Familial Adenomatous Polyposis (FAP)

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Familial Adenomatous Polyposis (FAP)










Familial adenomatous polyposis (FAP) is a significant genetic disorder primarily characterized by the development of numerous colorectal polyps. Here’s a concise overview of the condition:

  • Nature of the Condition: FAP involves the formation of hundreds, sometimes thousands, of polyps in the colon and rectum. These polyps are pre-cancerous and without proper treatment, they nearly always progress to colorectal cancer, usually by the age of 40.

  • Genetic Cause: The disorder is caused by mutations in the adenomatous polyposis coli (APC) gene, which plays a critical role as a tumor suppressor. Mutations in the APC gene lead to uncontrolled cell growth, resulting in the formation of numerous polyps.

  • Inheritance Pattern: FAP is inherited in an autosomal dominant pattern, meaning that inheriting just one mutated copy of the APC gene from one parent is enough to cause the disorder. This also means that individuals with FAP have a 50% chance of passing the mutated gene to each of their children.

  • Familial adenomatous polyposis (FAP) is a rare genetic disorder.
    • Incidence at birth is approximately 1 in 8,300.
    • Prevalence varies, with estimates in the European Union ranging from 1 in 11,300 to 1 in 37,600.
    • Accounts for less than 1% of colorectal cancer cases globally.
    • Manifests equally in both sexes.
    • Most patients are diagnosed before cancer develops due to early detection and management strategies.

Clinical Manifestations of Familial Adenomatous Polyposis (FAP)

  • Familial Adenomatous Polyposis (FAP) is often detected early, frequently before symptoms occur. When symptoms do appear, they typically include:

    • Blood in the stool or signs of anemia due to occult bleeding caused by the polyps.
    • Chronic diarrhea, which may be directly related to the presence of numerous polyps.
    • Extraintestinal manifestations, such as osteomas, which can lead to additional symptoms.
  • Characterized by numerous colorectal adenomas.
  • Extracolonic manifestations are also common.
  • Colonic Manifestations
    • Classic FAP
      • Defined by the presence of 100 or more adenomatous polyps.
      • Polyps typically develop in the second or third decade of life.
      • Untreated, nearly all individuals will develop colorectal cancer, typically by age 45.
    • Attenuated FAP (AFAP)
      • Milder form with fewer polyps, usually localized to the right colon.
      • Mean age at diagnosis is 44 years.
      • High risk of colorectal cancer, with onset at an older age compared to classic FAP.
  • Extracolonic Manifestations
    • Fundic gland polyps occur in the majority of FAP patients.
    • Duodenal polyps are common and can progress to cancer.
    • Desmoid tumors and various other benign growths are associated with FAP.
    • Multiple and bilateral retinal lesions (CHRPE) are a marker for FAP.
    • Risk for extraintestinal malignancies like thyroid cancer, hepatoblastoma, and CNS tumors.
  • FAP Variants
    • Gardner’s syndrome
      • Includes colonic polyposis with desmoid tumors and other extracolonic manifestations.
      • Considered a subset of FAP due to underlying APC mutation.
    • Turcot’s syndrome
      • Historically described the association of colon cancer with brain tumors.
      • Brain tumors linked to both FAP (medulloblastomas) and Lynch syndrome (gliomas).
  • Laboratory Features
    • Most patients are laboratory-normal but may present with iron deficiency anemia due to bleeding from adenomas.

Diagnosis of Familial Adenomatous Polyposis (FAP)

 

  • Suspected when a patient has 10 or more colorectal adenomas.
  • Applies to both symptomatic patients and asymptomatic individuals during screening.
  • Diagnosis considered in older patients with attenuated FAP (AFAP) upon detecting 10 or more adenomas.
  • Genetic Testing for APC Mutation
    • Necessary for a definitive diagnosis.
    • Recommended for individuals with 10 to 20 adenomas over their lifetime.
    • Higher number of adenomas and strong family history increase likelihood of FAP.
  • Genetic Counseling
    • Offered prior to genetic testing.
    • Important to consider other conditions like MUTYH associated polyposis if no mutation is found.
  • Testing for At-Risk Relatives
    • Mutation-specific testing for first-degree relatives of the index case.
    • Consider testing for first-degree relatives of any family member with an APC mutation.
    • Second-degree relatives may be offered testing if a family member declines or has passed away.
  • Genetic Testing for Children
    • Typically offered around age 10.
    • Not routinely recommended before age 10, unless family history includes colorectal cancer diagnosed under age 20.
  • Prediction Models
    • Used for counseling on the probability of finding an APC or MUTYH mutation.
    • Based on personal and family history.
  • Prenatal and Preimplantation Genetic Diagnosis (PGD)
    • Options for FAP patients planning a family.
    • Discuss the implications and processes involved.

