Inherited Polyposis Syndromes – Familial, Hereditary Colon Polyps

Several inherited polyposis syndromes have been identified and many of these have high risk for becoming malignant (cancerous). About 6% of colorectal cancer patients have inherited polyposis syndromes. Various polyposis syndromes are characterized by specific genetic abnormalities and clinical features. Inherited syndromes include adenomatous polyposis syndromes like familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer (HNPCC) and hamartomatous polyposis syndromes like Peutz-Jeghers syndrome.

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Familial Adenomatous Polyposis

Familial adenomatous polyposis is characterized by development of several hundreds to thousands of adenomatous polyps in the large bowel. It is an autosomal dominant disease that usually develops at a young age (8 to 34 years of age). It results from an inherited genetic abnormality of the adenomatous polyposis coli (APC) gene located on chromosome 5.

The APC gene is a tumor suppressor gene which regulates the intestinal epithelial cell growth. When the function of this gene is lost due to a genetic abnormality, the normal growth control of the mucosal epithelium is lost and leads to development of polyps. About 30% of patients develop the APC gene mutation sporadically, without any family history.

Signs and Symptoms of Familial Adenomatous Polyposis

The disease begins with multiple colonic adenomas in late childhood and usually manifests with symptoms by the third to fourth decade of life. Symptoms related to polyposis usually include :

  • bleeding from rectum
  • abdominal pain
  • bowel obstruction

The syndrome is characterized by extracolonic manifestations like desmoids tumors, gastro-duodenal polyps (stomach polyps), thyroid tumors, brain tumors and retinal pigment epithelial hypertrophic disorder.

Location of Polyps in Familial Adenomatous Polyposis

Polyps are found throughout the large bowel in this syndrome and untreated familial adenomatous polyposis patients have a very high risk of colorectal cancer. The syndrome accounts for 1% of patients developing colorectal cancer. Almost 90% of the patients with familial adenomatous polyposis may also have polyps in stomach or duodenum. About 10% of the patients with polyps in duodenum are at risk of developing adenocarcinoma of the duodenum. The duodenal polyps close to the ampulla (ampullary polyps) are known to have high malignant potential.

Turcot’s Syndrome

Turcot’s syndrome is a variant of familial adenomatous polyposis with a strong association to brain tumors and colonic polyps. The polyps are larger but fewer in number. Majority of the patients with Turcot’s syndrome have APC gene mutations while a few have mutations in DNA mismatch repair genes like hMLH1.

Gardner’s Syndrome

Gardner’s syndrome is also a variant of familial adenomatous polyposis with similar cancer risk potential. It also results from APC gene mutation but differs from familial polyposis due to the difference in extracolonic manifestations. The extracolonic manifestations include epidermal cysts, mandibular osteomas, supernumerary teeth, soft tissue tumors (like lipomas), desmoid tumors and retinal pigment epithelial hypertrophic disorder.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Hereditary nonpolyposis colorectal cancer, sometimes referred to as Lynch’s syndrome, is an inherited autosomal dominant genetic abnormality that is caused by mutations in DNA mismatch repair gene. The genes commonly mutated in these patients include hMLH1 and hMSH2. These gene mutations can also lead to DNA microsatellite instability (MSI).

HNPCC is the most common type of hereditary syndrome causing colorectal cancer. About 3 to 5% of all cases of colorectal cancers are associated with HNPCC. It is usually diagnosed in the 5th decade of life. The polyps in HNPCC are predominantly found on right colon and are limited to less than 100 in number. It has an 80% risk of becoming malignant (cancerous). There is also an increased risk of cancer in the small bowel. HNPCC is often associated with other tumors like ovary, pancreas, endometrial etc.

Hamartomatous Polyposis Syndromes

The hamartomatous polyposis syndromes are rare. It includes Peutz-Jeghers syndrome, Juvenile polyposis syndrome and Cowden’s syndrome. These syndromes are associated with abnormal development of tissue and accounts for less than 1% of the colorectal cancers.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome is a rare inherited autosomal dominant disorder. The disorder results from mutation in the serine-threonine kinase STK11 gene present on the chromosome 19. Patients suffering from the syndrome have intestinal polyps in association with some characteristic pigmentation of skin and mucosa. The syndrome is usually diagnosed in the third decade of life.

These intestinal polyps are predominantly found in the small intestine, but are not confined to it. Lesions can also be found in colon or stomach in many patients. The polyps of Peutz-Jeghers syndrome tend to have a core made of smooth muscles arising from the muscularis mucosa and hence cannot be called a true polyps.

The polyps are usually non-malignant but occasionally become malignant. The symptoms of the syndrome include bleeding and bowel obstruction. Polyps in the gallbladder, urinary bladder and nasal passages, ovarian tumors, and melanin spots on lips or oral mucosa are extraintestinal manifestations of Peutz-Jeghers syndrome.

Juvenile Polyposis

Juvenile polyposis is a rare inherited autosomal dominant syndrome. It is characterized by ten or more hamartomatous polyps throughout the small and large intestine. Juvenile polyposis has a 10% risk of colorectal cancer. It is caused by mutations in genes like the SMAD4 and PTEN. Patients usually present with rectal bleeding, anemia or abdominal pain in childhood or adolescence. Some congenital abnormalities like pulmonary arteriovenous malformations are seen with juvenile polyposis patients.

Cowden’s Syndrome

Cowden’s syndrome is a rare autosomal dominant disorder caused by genetic abnormalities in the tumor suppressor gene PTEN. The disorder is characterized by multiple gastrointestinal hamartomatous polyps which are free of malignant potential. These patients also have hamartomatous polyps of the skin and mucous membranes, papillomas in the oral cavity and keratoses of the hands and feet. Cowden’s syndrome is also associated with malignant tumors of thyroid and breast.

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