach, and congenital hypertrophy of retinal pigmented epithelium (CHRPE).

The presence of >100 colorectal adenomas has traditionally been used to distinguish the autosomal dominant condition FAP from multiple adenomas.

It is essential to obtain a tissue diagnosis, even when innumerable colorectal polyps are discovered in the child of an affected parent.

Children may develop an unrelated and self-limited lymphoid polyposis that is indistinguishable at endoscopy from FAP.

Since the phenotype does not usually develop until the second decade, less than 100 adenomas may be present in some affected children who are endoscoped prematurely.

Although the vast majority of colorectal polyps are typical adenomas, hyperplastic polyps and serrated adenomas may occasionally be diagnosed.

A phenotype fully consistent with FAP may present in subjects with no family history of the condition. This may be due to a new mutation (accounts for one in four of new diagnoses), non-paternity, adoption, or denial of a family history.

The FAP phenotype may also occur in subjects without a germline APC mutation. An explanation other than simple technical failure is the recently recognized autosomal recessive condition known as MUTYH- (formerly MYH-) associated polyposis (MAP).

A variant of FAP in which there is an autosomal dominant predisposition to multiple but fewer than 100 adenomas has been described as "attenuated FAP" (attenuated familial adenomatous polyposis).


- congenital hypertrophy of retinal pigment epithelium (CHRPE)
- supernumerary teeth
- unerupted teeth
- dental caries
- odontomas
- mammary fibrosis
- multiple colonic adenomatous polyps
- multiple gastric polyps
- multiple duodenal polyps
- mesenteric fibromatosis
- skull osteomas, especially involving the mandibular angle
- endosteal and exosteal osteomas
- epidermoid inclusion cysts
-  fibromas
-  lipomas
- lipofibromas
- increased skin pigmentation
- keloids

- tumors

  • adrenal carcinoma
  • thyroid papillary carcinoma
  • periampullary carcinoma
  • fibrosarcoma
  • colon carcinoma
  • upper GI tract lesion (24525509)
  • medulloblastoma
  • hepatoblastoma
  • intestinal carcinoid tumor
  • desmoid fibromatosis
  • astrocytoma

APC gene at 5q21

The initial identification of the causative gene occurred through the discovery of a large interstitial deletion in chromosome 5q in a subject with Gardner syndrome, confirmation of the 5q21 locus through linkage analysis, identification of the APC gene by positional cloning, and finally the demonstration of truncating mutations in APC in the germline of affected subjects.

The multifunctional APC protein is large and comprises several motifs and domains, allowing it to oligomerize and/or interact with multiple molecules that include β-catenin, α-catenin, GSK3β, axin, conductin, and tubulin.

Although the diagnosis of FAP may be confirmed by the demonstration of a germline APC mutation, truncating APC mutations are found in only 70–90% of individuals or families with the FAP phenotype.

Truncating mutations have been found throughout the APC gene. Most truncating mutations are fully penetrant but may be associated with a differing severity of colorectal polyposis and differing risks of the extra-colorectal manifestations.

Mutations in the central region of APC (codons 1290–1400) are associated with the most severe polyposis phenotype.

Two codons (1061 and 1309) are mutational hotspots and account for 11% and 17% of all germline mutations, respectively.

CHRPE is associated with mutations between codons 457 and 1444, while jaw osteomas and fibromatosis (desmoids tumors) are more prevalent in patients with mutations occurring after codon 1400.

Open references

- Upper GI tract lesions in familial adenomatous polyposis (FAP): enrichment of pyloric gland adenomas and other gastric and duodenal neoplasms. Wood LD, Salaria SN, Cruise MW, Giardiello FM, Montgomery EA. Am J Surg Pathol. 2014 Mar;38(3):389-93. doi : 10.1097/PAS.0000000000000146 PMID: 24525509 [Free]


- Fodde R, Smits R. Disease model: familial adenomatous polyposis. Trends Mol Med. 2001 Aug;7(8):369-73. PMID: 11516998

- Fearnhead NS, Britton MP, Bodmer WF. The ABC of APC. Hum Mol Genet. 2001 Apr;10(7):721-33. PMID: 11257105