Differential Diagnosis for Multiple Colorectal Adenomas

 

  • May be seen in MUTYH associated polyposis (MAP) which has an autosomal recessive inheritance pattern.
  • In MAP, family history typically lacks an autosomal dominant pattern of polyposis or colorectal cancer.
  • Attenuated FAP (AFAP) with few adenomas can be clinically similar to Lynch syndrome or sporadic adenomas.
  • Genetic testing is crucial for distinguishing between FAP, MAP, and Lynch syndrome.
  • Genetic Characteristics
    • FAP: Germline mutations in the APC gene.
    • MAP: Biallelic mutations in the MUTYH genes.
    • Lynch syndrome: Germline mutations in DNA mismatch repair genes.
  • Individuals with Multiple Adenomas but No Identified Mutation
    • Suggests the existence of as yet unidentified genes linked to multiple colorectal adenomas.
  • Study on Prevalence of APC and MUTYH Mutations
    • Examined individuals with personal or family history indicative of a polyposis syndrome.
    • Found APC mutations predominantly in individuals with a larger number of adenomas.
    • Detected MUTYH mutations across various ranges of adenoma numbers.
    • Significant portion of individuals with classic and attenuated polyposis did not have mutations in APC or MUTYH genes.

Management

 

  • Full Colonoscopy: Should be performed to evaluate the extent of colonic polyposis in gene carriers or at-risk family members.
  • Colectomy Recommendation: Strongly recommended at the time of initial diagnosis for patients with multiple large adenomas (>1 cm), those with villous histology, or high-grade dysplasia.
    • Timing of Surgery: Considered based on adenoma burden, aiming to minimize impact on personal and educational life, especially for adolescents.
    • Surgical Considerations:
      • Total Proctocolectomy with Ileoanal Anastomosis: Preferred for children with extensive polyposis involving the rectum.
      • Subtotal Colectomy: Considered for patients with attenuated adenomatous polyposis with minor rectal involvement.
      • Genetic Factors in Surgical Decision: Certain APC mutations may influence the choice between ileorectal anastomosis and total proctocolectomy.
    • Post-Surgical Surveillance:
      • Patients remain at risk for developing adenomas and adenocarcinoma in the ileal pouch, with varying risk percentages over time following surgery.
  • Chemoprevention:
    • NSAIDs: Drugs like sulindac and celecoxib have been used to reduce polyp numbers but cannot replace surgical intervention.
    • Celecoxib: Approved by the FDA as an adjunct to surgery for reducing the number of colonic polyps.
    • Duodenal Adenomas: COX-2 inhibitors may help in reducing the progression of duodenal adenomas.
  • Management of Attenuated FAP (AFAP):
    • Fewer adenomas (10 to 100), with a lower but significant risk of colon cancer.
    • Screening Recommendations: Start colonoscopic and endoscopic screening at age 20 to 25 years.
    • Surgical Intervention: Considered for those unable to be managed endoscopically.
  • Extra-Intestinal Manifestations and Surveillance:
    • Upper Endoscopy: Recommended from age 20 to 30 years onwards for monitoring duodenal adenomas and periampullary carcinomas.
    • Extraintestinal Tumors: Includes desmoids and others, where management strategies may vary.

