Basic Medical SciencesGastroenterologyGeneral SurgeryGeneticsHealth A-ZPathology

Familial Adenomatous Polyposis (FAP)

Definition, Subtypes, Causes, Genetic Inheritance, Diagnosis, Screening and Risk Reducing.

Familial Adenomatous Polyposis (FAP)

Classic familial adenomatous polyposis, called FAP or classic FAP, is a genetic condition. It is diagnosed when a person develops more than 100 adenomatous colon polyps. An adenomatous polyp is an area where normal cells that line the inside of a person’s colon form a mass on the inside of the intestinal tract.

The average age for polyps to develop in people with FAP is in the mid-teens. Most people with FAP will have multiple colon polyps by age 35. If FAP is not recognized and treated, there is a very high likelihood that a person will develop colorectal cancer.

Individuals with FAP also have an increased chance of developing cancer in other organs, including the stomachsmall intestine, and the pancreas and biliary tree. Risk for hepatoblastoma, a rare type of liver cancer, is increased in children with FAP.

A locally aggressive, non-cancerous tumor type called desmoid tumors/desmoid fibromatosis and a rare type of brain tumor called medulloblastoma can also occur in some individuals. Risk for papillary thyroid cancer is also increased.

Not all symptoms of FAP are cancer-related. Some additional features of FAP may include:

  • Osteomas, which are non-cancerous bony growths, usually found on the jaw
  • Extra, missing, or unerupted teeth
  • Congenital hypertrophy of the retinal pigment epithelium (CHRPE). This is an eye condition that is present at birth that does not affect vision, but it is a condition that an eye doctor may see during an examination with a special instrument called an ophthalmoscope.
  • Non-cancerous skin changes, such as epidermoid cysts and fibromas
  • Adrenal masses

Subtypes of Familial Adenomatous Polyposis (FAP)

There are subtypes of FAP which can vary with clinical features, including:

1. Classic FAP is typically characterized by more than 100 colorectal polyps as described above. Surgery to remove the colon is often the most effective way to manage the polyps and reduce the risk for colorectal cancer.

2. Attenuated FAP (AFAP) is often associated with multiple adenomatous colorectal polyps, such as 20 to 100 polyps. People with AFAP usually continue to develop adenomatous colon polyps during their lifetime and have an increased risk of developing colorectal cancer if the polyps are not removed.

People with AFAP tend to develop polyps later in life than individuals with classic FAP; however, the presentation can vary among families and careful surveillance is important. It has not yet been determined if families with AFAP have the same risk for other types of cancer as families with classic FAP.

Similarly, risks for some of the other, non-cancerous features associated with classic FAP have not been determined fully.

3. Gardner syndrome  is a variant of FAP. Like in FAP, people with Gardner syndrome develop multiple adenomatous colon polyps, but in addition, they also develop other tumors outside the gastrointestinal organs, which may include:

  • Epidermoid cysts, which are lumps in or under the skin
  • Fibromas, which are fibrous tumors
  • Desmoid tumors, which are non-cancerous fibrous tumors that can develop anywhere in the body
  • Osteomas, which are lumps in or on bone

4. Turcot syndrome  is considered a variant of either FAP or Lynch syndrome, rather than a distinct genetic condition by itself. People with Turcot syndrome tend to have multiple adenomatous colon polyps, an increased risk of colorectal cancer, and an increased risk of brain tumors.

The type of brain tumor generally depends on whether the Turcot syndrome is more similar to Lynch syndrome or more similar to FAP. The 2 most common types of brain tumors in Turcot syndrome are:

  • Glioblastoma. This type of brain tumor is a very aggressive form of astrocytoma that is commonly found in families who have features of Lynch syndrome.
  • Medulloblastoma. This type of brain tumor begins in the cerebellum, the back of the brain. Medulloblastoma most often occurs in children and is commonly found in families who have features of FAP.

