Familial Adenomatous Polyposis

  • What is familial adenomatous polyposis?

    Familial adenomatous polyposis (FAP) is a rare hereditary cancer syndrome associated with the development of colon cancer at an earlier than expected age. Familial adenomatous polyposis is characterized by the presence of gastrointestinal polyps, (abnormal tissue growths that develop from the lining of the large and small intestines, and less commonly, the stomach). Some of these polyps can become cancerous. Because familial adenomatous polyposis is hereditary, the risk of developing the features associated with FAP can be passed from generation to generation in a family.

  • Causes

    FAP is caused by alterations, also known as mutations, at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform their different functions within our bodies.

    There is a specific gene known as APC, located on chromosome 5 at position q21, that is altered in patients with familial adenomatous polyposis. The normal role of the APC gene is to produce a protein that helps regulate cell growth and division and cell death. When both copies of the APC gene are altered within a cell, such as those that line the intestines, the affected cell may divide in an uncontrolled fashion and acquire additional genetic alterations. If this occurs, abnormal cells may accumulate and develop into polyps and ultimately, if left untreated, colon cancer.

    How is familial adenomatous polyposis (FAP) inherited?

    With the exception of egg and sperm cells, each cell of the body normally has two working copies of the APC gene. In patients with familial adenomatous polyposis, however, each cell contains only one working APC gene copy. While the second copy is present, it is altered so that it does not function properly. A person carrying an alteration in one copy of the APC gene has a 50 percent (or 1 in 2) chance of passing this same alteration on to his or her children. Children who inherit the altered gene copy will have FAP and therefore will be at increased risk to develop colon cancer and other features associated with FAP.

    Approximately 75 percent to 80 percent of patients with familial adenomatous polyposis inherit an altered copy of the APC gene from a parent who also has FAP. In the remaining patients, FAP results from the occurrence of a “new” mutation in the APC gene in one of the father’s sperm, mother’s eggs or in a cell of the developing fetus. Therefore, these individuals will be the first ones in their family to carry this genetic change. Since they carry an altered gene copy, each of their future offspring will have a 50 percent chance of inheriting the genetic alteration.

  • Diagnosis

    The diagnosis of familial adenomatous polyposis relies on the presence of certain findings, such as colon polyps, and a positive family history of polyps and/or colon cancer. For example, FAP is commonly diagnosed when an individual has one of the following features:

    • 100 or more adenomatous polyps in the large and/or small intestines
    • Less than 100 adenomatous polyps and a relative with a known diagnosis of FAP

    In addition to developing polyps of the gastrointestinal tract, patients with familial adenomatous polyposis may also develop:

    • Benign (noncancerous) growths of the bones called osteomas
    • Dental problems such as unerupted teeth or extra or missing teeth
    • Occasionally, a benign finding of the retina (tissue lining the back of the eye) called congenital hypertrophy of the retinal pigmented epithelium (CHRPE)

    It is important to note that patients with familial adenomatous polyposis are at increased risk to develop other types of cancer in addition to cancer of the colon or stomach. For example, patients with FAP can develop soft tissue tumors known as desmoid tumors and, less commonly, cancers of the liver, thyroid, pancreas, brain and bile ducts (tubes that drain the gall bladder). Overall, the incidence of these other cancers is 10 percent to 15 percent in patients with FAP.

    Testing for familial adenomatous polyposis (FAP) 

    In order to confirm on a molecular level that an individual has FAP, he or she can undergo the process of genetic testing:

    • First, a blood or saliva sample is obtained from an affected individual.
    • DNA is isolated from the sample and the two copies of the APC gene are evaluated using a variety of methods and compared to the normal reference sequence for APC.
    • If an alteration in one APC gene copy is identified, the genetic counselor can next examine whether the alteration has been previously reported in other individuals with FAP.

    It is important to remember that not all patients with FAP carry a detectable alteration in the APC gene. Therefore, the failure to identify an alteration in the APC gene does not exclude a diagnosis of FAP.

    APC genetic test results can also provide important information for other family members. Knowing the specific alteration that is present in an individual with FAP allows for other family members to undergo testing to determine whether they also carry the alteration and could therefore develop the features of FAP.