Genetics of Familial Adenomatous Polyposis (FAP)

 

  • Caused by mutations in the APC gene on chromosome 5q21-q22.
  • Shows autosomal dominant inheritance with high penetrance for colonic symptoms but variable for extracolonic symptoms.
  • Up to 25 percent of cases arise from de novo mutations, with no family history of FAP.
  • APC Gene Mutations
    • More than 1000 mutations identified, most leading to frame shifts and premature stop codons.
    • Large deletions may account for up to 15 percent of FAP cases.
    • Both alleles of the APC gene must be inactivated for adenoma development.
    • Typically involves an inherited mutation and a somatic “second hit” in the other allele.
  • Role in Cancer
    • APC mutations are crucial for adenoma formation due to aberrant beta-catenin accumulation and cell growth gene activation.
    • Somatic APC mutations are present in about 80 percent of sporadic colorectal adenomas and cancers.
  • Mutation Location and Disease Severity
    • Mutation location within the APC gene affects severity of polyposis, cancer risk, onset age, survival, and extracolonic manifestations.
    • Classic FAP is linked to mutations between codons 169 to 1393.
    • Attenuated FAP (AFAP) is associated with mutations at the 5′ and 3′ ends of the APC gene.
  • Genotype-Phenotype Correlations
    • Variability within families and among individuals with the same mutation.
    • Specific mutations are linked to particular symptoms:
      • Codons 463 to 1444: Associated with retinal lesions (CHRPE).
      • Codons 1445 to 1578: Associated with desmoid tumors.
      • Codons 279 to 1309: Associated with duodenal polyposis.
      • Codons 686 to 1217: Associated with medulloblastoma.

Genetic Testing for FAP

 

  • No prospective trials to guide gene testing or screening in FAP.
  • Recommendations are based on observational studies and expert consensus.
  • Current Genetic Testing Practice
    • Available through various commercial labs.
    • Genetic counseling is recommended before testing.
    • Test first conducted on an affected family member.
  • If Mutation is Identified
    • The test can pinpoint at-risk family members.
    • Helps to determine which family members inherited the mutation.
  • If No Mutation is Found
    • Consider other conditions like MUTYH associated polyposis.
    • Treat gene tests as uninformative if no cause is found.
    • All at-risk family members should then undergo endoscopic screening.
  • Who Should Get Tested
    • Family members of patients with classic FAP, Gardner’s syndrome, or Turcot’s syndrome.
    • Children at risk are usually tested around age 10 to 12.
    • Testing is not advised before age 10 unless clinically indicated.
  • Utilizing Genetic Testing Responsibly
    • Offer counseling to discuss implications of testing.
    • Discuss prenatal genetic testing and preimplantation genetic diagnosis as preventive options.

Colonic Surveillance

  • Gene carriers and at-risk individuals to have annual flexible sigmoidoscopy or colonoscopy starting at age 10 to 12.
  • Surveillance until age 35 to 40 if no polyps are found.
  • Focus on the rectosigmoid in classic FAP using sigmoidoscopy.
  • Colonoscopy is recommended for attenuated FAP due to right-sided tumors.

Upper Intestinal Tumor Surveillance

  • Screening for gastric and duodenal polyps starts around age 25 to 30.

  • Intervals between screenings depend on the type of polyps found.

  • Symptoms related to the upper digestive tract warrant immediate investigation.

  • Duodenal Polyposis: Spigelman Classification

    Spigelman’s score and classification of duodenal polyposis

    Classification: no polyp: stage 0; 1 to 4 points: stage I; 5 to 6 points: stage II; 7 to 8 points: stage III; 9 to 12 points: stage IV.

    Factor 1 point 2 points 3 points
    Number of polyps 1-4 5-20 >20
    Polyp size, mm 1-4 5-10 >10
    Histology Tubulous Tubulovillous Villous
    Dysplasia Low grade — High grade
    • Stages 0 to IV based on polyp number, size, histology, and dysplasia.
    • Higher stages indicate increased risk for duodenal adenocarcinoma.
    • Screening intervals adjusted based on the stage of duodenal polyposis.

  • Fundic Gland Polyps

    • Common in FAP, usually with low malignant potential.
    • Surveillance based on duodenal polyposis; dysplasia in polyps may warrant more frequent checks.

  • Expert Recommendations

    • ASGE suggests screening with both end- and side-viewing endoscopes, starting around colectomy or in the early thirties.
    • European guidelines recommend beginning screening between ages 25 and 30, with intervals based on Spigelman stage.
    • Other expert groups offer additional surveillance recommendations for specific upper digestive tract findings.

