DiagnosisClinical DiagnosisThe APC-associated polyposis conditions include: (1) the overlapping, often indistinguishable phenotypes of familial adenomatous polyposis (FAP), Gardner syndrome, and Turcot syndrome and (2) attenuated FAP, which has a lower colonic polyp burden and lower cancer risk:Familial adenomatous polyposis (FAP) is diagnosed clinically in an individual with one of the following:One hundred or more colorectal adenomatous polyps
Note: (1) The diagnosis of FAP is generally considered in individuals with polyposis occurring before age 40 years. (2) The presence of 100 or more colorectal polyps is not specific to FAP; genetic testing of APC may help distinguish FAP from MUTYH-associated polyposis (MAP) (see Differential Diagnosis) or colonic polyposis conditions of unknown etiology. Fewer than 100 adenomatous polyps and a relative with FAPGardner syndrome is the association of colonic adenomatous polyposis, osteomas, and soft tissue tumors (epidermoid cysts, fibromas, desmoid tumors) [Gardner & Richards 1953].Turcot syndrome is the association of colonic adenomatous polyposis and CNS tumors, usually medulloblastoma.Attenuated FAP is considered in an individual with one of the following:Ten to 99 colonic adenomatous polyps
Note: Individuals with 100 or more polyps occurring at “advanced” ages (35 to 40 years or older) may be found to have attenuated FAP.A personal history of colorectal cancer before age 60 years and a family history of multiple adenomatous polypsCurrently, there is no consensus regarding the exact diagnostic criteria to be used for attenuated FAP. Nielsen et al [2007b] proposed the following diagnostic criteria for attenuated FAP:No family member with more than 100 polyps before age 30 years
ANDAt least two individuals with 10 to 99 adenomas diagnosed after age 30 years
OROne individual with 10 to 99 adenomas diagnosed after age 30 years and a first-degree relative with colorectal cancer with a few adenomasNote: (1) This proposed definition takes into account the variability in colonic phenotype seen in attenuated FAP (i.e., some individuals may have ≥100 polyps at a later age, although most have <100 polyps) [Burt et al 2004]. (2) One limitation in the proposed criteria is that they do not take into account APC mutation status: a significant proportion of persons with polyposis who do not have an identified APC mutation are found to have biallelic MUTYH mutations and therefore should be classified as having MUTYH-associated polyposis (see Differential Diagnosis).Knudsen et al [2010] proposed the following diagnostic criteria for attenuated FAP:Dominant mode of inheritance of colorectal adenomatosis
ANDFewer than 100 colorectal adenomas at age 25 years or olderNote: The criteria proposed by Knudsen and colleagues for attenuated FAP have several limitations: (1) they do not take into account APC mutation status; (2) they do not define how many polyps are needed for colorectal adenomatosis; (3) a dominant mode of inheritance may not be evident from the family history, given that 20%-25% of persons with an APC-associated polyposis condition represent simplex cases (i.e., a single occurrence in a family). Variable features not included in the diagnostic criteria of an APC-associated polyposis condition but potentially helpful in establishing the clinical diagnosis include: gastric polyps, duodenal adenomatous polyps, osteomas, dental abnormalities (especially supernumerary teeth and/or odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors (specifically epidermoid cysts and fibromas), desmoid tumors, and associated cancers.Molecular Genetic TestingGene. APC is the gene in which mutations cause APC-associated polyposis conditions.Clinical testingFull gene sequencing of all APC exons and intron-exon boundaries appears to be the most accurate clinical test available to detect APC mutations [Giardiello et al 2001]. 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: Individuals with a classic FAP phenotype are significantly more likely to have an APC mutation than individuals with a less severe colonic phenotype (i.e., <100 polyps) [Sieber et al 2002, Aretz et al 2005, Michils et al 2005, Aretz et al 2006].Fewer than 30% of individuals with attenuated phenotypes are expected to have an identifiable APC mutation [Lefevre et al 2006].Approximately 20% of individuals with an apparent de novo APC mutation (i.e. no family history of an affected individual) have somatic mosaicism [Hes et al 2007].
Note: In individuals with somatic mosaicism, sequencing of APC in DNA extracted from peripheral blood lymphocytes may fail to detect disease-causing mutations because of weak mutation signals [Aretz et al 2007, Hes et al 2007]. This, in part, may explain the lower mutation detection rate in simplex cases (i.e., a single occurrence in a family) than in persons with an affected parent.Protein truncation testing, which is positive in approximately 80% of individuals with classic FAP [Powell et al 1993], has largely been replaced by more sensitive whole-gene sequencing techniques.Duplication/deletion analysis. Methods commonly used to detect partial and whole-gene deletions or other large rearrangements include Southern blot analysis, multiplex ligation-dependent probe amplification (MLPA), and quantitative PCR. Approximately 8%-12% of individuals with an APC-associated polyposis condition and 100 or more polyps have a partial or whole APC deletion [Sieber et al 2002, Bunyan et al 2004, Aretz et al 2005, Michils et al 2005]. In one study, 19 of 296 (6%) individuals with ten or more adenomatous polyps who had no mutations in MUTYH (see Differential Diagnosis) or APC using sequencing, protein truncation testing, and denaturing gradient gel electrophoresis (a type of mutation scanning) had a large APC deletion detected by MLPA [Nielsen et al 2007b].
Interstitial deletions of chromosome 5q that include APC have been identified on routine chromosome analysis in several individuals with colonic polyposis and intellectual disability [Heald et al 2007]. In at least one individual, array comparative genomic hybridization (array CGH) detected a deletion that was not visible on routine cytogenetic studies [Heald et al 2007].