Causes of Classic FAP and its Subtypes

FAP is passed from generation to generation in a family. Genetic alterations in the APC gene that are present at birth are linked to FAP, AFAP, Gardner syndrome, and Turcot syndrome.

This type of change to a gene can also be called a genetic mutation, gene alteration, pathogenic or likely pathogenic germline variant, or a disruptive gene change. APC stands for adenomatous polyposis coli.

A genetic alteration which disrupts the function of the APC gene gives a person an increased lifetime risk of developing multiple colorectal polyps (from tens to hundreds), as well as colorectal cancer, and/or other cancers of the digestive tract.

Not all individuals with FAP have a family history of FAP. Up to 1 in 3 people with FAP develop a de novo (meaning “new”) germline mutation in APC.

Not all individuals with colorectal polyposis have FAP. Some individuals are found to carry 2 alterations in the MUTYH gene, also called the MYH gene, that is associated with a condition called MUTYH-Associated Polyposis (MAP). Individuals with FAP and MAP who have colorectal polyps classified as “adenoma or adenomatous” type.

However, individuals who have colorectal polyposis with polyps that are “hamartoma, inflammatory, or juvenile” types may have alterations in different genes, such as in cases of juvenile polyposis.

People who have FAP or AFAP can have a blood test to look for genetic alterations in the APC gene or the MUTYH gene. If a specific gene change that disrupts the gene’s function is found, other family members may be diagnosed with FAP or AFAP if they are tested and have the same gene mutation.

How are Classic FAP and its Subtypes Inherited?

Normally, every cell has 2 copies of each gene: 1 inherited from the mother and 1 inherited from the father. FAP with an APC gene mutation or alteration that is known to disrupt gene function follows an autosomal dominant inheritance pattern.

In autosomal dominant inheritance, this alternation in only 1 copy of the gene is sufficient to develop the condition. This means that a parent with this alteration may pass along a copy of their normal gene or a copy of the gene with the disruptive change.

Therefore, a child who has a parent with this change has a 50% chance of inheriting the same disruptive gene change. A brother, sister, or parent of a person who has this alteration also has a 50% chance of having the same disruptive gene change.

However, if the parents test negative for the genetic alteration (meaning each person’s test results found no disruptive gene change), the risk to the siblings significantly decreases but their risk may still be higher than an average risk.

Options exist for people interested in having a child when a prospective parent carries the genetic change that increases the risk for a hereditary cancer syndrome.

Preimplantation genetic diagnosis (PGD) is a medical procedure done in conjunction with in-vitro fertilization (IVF). It allows people who carry a specific known disruptive gene change to reduce the likelihood that their children will inherit the condition.

A woman’s eggs are removed and fertilized in a laboratory. When the embryos reach a certain size, 1 cell is removed and is tested for the hereditary condition in question. The parents can then choose to transfer embryos which do not have the disruptive gene change.

PGD has been in use for over 2 decades and has been used for several hereditary cancer predisposition syndromes. However, this is a complex procedure with financial, physical, and emotional factors to consider before starting.

For more information, talk with an assisted reproduction specialist at a fertility clinic.

How Common are Classic FAP and its Subtypes?

FAP and AFAP are uncommon. Specific estimates on how many people have FAP vary from 1 in 22,000 up to 1 in 7,000. Approximately 30% of people with FAP do not have any family history of the condition and are the first person in their family to be affected with the condition.

Most colorectal cancer is sporadic, meaning it occurs by chance, and is not related to FAP or other inherited syndromes. Less than 1% of all colorectal cancer is thought to be due to FAP.

Gardner syndrome and Turcot syndrome are both considered to be rare.

How are Classic FAP and its Subtypes Diagnosed?

Classic FAP is a clinical diagnosis. This means that it is typically diagnosed when the doctor finds many colorectal polyps, rather than by the results of a laboratory test. A person with more than 100 adenomatous colon polyps is considered to have FAP.

