Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[Includes: Familial Adenomatous Polyposis, Gardner Syndrome, Turcot Syndrome, Attenuated FAP]
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Authors:
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Cindy Solomon, MS
Randall W Burt, MD |
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Initial Posting:
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Last Update:
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Disease characteristics. APC-associated polyposis conditions include familial adenomatous polyposis (FAP), attenuated FAP, Gardner syndrome, and Turcot syndrome. FAP is a colon cancer predisposition syndrome in which hundreds to thousands of precancerous colonic polyps develop, beginning at a mean age of 16 years (range 7-36 years). By age 35 years, 95% of individuals with FAP have polyps; without colectomy, colon cancer is inevitable. The mean age of colon cancer diagnosis in untreated individuals is 39 years (range 34-43 years). Extracolonic manifestations are variably present and include 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. Attenuated FAP is characterized by a significant risk for colon cancer, but fewer colonic polyps (average of 30) than classic FAP, more proximally located polyps, and diagnosis of colon cancer at a later age; management may be substantially different. Gardner syndrome is characterized by colonic polyposis typical of FAP together with osteomas and soft tissue tumors. Turcot syndrome is the association of colonic polyposis and CNS tumors; the phenotypic features of Gardner syndrome and Turcot syndrome relate to the location of the APC mutation and are generally expressed in families with FAP.
Diagnosis/testing. APC-associated polyposis conditions are caused by mutations in the APC gene. The diagnosis of APC-associated polyposis conditions relies primarily upon clinical findings. Molecular genetic testing of APC detects disease-causing mutations in up to 95% of probands with typical FAP. Such testing is clinically available. Molecular genetic testing is most often used in the early diagnosis of at-risk family members and in the confirmation of the diagnosis of FAP or attenuated FAP in individuals with equivocal findings (e.g., fewer than 100 adenomatous polyps).
Management. Colectomy is advised in individuals with classic FAP when more than 20 or 30 adenomas or multiple adenomas with advanced histology have occurred. NSAIDs, especially sulindac, celecoxib, and rofecoxib, have caused regression of adenomas in FAP and decreased the number of polyps requiring ablation in the remaining rectum of persons with a subtotal colectomy. Endoscopic or surgical removal of duodenal adenomas is considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms. Osteomas may be removed for cosmetic reasons. Desmoid tumor treatments include surgical excision, nonsteroidal anti-inflammatory drugs (NSAIDs), anti-estrogens, cytotoxic chemotherapy, and radiation. Recommended surveillance of individuals who are known to have FAP or an APC disease-causing mutation and individuals who are at risk for FAP include screening for hepatoblastoma by ultrasound examination and measurement of serum alpha-fetoprotein concentration, sigmoidoscopy, colonoscopy, esophagogastroduodenoscopy, small bowel X-ray, and regular physical examinations. Use of molecular genetic testing for early identification of at-risk family members 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.
Genetic counseling. APC-associated polyposis conditions are 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 have a 50% risk of inheriting the altered APC gene. Prenatal testing is possible if a disease-causing mutation is identified in an affected family member; however, prenatal testing for typically adult-onset disorders is uncommon and requires careful genetic counseling.
The 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:
Gardner 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 (AFAP) is considered in an individual with:
Note: Variable features not included in the diagnostic criteria but potentially helpful in establishing the clinical diagnosis of an APC-associated polyposis condition 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.
Histology of adenomatous polyps
Dysplasia. Adenomatous polyps (often referred to as adenomas) are precancerous growths in which the surface epithelium of the gastrointestinal tract exhibits features of dysplasia. Dysplasia is characterized by branching of the microscopic glands, loss of goblet cells, and the following cellular features: loss of basilar polarity of the nucleus, increased nuclear/cytoplasmic ratio, increased basophylia of the cytoplasm, and loss of cytoplasmic glycogen. Dysplasia is graded as mild, moderate, or severe. Severe dysplasia is more likely to have cancer found somewhere within it, and is more likely to progress to cancer.