Note: Cytogenetic analysis and/or array CGH may be pursued when adenomatous polyposis is accompanied by developmental delay. Array CGH has been used to determine if APC is within cytogenetically visible chromosomal deletions that are close to APC [Wallerstein et al 2007]. Linkage analysis. When no disease-causing mutation is identified in an affected individual, linkage analysis can be considered in families with more than one affected family member belonging to different generations. Linkage studies are based on an accurate clinical diagnosis of an APC-associated polyposis condition in the affected family members and accurate understanding of genetic relationships in the family. Linkage analysis is dependent on the availability and willingness of family members to be tested. 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 [Petersen et al 1991, Burt et al 1992]. 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.Table 1. Summary of Molecular Genetic Testing Used in APC-Associated Polyposis ConditionsView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1, 2Test Availability APCSequence analysisSequence variants 3≤90% 4ClinicalDuplication / deletion analysis 5Duplication / deletion of one or more exons or the whole gene~8%-12% 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Detection rates are higher in classic polyposis than in attenuated colonic phenotypes [Sieber et al 2002, Aretz et al 2005, Michils et al 2005, Aretz et al 2006] and in individuals with a family history of polyposis than in those without affected family members in the previous generation [Truta et al 2005, Aretz et al 2007, Hes et al 2007].3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Giardiello et al [2001]5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Sieber et al [2002], Bunyan et al [2004], Aretz et al [2005], Michils et al [2005]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandIn individuals meeting the diagnostic criteria for FAP or individuals suspected of having an APC-associated polyposis condition, sequence analysis and duplication/deletion analysis of APC are performed.If no disease causing APC mutation is found, molecular genetic testing of MUTYH (see Differential Diagnosis) should be considered.Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family. Note: If no alteration in APC is identified in a family with more than one affected relative belonging to different generations, linkage analysis can be considered.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersDeletion 5q22. Interstitial deletions of chromosome 5q22 that include APC have been reported in individuals with attenuated adenomatous polyposis [Pilarski et al 1999] and classic adenomatous polyposis [Heald et al 2007]. In all reports, such individuals have had cognitive impairment, usually in the mild-to-moderate range; the majority have dysmorphic features [Heald et al 2007].}

Natural HistoryAPC-associated polyposis conditions include classic FAP, the two overlapping phenotypes Gardner syndrome and Turcot syndrome, and attenuated FAP.Classic FAPColorectal adenomatous polyps begin to appear, on average, at age 16 years (range 7-36 years) [Petersen et al 1991]. By age 35 years, 95% of individuals with classic FAP have polyps. Once they appear, the polyps rapidly increase in number; when colonic expression is fully developed, hundreds to thousands of colonic adenomatous polyps are typically observed. Without colectomy, colon cancer is inevitable. The average age of colon cancer diagnosis in untreated individuals is 39 years (range 34-43 years). Seven percent of untreated individuals with FAP develop colon cancer by age 21 years, 87% by 45 years, and 93% by 50 years [Bussey 1975]. Although rare, asymptomatic individuals in their 50s have been reported [Evans et al 1993]. Inter- and intrafamilial phenotypic variability are common [Giardiello et al 1994, Rozen et al 1999].Other Features Variably Present in FAPTable 2. Lifetime Risk for Extracolonic Cancer in FAPView in own windowSiteType of CancerLifetime Risk for CancerSmall bowel: duodenum or periampullaCarcinoma4%-12%Small bowel: distal to the duodenumRarePancreasAdenocarcinoma~1%ThyroidPapillary thyroid carcinoma1%-2%CNSUsually medulloblastoma<1%LiverHepatoblastoma1.6% Bile ductsAdenocarcinomaLow, but increasedStomachAdenocarcinoma<1% in Western culturesSmall-bowel polyps and cancer. Adenomatous polyps of the duodenum, observed in 50%-90% of individuals with FAP, are commonly found in the second and third portions of the duodenum [Kadmon et al 2001] and less frequently in the distal small bowel [Wallace & Phillips 1998]. A classification system for duodenal polyps, based on number and size of polyps, histology, and degree of dysplasia, has been developed [Spigelman et al 1989]. No clear association between the number of colonic polyps and the number of upper gastrointestinal polyps has been identified [Kadmon et al 2001]. Adenomatous polyps of the periampullary region (including the duodenal papilla and ampulla of Vater) are seen in at least 50% of individuals with classic FAP. Polyps in this area can cause obstruction of the pancreatic duct resulting in pancreatitis or biliary obstruction, both of which occur at increased frequency in FAP. These polyps are often small and require a side-viewing endoscope for visualization. Some theorize that pancreaticobiliary secretions (e.g., bile) affect the development of adenomas [Wallace & Phillips 1998], and may account for the observed increased risk for malignancy of polyps in the periampullary region [Kadmon et al 2001].Duodenal adenocarcinoma occurs most commonly in the periampullary area. It has been reported to occur between ages 17 and 81 years, with the mean age of diagnosis between 45 and 52 years [Wallace & Phillips 1998, Kadmon et al 2001]. The lifetime risk for small bowel malignancy is 4%-12%; the majority occurs in the duodenum. Small-bowel cancer distal to the duodenum occurs but is rare. Ruys et al [2010] identified only 17 cases of jejunal carcinoma and three cases of ilieal carcinoma in individuals with FAP reported