AFAP is suspected when a person has a history of more than 20, but fewer than 100, adenomatous colon polyps.

Gardner syndrome is suspected when a person has a multiple adenomatous colon polyps and/or colorectal cancer along with some of the non-cancerous features listed above.

Turcot syndrome is suspected when a person has multiple adenomatous colon polyps and/or colorectal cancer, along with either a glioblastoma or medulloblastoma brain tumor.

Blood tests are available to look for disruptive changes in the APC gene and/or MUTYH gene if FAP or its subtypes are suspected. If an alteration is found in the APC gene, other family members may be diagnosed with FAP or its subtypes if they are tested and have the same gene mutation.

What are the estimated cancer risks associated with classic FAP and its subtypes?

  • Colorectal cancer, up to 100% if polyps not removed
  • Desmoid tumor, 10% to 20%
  • Small bowel (intestines), 4% to 12%
  • Pancreatic/ampullary cancer, 2%
  • Papillary thyroid cancer, 2% to 25%
  • Hepatoblastoma, 1.5%
  • Brain or central nervous system tumor, less than 1%
  • Stomach cancer, 5%
  • Bile duct cancer, slightly increased risk
  • Adrenal gland cancer, slightly increased risk

The risks of cancer for people with Turcot syndrome depend on whether it appears to be more similar to Lynch syndrome or FAP.

Screening Options for Classic FAP and its Subtypes

ASCO recommends the following screening for people with FAP. It is important to discuss these options with your health care team, as each individual is different:

  • Sigmoidoscopy or colonoscopy every 1 to 2 years, starting at age 10 to 12 for people with FAP and a colonoscopy beginning at age 18 to 20 for people with AFAP.
  • Yearly colonoscopy once polyps are found until a colectomy is planned. There are different types of colon surgery for individuals with FAP and AFAP. People with classic FAP may require a total colectomy, due to a high number of polyps and the high risk of colorectal cancer. A total colectomy is the surgical removal of the entire colon. This is a major surgery and possible side effects may include the need for a colostomy. Talk with your health care team about what to expect during and after surgery.
  • After colon surgery, doctors will monitor the patient’s lower tract with sigmoidoscopy, and this surveillance should continue with regular frequency, depending on type of surgery.
    • every 6 to 12 months if some rectal tissue remains
    • every 1 to 4 years if all rectal tissue has been removed and there is a small intestinal pouch
  • Upper endoscopy(EGD) once colorectal polyps are found (or by age 25), whichever occurs first. This is to watch for duodenal polyps. Duodenal polyps increase a person’s risk for duodenal or ampullary cancer if they are not removed.
  • Ultrasound of the thyroid gland may be considered to monitor for thyroid cancer starting at age 25 to 30
  • Computed tomography(CT) scan or magnetic resonance imaging (MRI) may be recommended if a person has a personal or family history of desmoid tumors

The screening options for Gardner syndrome are considered to be similar to those for classic FAP, with the addition of regular skin examinations by a dermatologist, which is a doctor who specializes in diseases and conditions of the skin.

The screening options for Turcot syndrome are considered to be similar to those for Lynch syndrome or FAP, with the addition of screening for a brain tumor.

Screening options may change over time as new technologies are developed and more is learned about FAP and its subtypes. It is important to talk with your health care team about appropriate screening tests.

Are There Other Ways to Reduce Cancer Risks?

The risks for cancer in FAP and AFAP can be reduced through the removal of colorectal and duodenal polyps. Studies are being conducted to find out if medications may be effective in reducing cancer risks.

A recent clinical trial found that a combination of 2 medications, sulindac (Clinoril) and erlotinib (Tarceva), decreased the number of colorectal and duodenal polyps.

While this is promising, this treatment is not currently standard-of-care as further research is needed to determine the long-term outcomes.

Related Articles

Leave a Reply

Your email address will not be published. Required fields are marked *

Back to top button