Familial adenomatous polyposis

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. 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 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==

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, 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==

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 is definitive or by visually checking the intestinal tract itself. :: It is important to note that visual examination, or monitoring, cannot 'clear' a person of risk. It can only say what their condition is at the time. If at any point in their life the person develops numerous polyps, this would tend to suggest a diagnosis of FAP. (Absence of polyps does not 'clear' a person, as polyps can develop later in life; also a few polyps over time are not that uncommon in people without FAP. However a substantial number or a profusion of polyps would generally tend to suggest a diagnosis of FAP, and histopathology to determine whether or not any polyps are cancerous.) • Screening/monitoring programs involve visually examining the intestinal tract to check its healthy condition. It is undertaken as a routine matter every few years where there is cause for concern when either (a) a genetic test has confirmed the risk or (b) a genetic test has not been undertaken for any reason so the actual risk is unknown. Screening and monitoring allow polyposis to be detected visually before it can become life-threatening. • Treatment, typically surgery of some kind, is involved if polyposis has led to a large number of polyps, or a significant risk of cancer, or actual cancer. Family history NCBI states that "Although most individuals diagnosed with an APC-associated polyposis condition have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent." Asymptomatic individuals (and therefore asymptomatic family members) are also known to exist. == Prognosis ==

Prior to reaching the advanced stages of colorectal cancer, the polyps are confined to the inner wall and thickness of the intestinal tract and do not metastasize or 'spread'. So provided FAP is detected and controlled either at the pre-cancerous stage or when any cancerous polyps are still internal to the intestinal tract, surgery has a very high success rate of preventing or removing cancer, without recurrence, since the locations giving rise to cancer are physically removed in toto by the surgery. Following surgery, if a partial colectomy has been performed, colonoscopic surveillance of the remaining colon is necessary as the individual still has a risk of developing colon cancer. However, if this happened, it would be a fresh incident from polyps developing anew in the unremoved part of the colon subsequent to surgery, rather than a return or metastasis of any cancer removed by the original surgery. Desmoid tumors, with their infiltrative nature and potential proximity to vital structures, are the second highest cause of death. ==Epidemiology==

The incidence of the mutation is between 1 in 10,000 and 1 in 15,000 births. By age 35 years, 95% of individuals with FAP (>100 adenomas) 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).{{cite web |url=https://www.lecturio.com/concepts/familial-adenomatous-polyposis/| title=Familial Adenomatous Polyposis Attenuated FAP arises when APC is defective but still somewhat functional. As a result, it retains part of its ability to suppress polyps. Therefore, attenuated FAP manifests as colorectal cancer unusually late (age 40–70, average=55), and typically with few, or at least far fewer polyps (typically 30), than the more usual version of FAP, at an age when FAP is no longer considered much of a likelihood or risk according to usual FAP epidemiology. Comparison of FAP variants This table compares the different subtypes of FAP: == Polyposis registries ==

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 probands. The St. Mark's polyposis registry is the oldest in the world, started in 1924, and many other polyposis registries now exist. == See also ==