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<unk>  (>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<unk>  arises when APC is defective but still somewhat functional. As a result, it retains part of its ability to suppress polyps. Therefore, attenuated<unk>  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<unk> , at an age when<unk>  is no longer considered much of a likelihood or risk according to usual<unk>  epidemiology. Comparison of<unk>  variants This table compares the different subtypes of<unk> : Item<unk>  Attenuated<unk>  MUTYH Associated<unk>  Gene APC APC MUTYH Typical polyp manifestation Hundreds / thousands Under 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<unk>  in a relative Not 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<unk>  polyps, OR (b) Family history of 10 to 99 adenomas diagnosed after age 30 years ? Age at which polyps manifest 7–36 (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" ? Variability Inter- and intrafamilial phenotypic variability are common See<unk>  ? 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<unk>  but "CHRPE and desmoid tumors are rare" and also thyroid cancer is added. ? Other lifetime risks "Small bowel duodenum or periampulla carcinoma 4–12% distal to duodenum Rare; Pancreas Adenocarcinoma ~1%; Papillary thyroid carcinoma 1–2%; CNS typ. medulloblastoma <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<unk>  Different—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<unk>  ? Genotype-Phenotype Core condition 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<unk>  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<unk>  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<unk> . Sovaria states attenuated<unk>  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<unk> " and that rectal polyps are rare in attenuated<unk>  but not yet confirmed whether this also means rectal cancer risk is lower as well. ? Genotype–Phenotype Other extra-colonic conditions Prominent extracolonic manifestations often correlate (though not completely) with more distal APC mutations. General study of<unk>  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<unk> : In 24 individuals, the majority of mutations identified were 5' to codon 1220 Cetta et al. 2000; 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 individuals.. APC-associated polyposis conditions historically accounted for about 0.5% of all colorectal cancers; this figure is declining as more at-risk family members undergo successful treatment following early polyp detection and prophylactic colectomy." "Likely underdiagnosed, given the lower number of colonic polyps and lower risk for colorectal cancer compared to classic<unk> " ? Treatment of manifestations Classic<unk> : "Colectomy is recommended after adenomas emerge; colectomy may be delayed depending on the size and number of<unk>  polyps. Colectomy is usually advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have developed" "Colectomy may be necessary, but in approximately one third of individuals the colonic polyps are limited enough in number that surveillance with periodic colonoscopic polypectomy is sufficient" ? Surveillance (monitoring) activities once risk is established "Sigmoidoscopy or colonoscopy every 1–2 years, beginning at age ten to 12 years; colonoscopy, once polyps are detected; annual colonoscopy, if colectomy is delayed more than a year after polyps emerge (Age ten to 20 years with certain milder symptoms, delay in colectomy may be considered); Esophagogastroduodenoscopy (EGD) by age 25 years or prior to colectomy and repeated every 1–3 years; in some cases, endoscopic retrograde cholangiopancreatography (ERCP) to evaluate for adenomas of the common bile duct; small-bowel imaging when duodenal adenomas are detected or prior to colectomy, repeated every 1–3 years depending on findings; screening for hepatoblastoma (optimal interval unknown, one paper recommends "at least every three months"); annual physical examination, including evaluation for extraintestinal manifestations, and palpation of the thyroid with consideration of follow-up ultrasound examination and fine-needle aspiration if thyroid nodules are present" "Colonoscopy every two to three years, beginning at age 18 to 20 years; esophagogastroduodenoscopy (EGD) beginning by age 25 years or prior to colectomy and repeated every 1–3 years; in some cases, endoscopic retrograde cholangiopancreatography (ERCP) may be necessary to evaluate for adenomas of the common bile duct; annual physical examination with palpation of the thyroid with consideration of follow-up ultrasound examination and fine-needle aspiration if thyroid nodules are
Familial adenomatous polyposis
Hereditary nonpolyposis colorectal cancer
Juvenile polyposis syndrome
MUTYH-associated polyposis
Serrated polyposis syndrome
Pseudopolyps
Ogden syndrome
Polymerase proofreading-associated polyposis