Familial Adenomatous Polyposis (FAP)

Content of This Page

1- Introduction

2- Causes

3- Pathophysiology

4- Stages of The Disease

5- Diagnosis

6- Treatment

Introduction

Familial Adenomatous Polyposis (FAP) is a hereditary cancer syndrome characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, typically beginning in adolescence or early adulthood. If left untreated, nearly all individuals with classic FAP will develop colorectal cancer, usually by the age of 40–50 years. FAP is caused by a germline mutation in the APC gene (adenomatous polyposis coli), a tumor suppressor gene located on chromosome 5q21. It follows an autosomal dominant inheritance pattern, meaning a child of an affected parent has a 50% chance of inheriting the condition.

There are also attenuated forms of FAP (AFAP), where fewer polyps develop (usually <100), and cancer onset is later.

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Pathophysiology

  • Germline mutation in the APC gene (Adenomatous Polyposis Coli gene)

    • Located on chromosome 5q21–q22

    • Inherited in an autosomal dominant pattern

    • Mutation leads to uncontrolled cell growth and formation of multiple adenomatous polyps

  • De novo mutations

    • Occur in ~25–30% of cases with no family history

    • Spontaneous mutation in the APC gene

  • Loss of tumor suppressor function

    • APC gene normally regulates β-catenin and controls cell proliferation

    • Mutation disrupts this control, promoting polyp formation and progression to cancer

  • Attenuated FAP (AFAP)

    • Caused by specific mutations in different regions of the APC gene

    • Fewer polyps and later onset of colorectal cancer

  • MYH-associated polyposis (MAP) (FAP-like syndrome)

    • Caused by biallelic mutations in the MUTYH gene

    • Inherited in an autosomal recessive manner

    • Resembles attenuated FAP but is genetically distinct

 

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Pathophysiology

FAP results from a germline mutation in the APC gene, a tumor suppressor gene located on chromosome 5q21–q22. The APC gene plays a crucial role in regulating the Wnt signaling pathway, particularly by controlling the degradation of β-catenin, a protein that promotes cell proliferation. When the APC gene is mutated, this regulation is lost, leading to the accumulation of β-catenin in the nucleus. This abnormal buildup triggers the activation of genes that drive uncontrolled cell division, resulting in the formation of numerous adenomatous polyps in the colon and rectum. Since individuals inherit one defective copy of the APC gene (first “hit”), a second somatic mutation (second “hit”) in the normal allele leads to complete loss of function, initiating polyp formation. Over time, some of these polyps acquire additional mutations (e.g., in KRAS, p53), leading to dysplasia and eventual malignant transformation into colorectal cancer. The pathophysiological process also affects other tissues, explaining the extracolonic manifestations such as duodenal polyps, desmoid tumors, and congenital retinal changes.

Symptoms

-Gastrointestinal Symptoms:

  • Rectal bleeding (most common early symptom)

  • Diarrhea or change in bowel habits

  • Abdominal pain or discomfort

  • Mucus in stool

  • Unexplained weight loss

  • Iron deficiency anemia (due to chronic blood loss)

-Colorectal Findings:

  • Development of hundreds to thousands of adenomatous polyps in the colon and rectum, usually in adolescence

  • Risk of progression to colorectal cancer by age 40–50 if untreated

-Extracolonic Manifestations:

  • Upper GI polyps (especially in the duodenum and stomach)

  • Desmoid tumors (fibrous tumors, often in the abdomen)

  • Osteomas (benign bony growths, often on skull or jaw)

  • Dental abnormalities (extra or unerupted teeth)

  • Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)

  • Epidermoid cysts and fibromas

Diagnosis

1. Clinical and Family History

  • Positive family history of FAP or early-onset colorectal cancer

  • First-degree relatives of affected individuals are at high risk

  • Consider FAP if a person develops >100 adenomatous polyps, especially before age 40

2. Endoscopic Examination

  • Colonoscopy (gold standard):

    • Reveals hundreds to thousands of adenomatous polyps throughout the colon and rectum

    • Typically begins around age 10–15 years in at-risk individuals

  • Upper GI endoscopy (EGD):

    • To detect duodenal or gastric polyps, especially in patients with known FAP

3. Genetic Testing

  • APC gene mutation analysis:

    • Confirms diagnosis

    • Identifies affected family members

    • Recommended for at-risk relatives

  • MUTYH gene testing (if APC negative and FAP features present):

    • For diagnosing MUTYH-associated polyposis (MAP)

4. Imaging (if needed)

  • CT/MRI of abdomen:

    • To assess for desmoid tumors or intra-abdominal complications

  • Ophthalmologic exam:

    • To detect CHRPE (congenital hypertrophy of the retinal pigment epithelium), a marker associated with FAP

5. Diagnosis is confirmed by:

  • Clinical criteria: ≥100 adenomatous polyps

  • Or genetic testing showing a pathogenic APC gene mutation

Treatment

1. Prophylactic Surgery (Mainstay of Treatment)

Recommended to prevent colorectal cancer, usually between late teens and early 20s or earlier if polyps are numerous or show dysplasia.

  • Colectomy with ileorectal anastomosis (IRA)

    • Removes colon, spares rectum

    • Requires lifelong rectal surveillance

  • Proctocolectomy with ileal pouch-anal anastomosis (IPAA)

    • Removes colon and rectum, creates a pouch from the small intestine

    • Preferred in cases with rectal involvement or high polyp burden

  • Total proctocolectomy with end ileostomy

    • For patients not suitable for pouch surgery (e.g., poor continence or advanced disease)

2. Endoscopic Surveillance

  • Annual colonoscopy or sigmoidoscopy starting at age 10–12 in at-risk individuals

  • Upper GI endoscopy (for duodenal and gastric polyps) starting around age 20 and repeated every 1–3 years depending on findings

3. Medical Therapy (Adjunct)

  • NSAIDs (e.g., sulindac, celecoxib):

    • May reduce the number and size of polyps

    • Not a substitute for surgery

  • Investigational agents: COX-2 inhibitors, EGFR inhibitors, etc.

4. Management of Extracolonic Manifestations

  • Desmoid tumors: Managed with NSAIDs, anti-estrogens, chemotherapy, or surgery if symptomatic

  • Gastric/duodenal polyps: Monitored and biopsied; surgery if high-grade dysplasia or obstruction

  • Thyroid and liver screening: Periodic ultrasound to detect tumors (e.g., papillary thyroid cancer, hepatoblastoma)

5. Genetic Counseling and Family Screening

  • First-degree relatives should undergo genetic testing

  • Positive individuals require lifelong surveillance and early intervention

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