    Reproductive options

    Reproductive options exist for an individual with an alteration in the APC gene who does not wish to pass this alteration on to future children:

    • Prenatal diagnosis. DNA is isolated from the cells of the developing baby though one of two procedures, chorionic villus sampling (CVS) or amniocentesis, and is analyzed for alterations in the APC gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.
    • Preimplantation Genetic Diagnosis (PGD). For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the APC gene would be implanted. Before one can proceed with prenatal testing or PGD, an APC mutation must be identified in a parent with FAP.
  • Related conditions

    In addition to familial adenomatous polyposis, there are three related conditions that are also caused by alterations in the APC gene. These conditions are now considered to be variants of familial adenomatous polyposis. These include:

    • Gardner syndrome — characterized by the presence of multiple gastrointestinal polyps, osteomas and soft tissue growths (including epidermal cysts, fibromas and desmoid tumors)
    • Turcot syndrome — associated with the presence of gastrointestinal polyps and a type of central nervous system (brain) tumor known as medulloblastoma.
    • Attenuated FAP (AFAP)  — characterized by fewer polyps (average of about 30 polyps) compared to classis FAP, but still carries a significant risk to develop colon cancer if left untreated. The average age of onset of colon cancer is about 55 years (Lynch et al., 1995), which is about 15 years later than average age of colon cancer onset in classic FAP.

    Recently, another hereditary syndrome known as MYH-associated polyposis (MAP) was described in which affected individuals carry alterations in both copies of the MYH gene. MAP shares many clinical features with FAP including:

    • The development of gastrointestinal polyps
    • An increased risk to develop colon cancer
    • Other clinical features, including congenital hypertrophy of the retinal pigment epithelium (CHRPE), osteomas and dental anomalies (although these are seen less commonly in MAP compared to FAP)
    • Skin lesions, including:
      • Pilomatrixomas (benign tumors of the hair follicle)
      • Sebaceous gland adenomas (benign tumors of small glands in the skin)
      • Sebaceous gland carcinoma (malignant tumors of small glands in the skin)

    Some groups have reported an increased risk to develop other malignancies that are NOT typically associated with FAP, including ovarian cancer, bladder cancer, and possibly breast and endometrial cancer (Lindor, 2009; Vogt et al., 2009). However, the risk to develop these cancers has not been well-characterized for individuals with MAP.

    A careful and detailed review of an individual’s medical and family history is important in diagnosing an APC-associated polyposis condition. A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that indicates:

    • Which members of the family have developed cancer
    • Types of cancer in the family
    • Ages of onset
    • Presence of any clinical manifestations outside of the colon

    If the pattern of clinical features and/or cancers is suggestive of an APC-associated polyposis condition, the physician or counselor may recommend that genetic testing be performed.

    Even in cases where an individual does not meet all of the diagnostic criteria for FAP, it may still be recommended that an affected individual undergo genetic testing to investigate for the presence of an APC gene alteration.

    Because FAP shares features with MAP, additional genetic testing to investigate for alterations in the MYH gene may be recommended if no alteration is identified in the APC gene.

  • Cancer risks

    Cancers in the gastrointestinal tract

    Individuals carrying an alteration in one copy of the APC gene are born and develop normally, but they are at an increased risk to develop polyps in the gastrointestinal tract, particularly in the colon. These polyps often begin to develop by the age of 16 years (range 7 to 36 years). By the age of 35 years, up to 95 percent of patients with FAP have developed polyps in the colon and, without removal of the colon, patients will undoubtedly develop colon cancer. The average age of colon cancer diagnosis in untreated patients with FAP is 39 years (age 34 to 43 years).

    Cancers outside the gastrointestinal tract

    Individuals with familial adenomatous polyposis are also at increased risk to develop benign and malignant tumors outside of the gastrointestinal tract. These can include:

    • Desmoid tumors. These fibrous tumors occur in approximately 10 percent of children and adults with FAP. They are commonly found in the abdomen.
    • Adrenal masses. Benign tumors can develop within the adrenal gland, a small organ located on top of each kidney that secretes specific hormones. Adrenal masses have been found in 7 percent to 13 percent of individuals with FAP.

