familial adenomatous polyposis
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)
multiple colonic adenomatous polyps
multiple gastric polyps
multiple duodenal polyps
skull osteomas, especially involving the mandibular angle
endosteal and exosteal osteomas
epidermoid inclusion cysts
increased skin pigmentation
- adrenal carcinoma
- thyroid papillary carcinoma
- periampullary carcinoma
- colon carcinoma
- gastric adenocarcinoma
- intestinal carcinoid tumor
- desmoid fibromatosis
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.