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NORD is very grateful to Randall W. Burt, MD, Professor of Medicine, University of Utah School of Medicine; Senior Director for Prevention and Outreach, Huntsman Cancer Institute, University of Utah and Kory Jasperson, MS, Genetic Counselor, Huntsman Cancer Institute, University of Utah, for assistance in the preparation of this report.
Familial adenomatous polyposis (FAP) is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps (adenomatous polyps). If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum at a relatively young age. FAP is inherited in an autosomal dominant manner and caused by abnormalities (mutations) in the APC gene. Mutations in the APC gene cause a group of polyposis conditions that have overlapping features: familial adenomatous polyposis, Gardner syndrome, Turcot syndrome and attenuated FAP.
Classic FAP is characterized by hundreds to thousands of colorectal adenomatous polyps, with polyps appearing on average at age 16 years. Without colectomy, affected individuals usually develop colorectal cancer by the third or fourth decade of life. FAP is also associated with an increased risk for cancer of the small intestine including the duodenum, and cancer of the thyroid, pancreas, liver (hepatoblatoma), central nervous system (CNS), and bile ducts, although these typically occur in less than 10% of affected individuals.
Individuals with CNS tumors and colorectal polyposis have historically been defined as Turcot syndrome. Two-thirds of cases of Turcot syndrome develop from mutations in the APC gene. The remaining cases develop from mutations in the genes that cause hereditary non-polyposis colorectal cancer (HNPCC) also known as Lynch syndrome. Mutations in the APC gene are more commonly associated with medulloblastoma; mutations in the genes that cause HNPCC are more commonly associated with glioblastoma.
Extracolonic manifestations are variably present in FAP, including polyps of the stomach, duodenum and small bowel; and osteomas (bony growths), dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and soft tissue tumors including epidermoid cysts, fibromas and desmoid tumors. About 5% of individuals with FAP experience morbidity and/or mortality from desmoid tumors. The term Gardner syndrome is often used when colonic polyposis is accompanied by clinically obvious osteomas and soft tissue tumors.
Attenuated FAP is a variant of familial adenomatous polyposis. The disorder is characterized by an increased risk for colorectal cancer (although lower risk than classical FAP) but with fewer polyps (average of 30) and later age of onset of polyps and cancer than is typically seen in classic FAP. Extra-colonic manifestations are also associated with attenuated FAP.
Familial adenomatous polyposis is caused by germline (present in the first cell of the embryo) mutations in the APC gene and is inherited in an autosomal dominant manner, meaning that on average 50% of children of an affected parent will have the disease passed on to them.
Dominant genetic disorders occur when only a single copy or allele of a specific gene is mutated, thereby causing a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Familial adenomatous polyposis affects males and females in equal numbers. It occurs in approximately one in 5,000 to 10,000 individuals in the United States and accounts for about 0.5% of all cases of colorectal cancer. One estimate suggests that familial adenomatous polyposis affects 50,000 American families. According to national registries, familial adenomatous polyposis occurs in 2.29-3.2 per 100,000 individuals.
Features of the following disorders can be similar to those of the APC gene-associated polyposis conditions. Comparisons may be useful for a differential diagnosis:
MYH gene-associated polyposis (MAP) is an autosomal recessive cancer predisposition syndrome with a colonic phenotype similar to attenuated FAP. Mutations in the MYH gene are associated with this condition.
Hereditary non-polyposis colon cancer (HNPCC) or Lynch syndrome is an autosomal dominant cancer predisposition syndrome that causes a very high risk for colorectal and endometrial cancer in addition to an increased risk for cancers of the ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. Individuals with Lynch syndrome most often exhibit only one or several precancerous polys of the colon. Thus, Lynch syndrome is sometimes difficult to distinguish from attenuated FAP, as some individuals with attenuated FAP may have a low number of polyps.
Peutz-Jeghers syndrome is an autosomal dominant genetic condition characterized by multiple benign hamartomatous polyps (Peutz-Jeghers polyps) in the gastrointestinal system. Hamartomatous polyps have a much lower risk of becoming cancerous compared to adenomatous polyps. These polyps occur most often in the small intestine but also occur in the stomach and large intestine. Affected individuals also have dark skin discoloration, like freckles or spots around the lips and on the face but much darker,These pigmented spots often presents in childhood and can be also be seen around the eyes, and nostrils, and on the mucous membranes of the mouth and in the perianal area. Affected individuals have an increased risk for intestinal and other cancers. This condition can be distinguished from FAP by clinical features and histology (microscopic examination) of the polyps. (For more information on this disorder, choose "Peutz-Jeghers" as your search term in the Rare Disease Database)
Juvenile polyposis syndrome (JPS) is an autosomal dominant genetic condition characterized by a predisposition to gastrointestinal polyps. The term "juvenile" refers to the type of polyp as opposed to the age of onset. Polyps are usually diagnosed by 20 years of age and are usually benign, although malignant transformation can occur. JPS is associated with mutations in the SMAD4 and BMPR1A genes.
Cronkhite-Canada disease is a very rare acquired (not inherited) disease and is characterized by intestinal polyps, loss of taste and hair, and nail growth problems. It is difficult to treat because of malabsorption that accompanies the polyps. Cronkhite-Canada disease occurs primarily in older people (the average age is 59). There have been fewer than 400 cases reported in the past 50 years, primarily in Japan but also in the U.S. and other countries (For more information on this disorder, choose "Cronkhite-Canada" as your search term in the Rare Disease Database.)
Classical FAP is diagnosed clinically when an individual has 100 or more adenomatous colorectal polyps (typically occurring by the third decade of life) or fewer than 100 polyps and a relative with FAP. Genetic testing for mutations in the APC gene is available to confirm the diagnosis of FAP and the associated conditions. Younger individuals may have fewer polyps. A diagnosis is made in younger people by the presence of the typical polyps and in immediate relative with FAP or by genetic testing.
Partial or complete removal of the colon (colectomy) is usually recommended for individuals with classical FAP at an appropriate age, usually between the late teens and late 30s. Sulindac is a nonsteroidal antiinflammatory drug (NSAID) usually used for arthritis, but is sometimes prescribed for individuals with FAP who have had a colectomy to treat polyps in the remaining rectum. Polyps will almost always regress, but it is uncertain if the cancer risk is changed, so surveillance must be continued.
Removal of duodenal polyps is sometimes recommended if they cause symptoms, are large or contain large numbers of abnormal cells (dysplasia). This is to prevent them from becoming cancerous.
Desmoid tumors are benign, but may cause problems by compressing organs and/or blood vessels in the abdomen. These are treated variously with surgery, NSAIDs, anti-estrogen medications, chemotherapy and/or radiation depending on the details in each case. They are sometimes just followed when they do not grow.
Genetic counseling is recommended for individuals with familial adenomatous polyposis and their at-risk family members. This is very helpful to properly obtain and interpret genetic testing. Affected individuals should be screened clinically and endoscopically on a regular basis in order to identify cancerous and pre-cancerous tumors at an early stage. Colon cancer is virtually always prevented by screening and properly timed colectomy. This is similar for duodenal cancer. Other cancers are usually detected early, rather than prevented.
Prevention therapies (chemoprevention) are presently under study in several institutions. Information on these and other current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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National Cancer Institute: Genetics of Colorectal Cancer http://www.cancer.gov/cancertopics/pdq/genetics/colorectal/HealthProfessional/page1 Last modified 12/20/2013. Accessed Dec 26, 2013.
Report last updated: 2014/01/27 00:00:00 GMT+0