in the literature [Ruys et al 2010]. Pancreatic cancer. Although limited data exist, one study of 197 families with FAP revealed a relative risk for pancreatic cancer of 4.5 in individuals with FAP and their at-risk relatives compared to the general population risk. The lifetime pancreatic cancer risk to age 80 in individuals with FAP was estimated to be 1% [Giardiello et al 1993].Thyroid cancer. Thyroid cancers affect approximately 1%-2% of individuals with FAP [Cetta et al 2000, Truta et al 2003]. Familial occurrence and a female preponderance have been observed. In one small series of females with FAP, the prevalence was 12% [Herraiz et al 2007]. Papillary histology predominates and may commonly have a cribriform pattern.CNS. See Turcot syndrome.Hepatoblastoma. The risk for hepatoblastoma in FAP is 750 to 7500 times higher than in the general population, although the absolute risk is estimated at less than 2% [Aretz et al 2007]. The majority of hepatoblastomas occur prior to age three years [Aretz et al 2007].Gastric polyps and cancer. Gastric polyps can be either fundic gland or adenomatous [Bülow et al 1995]:Gastric fundic gland polyps (hamartomatous tumors located in the fundus and body of the stomach) occur in approximately half of individuals with FAP [Offerhaus et al 1999]. For a complete review of gastric fundic gland polyps and their relationship to FAP and attenuated FAP, see Burt [2003].Adenomatous polyps, the second most prevalent gastric lesion in individuals with FAP [Bülow et al 1995, Wallace & Phillips 1998], are usually confined to the gastric antrum [Offerhaus et al 1999].The risk for gastric cancer in individuals with FAP living in Western cultures is low, although it has been reported [Offerhaus et al 1999, Garrean et al 2008]. The rates of gastric cancer in persons of Japanese and Korean heritage with FAP may be tenfold higher than the general population [Garrean et al 2008]. Gastric adenocarcinoma is believed to arise most often from adenomas but may also develop from fundic gland polyps [Zwick et al 1997, Hofgartner et al 1999, Attard et al 2001].Extraintestinal ManifestationsOsteomas are bony growths found most commonly on the skull and mandible; however, they may occur in any bone of the body. Osteomas do not usually cause clinical problems and do not become malignant; they may appear in children prior to the development of colonic polyps.Dental abnormalities. Unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts (an odontogenic cyst associated with the crown of an unerupted tooth), and odontomas have been reported in approximately 17% of individuals with FAP compared to 1%-2% of the general population [Brett et al 1994].Congenital hypertrophy of the retinal pigment epithelium (CHRPE) refers to discrete, flat, pigmented lesions of the retina that are not age dependent and do not cause clinical problems. Visualization of CHRPE may require examination of the ocular fundus with an indirect ophthalmoscope through a dilated pupil. Observation of multiple or bilateral CHRPE may be an indication that an at-risk family member has inherited FAP, whereas isolated lesions may be seen in the general population [Chen et al 2006].Benign cutaneous lesions include epidermoid cysts and fibromas that may be found on any part of the body, including the face. They are mainly of cosmetic concern, as they do not appear to have malignant potential. Multiple pilomatricomas, although rare, have also been reported [Pujol et al 1995].Desmoid tumors develop in approximately 10%-30% of individuals with FAP [Sinha et al 2011, Nieuwenhuis et al 2011b]. The risk for desmoid tumors in individuals with FAP is more than 800 times the risk in the general population [Nieuwenhuis et al 2011a]. At least 7.5% of desmoid type fibromatoses are found in people with FAP [Nieuwenhuis et al 2011a]. These poorly understood, benign fibrous tumors are clonal proliferations of myofibroblasts that are locally invasive but do not metastasize [Clark et al 1999]. A pathologically distinct fibromatous lesion called a Gardner-associated fibroma (GAF) is hypothesized to be a precursor lesion [Wehrli et al 2001].The incidence of desmoid tumors in FAP is highest in the second and third decades of life, with 80% occurring by age 40 [Sinha et al 2011]. Approximately 65% of desmoid tumors in individuals with FAP occur within the abdomen or in the abdominal wall [Sinha et al 2011]. Desmoid tumors may compress abdominal organs or complicate abdominal surgery. About 5% of individuals with FAP experience morbidity and/or mortality from desmoid tumors, with the highest mortality rate reported for intra-abdominal tumors [Sinha et al 2011]. Abdominal desmoid tumors may occur spontaneously or following abdominal surgery [Bertario et al 2001]. The effect of pregnancy on desmoid tumor growth or development is unknown [Sinha et al 2011]. Independent predictors for desmoid tumor development include: an APC mutation 3' of codon 1399, family history of desmoid tumors, female gender, and previous abdominal surgery [Sinha et al 2011]. Positive family history of desmoid tumor was associated with the highest magnitude of risk; having a first-degree relative with a desmoid tumor was associated with a sevenfold increase in risk [Sinha et al 2011]. Desmoid tumors are best evaluated by CT scan [Clark & Phillips 1996] or MRI. A CT scoring system for desmoid tumors in FAP has been developed [Middleton et al 2003].Adrenal masses are reportedly two to four times more prevalent in FAP than in the general population [Rekik et al 2010]. Adrenal masses are found in 1%-3% of the general population; a retrospective analysis identified adrenal masses in 7.4% of individuals with FAP [Marchesa et al 1997], and a prospective study of 107 individuals with FAP found 13% with an adrenal mass greater than or equal to 1.0 cm on abdominal CT scan [Smith et al 2000b]. Most of the masses are asymptomatic adenomas found incidentally, although functional lesions and carcinomas do occur [Marchesa et al 1997, Rekik et al 2010].Pregnancy/hormone use. Limited information is available on