Villous changes. In addition to the dysplastic features of an adenomatous polyp, villous changes, characterized by elongated villi at the surface of the polyp, may develop.
Villous adenoma. When the majority of the polyp surface exhibits villous change, the polyp is called a villous adenoma. A greater risk of cancer is associated with villous features within an adenomatous polyp.
Tubular adenoma. If no villous features are present, the adenomatous polyp is called a tubular adenoma.
Tubulovillous adenoma. If some villous features are present, the adenomatous polyp is called a tubulovillous adenoma.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.
Gene. APC is the gene associated with APC-associated polyposis conditions.
Molecular genetic testing: Clinical uses
Molecular genetic testing: Clinical methods
Full gene sequencing. Mutation detection rate is up to 90%.
Mutation scanning. A variety of mutation scanning methods are used. Mutation detection rate is approximately 80-90%.
PTT alone. Most mutations in the APC gene cause premature truncation of the APC protein. A test based on this finding [Powell et al 1993] is positive in about 80% of individuals with FAP.
Duplication/deletion analysis. Among individuals with an APC-associated polyposis condition and more than 100 polyps, approximately 8-12% have an APC duplication or large deletion [Sieber et al 2002 , Bunyan et al 2004 , Aretz et al 2005 , Michils et al 2005]. Methods currently used to identify duplications/deletions include Southern blot analysis, multiplex ligation-dependent probe amplification (MLPA), and quantitative PCR.
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1. Detection of mutations using all methods listed below appears to be higher in typical FAP than in attenuated FAP [Sieber et al 2002
, Aretz et al 2005
, Michils et al 2005].
2. Sieber et al 2002 , Bunyan et al 2004 , Aretz et al 2005 , Michils et al 2005 |
Linkage analysis. Linkage analysis can be considered in families with more than one affected family member who belong to different generations. Linkage studies are based upon 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 in more than 95% of families with an APC-associated polyposis condition with greater than 98% accuracy [Petersen et al 1991 , Burt et al 1992]. Linkage testing is not available to families with a single affected individual, a situation that often occurs when an individual has a de novo gene mutation and no affected offspring.
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% of Families
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Genetic Mechanism
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Test Type
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Test Availability
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95%
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Clinical
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Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Colon cancer and/or polyps
I1307K mutation in the APC gene. A mutation in the APC gene at codon 1307 appears to create a hypermutable region that does not lead to classic FAP, but causes an increased risk of colon cancer [Laken et al 1997]. It is thought that 6% of all individuals of Ashkenazi Jewish ancestry have the I1307K mutation. Individuals with the I1307K mutation are predisposed to developing colon polyps but do not develop hundreds to thousands of polyps as in typical FAP. Individuals with the I1307K mutation have an approximate 10-20% lifetime risk of developing colon cancer. Individuals of Ashkenazi Jewish ancestry who have a family history of colon cancer or polyps, a personal history of colon cancer or polyps, or a heightened concern for colon cancer may be offered genetic testing for the I1307K mutation. The test is not appropriate for individuals who are not of Ashkenazi Jewish ancestry. While studies assessing the effectiveness of screening for colon polyps in individuals with the I1307K mutation have not been performed, some experts recommend that individuals who test positive for the mutation have a colonoscopy every two years starting at age 35 years or five to ten years earlier than the earliest colon cancer diagnosis in the family, while others recommend colonoscopy every three to five years starting at age 35 years or five to ten years earlier than the earliest colon cancer diagnosis in the family.
E1317Q mutation. Another missense variant in the APC gene, E1317Q, may be associated with a predisposition to colon adenomas and/or colon cancer [Frayling et al 1998 , Lamlum et al 2000 , Popat et al 2000 , Hahnloser et al 2003]; however, data are conflicting [Michils et al 2002]. The role of the E1317Q variant in colon cancer is uncertain and testing for this specific variant alone is not currently available on a clinical basis.
