Information on the following diseases can be found in the Related Disorders section of this report:

• Cronkhite-Canada disease
• Familial juvenile polyposis
• Multiple hamartoma syndrome
• Peutz-Jeghers syndrome

The most common symptoms of familial adenomatous polyposis are diarrhea and bleeding from the rectum caused by the growth of multiple polyps (adenomas) that carpet the walls of the colon and rectum. Additional symptoms may include abdominal pain, cramps, fatigue, vomiting, a change in bowel habits, blood in the stools, and/or weight loss. Chronic bleeding from the rectum may also result in low levels of circulating red blood cells (anemia). If familial adenomatous polyposis is left untreated, affected individuals usually develop colon cancer between the ages of 30 and 40 years. Some people with familial adenomatous polyposis have no symptoms (asymptomatic) until a malignancy is discovered.

People with familial adenomatous polyposis may also have benign tumors in other areas of the body, such as benign bone tumors (osteomas), tumors consisting of fibrous tissue (fibromas), and soft tissue tumors. Polyps may also form in the upper gastrointestinal tract, such as the small intestine.

Individuals with FAP may have a greater risk of developing certain types of cancer than the general population. The cancers that are most commonly associated with FAP include a malignant liver tumor (hepatoblastoma) and cancer affecting the thyroid or pancreas.

Approximately 10 percent of individuals with familial adenomatous polyposis develop desmoid tumors, benign fibrous tissue tumors that usually affect the abdomen or abdominal wall.

Many researchers believe that familial adenomatous polyposis should be regarded as a spectrum of symptoms that should include three other disorders (i.e., Gardner syndrome, Turcot syndrome, and attenuated adenomatous polyposis coli).

Gardner syndrome, a variant of familial adenomatous polyposis, is a rare disorder characterized by multiple growths (polyps) in the colon (often 1,000 or more), extra teeth (supernumerary), bony tumors of the skull (osteomas), and fatty cysts and/or fibrous tumors in the skin (epithelial cysts or fibromas). A mutation to the same gene (APC gene) leads to both FAP and Gardner syndrome. (For more information on this disorder, choose "Gardner" as a search term in the Rare Disease Database.)

Debate exists in the medical literature as to whether Turcot syndrome is a variant of familial adenomatous polyposis. Two-thirds of cases of Turcot syndrome develop from mutations to the APC gene. The remaining cases of Turcot syndrome develop from mutations to different genes. Turcot syndrome is an extremely rare disorder characterized by the formation of polyps in the colon and tumors of the central nervous system (i.e., medulloblastoma, glioblastoma, or ependymoma). Symptoms may include diarrhea, bleeding from the rectum, and/or abdominal discomfort. Neurological symptoms vary greatly and depend on the type and location of the central nervous system tumor. (For more information on this disorder, choose "Turcot" as your search term in the Rare Disease Database.)

Attenuated adenomatous polyposis coli (AAPC), also known as flat adenoma syndrome, is a rare variant of familial adenomatous polyposis. The disorder is characterized by the formation of numerous polyps and benign tumors (adenomas) in the abdomen. In attenuated adenomatous polyposis coli, significantly fewer polyps form than in FAP. As in FAP, individuals with AAPC are at a great risk of developing colon cancer, although this occurs ten to fifteen years later in life than it does with FAP.
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Familial adenomatous polyposis of the colon is usually inherited as an autosomal dominant trait. Cases in which a positive family history has not been found are thought to represent new genetic changes (mutations) that occurred randomly for unknown reasons (sporadically). One-third of cases where no family history is present are estimated to be new genetic mutations.

Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

A gene responsible for the disorder, known as the APC gene (for "adenomatous polyposis coli"), has been mapped to the long arm (q) of chromosome 5 (5q21-q22). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered.

In individuals with familial adenomatous polyposis of the colon, the disorder appears to result from mutation of the APC gene or loss (deletion) of genetic material from chromosome 5q, including the APC gene. Evidence suggests that the APC gene functions as a tumor suppressor gene.
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Familial adenomatous polyposis is a group of rare disorders that 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 one percent 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.