the effect of pregnancy on females with FAP. In one study of 58 Danish women with FAP, the same frequency of fertility, pregnancy, and delivery was observed as in a control population [Johansen et al 1990]. A larger study of 162 women with FAP compared fertility rates before and after two types of colorectal surgery with a control population. Women with FAP who had not yet undergone surgery had the same fertility as a control population of normal women. Additionally, those women with FAP who had a colectomy with ileorectal anastomosis (IRA) had the same fertility as the control population. Fertility was significantly reduced in women with FAP who had a proctocolectomy with ileal pouch-anal anastomosis (IPAA) compared to the control population [Olsen et al 2003]. In another study, the prevalence of self-reported fertility problems was similar among individuals with FAP who had undergone IRA, IPAA, or proctocolectomy with ileostomy [Nieuwenhuis et al 2010]. However, those who had their first surgical procedure at a younger age had more postoperative fertility problems [Nieuwenhuis et al 2010]. Little evidence supports an association between desmoid tumor development or growth and pregnancy [Sinha et al 2011].Women who have undergone colectomy are considered to have the same risk for obstetric complications as any other woman who has had major abdominal surgery.As anti-estrogen medications have been successfully used in the treatment of desmoid tumors, the development of desmoid tumors is thought to be affected by hormones important in pregnancy. However, one study has shown that women who had a previous pregnancy and developed a desmoid tumor had significantly fewer complications from the desmoid tumor than those who had never had a pregnancy [Church & McGannon 2000].In a study of women with FAP at the time of their colectomy, no association was found between pregnancy history and colonic polyp severity; however, the proportion of parous women with severe duodenal disease was significantly higher than the proportion of nulliparous women [Suraweera et al 2007].Some studies have suggested that female hormones protect against colorectal cancer development in the general population. In one woman, reduction in polyps after use of oral contraceptives was observed [Giardiello et al 2005].Gardner SyndromeGardner syndrome (GS) is the association of colonic adenomatous polyposis of classic FAP with osteomas and soft tissue tumors (epidermoid cysts, fibromas, desmoid tumors) [Gardner & Richards 1953]. When these findings are prominent, many clinicians continue to use the term Gardner syndrome. However, they can occur in any individual with FAP, whether or not other extraintestinal findings are present.Gardner syndrome was once thought to be a distinct clinical entity; however, it is now known that mutations in APC give rise to both classic FAP and Gardner syndrome. Other manifestations of FAP, such as upper gastrointestinal polyposis, are also found in Gardner syndrome. Some correlation exists between extraintestinal growths and mutation location in APC. See Genotype-Phenotype Correlations.Turcot SyndromeTurcot syndrome is the association of colonic polyposis or colorectal cancer and CNS tumors. The molecular basis of most Turcot syndrome is either a mutation in APC associated with FAP or a mutation in one of the mismatch repair genes associated with Lynch syndrome [Hamilton et al 1995]. The CNS tumors in individuals with APC mutations are typically medulloblastoma, whereas those with mismatch repair mutations are usually glioblastoma multiforme. The risk for CNS tumors is substantially increased in persons with FAP, although the absolute risk is only approximately 1%. Families with APC-associated polyposis conditions in which multiple individuals have CNS tumors raise the possibility of mutation specificity or modifying genes. Similar to Gardner syndrome, Turcot syndrome was once thought to be a distinct clinical entity, however, it is now assumed that all individuals with an APC mutation are at increased risk for brain tumors, albeit a relatively low lifetime risk. Attenuated FAPAttenuated FAP is characterized by fewer colonic polyps (average of 30) than classic FAP but a significant risk for colorectal cancer. Polyps tend to be found more proximally in the colon than in classic FAP.The exact lifetime risk for colorectal cancer in attenuated FAP is unclear; the cumulative risk by age 80 years is estimated to be approximately 70% [Neklason et al 2008]. The average age of colon cancer diagnosis in individuals with attenuated FAP is 50 to 55 years — ten to 15 years later than in those with classic FAP, but earlier than in those with sporadically occurring colon cancer [Spirio et al 1993, Giardiello et al 1997].In two large kindreds with attenuated FAP and an identical APC germline mutation [Burt et al 2004, Neklason et al 2008]:The median number of adenomatous polyps in 120 mutation-positive individuals was 25 (range 0-470).Forty-four of 120 (~37%) mutation-positive individuals with detailed colonoscopy records available had fewer than ten adenomatous polyps.Three of the 44 mutation-positive individuals with fewer than ten polyps had colorectal cancer; one of the three was diagnosed before age 30 years.Additional findings in attenuated FAP can include the following:Upper gastrointestinal polyps and cancersExtraintestinal manifestations of FAP; however, CHRPE and desmoid tumors are rare [Burt 2003, Knudsen et al 2003, Burt et al 2004].Thyroid cancer [Truta et al 2003, Burt et al 2004]

