Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) is a rare genetic disorder that significantly increases the risk of developing colorectal cancer due to the formation of numerous polyps in the large intestine. It is primarily caused by mutations in the APC gene, which is a crucial tumor suppressor, though a second gene, MUTYH, can also play a role in some cases. FAP is inherited in an autosomal dominant manner through the APC mutation, meaning that just one copy of the mutated gene from a parent can cause the condition. Symptoms may initially be absent, but when they occur, they can include rectal bleeding, abdominal pain, and changes in bowel habits. Diagnosis typically involves genetic testing and endoscopic procedures to identify and treat polyps. Treatment often requires surgical intervention, such as colectomy, to remove affected sections of the intestine. Regular monitoring is essential even after surgery, as there is a significant risk of new polyp formation. While there are no definitive prevention strategies for FAP, ongoing research is exploring the potential role of certain medications in reducing polyp development.
Familial adenomatous polyposis
ALSO KNOWN AS: FAP
DEFINITION Familial adenomatous polyposis (FAP) is a rare, inherited type of colorectal cancer. FAP results in the development of hundreds of polyps inside the large intestine.
Risk Factors
The primary risk factor for FAP is having family members with this condition.
Etiology and Genetics
Mutations in either of two different genes are known to cause familial adenomatous polyposis. In the majority of cases, the mutation is localized in the APC gene, which is found on the long arm of chromosome 5 at position 5q21-q22. This gene encodes a very large protein (2,843 amino acids) that is partitioned into several domains, each with its own distinct function. It serves as a tumor suppressor in cells by antagonizing one signaling pathway while being an essential component of a second signaling pathway for the production of beta-catenin. Beta-catenin is a protein necessary for the development and continuity of the epithelial tissue that lines organ surfaces. One of its functions is to regulate normal cell growth and behavior, and altered or missing copies of this protein can lead to polyp formation and ultimately colorectal cancer.
A second gene associated with FAP is the MUTYH gene, located on the short arm of chromosome 1 at position 1p34.3-p32.1. This gene specifies an important enzyme in a deoxyribonucleic acid (DNA) repair pathway that is active during DNA replication. Individuals with a mutation in this gene that causes a nonfunctional enzyme to be produced will be unable to repair some errors, and the accumulated mistakes increase the likelihood of overgrowth in the intestinal epithelia, leading to polyp formation.
The inheritance pattern for FAP critically depends on the gene in which the mutation (or mutations) occurs. Mutations in the APC gene are inherited in an autosomal dominant fashion, meaning that a single copy of the mutation is sufficient to cause full expression of the disease. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children. Many cases of APC-associated FAP, however, result from a spontaneous new mutation, so in these instances affected individuals will have unaffected parents.
Mutations in the MUTYH gene are inherited in an autosomal recessive pattern. In this case, both copies of the gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected. If one parent has MUTYH-associated FAP and the other is a carrier, there is a 50 percent probability that each child will be affected.
Symptoms
In the early stages, there may be no symptoms of FAP. When symptoms do occur, they may include bright red blood in the stool, diarrhea, constipation, cramping pain in the stomach, consistent decrease in the size of stool, weight loss, bloating, and fatigue.
Screening and Diagnosis
The doctor will ask about a patient’s symptoms and medical history and will perform a physical exam. Tests may include a DNA analysis, in which blood samples are taken from members of the patient’s family to determine if the patient has the defective gene; and an endoscopy, in which a thin, lighted, telescope-like tube is inserted into the colon to check for polyps. The endoscopy may be a limited exam of the rectum with a proctoscope, a more extensive exam of the rectum and sigmoid colon with a sigmoidoscope, or a complete exam of the entire large intestine with a colonoscope. If a polyp is found during endoscopy, a small sample will be removed and sent to a lab for testing; this test is called a biopsy.
Treatment and Therapy
FAP is treated with surgery. Since FAP causes so many polyps, they cannot be removed individually. Therefore, the goal of surgery is to remove the portion of the intestine that contains the cancerous or precancerous polyps. The surgical procedure used depends on the length of intestine involved.
For reasons not entirely understood, rectal polyps will often regress or disappear after a more limited surgery that does not require the removal of the rectum. Therefore, the surgeon often will leave the rectum in place and remove the rest of the large bowel. If the polyps in the rectum do not disappear, then the rectum will likely need to be removed as well.
There are three main surgical treatments for FAP. A colectomy with ileorectal anastomosis (IRA) is the most common procedure for patients with few polyps in the rectum. The colon is removed, but five inches of the rectum remain. The small intestine is surgically joined to the upper rectum. This procedure preserves sphincter tone and allows for relatively normal sensation of the need to have a bowel movement.
In a restorative proctocolectomy (pouch) the colon and rectum are removed, leaving the anal canal and anal sphincter muscles. An artificial rectum (pouch) is created from the lower end of the small intestine. The pouch is attached to the anus in order to control bowel actions. This operation is usually done in two stages.
In a total proctocolectomy with permanent ileostomy the colon, rectum, and anus are removed. After that, a permanent ileostomy (opening in the abdomen) is created. A bag is attached to collect waste through the ileostomy. This type of surgery is not used very often, unless the rectum contains many polyps and they do not regress after a lesser surgery.
If only a portion of the bowel is removed at surgery, the remaining bowel will need to be inspected by endoscopy every three to six months for the rest of a patient’s life. Because the risk of developing other polyps that could grow to become cancer is so high, it is crucial for a patient’s doctor to keep a very close watch on the remaining bowel. If more polyps arise, further surgery may be required.
Prevention and Outcomes
There are no guidelines for the prevention of FAP. There are some preliminary studies evaluating the use of cyclooxygenase antagonists, such as Vioxx or Celebrex, to prevent the development of colorectal polyps. However, it is too early to tell if these drugs have any effect on the development of cancerous polyps in FAP.
Bibliography
Badash, Michelle. “Familial Adenomatous Polyposis.” EBSCO Health Library. EBSCO Information Services, 28 May 2014. Web. 22 July 2014.
Delaini, Gian Gaetano, ed. Inflammatory Bowel Disease and Familial Adenomatous Polyposis: Clinical Management and Patients’ Quality of Life. New York: Springer, 2006. Print.
“Familial Adenomatous Polyposis.” Cancer.Net. Amer. Soc. of Clinical Oncology, May 2013. Web. 22 July 2014.
“Familial Adenomatous Polyposis.” Genetics Home Reference. Natl. Lib. of Medicine, Oct. 2013. Web. 22 July 2014.
Finn, Robert. “Treatment Is Key to Cancer Prevention in FAP Patients.” Family Practice News 34.8 (2004): 23.
Lefevre, J. H., et al. “APC, MYH, and the Correlation Genotype-Phenotype in Colorectal Polyposis.” Annals of Surgical Oncology 16.4 (2009): 871–77.
Menon, Gopal, et al. Familial Denomatous Polyposis. StatPearls, National Library of Medicine, 5 May 2024, www.ncbi.nlm.nih.gov/books/NBK538233/. Accessed 5 Sept. 2024.
Sriranganathan, Danujan, Yakup Kilic, Mohammed Nabil Quraishi, and Jonathan P. Segal. "Prevalence of Pouchitis in Both Ulcerative Colitis and Familial Adenomatous Polyposis: A Systematic Review and Meta-Analysis." Colorectal Disease, vol. 24, no. 1, Jan. 2022, pp. 27-39, DOI: 10.1111/codi.15995. Accessed 5 Sept. 2024.