Familial adenomatous polyposis

Symptoms

What are the main symptoms of familial adenomatous polyposis?

The main symptom of familial adenomatous polyposis is development of colon polyps. However, colon polyps often do not cause any symptoms and are only found on a test that helps doctors see into the colon called colonoscopy. Some people with colon polyps may experience rectal bleeding, change in color of the stool (blood may make the stool appear black or it may have red streaks), or change in bowel habits including constipation or diarrhea, pain, nausea, vomiting, or iron deficiency.

Symptoms of colon cancer may include: a change in bowel habits including constipation, diarrhea, or narrowing of the stool, which lasts for more than a few days, feeling that you need to have a bowel movement but the feeling is not relieved by doing so, blood in the stool, rectal bleeding, cramping or abdominal pain, weakness, fatigue, and unintended weight loss.

The types of cancer that are suggestive of familial adenomatous polyposis include: colon cancer, ten to hundreds to thousands of adenomatous polyps, small intestinal polyps or cancer, stomach polyps (fundic gland polyps), pancreatic cancer, thyroid cancer, brain tumor (medulloblastomas are most common), and hepatoblastoma (tumor of the liver) in children. There are other, non-cancerous, findings that are also suggestive of familial adenomatous polyposis which include: osteoma (bony growth, usually on the head), epidermoid or sebaceous cysts (small lumps under the surface of the skin or of the oil glands of the skin), desmoid (abnormal growth of tissue typically arising in abdomen), CHRPE (a spot on the retina of the eye), cysts on the jawline, and extra teeth or baby teeth that never fell out.

References
  • Colorectal Cancer. (n.d.). Retrieved November 25, 2019, from http://www.cancer.org/cancer/colonandrectumcancer/.
  • Colon polyps. (2019, October 19). Retrieved November 25, 2019, from http://www.mayoclinic.org/diseases-conditions/colon-polyps/basics/symptoms/con-20031957.
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Are there earlier onset, later onset, or variant forms of familial adenomatous polyposis?

What health problems should I look for in familial adenomatous polyposis?

Any other diseases that look a lot like familial adenomatous polyposis(phenocopies, differential diagnoses)?

Is there one or two characteristic "odd" or "unusual" symptom or clinical feature of familial adenomatous polyposis?

Is there variable expression or incomplete penetrance in familial adenomatous polyposis?

If this is a predisposition gene causing familial adenomatous polyposis , what are the chances I will get cancer?

Are there earlier onset, later onset, or variant forms of familial adenomatous polyposis?

There are different forms of familial adenomatous polyposis that can be told apart based on the number of polyps in the colon, other health issues seen in association with the polyps, and/or the gene changes causing the condition. Genes are made up of a combination of different letters, and the order of these letters is important for the gene to function properly. Mutations in the APC gene are responsible for both FAP and milder form, attenuated FAP (AFAP). The APC gene is a very large gene, and mutations towards the center of the APC gene most often cause classic FAP. Whereas, mutations towards the ends of the APC gene usually cause attenuated FAP. Mutations towards the end of the genes have also been associated with a higher risk for developing the non-cancerous features including: osteomas, CHRPE (a spot on the retina of the eye), desmoid (an abnormal growth of tissue), extra teeth, and cysts. Deletions of the entire APC gene or pieces missing from the gene have also been associated with attenuated FAP. There are different mutations in different regions of the gene that have been associated with earlier and later onset polyps.

MUTYH-associated polyposis has a mutation in the MUTYH gene that is responsible for an earlier onset and more severe version of the condition. The mutation is: c.536A>G, which means there is a change in the letter A to G 536 letters into the gene. In general, individuals who have a mutation in the MUTYH gene, associated with MUTYH-associated polyposis, do not always develop colon polyps or colon cancer, and this is known as incomplete penetrance.