Genotype-Phenotype CorrelationsAlthough variation occurs among and within individuals and among and within families with identical APC mutations [Giardiello et al 1994, Friedl et al 2001], much effort has gone into making genotype-phenotype correlations. Some have suggested basing management strategies on these associations [Vasen et al 1996], whereas others feel that therapeutic decisions should not be based on genotype [Friedl et al 2001].While not in routine use at present, the following correlations may become important in management decisions in the future (see Table 3 for reference sequences for mutations discussed in this section):The most frequent APC mutation is located at codon 1309 (c.3927_3931delAAAGA) [Friedl & Aretz 2005]. Mutations at this codon lead to a high number of colonic adenomas at an early age [Friedl et al 2001, Bertario et al 2003].The average age of onset in individuals with colonic symptoms [Friedl et al 2001] varied by mutation location:At codon 1309: age 20 yearsBetween codon 168 and 1580 (excluding 1309): age 30 years5' of codon 168 and 3' of codon 1580: age 52 yearsProfuse polyposis (an average of 5000 polyps) has been reported with mutations in codons 1250-1464 [Nagase et al 1992].Attenuated FAP is associated with the following:Mutations (usually truncating mutations) in the 5' part of the gene (codons 1-177) [Sieber et al 2006], exon 9 [van der Luijt et al 1995, Soravia et al 1998, Sieber et al 2006], and the distal 3' end of the gene [Friedl et al 1996, van der Luijt et al 1996, Walon et al 1997, Sieber et al 2006]Interstitial deletions of chromosome 5q22 that include APC [Pilarski et al 1999]Partial and whole-gene deletions [Nielsen et al 2007a]Somatic mosaicism for APC mutations that are generally associated with classic FAP [Friedl & Aretz 2005, Aretz et al 2007, Hes et al 2007]A fourfold increased risk for duodenal adenomas was found in individuals with mutations between codons 976 and 1067 in one study of Italian individuals with FAP [Bertario et al 2003].Prominent extracolonic manifestations often correlate (though not completely) with more distal APC mutations. A retrospective study of 190 individuals with FAP that evaluated nine extracolonic manifestations (desmoid tumors, osteomas, epidermoid cysts, duodenal adenomas, gastric polyps, hepatoblastoma, dental anomalies, periampullary cancers, and brain tumors) [Wallis et al 1999] revealed that:Individuals with mutations in codons 1395-1493 have significantly higher rates of desmoid tumors, osteomas, and epidermoid cysts than those with mutations in codons 177-452;Individuals with 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.Desmoid tumors show the following correlations:After reviewing combined data on 2098 individuals with FAP, Sinha et al [2011] found that APC mutations 3’ to codon 1399 were associated with desmoid tumor development with an odds ratio of 4.37. A study of 269 individuals with identifiable APC mutations found 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 [Friedl et al 2001].Several families with severe desmoid tumors with mutations at the extreme 3' end of the gene have been reported [Eccles et al 1996, Scott et al 1996, Couture et al 2000].Nieuwenhuis & Vasen [2007] revealed a consistent association of desmoid tumors with mutations distal to codon 1444.CHRPE is associated with:Mutations between codons 311 and 1444 [Nieuwenhuis & Vasen 2007];Whole APC gene deletions [Aretz et al 2005].In individuals with thyroid cancer and FAP:In 24 individuals, the majority of mutations identified were 5' to codon 1220 [Cetta et al 2000];Nine of 12 individuals had APC mutations identified proximal to the mutation cluster region (codons 1286-1513) [Truta et al 2003].A review of the literature up to August 2006 and a report of additional cases by Nielsen et al [2007a] revealed 89 submicroscopic APC deletions (42 partial and 47 whole-gene deletions). Most partial and whole APC deletions are associated with 100-2000 colonic adenomas, although attenuated FAP has been seen [Nielsen et al 2007a]. Extracolonic findings were seen in 36% of cases, with no significant differences in those with partial vs. whole-gene deletions [Nielsen et al 2007a].

Differential DiagnosisAPC-associated polyposis conditions may be distinguished from other inherited colon cancer conditions and other gastrointestinal polyposis syndromes by molecular genetic testing, histopathologic findings, and phenotypic characteristics. Hereditary disorders to consider in the differential diagnosis include the following:MUTYH-associated polyposis (MAP). The colonic phenotype of MAP is similar to attenuated FAP but is inherited in an autosomal recessive manner. Germline biallelic mutations in MUTYH predispose individuals to multiple adenoma or polyposis coli. If an APC mutation is not identified in an individual with colonic polyposis, molecular genetic testing of MUTYH should be considered [Sieber et al 2003].
Biallelic MUTYH mutations have been found in a few individuals diagnosed with colorectal cancer at age 50 years or younger who have had few or no polyps [Wang et al 2004]. The frequency of duodenal polyposis is between 4% and 25% among individuals with biallelic MUTYH mutations; extraintestinal findings are also noted on occasion [Aretz et al 2006].
In one study of individuals with polyposis without an identified APC mutation, the detection rate of MUTYH mutations varied by the colonic severity [Aretz et al 2006]; biallelic MUTYH mutations were found in:Forty of 227 (18%) individuals diagnosed with ten to 100 polyps after age 25 years or more than 100 polyps after age 45 years;Seven of 26 (27%) individuals with more than 100 polyps diagnosed between ages 35 and 45 years;None of 41 individuals with more than 100 polyps diagnosed before 35 years of age;One individual with approximately 1,000 polyps diagnosed at age 68 years.Lynch syndrome (hereditary non-polyposis colon cancer; HNPCC), primarily caused by a heterozygous germline mutation in one of four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2), is characterized by an increased risk for colorectal cancer and other cancers (e.g., of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, skin). It may be difficult to distinguish between Lynch syndrome and attenuated FAP in individuals with early-onset colorectal cancer and few adenomatous colonic polyps [Cao et al 2002]. In this situation, family history of extracolonic cancers and manifestations as well as microsatellite instability (MSI) testing and/or immunohistochemistry (IHC) testing on a tumor block from a cancer may be helpful in deciding which condition is more likely.
