Familial adenomatous polyposis
(Redirected from Familial intestinal polyposis)
Familial Adenomatous Polyposis (FAP)[edit | edit source]
Familial Adenomatous Polyposis (FAP) is an autosomal dominant inherited condition characterized by the formation of numerous adenomatous polyps mainly in the epithelium of the large intestine. Although these polyps are initially benign, they can transform into colon cancer if not treated. FAP exists in three known variants: FAP and attenuated FAP are caused by defects in the APC gene on chromosome 5, while autosomal recessive FAP, or MYH-associated polyposis, results from mutations in the MUTYH gene on chromosome 1. FAP is the most severe and common form. Early detection and removal of the polyps can significantly reduce the risk of cancer spreading beyond the colon.
Root Cause[edit | edit source]
The genetic mutation in FAP affects tumor suppressor genes, diminishing the body's defense against aged cells turning cancerous. This alteration allows cells of the intestinal wall to evolve into cancerous polyps over time. Attenuated familial adenomatous polyposis, a less severe form, results from a partially functional APC gene, leading to fewer polyps and a later onset of cancer, typically between 40 and 70 years old. The autosomal recessive variant necessitates both parents to be carriers.
Symptoms and Diagnosis[edit | edit source]
Patients develop hundreds to thousands of polyps in the colon and sometimes other areas, which may bleed or lead to anemia. Advanced cases can lead to weight loss, altered bowel habits, or metastasis. Diagnosis is confirmed through colonoscopy, genetic testing, or observing clinical presentation. It's crucial for at-risk individuals to undergo regular intestinal tract monitoring from puberty or early adulthood.
Genetics[edit | edit source]
FAP's genetics involve mutations in the APC gene or the MUTYH gene, leading to a lack of proper tumor suppression. The APC gene plays a key role in cell communication and growth regulation, while the MUTYH gene is involved in DNA repair. Mutations in these genes disrupt normal cellular functions, increasing cancer risk.
Management[edit | edit source]
Management of FAP includes identifying at-risk individuals through family history or genetic testing, regular monitoring of the intestinal tract, and surgical intervention when necessary. Prophylactic surgery, such as colectomy, is often recommended to prevent colon cancer. Medications, like NSAIDs, may slow polyp malignancy, but surgery is a primary treatment to remove the affected colon sections.
Prognosis[edit | edit source]
Early detection and treatment of FAP significantly improve outcomes. If polyps are confined to the colon's inner wall, surgical removal can prevent cancer spread. Post-surgery, regular monitoring is essential to detect any new polyps in the remaining colon sections.
Epidemiology[edit | edit source]
FAP affects 1 in 10,000 to 1 in 15,000 births. Without treatment, colon cancer is almost inevitable by middle age. The attenuated form of FAP presents fewer polyps and a later onset of cancer, providing different management options.
Comparison of FAP variants[edit | edit source]
Item | FAP | Attenuated FAP | MYH Associated FAP |
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 FAP 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 adenomatous 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 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 [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 FAP | 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 FAP) | ? |
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 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 [Other extra-colonic conditions] | 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 [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 FAP" | ? |
Treatment of manifestations | Classic FAP: "Colectomy is recommended after adenomas emerge; colectomy may be delayed depending on the size and number of adenomatous 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 present. Colectomy usually advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have developed." Sovaria states as at 1998 that "colonoscopy, as opposed to sigmoidoscopy, should be advised for endoscopic surveillance, because of the right-side location of colorectal adenomas; UGI endoscopic surveillance is warranted in an attempt to detect premalignant gastric or duodenal tumors; individuals affected with [attenuated FAP] may require total colectomy with ileo-rectal anastomosis only when prophylactic colectomy is advised" | ? |
Decision to monitor | "Early recognition may allow for timely intervention and improved final outcome; thus, surveillance of asymptomatic, at-risk children for early manifestations is appropriate; genetic testing is more cost effective than sigmoidoscopy in determining who in the family is affected; individuals diagnosed with APC-associated polyposis conditions as a result of having an affected relative have a significantly greater life expectancy than those individuals diagnosed on the basis of symptoms.. As colon monitoring for those at risk for classic FAP begins as early as age ten to 12 years, molecular genetic testing is generally offered to children at risk for classic FAP by age ten years. Genetic testing at birth may also be warranted, as some parents and pediatricians may consider hepatoblastoma screening from infancy to age five years in affected offspring.. No evidence points to an optimal age at which to begin screening." | See FAP. Also "Colon screening for those with attenuated FAP begins at age 18 to 20 years; thus, molecular genetic testing should be offered to those at risk for attenuated FAP at approximately age 18 years." | ? |
Inheritance and implications of confirmed diagnosis for other close relatives | APC-associated polyposis conditions are inherited in an autosomal dominant manner. Approximately 20–25% have the altered gene as the result of a de novo gene mutation. Little or no evidence of maternal/paternal bias, or effect related to advanced paternal age, in de novo mutations. Siblings have classic 50% risk of sharing the condition if inherited and not de novo and a "low" but slightly higher risk than general if de novo, therefore genetic testing should be offered. Offspring each have a 50% chance of inheritance. Other family members are at risk if their parents share the same mutation. Germline mosaicism has been documented in asymptomatic cases. Prenatal testing is possible via fetal extracted DNA. | See FAP | ? |
Polyposis registries[edit | edit source]
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.
Glossary[edit | edit source]
- Adenomatous polyps - Benign growths that may develop into cancer if not removed.
- Autosomal dominant - A pattern of inheritance where a mutation in just one of the two gene copies is sufficient to cause a disorder.
- Chromosome 5 - One of the 23 pairs of human chromosomes, home to the APC gene associated with FAP.
- Chromosome 1 - One of the 23 pairs of human chromosomes, where the MUTYH gene associated with autosomal recessive FAP is located.
- Colonoscopy - A diagnostic procedure to examine the interior of the colon for polyps and cancer.
- Genetic testing - Testing conducted to identify genetic mutations associated with diseases like FAP.
See also[edit | edit source]
External links[edit | edit source]
Classification | |
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External resources |
Familial adenomatous polyposis Resources | |
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