Familial Adenomatous Polyposis

name: Familial Adenomatous Polyposis
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-01-26T02:55:13Z'
description: >-
  Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary cancer
  syndrome caused by germline pathogenic variants in the APC tumor suppressor gene.
  It is characterized by the development of hundreds to thousands of adenomatous
  polyps in the colon and rectum, with virtually 100% lifetime risk of colorectal
  cancer if untreated. FAP exemplifies the adenoma-carcinoma sequence and the role
  of Wnt/β-catenin pathway dysregulation in colorectal tumorigenesis. Extracolonic
  manifestations include desmoid tumors, duodenal adenomas, osteomas (Gardner syndrome),
  and congenital hypertrophy of the retinal pigment epithelium (CHRPE).
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Polyposis Syndrome
parents:
- hereditary cancer-predisposing syndrome
has_subtypes:
- name: Classic FAP
  description: >-
    Characterized by >100 colorectal adenomatous polyps, typically appearing in
    adolescence with polyposis by age 20-30. Without prophylactic colectomy,
    colorectal cancer develops by age 40 on average. Caused by mutations in the
    mutation cluster region (MCR) of APC.
- name: Attenuated FAP (AFAP)
  description: >-
    Milder phenotype with fewer polyps (10-100), later onset of polyposis,
    right-sided colon predominance, and delayed colorectal cancer risk (average
    age 50-55). Associated with mutations at the 5' or 3' ends of APC or in
    the alternatively spliced region of exon 9.
- name: Gardner Syndrome
  description: >-
    FAP variant with prominent extracolonic manifestations including osteomas
    (especially mandible and skull), epidermoid cysts, desmoid tumors, and
    dental abnormalities. Historically considered separate but now recognized
    as FAP with variable expressivity.
pathophysiology:
- name: APC Tumor Suppressor Loss
  description: >-
    Germline heterozygous APC mutations result in one functional allele. Somatic
    loss or mutation of the remaining wild-type allele (second hit) eliminates
    APC function, initiating adenoma formation. This follows Knudson's two-hit
    hypothesis for tumor suppressor gene inactivation.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  downstream:
  - target: Wnt/β-Catenin Pathway Activation
    description: APC loss prevents β-catenin degradation
  evidence:
  - reference: PMID:28668823
    supports: SUPPORT
    snippet: >-
      In agreement with Knudson's 'two-hit' theory, the inactivation of the residual
      APC gene in FAP is a critical step in the development of both colorectal
      cancer and desmoids.
    explanation: >-
      Confirms that FAP follows the two-hit mechanism for both colorectal cancer
      and desmoid tumor development.
- name: Wnt/β-Catenin Pathway Activation
  description: >-
    APC normally functions in the destruction complex (with Axin, GSK3β, CK1)
    to phosphorylate β-catenin, targeting it for ubiquitination and proteasomal
    degradation. Loss of APC allows β-catenin to accumulate, translocate to the
    nucleus, and activate Wnt target genes driving proliferation.
  biological_processes:
  - preferred_term: Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  downstream:
  - target: Uncontrolled Intestinal Epithelial Proliferation
    description: β-catenin activates proliferative and stemness genes
- name: Uncontrolled Intestinal Epithelial Proliferation
  description: >-
    Nuclear β-catenin activates TCF/LEF transcription factors, driving expression
    of Wnt target genes including MYC, CCND1 (cyclin D1), and others that promote
    cell cycle progression. This results in uncontrolled proliferation of
    intestinal crypt cells, forming adenomatous polyps.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Adenoma Formation
    description: Hyperproliferative epithelium forms adenomatous polyps
- name: Adenoma Formation
  description: >-
    Sustained Wnt pathway activation drives adenoma development. Adenomas are
    benign neoplasms but represent the first step in the adenoma-carcinoma
    sequence. In FAP, hundreds to thousands of adenomas develop, dramatically
    increasing the probability that one will progress to carcinoma.
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  - preferred_term: rectum
    term:
      id: UBERON:0001052
      label: rectum
  downstream:
  - target: Colorectal Cancer Progression
    description: Accumulated mutations drive adenoma-to-carcinoma progression
- name: Colorectal Cancer Progression
  description: >-
    Adenomas acquire additional mutations in KRAS, TP53, SMAD4, and other genes
    through the adenoma-carcinoma sequence. In FAP, the large number of adenomas
    makes it virtually certain that at least one will progress to invasive
    adenocarcinoma without intervention.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
phenotypes:
- category: Gastrointestinal
  name: Colorectal Polyposis
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Hundreds to thousands of adenomatous polyps carpet the colon and rectum.
    Polyps typically appear in adolescence in classic FAP. The number and
    density of polyps correlates with mutation location in APC.
  phenotype_term:
    preferred_term: Large intestinal polyposis
    term:
      id: HP:0030255
      label: Large intestinal polyposis
- category: Neoplastic
  name: Colorectal Cancer
  frequency: VERY_FREQUENT
  description: >-
    Without prophylactic surgery, colorectal cancer develops in nearly 100%
    of patients with classic FAP, typically by age 40. The average age of
    cancer diagnosis is 39 years without surveillance/intervention.
  phenotype_term:
    preferred_term: Colon cancer
    term:
      id: HP:0003003
      label: Colon cancer
- category: Gastrointestinal
  name: Duodenal Adenomas
  frequency: VERY_FREQUENT
  description: >-
    Duodenal adenomas, especially periampullary, occur in 80-90% of FAP patients.