Surveillance for benign extraintestinal manifestations

  • Adrenal tumors
    • Lifetime prevalence of 7 to 13 percent in individuals with FAP, typically presenting after age 14.
    • Rarely malignant, routine surveillance not recommended.
    • Awareness of symptoms related to hormonal excess is important.
    • Surgery indicated for masses larger than 6 cm due to potential malignancy.
  • Desmoid tumors
    • Lifetime prevalence of about 20 percent, with peak incidence around age 30.
    • Increased risk in those with a family history of desmoids, personal history of osteomas, and post abdominal surgery.
    • No routine surveillance recommended; imaging considered if symptoms suggest organ obstruction.
    • First-line therapy is usually non-surgical, except for tumors in the abdominal wall or extra-abdominal locations.
  • Osteomas and dental abnormalities
    • Osteomas occur most commonly in the skull and mandible, with a 20 percent lifetime risk.
    • No specific surveillance recommended; referral to dental surgeon if complications arise.
  • Management of colonic polyposis
    • Full colonoscopy and initial upper endoscopic exam are recommended upon establishment of polyposis.
    • Timing and type of surgery discussed based on the number, size, and histology of adenomas.
    • Colectomy strongly recommended for those with large adenomas or advanced pathology.
    • Post-colectomy, regular surveillance of any remaining rectum or the ileal pouch is essential.
  • Chemoprevention
    • NSAIDs like sulindac and celecoxib can cause regression of adenomas but do not replace colectomy.
    • Celecoxib approved by FDA as an adjunct to surgical therapy.
    • Potential role in preventing progression of duodenal adenomas and used to slow polyp development.
  • Attenuated FAP (AFAP)
    • Fewer colonic adenomas (10 to 100) with a later age of onset for both polyps and cancer.
    • Colonoscopic and endoscopic screening recommended starting at age 20 to 25.
    • Prophylactic colectomy considered for those with numerous adenomas.
    • Upper endoscopy recommended starting at age 20 to 30 and then at intervals based on polyp burden.

MUTYH-Associated Polyposis (MAP)

 

  • Genetic Basis: Autosomal recessive condition caused by biallelic mutations in the MUTYH gene.
  • Common Mutations: The two most frequently observed mutations in Caucasian populations are Y179C and G396D, though about 20% of cases involve other mutations.
  • Cancer Risk: Carriers of biallelic mutations have a substantially increased risk of colon cancer, estimated to be 28 times higher than the general population.

Clinical Spectrum

  • Phenotypic Variability: Ranges from a presentation similar to attenuated FAP with fewer than 100 adenomas to a phenotype overlapping classic FAP with up to 500 adenomas.
  • Cancer Presentation: Includes early onset colon cancer under 50 years without noticeable polyposis in some cases.
  • Colorectal Cancer Features: Higher incidence and predominance of right-sided colon cancers at diagnosis compared to AFAP, with a mean age of diagnosis around 45 years.

Extracolonic Manifestations

  • Gastroduodenal Polyps and Cancers
  • Extraintestinal Cancers: Includes risks for ovarian, bladder, skin, and potentially breast cancer.
  • Other Features: Osteomas, dental cysts, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and the Muir-Torre phenotype with sebaceous gland tumors.

Screening Recommendations

  • Diagnosis Establishment: Suggested for individuals with >10 to 20 colorectal adenomas who test negative for APC mutations (suggesting absence of FAP) or those showing signs of recessive inheritance.
  • Biallelic Carriers:
    • Colonoscopy: Starting from age 18 is sometimes recommended, though guidelines vary.
    • Upper and Lower Endoscopy: May start from age 25 to 30.
    • Surgical Decisions: Based on clinical and endoscopic findings rather than solely on genetic mutation analysis.
  • Breast Cancer Screening: For women with biallelic mutations, including semiannual clinical breast exams, annual mammograms, and monthly self-examinations are considered.

Monoallelic MUTYH Carriers

  • Cancer Risk: The risk for colorectal cancer in monoallelic carriers is less clear but could be slightly elevated, particularly for those with the Y179C mutation.
  • Population Prevalence: Up to 1% of the general population may carry a monoallelic MUTYH mutation, impacting clinical considerations for the family members of individuals with MAP.

Management Implications

  • Surveillance Frequency and Scope: Should be tailored based on individual risk profiles, genetic findings, and clinical presentation.
  • Family Screening: Due to the autosomal recessive nature of MAP, screening considerations may also extend to siblings and both parents of diagnosed individuals, even if they are asymptomatic.

