The development of familial adenomatous polyposis is the result of multiple genetic mutations. Genes involved in the pathogenesis of familial adenomatous polyposis include APC and MUTYH genes. Many patients with familial adenomatous polyposis have a positive family history of colorectal cancer or polyps. However, some of the patients with familial adenomatous polyposis may have no previous family history. Loss of APC gene function is believed to be the first event in pathogenesis of colon cancer leading to formation of an adenoma. Three hundred mutations of APC gene have been discovered for familial adenomatous polyposis. These mutations have premature stop codons and lead to a truncated protein. Familial adenomatous polyposis has autosomal dominant inheritance pattern if it results from mutations in the APC gene and autosomal recessive inheritance pattern if it results from mutations in the MUTYH gene. APC gene mutation is found in 6% of Ashkenazi Jews. Familial adenomatous polyposis is associated with different malignancies including stomach cancer, periampullary cancer, pancreatic cancer, hepatoblastoma, bile duct cancer, papillary thyroid cancer, and medulloblastoma. Duodenal adenoma, adrenal masses, desmoid tumor, osteomas, congenital hypertrophy of the retinal pigment epithelium, epidermoid cysts, and fibromas are associated with familial adenomatous polyposis. On gross pathology, numerous polyps are characteristic finding of familial adenomatous polyposis.

• Familial adenomatous polyposis is a genetic disorder that is caused by mutation in APC and MUTYH genes.^[1]
• Many of patients with familial adenomatous polyposis have a positive family history of colorectal cancer or polyps. However, some of the patients with familial adenomatous polyposis have no previous family history.
• Germline mosaicism might be responsible for sudden manifestation of familial adenomatous polyposis.^[2]
• Loss of APC gene function is believed to be the first event in pathogenesis of colon cancer leading to formation of an adenoma.^[3]

• Familial adenomatous polyposis may have different inheritance patterns and genes involved.^[5]
• Familial adenomatous polyposis is due to mutations in different genes, including:^[6][7]
  • APC gene, which is located on chromosome 5 in band q21 or band q22 (5q21-q22)
    • APC gene is a tumor suppressor gene that has an essential role in cell adhesion, signal transduction and transcriptional regulation.
    • Three hundred mutations of APC gene have been discovered for familial adenomatous polyposis.
    • These mutations of APC gene have premature stop codons and lead to a truncated protein.
    • APC gene mutation is seen in 6% of Ashkenazi Jews.^[8]
    • APC gene mutation is seen in about 28% of those of Ashkenazi descent with a family history of colorectal cancer.
  • MUTYH gene, which is located on chromosome 1 between bands p34.2 and p32.1 (1p34.3-p32.1)
• Familial adenomatous polyposis has autosomal dominant inheritance pattern if it results from mutations in the APC gene.
• Familial adenomatous polyposis has autosomal recessive inheritance pattern if it results from mutations in the MUTYH gene.

Familial adenomatous polyposis is associated with other intestinal and extra intestinal conditions such as:^[9][10][1]

• Duodenal adenoma
• Stomach cancer
  • The risk is approximately 0.5%.
• Periampullary cancer
  • The risk is approximately 10%.
• Pancreatic cancer
  • The risk is approximately 2%.
• Hepatoblastoma
  • The risk is approximately 1.5%.
• Bile duct cancer

• Adrenal masses
• Desmoid tumor
  • The risk is approximately 10% to 20%.
  • It mostly happens in small bowel mesentery.
• Papillary thyroid cancer
  • The risk is approximately 2% to 25%.
• Medulloblastoma
• Epidermoid cysts and fibromas
• Osteomas
  • It is a benign bony growth mainly on jaw
• Congenital hypertrophy of the retinal pigment epithelium

On gross pathology, numerous polyps are characteristic findings of familial adenomatous polyposis.

• On microscopic histopathological analysis, serration of the luminal surface and normal nuclei are characteristic findings of hyperplastic polyps.
• On microscopic histopathological analysis, branched tubular glands are characteristic findings of tubular adenoma.
• On microscopic histopathological analysis, long finger-like projections are characteristic findings of villous adenoma.
• On microscopic histopathological analysis, branched and dilated glands, no cytological atypia, eosinophilic cytoplasm, and luminal epithelial tufting are characteristic findings of sessile serrated adenoma.

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