familial adenomatous polyposis familial adenomatous polyposis familial adenomatous polyposis (fap) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. while these polyps start out benign, malignant transformation into colon cancer occurs when they are left untreated. three variants are known to exist, fap and attenuated fap (originally called hereditary flat adenoma syndrome) are caused by apc gene defects on chromosome 5 while autosomal recessive fap (or mutyh-associated polyposis) is caused by defects in the mutyh gene on chromosome 1. of the three, fap itself is the most severe and most common; although for all three, the resulting colonic polyps and cancers are initially confined to the colon wall. detection and removal before metastasis outside the colon can greatly reduce and in many cases eliminate the spread of cancer. familial adenomatous polyposisother namesfapendoscopic image of sigmoid colon of patient with familial adenomatous polyposisspecialtygastroenterology, oncologycomplicationscolorectal cancerusual onset<35 years of agedurationlifelongtypesclassical or attenuatedcausesapc gene mutationdiagnostic methodcolonoscopy genetic testingdifferential diagnosislynch syndrome, mutyh-associated polyposistreatmentcolonoscopy polypectomy upper endoscopycolectomyfrequency1 in 10,000 - 15,000 the root cause of fap is understood to be a genetic mutation—a change in the body's tumour suppressor genes that prevent development of tumours. the change allows numerous cells of the intestinal wall to develop into potentially cancerous polyps when they would usually reach the end of their life; inevitably one or more will eventually progress and give rise to cancer (7% risk by age 21, rising to 87% by age 45 and 93% by age 50). these gene changes do not trigger cancer, but rather, they reduce the body's ability to prevent cells from becoming cancerous. even with the gene change, it may still take time before a cell actually does develop that is cancerous as a result, and the gene may in some cases still partially operate to control tumours, therefore cancer from fap takes many years to develop and is almost always an adult-onset disease. the second form of fap, known as attenuated familial adenomatous polyposis has the apc gene functional but slightly impaired. it is therefore somewhat able to operate as usual. attenuated fap still presents a high 70% lifetime risk of cancer (as estimated), but typically presents with far fewer polyps (typically 30) rather than the hundreds or thousands usually found in fap, and arises at an age when fap is usually no longer considered likely—typically between 40 and 70 years old (average 55) rather than the more usual 30s upward. because it has far fewer polyps, options for management may be different. the third variant, autosomal recessive familial adenomatous polyposis or mutyh-associated polyposis, is also milder and, as its name suggests, requires both parents to be 'carriers' to manifest the condition. in some cases fap can manifest higher in the colon than usual (for example, the ascending colon, or proximal to the splenic flexure, or in the stomach or duodenum) where they show no symptoms until cancer is present and greatly advanced. apc mutations have been linked to certain other cancers such as thyroid cancer. as the mutation causing fap is autosomal dominant, it can be inherited directly from either parent to a child. a genetic blood test of the apc gene exists that can determine whether it is present, and therefore can predict the possibility of fap. individuals at risk (due to family links or genetic testing) are usually offered routine monitoring of the intestinal tract every 1–3 years for life, from puberty for fap and early adulthood for attenuated forms. colon resection surgery is recommended if numerous colon polyps are found due to high risk of early death from colon cancer. international polyposis registries exist that track known cases of fap or apc gene defects, for research and clinical purposes. mutation of apc also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer. signs and symptoms from early adolescence, patients with this condition gradually (and much of the time asymptomatically) develop hundreds to thousands of colorectal polyps (and sometimes polyps elsewhere)—small abnormalities at the surface of the intestinal tract, especially in the large intestine including the colon or rectum. 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. fap can also develop 'silently' in some individuals, giving few or no signs until it has developed into advanced colorectal cancer. because familial polyposis develops very gradually over years, and can also manifest in an 'attenuated' form even more gradually, polyps resulting from fap can lead to cancer developing at any point from adolescence to old age. depending on the nature of the defect in the apc gene, and whether it is the full or attenuated form, familial polyposis may manifest as polyps in colon or in the duodenal tract, or in any combination of these. therefore, an absence of polyps in, for example, the rectum, may not of itself be sufficient to confirm absence of polyps. it may be necessary to consider and visually examine other possible parts of the intestinal tract. colonoscopy is preferred over sigmoidoscopy for this, as it provides better observation of the common right-side location of polyps. chrpe - congenital hypertrophy of the retinal pigment epithelium the genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g., of