Familial adenomatous polyposis (FAP) is a significant genetic disorder primarily characterized by the development of numerous colorectal polyps. Here’s a concise overview of the condition:

  • Nature of the Condition: FAP involves the formation of hundreds, sometimes thousands, of polyps in the colon and rectum. These polyps are pre-cancerous and without proper treatment, they nearly always progress to colorectal cancer, usually by the age of 40.

  • Genetic Cause: The disorder is caused by mutations in the adenomatous polyposis coli (APC) gene, which plays a critical role as a tumor suppressor. Mutations in the APC gene lead to uncontrolled cell growth, resulting in the formation of numerous polyps.

  • Inheritance Pattern: FAP is inherited in an autosomal dominant pattern, meaning that inheriting just one mutated copy of the APC gene from one parent is enough to cause the disorder. This also means that individuals with FAP have a 50% chance of passing the mutated gene to each of their children.

  • Familial adenomatous polyposis (FAP) is a rare genetic disorder.
    • Incidence at birth is approximately 1 in 8,300.
    • Prevalence varies, with estimates in the European Union ranging from 1 in 11,300 to 1 in 37,600.
    • Accounts for less than 1% of colorectal cancer cases globally.
    • Manifests equally in both sexes.
    • Most patients are diagnosed before cancer develops due to early detection and management strategies.

Clinical Manifestations of Familial Adenomatous Polyposis (FAP)

  • Familial Adenomatous Polyposis (FAP) is often detected early, frequently before symptoms occur. When symptoms do appear, they typically include:

    • Blood in the stool or signs of anemia due to occult bleeding caused by the polyps.
    • Chronic diarrhea, which may be directly related to the presence of numerous polyps.
    • Extraintestinal manifestations, such as osteomas, which can lead to additional symptoms.
  • Characterized by numerous colorectal adenomas.
  • Extracolonic manifestations are also common.
  • Colonic Manifestations
    • Classic FAP
      • Defined by the presence of 100 or more adenomatous polyps.
      • Polyps typically develop in the second or third decade of life.
      • Untreated, nearly all individuals will develop colorectal cancer, typically by age 45.
    • Attenuated FAP (AFAP)
      • Milder form with fewer polyps, usually localized to the right colon.
      • Mean age at diagnosis is 44 years.
      • High risk of colorectal cancer, with onset at an older age compared to classic FAP.
  • Extracolonic Manifestations
    • Fundic gland polyps occur in the majority of FAP patients.
    • Duodenal polyps are common and can progress to cancer.
    • Desmoid tumors and various other benign growths are associated with FAP.
    • Multiple and bilateral retinal lesions (CHRPE) are a marker for FAP.
    • Risk for extraintestinal malignancies like thyroid cancer, hepatoblastoma, and CNS tumors.
  • FAP Variants
    • Gardner’s syndrome
      • Includes colonic polyposis with desmoid tumors and other extracolonic manifestations.
      • Considered a subset of FAP due to underlying APC mutation.
    • Turcot’s syndrome
      • Historically described the association of colon cancer with brain tumors.
      • Brain tumors linked to both FAP (medulloblastomas) and Lynch syndrome (gliomas).
  • Laboratory Features
    • Most patients are laboratory-normal but may present with iron deficiency anemia due to bleeding from adenomas.

Diagnosis of Familial Adenomatous Polyposis (FAP)

 

  • Suspected when a patient has 10 or more colorectal adenomas.
  • Applies to both symptomatic patients and asymptomatic individuals during screening.
  • Diagnosis considered in older patients with attenuated FAP (AFAP) upon detecting 10 or more adenomas.
  • Genetic Testing for APC Mutation
    • Necessary for a definitive diagnosis.
    • Recommended for individuals with 10 to 20 adenomas over their lifetime.
    • Higher number of adenomas and strong family history increase likelihood of FAP.
  • Genetic Counseling
    • Offered prior to genetic testing.
    • Important to consider other conditions like MUTYH associated polyposis if no mutation is found.
  • Testing for At-Risk Relatives
    • Mutation-specific testing for first-degree relatives of the index case.
    • Consider testing for first-degree relatives of any family member with an APC mutation.
    • Second-degree relatives may be offered testing if a family member declines or has passed away.
  • Genetic Testing for Children
    • Typically offered around age 10.
    • Not routinely recommended before age 10, unless family history includes colorectal cancer diagnosed under age 20.
  • Prediction Models
    • Used for counseling on the probability of finding an APC or MUTYH mutation.
    • Based on personal and family history.
  • Prenatal and Preimplantation Genetic Diagnosis (PGD)
    • Options for FAP patients planning a family.
    • Discuss the implications and processes involved.

