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| {{SK}} Familial polyposis coli; adenomatous polyposis of colon; APC; adenomatous polyposis coli; colon cancer, familial; familial intestinal polyposis; familial multiple polyposis; familial multiple polyposis syndrome; familial polyposis syndrome; FAP; hereditary polyposis coli; MYH-associated polyposis; polyposis coli | | {{SK}} Familial polyposis coli; adenomatous polyposis of colon; APC; adenomatous polyposis coli; colon cancer, familial; familial intestinal polyposis; familial multiple polyposis; familial multiple polyposis syndrome; familial polyposis syndrome; FAP; hereditary polyposis coli; MYH-associated polyposis; polyposis coli |
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| ==Overview== | | ==[[Familial adenomatous polyposis overview|Overview]]== |
| '''Familial adenomatous polyposis''' ('''FAP''') is an inherited condition in which numerous [[Polyp (medicine)|polyp]]s form mainly in the [[epithelium]] of the [[colon (anatomy)|large intestine]]. While these polyps start out [[benign]], [[malignant|malignant transformation]] into [[colorectal cancer|colon cancer]] occurs 100% of the time when not treated.
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| ==Epidemiology==
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| The incidence of the mutation is between 1 in 10,000 and 1 in 15,000 births.
| | ==[[Familial adenomatous polyposis historical perspective|Historical Perspective]]== |
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| By age 35 years, 95% of individuals with FAP have polyps. Without colectomy, colon cancer is virtually inevitable. The mean age of colon cancer in untreated individuals is 39 years (range 34-43 years).
| | ==[[Familial adenomatous polyposis classification|Classification]]== |
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| ==Pathophysiology==<!-- This section is linked from [[Cancer]] --> | | ==[[Familial adenomatous polyposis pathophysiology|Pathophysiology]]== |
| FAP is due to mutations in the ''[[APC (gene)|APC]]'' gene, which is located on [[chromosome]] 5 in band q21 or band q22 (5q21-q22), or in the ''[[MUTYH]]'' gene, which is located on chromosome 1 between bands p34.2 and p32.1 (5p34.3-p32.1).
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| ''[[APC (gene)|APC]]'' is a [[tumour suppressor gene]], acting as a "gatekeeper" to prevent development of tumours. Mutation of ''APC'' also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.
| | ==[[Familial adenomatous polyposis causes|Causes]]== |
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| Although the polyps are inherently benign, the first step of the [[Knudson hypothesis|two-hit hypothesis]] has already taken place: the inherited APC mutation. Often, the remaining "normal" [[allele]] is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in [[p53]] or ''KRAS'') to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated [[epithelium|epithelial]] cells.
| | ==[[Familial adenomatous polyposis differential diagnosis|Differentiating Familial adenomatous polyposis from other Diseases]]== |
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| The normal function of the ''APC'' gene product is still being investigated; it is present both the [[cell nucleus]] and the membrane. The canonical tumor-suppressor function of Apc is suppression of the oncogenic protein [[beta-catenin]]. However, other tumor-suppressor functions of Apc may be related to cell adherence and [[cytoskeleton]] organization.
| | ==[[Familial adenomatous polyposis epidemiology and demographics|Epidemiology and Demographics]]== |
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| ''[[MUTYH]]'' encodes [[DNA repair]] enzyme MYH glycosylase. During normal cellular activities, [[guanine]] sometimes becomes altered by [[oxygen]], which causes it to pair with [[adenine]] instead of [[cytosine]]. MYH glycosylase fixes these mistakes by [[base excision repair]], such that [[mutation]]s do not accumulate in the [[DNA]] and lead to tumor formation. When MYH glycosylase does not function correctly, DNA errors may accrue to initiate tumorigenesis with a clinical presentation similar to that in patients with Apc mutations.
| | ==[[Familial adenomatous polyposis risk factors|Risk Factors]]== |
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| ===Animal Models=== | | ==[[Familial adenomatous polyposis natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| The "ApcMin" mouse model was isolated in 1990 and harbors an Apc allele with a stop codon at position 850. Heterozygosity for this mutation results in a fully penetrant phenotype, with mice on a sensitive background developing over 100 tumors in the intestinal tract. Many other models have since appeared, including a model of attenuated FAP (the 1638N model) and several conditional mutants that allow for tissue-specific or temporal ablation of gene function.
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| In 2007, the "ApcPirc" rat model was isolated with a stop codon at position 1137 <ref>{{cite journal |author=Amos-Landgraf J, Kwong LN, Dove WF, ''et al'' |title=[A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer.] |journal=PNAS |volume=104 |issue=10 |pages=4036-4041 |year=2007 |pmid=17360473 |doi=}}</ref>. In contrast to the mouse models where >90% of tumors form in the small intestine, the Pirc rat forms tumors preferentially (>60%) in the large intestine, similar to the human clinical presentation.