the duodenum and stomach (particularly ampullary adenocarcinoma). other signs that may point to fap are the development of gardner fibromas and desmoid tumors (benign skin tumors that may be apparent before other signs of fap), pigmented lesions of the retina ("chrpe—congenital hypertrophy of the retinal pigment epithelium"), jaw cysts, sebaceous cysts, and osteomata (benign bone tumors). the combination of polyposis, osteomas, fibromas and sebaceous cysts is termed gardner's syndrome (with or without abnormal scarring). genetics 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. the incidence of malignancy in these cases approaches 100%. in most cases, an affected person has one parent with the condition. apc gene mutation variants the apc is a tumour suppressor gene responsible for the production of adenomatous polyposis coli (apc), a large multifunction tumour-suppressing protein which acts as a "gatekeeper" to prevent development of tumours. (apc regulates β-catenin, a protein that plays a crucial role in cell communication, signalling, growth, and controlled destruction, but which left uncontrolled also gives rise to numerous cancers). a flaw in the apc gene means apc is not as effective as it should be, and over time it is likely that some cells that should have been controlled by apc will not be, and will instead continue to develop and become cancerous. in familiar polyposis they usually manifest as polyps—small abnormalities on the surface of the intestinal tract. although the polyps are inherently benign, the first step of the 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 epithelial cells. the normal function of the apc gene product is still being investigated; it is present in both the cell nucleus and the membrane. the canonical tumor-suppressor function of apc is suppression of β-catenin, but other tumor-suppressor functions of apc may be related to cell adherence and cytoskeleton organization. mutation of apc also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer. mutyh gene mutation variants main article: mutyh-associated polyposis 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 mutations 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. 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. animal models the "apcmin" mouse model was described in 1990 and carries an apc allele with a stop codon at position 850. heterozygosity for this mutation results in a fully penetrant phenotype on most genetic backgrounds, with mice on a sensitive background developing over 100 tumors in the intestinal tract. the number and location of the intestinal tumors are modified by unlinked genes. 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. for more information see mouse models of colorectal and intestinal cancer. in 2007, the "apcpirc" rat model was isolated with a stop codon at position 1137. 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. diagnosis micrograph of a tubular adenoma, the colorectal cancer precursor most commonly associated with fap making the diagnosis of fap before the development of colon cancer is important not just for the individual, but also for the sake of other family members who may be affected. two diagnostic methods exist: colonoscopy is the usual diagnostic test of choice as it favours the common right-side location of polyps better than sigmoidoscopy if the mutation is attenuated fap, and can confirm or allow (a) the actual clinical presentation and any change to the condition, of the 'at risk' individual, (b) quantification of polyps throughout the colon, (c) a histologic diagnosis (cell/cancer type detection) and (d) where polyps exist, it can suggest whether outpatient excision (removal) is viable or surgery is recommended. barium enema and virtual colonoscopy (a form of medical imaging) can also be used to suggest the diagnosis of fap. genetic testing provides the ultimate diagnosis in 95% of cases; 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 p34.3 and p32.1 (1p34.3–p32.1). testing can only show if an individual is susceptible to fap or rule it out (i.e., whether or not they inherited the defective apc gene). it cannot determine the actual condition of a patient; this can only be found by direct physical examination. ncbi states that physicians must ensure they understand the "risks, benefits, and limitations" of any genetic test done since in 1997 "for almost one-third of individuals assessed for fap, the physician misinterpreted the test results". once the diagnosis of fap is made, close colonoscopic surveillance with polypectomy is required. 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. ultrasound of the abdomen and blood tests evaluating liver function are often performed to rule out metastasis to the liver. management colectomy specimen showing numerous polyps throughout the large bowel because of the way familial polyposis develops, it is possible to have the genetic condition, and therefore be at risk, but have no polyps or issues so far. therefore, an individual may be diagnosed "at risk of" fap, and require routine monitoring, but not (yet) actually have fap (i.e., carries a defective gene but as yet appears not to have any actual medical issue as a result of this). clinical management can cover several areas: identifying those individuals who could be at risk of fap: usually from family medical history or genetic testing diagnosis (confirming whether they have fap)—this can be done either by genetic testing, which