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." in addition around 20% of cases are a de novo mutation, and of those with an apparent de novo apc mutation (i.e. no known family history) 20% have somatic mosaicism. asymptomatic individuals (and therefore asymptomatic family members) are also known to exist. monitoring monitoring involves the provision of outpatient colonoscopy, and occasionally upper gastric tract esophagogastroduodenoscopy (egd, to search for premalignant gastric or duodenal cancers), typically once every 1–3 years, and/or a genetic blood test to definitively confirm or deny susceptibility. a small number of polyps can often be excised (removed) during the procedure if found, but if there are more severe signs or numbers, inpatient surgery may be required. ncbi states that when an individual is identified as having fap, or the mutations resulting in fap: "it is appropriate to evaluate the parents of an affected individual (a) with molecular genetic testing of apc if the disease-causing mutation is known in the proband or (b) for clinical manifestations of apc-associated polyposis conditions". treatment treatment for fap depends on the genotype. most individuals with the apc mutation will develop colon cancer by the age of 40, although the less-common attenuated version typically manifests later in life (40–70). accordingly, in many cases, prophylactic surgery may be recommended before the age of 25, or upon detection if actively monitored. there are several surgical options that involve the removal of either the colon or both the colon and rectum. rectum involved: the rectum and part or all of the colon are removed. the patient may require an ileostomy (permanent stoma where stool goes into a bag on the abdomen) or have an ileo-anal pouch reconstruction. 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 partly or fully removed and the small bowel (ileum) can be directly connected to the rectum instead (ileorectal anastomosis). rectum not involved: the portion of the colon manifesting polyps can be removed and the ends 'rejoined' (partial colectomy), a surgery that has a substantial healing time but leaves quality of life largely intact. prophylactic colectomy is indicated if more than a hundred polyps are present, if there are severely dysplastic polyps, or if multiple polyps larger than 1 cm are present. treatment for the two milder forms of fap may be substantially different from the more usual variant, as the number of polyps is far fewer, allowing more options. various medications are being investigated for slowing malignant degeneration of polyps, most prominently the non-steroidal anti-inflammatory drugs (nsaids). nsaids have been shown to significantly decrease the number of polyps but do not usually alter management since there are still too many polyps to be followed and treated endoscopically. the drug eflornithine, an inhibitor of ornithine decarboxylase typically used to treat trypanosomiasis, is being investigated as a potential preventive medication in combination with the nsaid celecoxib for treatment of fap. another investigational agent is sulindac, also used in combination with nsaids. 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. 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). 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: item fap attenuated fap mutyh associated fap geneapcapcmutyh typical polyp manifestationhundreds / thousandsunder 100 (0–470, typ. 30), sometimes flat rather than polypoid morphology, and more proximal to the splenic flexure. in a study of 120 individuals 37% (n=44) had <10 polyps; 3 of these 44 had colorectal cancer]. gastric fundic polyps and duodenal adenomas are also seen. therefore, polyps and cancers may manifest in the upper portion of the colon or upper gastrointestinal tract rather than the usual locations ? typical core diagnostic criteria(a) 100+ polyps and age under 40, or (b) polyps and fap in a relativenot settled as yet. (a) no family history of 100+ polyps before age 30 plus one of 10–99 polyps / 100+ polyps and aged over 35 to 40 / colorectal cancer before age 60 and relatives with multiple adenomatous polyps, or (b) family history of 10 to 99 adenomas diagnosed after age 30 years ? age at which polyps manifest7–36 (typ. 16), rapidly increasing thereafter ? ? colorectal cancer risk (penetrance) and age if untreated"inevitable.. virtually 100%": 7% by age 21, 87% by age 45, 93% by age 50. typical ages: 34–43 (avg.39)"lower.. less well known.. estimated 70% by age 80". sovaria states as at 1998, "average age at crc diagnosis is ~58 years" ? variabilityinter- and intrafamilial phenotypic variability are commonsee fap ? possible non-colon manifestations"polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (chrpe), soft tissue tumors, desmoid tumors, and associated cancers"as for fap but "chrpe and desmoid tumors are rare" and also thyroid cancer is added. ? other lifetime risks"small bowel carcinoma 4–12% rare; pancreas adenocarcinoma ~1%; papillary thyroid carcinoma 1–2%; cns <1%; liver hepatoblastoma 1.6%; bile ducts adenocarcinoma low but increased; stomach adenocarcinoma <1% in western cultures." ? ? inheritance"inherited in an autosomal dominant manner. approximately 75%-80% of individuals with apc-associated polyposis conditions have an affected parent. offspring of an affected individual are at a 50% risk of inheriting the disease-causing mutation"same as fapdifferent—recessive (requires 2 parents to be carriers) genetic overview and genetic detection"full gene sequencing of all apc exons and intron-exon boundaries appears to be the most accurate clinical test available. most apc mutations are nonsense or frameshift mutations that cause premature truncation of the apc protein.. the likelihood of detecting an apc mutation is highly dependent on the severity of colonic polyposis and on the family history.. ◦approximately 20% of individuals with an apparent de novo apc mutation.. the markers used for linkage analysis of apc-associated polyposis conditions are highly informative and very tightly linked to the apc locus; thus, they can be used with greater than 98% accuracy in more than 95% of families with an apc-associated polyposis condition. linkage testing is not possible for families with a single affected individual, a situation that often occurs when an individual has a de novo gene mutation and no affected offspring.. if no disease causing apc mutation is found, molecular genetic testing of mutyh (see differential diagnosis) should be considered.""fewer than 30% of individuals with attenuated phenotypes are expected to have an identifiable apc mutation" (see also details under fap) ? genotype-phenotype most frequent apc mutation is at codon 1309 and lead to a high number of polyps at an early age (~20). profuse polyposis (avg=5000) reported with mutations in codons 1250–1464. most partial and whole apc deletions are associated with 100–2000 colonic adenomas, although attenuated fap has been seen. sample typical onset ages: between codon 168 and 1580 (excluding 1309) = 30 years, 5' of codon 168 and 3' of codon 1580 = 52 years.attenuated fap is associated with mutations (typically truncating) in the 5' part of the gene (codons 1–177), exon 9, and the distal 3' end of the gene; interstitial deletions of chromosome 5q22 that include apc; partial and whole-gene deletions; and somatic mosaicism for apc mutations that are generally associated with classic fap. sovaria states attenuated fap is "caused by mutations in three distinct regions of the apc gene—the 5′ end in the region spanning exons 4 and 5, exon 9, and the extreme 3′ end. phenotypic expression in these three groups of kindreds is variable but is definitely milder than that in classical fap" and that rectal polyps are rare in attenuated fap but not yet confirmed whether this also means rectal cancer risk is lower as well. ? genotype–phenotype prominent extracolonic manifestations often correlate (though not completely) with more distal apc mutations. general study of fap plus extracolonic symptoms showed: mutations in codons 1395–1493 has significantly higher rates of desmoid tumors, osteomas, and epidermoid cysts than those with mutations in codons 177–452; mutations in codons 1395–1493 have significantly higher rates of desmoid tumors and osteomas than those with mutations in codons 457–1309; no individuals with mutations in codons 177–452 developed osteomas or periampullary cancers; only individuals with mutations in codons 457–1309 developed hepatoblastoma and/or brain tumors. duodenal adenomas: fourfold increased risk with mutations between codons 976 and 1067. desmoid tumors: mutations 3' to codon 1399 were associated with desmoid tumor development with an odds ratio of 4.37; desmoid tumors in 20% of individuals with mutations 5' to codon 1444, 49% of individuals with mutations 3' to codon 1444, and 61% of individuals with mutations in codons 1445–1580; several families with severe desmoid tumors had mutations at the extreme 3' end; consistent association of desmoid tumors with mutations distal to codon 1444. chrpe is associated with: mutations between codons 311 and 1444; whole apc gene deletions. thyroid cancer and fap: in 24 individuals, the majority of mutations identified were 5' to codon 1220 ; 9 of 12 individuals had apc mutations identified proximal to the mutation cluster region (codons 1286–1513). general review of the literature (to august 2006): revealed 89 submicroscopic apc deletions (42 partial and 47 whole-gene deletions). extracolonic findings were seen in 36% of cases, with no significant differences in those with partial vs. whole-gene deletions. ? ? prevalence"2.29 to 3.2 per 100,000