Although familial adenomatous polyposis may be diagnosed in teenagers and people over the age of 45, the majority of affected individuals are between the ages of 20 and 45 years. Approximately, .5 percent of all cases of colon cancer arise from familial adenomatous polyposis.
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Symptoms of the following disorders can be similar to those of familial adenomatous polyposis. Comparisons may be useful for a differential diagnosis:

Peutz-Jeghers syndrome (Intestinal Polyposis, Type II) is a rare, inherited gastrointestinal disorder characterized by the development of polyps on the mucous lining of the intestine and dark discolorations on the skin and mucous membranes. Symptoms include nausea, vomiting, and abdominal pain that occurs because of a form of intestinal obstruction (intussusception). Additional symptoms include bleeding from the rectum and dark skin discolorations around the lips, inside the cheeks, and on the arms. Severe rectal bleeding can cause anemia and episodes of recurring, severe abdominal pain. Peutz-Jeghers syndrome is inherited as an autosomal dominant trait. (For more information on this disorder, choose "Peutz-Jeghers" as your search term in the Rare Disease Database.)

Cronkhite-Canada disease (allergic granulomatous angiitis) is an extremely rare gastrointestinal disorder characterized by the formation of polyps in the intestines, the loss of scalp hair (alopecia), abnormally dark discoloration of patches of skin (hyperpigmentation), and the loss of finger and/or toenails. Symptoms may include abdominal pain, cramping, and diarrhea. There is some evidence that this disease may be hereditary. (For more information on this disorder, choose "Cronkhite-Canada" as your search term in the Rare Disease Database.)

Familial juvenile polyposis is characterized by small multiple growth (polyps) within the gastrointestinal system. Symptoms may include gastrointestinal bleeding, abdominal pain, diarrhea, rectal prolapse, collapse of a portion of the bowel into itself (intrussusecption), and/or gastrointestinal obstruction. Some affected individuals may experience protein loss, malnutrition, and a feeling of general ill health (cachexia). Individuals affected by familial juvenile polyposis may have an increased risk of colon cancer. Additional symptoms may include clubbing of the fingers and toes, failure to thrive, low levels of circulating red blood cells (anemia). Familial juvenile polyposis is inherited as an autosomal dominant trait. Familial juvenile polyposis may be caused by mutations in the PTEN gene on the long arm of chromosome 10 (10q22.3-q24.1) or mutations in the SMAD4 gene also known as DPC4 gene, located on the long arm of chromosome 18 (18q21.1).

Multiple hamartoma syndrome, also known as Cowden disease, is an extremely rare inherited disorder characterized by the development of many benign, tumor-like growths (hamartomas) affecting multiple organ systems of the body, especially the skin, mucous membranes, breast, and thyroid. Affected individuals also develop characteristic skin abnormalities such as wart-like lesions (verrucous) of the face and limbs; bumps resembling cobblestones on the gums and the mucous lining of the cheeks (buccal mucosa); and/or tiny, benign tumors in the roots of the hair on the face (trichilemmomas). Hamartomas affecting the skin include those made up of connective tissue cells (fibromas), fat cells (lipomas), or small blood vessels just under the surface of the skin (hemangiomas). Other characteristic findings may include neurologic symptoms such as tremors, seizures, impaired coordination of voluntary movement (ataxia), and delayed development of skills that require coordination of movements (psychomotor retardation). Individuals with multiple hamartoma syndrome are at a high risk of developing certain malignancies (e.g., dysplastic cerebellar gangliocytoma, breast cancer, primary neuroendocrine skin carcinoma, renal cell adenocarcinoma). In some cases, skeletal abnormalities may be present including abnormal side-to-side (scoliosis), front-to-back (kyphosis), or backward (lordosis) curvature of the spine (scoliosis). Multiple hamartoma syndrome is inherited as an autosomal dominant trait.
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Diagnosis
A diagnosis of familial adenomatous polyposis is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Because children of an affected parent have a 50 percent risk of developing familial adenomatous polyposis, regular screening via sigmoidoscopy is required until approximately age 35 to 40 to help ensure early detection and prompt, appropriate treatment. During sigmoidoscopy, a viewing instrument is used to examine the rectum and the last part of the large intestine (sigmoid colon). In addition, in some cases, DNA testing may be available to help detect family members who have inherited certain changes (mutations) of the APC gene, potentially diagnosing the disorder before polyp development. In addition, x-rays of the large intestine may reveal the presence of polyps.