Differential Diagnosis for Multiple Colorectal Adenomas

 

  • May be seen in MUTYH associated polyposis (MAP) which has an autosomal recessive inheritance pattern.
  • In MAP, family history typically lacks an autosomal dominant pattern of polyposis or colorectal cancer.
  • Attenuated FAP (AFAP) with few adenomas can be clinically similar to Lynch syndrome or sporadic adenomas.
  • Genetic testing is crucial for distinguishing between FAP, MAP, and Lynch syndrome.
  • Genetic Characteristics
    • FAP: Germline mutations in the APC gene.
    • MAP: Biallelic mutations in the MUTYH genes.
    • Lynch syndrome: Germline mutations in DNA mismatch repair genes.
  • Individuals with Multiple Adenomas but No Identified Mutation
    • Suggests the existence of as yet unidentified genes linked to multiple colorectal adenomas.
  • Study on Prevalence of APC and MUTYH Mutations
    • Examined individuals with personal or family history indicative of a polyposis syndrome.
    • Found APC mutations predominantly in individuals with a larger number of adenomas.
    • Detected MUTYH mutations across various ranges of adenoma numbers.
    • Significant portion of individuals with classic and attenuated polyposis did not have mutations in APC or MUTYH genes.

Management

 

  • Full Colonoscopy: Should be performed to evaluate the extent of colonic polyposis in gene carriers or at-risk family members.
  • Colectomy Recommendation: Strongly recommended at the time of initial diagnosis for patients with multiple large adenomas (>1 cm), those with villous histology, or high-grade dysplasia.
    • Timing of Surgery: Considered based on adenoma burden, aiming to minimize impact on personal and educational life, especially for adolescents.
    • Surgical Considerations:
      • Total Proctocolectomy with Ileoanal Anastomosis: Preferred for children with extensive polyposis involving the rectum.
      • Subtotal Colectomy: Considered for patients with attenuated adenomatous polyposis with minor rectal involvement.
      • Genetic Factors in Surgical Decision: Certain APC mutations may influence the choice between ileorectal anastomosis and total proctocolectomy.
    • Post-Surgical Surveillance:
      • Patients remain at risk for developing adenomas and adenocarcinoma in the ileal pouch, with varying risk percentages over time following surgery.
  • Chemoprevention:
    • NSAIDs: Drugs like sulindac and celecoxib have been used to reduce polyp numbers but cannot replace surgical intervention.
    • Celecoxib: Approved by the FDA as an adjunct to surgery for reducing the number of colonic polyps.
    • Duodenal Adenomas: COX-2 inhibitors may help in reducing the progression of duodenal adenomas.
  • Management of Attenuated FAP (AFAP):
    • Fewer adenomas (10 to 100), with a lower but significant risk of colon cancer.
    • Screening Recommendations: Start colonoscopic and endoscopic screening at age 20 to 25 years.
    • Surgical Intervention: Considered for those unable to be managed endoscopically.
  • Extra-Intestinal Manifestations and Surveillance:
    • Upper Endoscopy: Recommended from age 20 to 30 years onwards for monitoring duodenal adenomas and periampullary carcinomas.
    • Extraintestinal Tumors: Includes desmoids and others, where management strategies may vary.