    They carry risk of progression to duodenal/ampullary adenocarcinoma, which
    is a leading cause of death in post-colectomy FAP patients.
  phenotype_term:
    preferred_term: Small intestinal polyposis
    term:
      id: HP:0030256
      label: Small intestinal polyposis
- category: Musculoskeletal
  name: Desmoid Tumors
  frequency: FREQUENT
  description: >-
    Desmoid tumors (aggressive fibromatoses) occur in 10-15% of FAP patients,
    often in the mesentery or abdominal wall. They can cause significant
    morbidity through local invasion and compression. More common with 3' APC
    mutations and after abdominal surgery.
  phenotype_term:
    preferred_term: Desmoid tumor
    term:
      id: HP:6001034
      label: Desmoid tumor
  evidence:
  - reference: PMID:28668823
    supports: SUPPORT
    snippet: >-
      Among associated lesions in FAP, desmoid tumors represent a common possible
      life-threatening condition that requires special attention. They are rare
      tumors occurring with a particularly high incidence in FAP, especially after
      surgery.
    explanation: >-
      Review confirms desmoid tumors are a serious complication of FAP with
      particularly high incidence after abdominal surgery.
- category: Musculoskeletal
  name: Osteomas
  frequency: FREQUENT
  description: >-
    Benign bony growths, particularly of the mandible and skull. Characteristic
    of Gardner syndrome phenotype. May be detected radiographically before
    polyposis becomes apparent.
  phenotype_term:
    preferred_term: Osteoma
    term:
      id: HP:0100246
      label: Osteoma
- category: Ophthalmologic
  name: Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)
  frequency: FREQUENT
  description: >-
    Pigmented lesions of the retinal pigment epithelium present from birth.
    Multiple bilateral CHRPE lesions are highly specific for FAP and can be
    detected before polyp development, aiding early diagnosis.
  phenotype_term:
    preferred_term: Abnormality of retinal pigmentation
    term:
      id: HP:0007703
      label: Abnormality of retinal pigmentation
biochemical:
- name: APC Genetic Testing
  notes: >-
    Molecular testing identifies germline APC mutations in 70-90% of classic FAP
    families. Mutations include truncating variants, large deletions, and deep
    intronic variants. Genotype-phenotype correlations exist: mutations in the
    MCR (codons 1250-1464) cause severe polyposis; 5'/3' mutations cause AFAP.
genetic:
- name: APC
  association: Germline Loss-of-Function Mutations
  inheritance:
  - name: Autosomal Dominant
  notes: >-
    APC (5q22.2) encodes adenomatous polyposis coli, a key component of the
    β-catenin destruction complex. Most germline mutations are truncating
    (nonsense, frameshift) resulting in loss of function. De novo mutations
    account for 20-30% of cases. Mutation location correlates with phenotype:
    MCR mutations (codons 1250-1464) cause classic severe FAP; 5' mutations
    (before codon 157) and 3' mutations (after codon 1595) cause attenuated FAP.
  evidence:
  - reference: PMID:28668823
    supports: PARTIAL
    snippet: >-
      Several lines of evidence show that germline mutations affect the functional
      domains of the APC gene that are responsible for interactions of the transcript
      with β-catenin, whereas somatic second mutations involve the downstream region
      of the gene.
    explanation: >-
      Supports APC domain involvement and second-hit pattern, but does not fully
      cover all detailed genotype-phenotype and de novo rate claims in this entry.
treatments:
- name: Prophylactic Colectomy
  description: >-
    Surgical removal of the colon is the primary management to prevent colorectal
    cancer. Options include total proctocolectomy with ileal pouch-anal anastomosis
    (IPAA) or subtotal colectomy with ileorectal anastomosis (IRA). Timing is
    typically in late teens/early twenties or when polyp burden becomes
    unmanageable endoscopically.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Endoscopic Surveillance
  description: >-
    Annual colonoscopy beginning at age 10-12 in at-risk individuals to detect
    polyp development. Upper endoscopy every 1-4 years to monitor duodenal
    adenomas using Spigelman staging. Surveillance of rectal stump or pouch
    after colectomy.
  treatment_term:
    preferred_term: colonoscopy
    term:
      id: MAXO:0001184
      label: colonoscopy
- name: Genetic Counseling
  description: >-
    Genetic counseling and testing for at-risk family members. Children of
    affected parents have 50% risk. Predictive testing allows targeted
    surveillance in mutation carriers and reassurance for non-carriers.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
- name: Chemoprevention
  description: >-
    Sulindac and celecoxib (COX-2 inhibitors) have demonstrated ability to
    reduce polyp number and size but do not eliminate cancer risk. Used as
    adjunct to surveillance, not as alternative to surgery.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
disease_term:
  preferred_term: familial adenomatous polyposis 1
  term:
    id: MONDO:0021056
    label: familial adenomatous polyposis 1