Biallelic mutations in the mismatch repair genes, although rare, have been reported. Affected individuals frequently have brain tumors, hematologic malignancies, and/or colorectal or other Lynch syndrome cancers in childhood [De Vos et al 2005, Felton et al 2007]. Café-au-lait spots and/or axillary/inguinal freckling are seen in most individuals, and multiple colorectal adenomas mimicking attenuated FAP may also be present [Felton et al 2007, Jasperson et al 2010].Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal Peutz-Jeghers type polyps and mucocutaneous pigmentation, neither of which are present in APC-associated polyposis conditions. PJS polyps are often symptomatic and most prevalent in the small intestine (jejunum, ileum, and duodenum, respectively) but can occur elsewhere in the gastrointestinal tract. PJS is inherited in an autosomal dominant manner. Molecular genetic testing of STK11 reveals disease-causing mutations in most cases.PTEN hamartoma tumor syndrome (PHTS). Cowden syndrome (CS), the most common presentation of PHTS, is associated with multiple colorectal polyps, although unlike APC-associated polyposis conditions, hamartomatous polyps (juvenile polyps, lipomas and ganglioneuromas) predominate and colon cancer is an uncommon finding. The only other shared feature between CS and the APC-associated polyposis conditions is an increased risk for thyroid cancer. Approximately 80% of individuals who meet the diagnostic criteria for CS have a detectable PTEN mutation.Juvenile polyposis syndrome (JPS) is characterized by predisposition for hamartomatous polyps, which is often the distinguishing feature between the APC-associated polyposis conditions and JPS. The hamartomatous polyps occur in the GI tract, specifically in the stomach, small intestine, colon, and rectum. Most individuals with JPS have some polyps by age 20 years. Some individuals may have only four or five polyps over their lifetime; others in the same family may have more than 100. Most juvenile polyps are benign; however, malignant transformation can occur. JPS is inherited in an autosomal dominant manner. Approximately 20% of individuals with JPS have SMAD4 mutations, while 20% have BMPR1A mutations; none have been found to have APC mutations. Hereditary mixed polyposis syndrome (HMPS) is associated with an increased risk for colorectal tumors including juvenile polyps, adenomatous polyps, hyperplastic polyps, polyps containing mixed histology, and carcinomas. A locus associated with HMPS has been mapped to 15q13-q14 [Jaeger et al 2003]. HMPS appears to be inherited in an autosomal dominant manner.Neurofibromatosis type 1 (NF1). Individuals with NF1 may exhibit multiple intestinal polypoid neurofibromas or ganglioneuromas in the small bowel, stomach, and colon.Acquired conditions to be considered in the differential diagnosis include the following:Cronkhite-Canada syndrome, characterized by generalized gastrointestinal hamartomatous polyposis, cutaneous hyperpigmentation, hair loss, and nail atrophyNodular lymphoid hyperplasia, a lymphoproliferative disorder resulting in hyperplastic lymphoid nodules in small bowel, stomach, and colon; may be associated with common variable immunodeficiency syndromeLymphomatous polyposis, characterized by occurrence of primary extranodal lymphomas in the gastrointestinal tract. Two types include multiple lymphomatous polyposis and Mediterranean-type lymphoma.Inflammatory polyposis, characterized by acquired, non-neoplastic polyps associated with inflammatory bowel disease, most commonly ulcerative colitisSporadic colorectal tumors. The majority of colorectal tumors not known to be familial have been associated with a somatic mutation in APC [Miyoshi et al 1992, Powell et al 1992, Smith et al 1993] that is believed to occur early in colorectal tumorigenesis [Fearon & Vogelstein 1990].Other:Serrated polyposis (previously termed hyperplastic polyposis), comprising multiple colorectal serrated polyps (hyperplastic polyps, sessile serrated adenomas/polyps and traditional serrated adenomas). It is unknown whether this condition is inherited or acquired [Snover et al 2010]. Although serrated polyps typically predominate, individuals with serrated polyposis frequently have multiple colorectal adenomas [Kalady et al 2011]. Individuals with serrated polyposis may also have a family history of colorectal cancer, although it is uncommon for more than one member of a family to meet the diagnostic criteria for serrated polyposis. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with an APC-associated polyposis condition, the following evaluations are recommended:Personal medical history with particular attention to features of APC-associated polyposis (colon cancer, colon polyps, rectal bleeding, diarrhea, abdominal pain)Family history with particular attention to features of APC-associated polyposisPhysical examination with particular attention to extraintestinal manifestations of APC-associated polyposisOphthalmologic evaluation for presence of congenital hypertrophy of the retinal pigment epithelium (CHRPE) (optional)Colonoscopy with review of pathologyConsideration of upper GI tract evaluation, including endoscopy with a side-viewing scope; if symptomatic, small-bowel imaging such as small-bowel enteroclysis (an x-ray that looks at how contrast moves through the area) or abdominal and pelvic CT with contrastNote: Smith et al [2000b] and Ferrández et al [2006] found no evidence to warrant screening for adrenal masses in FAP.Treatment of ManifestationsColonic polyps. Practice parameters, including information on surgery, have been outlined by the National Comprehensive Cancer Network (NCCN) [Burt et al 2010; click for full text], the American Society of Colon and Rectal Surgeons [Church et al 2003b; click for full text], the American Society of Clinical Oncology (), and the Society of Surgical Oncology [Guillem et al 2006].For individuals with 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. For individuals with attenuated FAP, 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 (see Surveillance).Types of colectomy include the following:Restorative proctocolectomyProctocolectomy with ileal pouch anal anastomosisStapled anastomosis without mucosectomy