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| ==Diagnosis== | | ==Diagnosis== |
| Making the diagnosis of FAP before the development of colon cancer is important insofar as not only the individual but also affected family member's survival is at stake. Colonoscopy is considered the diagnostic test of choice as it can provide not only a quantification of polyps throughout the colon but also a histologic diagnosis. [[Barium enema]] and [[virtual colonoscopy]] can suggest the diagnosis of FAP.
| | [[Familial adenomatous polyposis history and symptoms| History and Symptoms]] | [[Familial adenomatous polyposis physical examination | Physical Examination]] | [[Familial adenomatous polyposis laboratory findings|Laboratory Findings]] | [[Familial adenomatous polyposis chest x ray|Chest X Ray]] | [[Familial adenomatous polyposis CT|CT]] | [[Familial adenomatous polyposis MRI|MRI]] | [[Familial adenomatous polyposis ultrasound|Ultrasound]] | [[Familial adenomatous polyposis other imaging findings|Other Imaging Findings]] | [[Familial adenomatous polyposis other diagnostic studies|Other Diagnostic Studies]] |
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| Once the diagnosis of FAP is made, close [[colonoscopy|colonoscopic]] surveillance with [[polypectomy]] is required. [[Prophylaxis|Prophylactic]] [[colectomy]] is indicated if more than a hundred polyps are present, there are severely dysplastic polyps, or multiple polyps larger than 1 cm are present. When partial colectomy is performed, colonoscopic surveillance of the remaining colon is necessary as the individual still carries significant risk of developing colon cancer.
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| [[medical ultrasonography|Ultrasound]] of the abdomen and [[blood test]]s evaluating [[liver function tests|liver function]] are often performed to rule out [[metastasis]] to the liver.
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| [[Genetic testing]] provides the ultimate diagnosis in 95%; [[genetic counseling]] is usually needed in families where FAP has been diagnosed. Testing may also aid in the diagnosis of borderline cases in families that are otherwise known to have the FAP mutation.
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| ===Signs and symptoms===
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| From early adolescence and onwards, patients with this condition develop hundreds to thousands of polyps. These may bleed, leading to blood in the stool. If the blood is not visible, it is still possible for the patient to develop [[anemia]] due to gradually developing iron deficiency. If malignancy develops, this may present with [[weight loss]], altered bowel habit, or even [[metastasis]] to the [[liver]] or elsewhere.
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| The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g. of the [[duodenum]] and [[stomach]]. Other signs that may point at FAP are pigmented lesions of the [[retina]] ("CHRPE - congenital hypertrophy of the retinal pigment epithelium"), jaw cysts, [[sebaceous cyst]]s, and [[osteoma]]ta (benign bone tumors). The combination of polyposis, osteomas, [[fibroma]]s and [[sebaceous cyst]]s is termed ''[[Gardner syndrome]]'' (with or without abnormal scarring).
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| ==Genetics==
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| Familial adenomatous polyposis can have different inheritance patterns and different genetic causes. When this condition results from mutations in the ''APC'' gene, it is inherited in an [[autosomal dominant]] pattern, which means one copy of the altered gene is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition. | |
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| Mutations in the ''MUTYH'' gene are inherited in an [[autosomal recessive]] pattern, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.
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| [[Prenatal testing]] is possible if a disease-causing mutation is identified in an affected family member; however, prenatal testing for typically adult-onset disorders is uncommon and requires careful [[genetic counseling]].
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| Because of the genetic nature of FAP, polyposis registries have been developed around the world. The purpose of these registries is to increase knowledge about the transmissibility of FAP, but also to document, track, and notify family members of affected individuals. One study has shown that the use of a registry to notify family members (call-ups) significantly reduced mortality when compared with [[proband]]s.<ref>{{cite journal |author=Reyes Moreno J, Ginard Vicens D, Vanrell M, ''et al'' |title=[Impact of a registry on the survival familial adenomatous polyposis.] |language=Spanish; Castilian |journal=Medicina clínica |volume=129 |issue=2 |pages=51-2 |year=2007 |pmid=17588361 |doi=}}</ref> The [http://www.polyposisregistry.org.uk/index.htm St. Mark's polyposis registry] is the oldest in the world, started in 1924, and many other [[polyposis registries]] now exist.
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| ==Treatment== | | ==Treatment== |
| Treatment for FAP depends on the genotype. Most individuals with the APC mutation will develop colon cancer by the age of 40. Therefore, prophylatic surgery is generally recommended before the age of 25. There are several surgical options that involve the removal of either the colon or both the colon and rectum. The decision to remove the rectum depends on the number of polyps in the rectum as well as the family history. If the rectum has few polyps, the colon is removed and the small bowel (ileum) is connected to the rectum (ileorectal anastomosis). If the rectum is involved then the colon and rectum are removed and a patient may require an ileostomy (permanent stoma where stool goes into a bag on the abdomen) or have an ileoanal pouch reconstruction.
| | [[Familial adenomatous polyposis medical therapy|Medical Therapy]] | [[Familial adenomatous polyposis surgery|urgery]] | [[Familial adenomatous polyposis primary prevention|Primary Prevention]] | [[Familial adenomatous polyposis secondary prevention|Secondary Prevention]] | [[Familial adenomatous polyposis cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Familial adenomatous polyposis future or investigational therapies|Future or Investigational Therapies]] |
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| Various medications are being investigated for slowing malignant degeneration of polyps, most prominently the [[non-steroidal anti-inflammatory drug]]s (NSAIDs). The NSAIDS have been shown to significantly decrease the number of polyps but does not usually alter management since there are still too many polyps to be followed and treated endoscopically.
| | ==Case Studies== |
| | [[Familial adenomatous polyposis case study one|Case#1]] |
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| ==References== | | ==References== |
| {{reflist|2}} | | {{reflist|2}} |
| * Gardner EJ. ''A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum.'' Am J Hum Genet 1951;3:167-76. PMID 14902760 | | * Gardner EJ. ''A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum.'' Am J Hum Genet 1951;3:167-76. PMID 14902760 |
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| ==External links==
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| * {{Cancerindex|APC}}
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| * {{DiseasesDB|4678}}
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| * {{OMIM|175100}}
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| *[http://www.fapgene.co.uk www.fapgene.co.uk]
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| [[Category:Gastroenterology]] | | [[Category:Gastroenterology]] |