    Some cancers that do not involve the colon have a slightly increased incidence in individuals with familial adenomatous polyposis as compared to individuals without FAP. A person with FAP has the following lifetime risks of developing these other cancers:

    • Small bowel cancer — 4 percent to 12 percent
    • Pancreatic cancer — approximately 2 percent
    • Thyroid cancer — 1 percent to 2 percent
    • Brain cancer (medulloblastoma) — less than 1 percent
    • Liver cancer (hepatoblastoma) — less than 2 percent
    • Bile duct cancer — very low risk, but increased in people with FAP
  • Cancer screening protocol

    For children

    Regardless of whether the parents of a child with polyps decide to pursue testing for APC mutations in their family, it is recommended that they consider the following surveillance measures:

    For children, recommended surveillance measures include:

    • Annual physical examination by a doctor
    • Although no hepatoblastoma screening recommendations have been made for patients with familial adenomatous polyposis, the following screening recommendations for other conditions with increased risk of hepatoblastoma may be considered: Abdominal ultrasound examination to screen for hepatoblastoma and adrenal masses every three months from infancy to age 4-5 years. Serial examination of serum alpha-fetoprotein (AFP) levels as an additional screen for hepatoblastoma at least every three months until the age of 4-5 years. AFP is a protein released by hepatoblastoma tumors and can be a highly sensitive way to detect these cancers.
    • Sigmoidoscopy or colonoscopy to screen for colonic polyps every one to two years, beginning at age 10 to 12 years, or 10 years prior to the earliest cancer diagnosis in the family. Both of these procedures allow for an internal examination of the colon; however, a colonoscopy looks at the entire large bowel while a sigmoidoscopy examines only a specific portion of the large bowel.

    Children should be encouraged to lead as healthy a lifestyle as possible. They should eat a balanced diet, avoid excess sun exposure and always wear sun block and a hat when outdoors in the sunlight. As adolescents, they should be discouraged from smoking cigarettes or cigars and should not be exposed second hand smoke.  Parents should watch for symptoms of illness and have their children evaluated promptly if these occur.

    For adults

    Adults within the family should pursue a healthy lifestyle, avoid tobacco use and excess alcohol consumption, use protective measures when in the sun and follow published guidelines for cancer surveillance, which include:

    • A complete physical examination every 12 months, including evaluation for manifestations outside of the colon, usually for cosmetic concerns
    • Annual thyroid examination starting in the late teenage years. Annual thyroid ultrasound may be considered (it is better at detecting small thyroid nodules that might be missed by physical examination), although data to support this recommendation are lacking.
    • Colonoscopy every one to two years once polyps are detected.
    • Annual colonoscopy, if colectomy (removal of all or part of the colon) is delayed more than a year after polyps emerge.
    • Esophagogastroduodenoscopy (EGD), which allows for visualization of the upper gastrointestinal tract, beginning by age 25 years or prior to colectomy and repeated every one to three years. The frequency of EGD depends on the severity of adenomas that are found in the stomach and/or upper intestines.
    • Small-bowel imaging when adenomas are detected in the duodenum (part of the small intestine) or prior to colectomy, repeated every one to three years depending on findings and presence of symptoms.
  • Support and information

    Clinical services

    We recommend that children with a diagnosis of familial adenomatous polyposis, or those suspected of having familial adenomatous polyposis, contact the Division of Gastroenterology, Hepatology and Nutrition at The Children's Hospital of Philadelphia to discuss issues related to the management of this condition.

    Adults who have familial adenomatous polyposis or who would like more information about familial adenomatous polyposis may contact the Gastrointestinal (GI) Cancer Risk Evaluation Program at the Hospital of the University of Pennsylvania.

  • References

    Lindor, N.M. (2009). Hereditary-colorectal cancer: MYH-associated polyposis and other newly-identified disorders. Best Practices & Research Clinical Gastroenterology, 23, 75-87.

    Lynch, H.T., Smyrk, T., McGinn, T., Lanspa, S., Cavalieri, J., Lynch, J., Slominski-Castor, S., Cayouette, M.C., Priluck, I., & Luce, M.C. (1995). Attenuated familial adenomatous polyposis (AFAP): A phenotypically and genotypically distinctive variant of FAP. Cancer, 76, 2427-2433.

    Vogt, S., Jones, N., Christian, D., Engel, C., Nielsen, M., Kaufmann, A., Steinke, V., Vasen, H.F., Propping, P., Sampson, J.R., Hes, F.J., & S. Aretz. (2009). Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology, 137, 1976-1985.

Reviewed by Kristin Zelley, MS, Kim E. Nichols, MD on September 03, 2012