Diagnostic testing for familial adenomatous polyposis may also include direct visual examination of the intestines by the insertion of a flexible, tube-like instrument (colonoscope) into the rectum (colonoscopy) or the removal and microscopic examination of small samples of rectal tissue (biopsy). Genetic counseling is essential for people with familial adenomatous polyposis and their families.

Treatment
Without treatment, nearly all individuals with familial adenomatous polyposis may develop colorectal cancer before age 40. Surgical removal of the large intestine and the rectum (proctocolectomy) may prevent the risk of such malignancies. However, if procedures are performed to remove the large intestine and surgically join the rectum and small intestine (ileoproctostomy), rectal polyps may regress. Therefore, some physicians may recommend such procedures as an alternative to proctocolectomy. In such cases, the remaining rectal region must be regularly examined through sigmoidoscopy to ensure prompt detection and surgical removal or destruction of any new polyps.

In some affected individuals, rapid development of new polyps may necessitate additional surgical treatment, such as removal of the rectum and surgical creation of a connection between the small intestine and the abdominal wall (ileostomy). In other cases, physicians may initially recommend other surgical procedures, such as a technique in which the large intestine is removed (colectomy) and the small intestine and the anus are surgically joined (ileoanal anastomosis).

The medication celecoxib (Celebrex) has been approved by the Food and Drug Administration (FDA) as a therapy to be used in conjunction with regular endoscopic monitoring and appropriate surgical measures for individuals with Familial Adenomatous Polyposis. Celebrex is a nonsteroidal anti-inflammatory drug (NSAID) that is also indicated to alleviate symptoms associated with inflammation and/or degenerative changes of the joints (i.e., as in rheumatoid arthritis and osteoarthritis). In those with Familial Polyposis, precancerous (or "adenomatous") polyps within the colon and rectum express abnormally high levels of an enzyme known as COX-2. Celebrex functions as a "COX-2 inhibitor," selectively inhibiting the enzyme. In a six-month clinical trial with 83 affected individuals, therapy with Celebrex by mouth (orally) twice daily reduced the number of adenomatous colorectal polyps by an average of 28 percent as compared to a five percent reduction in those who received placebo. (A placebo is a harmless, inactive substance that may be used in investigational studies to compare the effects of an experimental drug with those of an inactive agent.) Frequent side effects included diarrhea and discomfort in the upper, middle region of the abdomen after meals (dyspepsia). As with other NSAIDs, because such therapy may be associated with serious gastrointestinal (GI) effects (e.g., ulceration, perforation), affected individuals and their physicians should always remain alert to any signs of GI bleeding. In addition, individuals with known allergic reactions to Celebrex, aspirin, other NSAIDs, or certain medications known as sulfonamides should not receive therapy with Celebrex (contraindicated). The clinical trial did not evaluate the effect of Celebrex therapy on potentially lowering GI cancer risk. However, further studies will be conducted by the drug's co-promoters, Searle and Pfizer Inc., to assess the potential clinical benefit such therapy may have concerning the development of cancer. (This clinical trial was also sponsored by the National Cancer Institute's Division of Cancer Prevention. For further information on the National Cancer Institute, please see the "Resources" section of this report below.)
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James A. DiSario, MD, of the University of Utah, is presently recruiting patients for a chemoprevention trial involving persons with Familial Adenomatous Polyposis. The study is designed to test the efficacy of exisulind, a derivative of sulindae. This project is a placebo-controlled, double blind clinical trial with a primary objective of inhibiting the growth of duodenal polyps. The treatment period is three years.

For more information, contact Angela Giampaolo, (800) 444-8638 Ext. 79014, University of Utah, 50 North Medical Drive, GI Division, 4R118-SOM, Salt Lake City, Utah, 84132; E-mail: angela.giampaolo@hci.utah.edu or james.disario@hsc.utah.edu.