When the colon polyps are found with other very specific health problems, familial adenomatous polyposis can be called Gardner or Turcot syndrome. Gardner syndrome has been used in the past to describe individuals with FAP who also have cysts on their face, desmoids, extra teeth, or cysts on their jawline. Turcot syndrome has been used in the past to describe individuals who with FAP, who also have multiple individuals in their family who also have CNS (central nervous system or brain) tumors.

References
  • Friedl W, Caspari R, Sengteller M, Uhlhaas S, Lamberti C, Jungck M, Kadmon M, Wolf M, Fahnenstich J, Gebert J, Moslein G, Mangold E, Propping P. Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut. 2001;48:515-21
  • Nielsen M, Bik E, Hes FJ, Breuning MH, Vasen HF, Bakker E, Tops CM, Weiss MM. Genotype-phenotype correlations in 19 Dutch cases with APC gene deletions and a literature review. Eur J Hum Genet. 2007a;15:1034-42.
  • Nielsen M, Joerink-van de Beld MC, Jones N, Vogt S, Tops CM, Vasen HF, Sampson JR, Aretz S, Hes FJ. Analysis of MUTYH genotypes and colorectal phenotypes in patients with MUTYH-associated polyposis. Gastroenterology. 2009b;136:471-6.
What health problems should I look for in familial adenomatous polyposis?

Colon polyps often do not cause any symptoms. But, some people with colon polyps may experience rectal bleeding, change in color of the stool (blood may make the stool appear black or it may have red streaks), change in bowel habits including constipation or diarrhea, pain, nausea, vomiting, or iron deficiency.

Symptoms of colon cancer may include: a change in bowel habits including constipation, diarrhea, or narrowing of the stool, which lasts for more than a few days, feeling that you need to have a bowel movement but the feeling is not relieved by doing so, blood in the stool, rectal bleeding, cramping or abdominal pain, weakness, fatigue, and unintended weight loss.

Familial adenomatous polyposis should be considered whenever an individual has a personal history of 20 or more adenoma polyps.

FAP should also be considered when there is a personal or family history of:

  • Colon polyps
  • Colon cancer
  • Hepatoblastoma
  • Desmoid tumors
  • Papillary thyroid cancer
  • Sebaceous or epidermoid cysts
  • Extra teeth or baby teeth that never fell out
  • CHRPE (spot on the retina of the eye)
  • Stomach polyps
References
  • Colorectal Cancer Risk Factors. (n.d.). Retrieved from http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-risk-factors.
  • Colon polyps. (2019, October 19). Retrieved November 25, 2019, from http://www.mayoclinic.org/diseases-conditions/colon-polyps/basics/symptoms/con-20031957.
  • http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf (login required)
  • Schneider, K. (2013). , 3rd Ed.
Any other diseases that look a lot like familial adenomatous polyposis(phenocopies, differential diagnoses)?

The differential diagnosis for familial adenomatous polyposis includes:

  • Lynch syndrome- associated with up to an 80% lifetime risk for colon cancer, a 40% life time risk for endometrial cancer, and up to a 15% lifetime risk for stomach cancer
  • Peutz-Jeghers syndrome- Up to a 30% lifetime risk for breast cancer, colon hamartomatous polyps, and an increased risk for gastric cancer
  • Cowden syndrome- Associated with a 25-50% lifetime risk for breast cancer and an increased risk for colon cancer including GI hamartomas
  • MUTYH-Associated polyposis (MAP)- causes a 43-almost 100% increased life time risk for colon cancer, an increased risk for colon polyps, and up to a 4% lifetime risk to develop duodenum cancer (upper part of the small intestine)
  • Juvenile Polyposis Syndrome - Associated with a greater than 90% lifetime risk for developing juvenile polyps, an increased lifetime risk for developing colon cancer, and an increased risk for stomach and small intestinal cancer
  • POLE/POLD1 genes- Associated with multiple polyps and an increased risk for colon cancer
  • Li Fraumeni syndrome- up to a 90% life timerisk for breast cancer, and an increased risk for colon cancer
References
  • Lindor, N.M., et. al. (2007). Concise handbook of familial cancer susceptibility syndromes. Journal of the National Cancer Institute. Monographs, (38), 1-93.
  • Schneider, K. (2013). , 3rd Ed
Is there one or two characteristic "odd" or "unusual" symptom or clinical feature of familial adenomatous polyposis?