ORMucosectomy with handsewn anastomosisTotal colectomy with ileorectal anastomosis; often used for individuals with attenuated FAP or in instances in which the rectum is spared of polypsTotal proctocolectomy with permanent ileostomy
Note: This procedure is rarely needed.A study of individuals with FAP and ileal pouches found that 57% had adenomatous polyps in the ileal pouch. No apparent relationship between the development of pouch adenomas and the severity of polyps in the colon or duodenum was found [Groves et al 2005].Cancer in the surgical transition zone has been reported [Ooi et al 2003] but very rarely occurs.Small-bowel polyps. Endoscopic or surgical removal of duodenal and/or ampullary adenomas should be considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms [Wallace & Phillips 1998, Saurin et al 1999, Kadmon et al 2001].Pancreaticoduodenectomy (Whipple procedure) may occasionally be necessary to treat severe duodenal adenomas.Osteomas may be removed for cosmetic reasons.Desmoid tumors. Available treatments include surgical excision (associated with high rates of recurrence), nonsteroidal anti-inflammatory drugs (NSAIDs), anti-estrogens, cytotoxic chemotherapy, and radiation [Griffioen et al 1998, Clark et al 1999, Smith et al 2000a, Tonelli et al 2003, Gega et al 2006]. A review of desmoid treatments can be found in Guillem et al [2006].Nonsteroidal anti-inflammatory drugs (NSAIDs), especially sulindac [Steinbach et al 2000, Higuchi et al 2003, Keller & Giardiello 2003], have been shown to cause regression of adenomas in FAP and to decrease the number of polyps requiring ablation in the remaining rectum of individuals who have had a colectomy with ileorectal anastomosis. Withdrawal from the market of rofecoxib in 2005 because of untoward cardiovascular and cerebrovascular events and the observation that similar events occur with the doses of celecoxib needed for adenoma regression has brought into question the long-term use of these agents for treatment of FAP.Note: NSAID use before colectomy remains experimental (see Therapies Under Investigation). Prevention of Primary ManifestationsColectomy is advised to reduce the risk for colorectal cancer when more than 20 or 30 adenomas or multiple adenomas with advanced histology have developed. To reduce the risk for duodenal/ periampullary adenocarcinoma, endoscopic or surgical removal of duodenal and/or ampullary adenomas should be considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms.SurveillanceIndividuals known to have FAP or an APC disease-causing mutation and individuals at risk for FAP who have not undergone molecular genetic testing or are members of families in which molecular genetic testing did not identify a disease-causing mutation [Giardiello et al 2001]:Sigmoidoscopy or colonoscopy every one to two years, beginning at age ten to 12 yearsColonoscopy, once polyps are detectedAnnual colonoscopy, if colectomy is delayed more than a year after polyps emerge. In individuals age ten to 20 years in whom adenomas are smaller than 6.0 mm and without villous component, delay in colectomy may be considered.Esophagogastroduodenoscopy (EGD) beginning by age 25 years or prior to colectomy and repeated every one to three years
Note: (1) The frequency of EGD depends on the severity of duodenal adenomas; Spigelman staging criteria can help determine the frequency.
(2) A side-viewing instrument should be used to visualize the duodenal papilla.
(3) As adenomatous tissue is commonly found at the papilla, biopsy may be justified if no polyps are visualized but the papilla seems enlarged.
(4) In some cases, endoscopic retrograde cholangiopancreatography (ERCP) may be necessary to evaluate for adenomas of the common bile duct.
(5) The utility of video capsule endoscopy (VCE) in screening for small-bowel lesions in FAP is unclear. Inaccurate identification of large polyps in the proximal small bowel and the inability to view the ampulla call into question the use of VCE in APC-associated polyposis conditions [Wong et al 2006].Small-bowel imaging (small-bowel enteroclysis or abdominal and pelvic CT with orally administered contrast) when duodenal adenomas are detected or prior to colectomy, repeated every one to three years depending on findings and presence of symptomsScreening for hepatoblastoma: efficacy in individuals with FAP is unclear. Screening protocols in Beckwith-Wiedemann syndrome, in which the risk for hepatoblastoma is also increased, often include frequent (every 2-3 months) abdominal ultrasound examinations and measurement of serum alpha-fetoprotein concentrations and have resulted in early detection of hepatoblastomas [Tan & Amor 2006]. Screening for hepatoblastoma in FAP using the same protocol may be considered from infancy to age five years. However, the optimal interval for hepatoblastoma screening in FAP is not known, although it has been recommended that screening should occur at least every three months [Hirschman et al 2005, Aretz et al 2007].Annual physical examination, including evaluation for extraintestinal manifestations, usually for cosmetic concerns, and palpation of the thyroid with consideration of follow-up ultrasound examination and fine-needle aspiration if thyroid nodules are present [Herraiz et al 2007]Individuals who have undergone colectomyIf total colectomy with ileo-anal pull-through was performed, routine endoscopic surveillance of the ileal pouch every two yearsIf subtotal colectomy was performed, surveillance of the remaining rectum every six to 12 months, depending on the number of polyps that develop. Cancer may still occur in the remaining rectum, but the risk is low with the current management [Church et al 2003a].Individuals known to have attenuated FAPColonoscopy every two to three years, beginning at age 18 to 20 yearsColectomy: usually advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have developed (See Individuals who have undergone colectomy.)Esophagogastroduodenoscopy (EGD) beginning by age 25 years or prior to colectomy and repeated every one to three years
Note: (1) The frequency of EGD depends on the severity of duodenal adenomas; Spigelman staging criteria can help determine the frequency of exams.
(2) A side-viewing instrument should be used to visualize the duodenal papilla.
(3) Because adenomatous tissue is commonly found at the papilla, biopsy may be justified if no polyps are visualized but the papilla seems enlarged.