The Food and Drug Administration (FDA) has approved testing of the orphan product FGN-1 for the suppression and control of colonic adenomatous polyps in familial adenomatous polyposis. More study is needed to determine the long-term safety and effectiveness of this treatment. FGN-1 is being sponsored by:

Cell Pathways, Inc.
1700 Broadway, Suite
2000 Denver, CO 80290

It is hoped that the identification of the gene that causes familial adenomatous polyposis will lead to a better understanding of its causes and the development of more effective treatments. The National Cancer Institute has many ongoing research projects on familial adenomatous polyposis that may lead to a better understanding of this group of diseases.

Blood samples are needed for genetic research on familial adenomatous polyposis. The French pharmaceutical company Genethon is conducting such studies. Interested individuals should contact:

Association Francaise Contre Les Myopathies 1 Rue de I'Internationale 91002 EVRY CEDEX (FRANCE)

A drug known as exisulind (Aptosyn) is being studied as a potential treatment for individuals with familial adenomatous polyposis. Initial studies conducted at the Cleveland Clinic Foundation have shown that the drug reduces polyp formation in affected individuals. More research is needed to determine the long-term safety and effectiveness of this drug for the treatment of familial adenomatous polyposis.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 175100; 5/12/00. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?175100.

TEXTBOOKS
Beers MH, et al., eds. The Merck Manual. 17th ed. Whitehouse Station, NJ; Merck Research Laboratories; 1999:327-8.

Fauci AS, et al., eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY; McGraw-Hill Companies, Inc.; 1998:572-3.

Buyse ML. Birth Defects Encyclopedia. Dover, MA; Blackwell Scientific Publications, Inc.; 1990:983-6.

Sleisenger MH, et al. Gastrointestinal Disease. 4th ed. Philadelphia, PA; W.B. Saunders Company; 1989:1487-91, 1509-10.

Yamada T, et al. Textbook of Gastroenterology. 2nd ed. J.B. Lippincott Company; 1995:1944-54.

JOURNAL ARTICLES
van Stolk R, et al., Phase I trial of exisulind (sulindac sulfone, FGN-1 as a chemoprotective agent in patients with familial adenomatous polyposis. Clin Cancer Res. 2000;6:78-89.

Lal G, et al., Familial adenomatous polyposis. Semin Surg Oncol. 2000;18:314-23.

Gebert JF, et al. Combined molecular and clinical approaches for the identification of families with familial adenomatous polyposis coli. Ann Surg. 1999;229:350-361.

Berk T, et al. Negative genetic test result in familial adenomatous polyposis: clinical screening implications. Dis Colon Rectum. 1999;42:307-310.

Bonaiti-Pellie C, Genetic risk factors in colorectal cancer. Eur J Cancer Prev. 1999;9:S27-33.

Howe JR, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998;280:1086-1088.

Kinzler KW, et al. Landscaping the cancer terrain. Science. 1998;280:1036-1037.

Giardiello FM, et al. The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med. 1997;336:823-827.

Winawer SJ, et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. N Engl J Med. 1996;334:82-87.

Clark SK, et al., Desmoids in familial adenomatous polyposis. Br J Surg. 1996:83:1494-504.

Foulkes WD, A tale of four syndromes: familial adenomatous polyposis, Gardner syndrome, attenuated APC and Turcot syndrome. QJM. 1995:88:853-63.

Tjandra JJ, et al. Similar functional results after restorative proctocolectomy in patients with familial adenomatous polyposis and mucosal ulcerative colitis. Am J Surg. 1993; 165:322-325.

Galandiuk S, et al. Expression of hormone receptors, cathepsin D, and HER-2/neu oncoprotein in normal colon and colonic disease. Arch Surg. 1993;128:637-642.

Penna C, et al. Function of ileal J pouch-anal anastomosis in patients with familial adenomatous polyposis. Br J Surg. 1993;80:765-767.

Burt RW, et al. Population genetics of colonic cancer. Cancer. 1992;70:1719-1722.

Rhodes M, et al. Overview of screening and management of familial adenomatous polyposis. Gut. 1992;33:125-131.

Konsker KA. Familial adenomatous polyposis: case report and review of extracolonic manifestations. Mt Sinai J Med. 1992;59:85-91.

Lynch HT, et al., Hereditary flat adenoma syndrome: a variant of familial adenomatous polyposis? Dis Colon Rectum. 1992;35:411-21.