Genetics of Familial Adenomatous Polyposis (FAP)

 

  • Caused by mutations in the APC gene on chromosome 5q21-q22.
  • Shows autosomal dominant inheritance with high penetrance for colonic symptoms but variable for extracolonic symptoms.
  • Up to 25 percent of cases arise from de novo mutations, with no family history of FAP.
  • APC Gene Mutations
    • More than 1000 mutations identified, most leading to frame shifts and premature stop codons.
    • Large deletions may account for up to 15 percent of FAP cases.
    • Both alleles of the APC gene must be inactivated for adenoma development.
    • Typically involves an inherited mutation and a somatic “second hit” in the other allele.
  • Role in Cancer
    • APC mutations are crucial for adenoma formation due to aberrant beta-catenin accumulation and cell growth gene activation.
    • Somatic APC mutations are present in about 80 percent of sporadic colorectal adenomas and cancers.
  • Mutation Location and Disease Severity
    • Mutation location within the APC gene affects severity of polyposis, cancer risk, onset age, survival, and extracolonic manifestations.
    • Classic FAP is linked to mutations between codons 169 to 1393.
    • Attenuated FAP (AFAP) is associated with mutations at the 5′ and 3′ ends of the APC gene.
  • Genotype-Phenotype Correlations
    • Variability within families and among individuals with the same mutation.
    • Specific mutations are linked to particular symptoms:
      • Codons 463 to 1444: Associated with retinal lesions (CHRPE).
      • Codons 1445 to 1578: Associated with desmoid tumors.
      • Codons 279 to 1309: Associated with duodenal polyposis.
      • Codons 686 to 1217: Associated with medulloblastoma.

Genetic Testing for FAP

 

  • No prospective trials to guide gene testing or screening in FAP.
  • Recommendations are based on observational studies and expert consensus.
  • Current Genetic Testing Practice
    • Available through various commercial labs.
    • Genetic counseling is recommended before testing.
    • Test first conducted on an affected family member.
  • If Mutation is Identified
    • The test can pinpoint at-risk family members.
    • Helps to determine which family members inherited the mutation.
  • If No Mutation is Found
    • Consider other conditions like MUTYH associated polyposis.
    • Treat gene tests as uninformative if no cause is found.
    • All at-risk family members should then undergo endoscopic screening.
  • Who Should Get Tested
    • Family members of patients with classic FAP, Gardner’s syndrome, or Turcot’s syndrome.
    • Children at risk are usually tested around age 10 to 12.
    • Testing is not advised before age 10 unless clinically indicated.
  • Utilizing Genetic Testing Responsibly
    • Offer counseling to discuss implications of testing.
    • Discuss prenatal genetic testing and preimplantation genetic diagnosis as preventive options.

Colonic Surveillance

  • Gene carriers and at-risk individuals to have annual flexible sigmoidoscopy or colonoscopy starting at age 10 to 12.
  • Surveillance until age 35 to 40 if no polyps are found.
  • Focus on the rectosigmoid in classic FAP using sigmoidoscopy.
  • Colonoscopy is recommended for attenuated FAP due to right-sided tumors.

Upper Intestinal Tumor Surveillance

  • Screening for gastric and duodenal polyps starts around age 25 to 30.

  • Intervals between screenings depend on the type of polyps found.

  • Symptoms related to the upper digestive tract warrant immediate investigation.

  • Duodenal Polyposis: Spigelman Classification

    Spigelman’s score and classification of duodenal polyposis

    Classification: no polyp: stage 0; 1 to 4 points: stage I; 5 to 6 points: stage II; 7 to 8 points: stage III; 9 to 12 points: stage IV.

    Factor 1 point 2 points 3 points
    Number of polyps 1-4 5-20 >20
    Polyp size, mm 1-4 5-10 >10
    Histology Tubulous Tubulovillous Villous
    Dysplasia Low grade — High grade
    • Stages 0 to IV based on polyp number, size, histology, and dysplasia.
    • Higher stages indicate increased risk for duodenal adenocarcinoma.
    • Screening intervals adjusted based on the stage of duodenal polyposis.

  • Fundic Gland Polyps

    • Common in FAP, usually with low malignant potential.
    • Surveillance based on duodenal polyposis; dysplasia in polyps may warrant more frequent checks.

  • Expert Recommendations

    • ASGE suggests screening with both end- and side-viewing endoscopes, starting around colectomy or in the early thirties.
    • European guidelines recommend beginning screening between ages 25 and 30, with intervals based on Spigelman stage.
    • Other expert groups offer additional surveillance recommendations for specific upper digestive tract findings.