Having more than 20 adenomatous polyps is considered unusual in the general population and is suggestive of familial adenomatous polyposis.

CHRPE (congenital hypertrophy or hyperplasia of the retinal pigment epithelium) are benign (non-cancerous) lesions on the retina that are highly suggestive of FAP. Singular lesions would not lead to the diagnosis of FAP but the presence of 4 or more lesions is highly specific for the diagnosis of FAP. CHRPE has been reported in up to 90% of patients with FAP. However, genetic testing is still the standard of care for diagnosing FAP.

References
  • Half, E., Bercovich, D., & Rozen, P. (2009). Familial adenomatous polyposis. Orphanet journal of rare diseases, 4(1), 22.
  • Nusliha, A. et al. (2014). Congenital hypertrophy of retinal pigment epithelium (CHRPE) in patients with familial adenomatous polyposis (FAP); a polyposis registry experience. BMC Research Notes, (7), 734.
Is there variable expression or incomplete penetrance in familial adenomatous polyposis?

Some individuals may develop cancer earlier or later than others within their family or between different families, which is known as a variable age of onset. Individuals who have a mutation in the APC gene may never develop the cancerous (or non-cancerous) findings associated with familial adenomatous polyposis, which is known as incomplete penetrance, while other individuals may develop some of these findings and their family members may develop different findings associated with familial adenomatous polyposis, and this is known as variable expression.

References
  • Jasperson, K. W. (2017, February 2). APC-Associated Polyposis Conditions. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK1345/.
  • Nielsen, M., Lynch, H,. Infante, E., et al. MUTYH-Assocaited Polyposis. (2012). In: Pagon RA, Adam MP, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  • Sieber, O. M., Lipton, L., Crabtree, M., Heinimann, K., Fidalgo, P., Phillips, R. K., ... & Tomlinson, I. P. (2003). Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. New England Journal of Medicine, 348(9), 791-799.
If this is a predisposition gene causing familial adenomatous polyposis , what are the chances I will get cancer?

If you have inherited a gene change in the APC gene and have familial adenomatous polyposis, this increases the lifetime risk of developing colon cancer to 100%. There is a 95% lifetime risk of developing colon polyps by the age of 35. The life time risk of developing small intestinal polyps is 50-90%. The lifetime risk for developing desmoid tumors is 10-30%, the life time risk for developing duodenum (upper part of the small intestine) cancer is 4-12%, the life time risk for developing pancreatic cancer is 2%, the lifetime risk for developing a brain tumor is less than 1%, the lifetime risk for developing hepatoblastoma is 1%, and the lifetime risk for developing thyroid cancer is 2%.

If you have inherited a gene change in the MUTYH gene and have MUTYH-associated polyposis, this increases the lifetime risk of developing colon cancer from 43-100%. There is also a 4% increased risk for developing duodenum cancer (cancer in the upper part of the small intestine).

References
  • Spigelman, A. D., Talbot, I. C., Penna, C., Nugent, K. P., Phillips, R. K., Costello, C., & DeCosse, J. J. (1994). Evidence for adenoma-carcinoma sequence in the duodenum of patients with familial adenomatous polyposis. The Leeds Castle Polyposis Group (Upper Gastrointestinal Committee). Journal of clinical pathology, 47(8), 709-710.
  • Nieuwenhuis, M. H., Mathus-Vliegen, E. M., Baeten, C. G., Nagengast, F. M., van der Bijl, J., van Dalsen, A. D., ... & Vasen, H. F. A. (2011). Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients. British journal of cancer, 104(1), 37-42.

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