(4) 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 [Herraiz et al 2007]At-risk family members who, on molecular genetic testing, have not inherited the disease-causing APC mutation previously identified in an affected family member:Colon cancer screening for individuals at average risk beginning at age 50 yearsEvaluation of Relatives at RiskRecommended genetic testing for at-risk family members. Early recognition of APC-associated polyposis conditions may allow for timely intervention and improved final outcome; thus, surveillance of asymptomatic, at-risk children for early manifestations is appropriate [American Gastroenterological Association 2001 (click for full text; registration required), Joint Test and Technology Transfer Committee Working Group 2000 (click for full text)].Use of molecular genetic testing for early identification of at-risk family members (see Genetic Counseling) improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the disease-causing mutation. A cost analysis comparing molecular genetic testing and sigmoidoscopy screening for individuals at risk for APC-associated polyposis conditions shows that genetic testing is more cost effective than sigmoidoscopy in determining who in the family is affected [Cromwell et al 1998]. Additionally, 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 [Heiskanen et al 2000].As colon screening 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. 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.Note: No evidence points to an optimal age at which to begin screening; thus, the ages at which testing is performed and screening initiated may vary by center, family history, hepatoblastoma screening, and/or parents'/child's needs.Therapies Under InvestigationIn a small phase I study, celecoxib reduced colorectal polyps in children with FAP pre-colectomy [Lynch et al 2010]. Celecoxib is associated with increased cardiovascular risk and therefore long-term safety is still a concern [Solomon et al 2008]. Although aspirin use in individuals with FAP showed a trend toward reduced polyp number and size in the CAPP1 (Colorectal Adenoma/Carcinoma Prevention Programme) study, the evidence did not support long-term aspirin use in affected individuals [Burn et al 2011]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. OtherNSAIDs have been used unsuccessfully in an attempt to prevent the emergence of colonic adenomatous polyposis [Giardiello et al 2002].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. APC-Associated Polyposis Conditions: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDAPC5q22​.2Adenomatous polyposis coli proteinAPC @ ZAC-GGMAPCData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for APC-Associated Polyposis Conditions (View All in OMIM) View in own window 175100FAMILIAL ADENOMATOUS POLYPOSIS 1; FAP1 611731APC GENE; APCNormal allelic variants. The gene is alternatively spliced in multiple coding and noncoding regions; the main transcript has 15 exons with 8532 base pairs that code for 2843 amino acids and result in a 311.8-kd protein. Exon 15 is large and comprises more than three quarters of the coding region of the gene.Pathologic allelic variants. More than 826 germline mutations have been found in families with an APC-associated polyposis condition [Beroud et al 2000]. Mutations almost always cause a premature truncation of the APC protein, usually through single amino-acid substitutions or frameshifts. While mutations have been found scattered throughout the gene, they are predominantly located in the 5' end of the gene. The most common germline APC mutation is c.3927_3931delAAAGA. (For more information, see Table A.)Table 3. Selected APC Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias ¹)Reference Sequences Normalc.5465T>Ap.Val1822Asp
(D1822V)NM_000038​.3
NP_000029​.2Uncertain clinical significancec.3949G>Cp.Glu1317GlnPredisposition to colon cancerc.3920T>Ap.Ile1307LysPathologicc.3927_3931delAAAGAp.Glu1309Aspfs*4See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. The APC protein has been localized to the nucleus and membrane/cytoskeleton in human epithelial cells [Neufeld & White 1997]. It has also been shown to homodimerize [Joslyn et al 1993] and bind to other proteins including GSK3b [Rubinfeld et al 1996], b-catenin [Rubinfeld et al 1993, Su et al 1993], g-catenin [Hulsken et al 1994, Rubinfeld et al 1995], tubulin [Munemitsu et al 1994, Smith et al 1994], EB1 [Su et al 1995], and hDLG, a homolog of the Drosophila discs large tumor-suppressor protein [Matsumine et al 1996]. The APC protein product is a tumor suppressor. APC protein forms a complex with glycogen synthase kinase 3b (GSK-3b) [Rubinfeld et al 1996], which targets b-catenin, a protein involved in both cell adhesion and intracellular signal transduction [Korinek et al 1997, Morin et al 1997, Nakamura 1997, Peifer 1997, Rubinfeld et al 1997]. The presence of normal APC protein appears to maintain normal apoptosis and may also decrease cell proliferation, probably through its regulation of b-catenin. This pathway is normally involved with Wingless-Wnt signaling, which participates in several known cell growth functions.The APC protein has been shown to accumulate at the kinetochore during mitosis, contribute to kinetochore-microtubule attachment, and play a role in chromosome segregation in mouse embryonic stem cells [Fodde et al 2001, Kaplan et al 2001]. The APC protein may play a role in chromosomal instability, the presence of which is often observed when APC function is lost.Other possible roles for the APC protein include: regulation of cell migration up the colonic crypt and cell adhesion through association with E-cadherin, regulation of cell polarity through association with GSK3b, and other functions related to association with microtubule bundles [Nathke et al 1996, Barth et al 1997, Etienne-Manneville & Hall 2003]. Goss & Groden [2000] provide an excellent review of the function of the APC protein.Abnormal gene product. Disease-causing mutations in APC most often result in truncated protein products. Experiments have localized normal full-length APC protein to the membrane/cytoskeleton and nuclear fractions of human epithelial cells but demonstrated that colon cancer cells containing only mutant APC genes revealed no truncated APC protein in nuclear fractions [Neufeld & White 1997].When APC is mutated and abnormal protein is present, high levels of free cytosolic b-catenin result. Free b-catenin migrates to the nucleus, binds to a transcription factor Tcf-4 or Lef-1 (T cell factor-lymphoid enhancer factor), and may activate expression of genes such as the oncogenes c-Myc and cyclin D1 [Chung 2000]. The specific genes targeted are not yet known but may include those increasing proliferation or decreasing apoptosis. Because APC may be important in cell migration, abnormal APC protein may disrupt normal cellular positioning in the colonic crypt. Additionally, mutations in APC are thought to contribute to chromosomal instability in colorectal cancers [Fodde et al 2001].