Surveillance for benign extraintestinal manifestations

  • Adrenal tumors
    • Lifetime prevalence of 7 to 13 percent in individuals with FAP, typically presenting after age 14.
    • Rarely malignant, routine surveillance not recommended.
    • Awareness of symptoms related to hormonal excess is important.
    • Surgery indicated for masses larger than 6 cm due to potential malignancy.
  • Desmoid tumors
    • Lifetime prevalence of about 20 percent, with peak incidence around age 30.
    • Increased risk in those with a family history of desmoids, personal history of osteomas, and post abdominal surgery.
    • No routine surveillance recommended; imaging considered if symptoms suggest organ obstruction.
    • First-line therapy is usually non-surgical, except for tumors in the abdominal wall or extra-abdominal locations.
  • Osteomas and dental abnormalities
    • Osteomas occur most commonly in the skull and mandible, with a 20 percent lifetime risk.
    • No specific surveillance recommended; referral to dental surgeon if complications arise.
  • Management of colonic polyposis
    • Full colonoscopy and initial upper endoscopic exam are recommended upon establishment of polyposis.
    • Timing and type of surgery discussed based on the number, size, and histology of adenomas.
    • Colectomy strongly recommended for those with large adenomas or advanced pathology.
    • Post-colectomy, regular surveillance of any remaining rectum or the ileal pouch is essential.
  • Chemoprevention
    • NSAIDs like sulindac and celecoxib can cause regression of adenomas but do not replace colectomy.
    • Celecoxib approved by FDA as an adjunct to surgical therapy.
    • Potential role in preventing progression of duodenal adenomas and used to slow polyp development.
  • Attenuated FAP (AFAP)
    • Fewer colonic adenomas (10 to 100) with a later age of onset for both polyps and cancer.
    • Colonoscopic and endoscopic screening recommended starting at age 20 to 25.
    • Prophylactic colectomy considered for those with numerous adenomas.
    • Upper endoscopy recommended starting at age 20 to 30 and then at intervals based on polyp burden.

MUTYH-Associated Polyposis (MAP)

 

  • Genetic Basis: Autosomal recessive condition caused by biallelic mutations in the MUTYH gene.
  • Common Mutations: The two most frequently observed mutations in Caucasian populations are Y179C and G396D, though about 20% of cases involve other mutations.
  • Cancer Risk: Carriers of biallelic mutations have a substantially increased risk of colon cancer, estimated to be 28 times higher than the general population.

Clinical Spectrum

  • Phenotypic Variability: Ranges from a presentation similar to attenuated FAP with fewer than 100 adenomas to a phenotype overlapping classic FAP with up to 500 adenomas.
  • Cancer Presentation: Includes early onset colon cancer under 50 years without noticeable polyposis in some cases.
  • Colorectal Cancer Features: Higher incidence and predominance of right-sided colon cancers at diagnosis compared to AFAP, with a mean age of diagnosis around 45 years.

Extracolonic Manifestations

  • Gastroduodenal Polyps and Cancers
  • Extraintestinal Cancers: Includes risks for ovarian, bladder, skin, and potentially breast cancer.
  • Other Features: Osteomas, dental cysts, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and the Muir-Torre phenotype with sebaceous gland tumors.

Screening Recommendations

  • Diagnosis Establishment: Suggested for individuals with >10 to 20 colorectal adenomas who test negative for APC mutations (suggesting absence of FAP) or those showing signs of recessive inheritance.
  • Biallelic Carriers:
    • Colonoscopy: Starting from age 18 is sometimes recommended, though guidelines vary.
    • Upper and Lower Endoscopy: May start from age 25 to 30.
    • Surgical Decisions: Based on clinical and endoscopic findings rather than solely on genetic mutation analysis.
  • Breast Cancer Screening: For women with biallelic mutations, including semiannual clinical breast exams, annual mammograms, and monthly self-examinations are considered.

Monoallelic MUTYH Carriers

  • Cancer Risk: The risk for colorectal cancer in monoallelic carriers is less clear but could be slightly elevated, particularly for those with the Y179C mutation.
  • Population Prevalence: Up to 1% of the general population may carry a monoallelic MUTYH mutation, impacting clinical considerations for the family members of individuals with MAP.

Management Implications

  • Surveillance Frequency and Scope: Should be tailored based on individual risk profiles, genetic findings, and clinical presentation.
  • Family Screening: Due to the autosomal recessive nature of MAP, screening considerations may also extend to siblings and both parents of diagnosed individuals, even if they are asymptomatic.

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