Deletion 5q22. Interstitial deletions of chromosome 5q22, which includes the APC gene, have been reported in individuals with adenomatous polyposis and mental retardation [Pilarski et al 1999]. Large deletions are only rarely cytogenetically visible and are sometimes detectable using fluorescence in situ hybridization (FISH).
APC-associated polyposis conditions include classic FAP and two overlapping phenotypes, Gardner syndrome and Turcot syndrome, and attenuated FAP.
Colorectal adenomatous polyps begin to appear at an average age of 16 years (range 7-36 years) [Petersen et al 1991]. By age 35 years, 95% of individuals 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]. Interfamilial and intrafamilial phenotypic variability is common [Giardiello et al 1994 , Rozen et al 1999].
Other features that are variably present in FAP:
Gastric polyps. Gastric polyps can either be fundic-gland or adenomatous [Bulow et al 1995].
Adenomatous polyps of the small bowel. 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]. The presence and number of adenomatous polyps are dependent upon the specific location in the small bowel [Wallace & Phillips 1998]. Adenomatous polyps of the duodenum are observed in 50-90% of individuals with FAP, and are commonly found in the second and third portions of the duodenum [Kadmon et al 2001]. No clear association has been identified between the number of colonic polyps and the number of upper gastrointestinal polyps [Kadmon et al 2001]. The lifetime risk of small bowel malignancy is 4-12%; the majority occur in the duodenum.
Adenomatous polyps of the periampullary region (including the duodenal papilla and ampulla of Vater) are seen in at least 50% of individuals. Polyps in this area can cause obstruction of the pancreatic duct resulting in pancreatitis, which occurs at increased frequency in FAP. These polyps are often small and require a side-viewing endoscope for visualization. Some theorize that pancreaticobiliary secretions, such as bile, affect the development of adenomas and cancer in this area [Wallace & Phillips 1998 , Kadmon et al 2001]. The risk of malignancy of polyps in the periampullary region is higher than that of adenomas in other parts of the duodenum [Kadmon et al 2001].
Extraintestinal manifestations. Mutations in certain locations of the APC gene appear to favor the occurrence of extraintestinal manifestations that tend to run true in families.
Osteomas. Osteomas 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. Osteomas 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, 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). CHRPE are discrete, flat, pigmented lesions of the retina that do not cause clinical problems. It is thought that CHRPE are present at birth. Observation of multiple or bilateral CHRPE may be an indication that an at-risk family member has inherited FAP, whereas isolated or unilateral lesions may be seen in the general population. Visualization of CHRPE may require examination of the ocular fundus with an indirect ophthalmoscope through a dilated pupil.
Benign cutaneous lesions. These lesions include epidermoid cysts and fibromas that may be found on any part of the body, including the face, and are mainly of cosmetic concern.
Desmoid tumors. Approximately 10% of children and adults with FAP develop desmoid tumors [Gurbuz et al 1994 , Clark & Phillips 1996]. The risk of desmoid tumors in individuals with FAP is 852 times the risk in the general population [Gurbuz et al 1994]. 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]. Desmoid tumors form predominantly within the abdomen or in the abdominal wall, but may also occur extra-abdominally. Desmoid tumors may compress abdominal organs or complicate abdominal surgery. About 5% of individuals with FAP experience morbidity and/or mortality from desmoid tumors. Abdominal desmoid tumors may occur spontaneously or following abdominal surgery, pregnancy, and oral contraceptive use [Bertario et al 2001]. Independent predictors for desmoid tumor development include an APC mutation 3' of codon 1444, family history of desmoids, female gender, and the presence of osteomas [Bertario et al 2001]. Desmoid tumors are best evaluated by CT scan [Clark & Phillips 1996] or MRI. A CT scoring system for desmoids in FAP has been developed [Middleton et al 2003].
Adrenal masses. Although not thoroughly studied, a statistically significant association between adrenal masses and FAP has been reported. 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 2000]. Most of these masses appeared to be adrenocortical adenomas without endocrinopathy or hypertension. Smith et al (2000) found no evidence to warrant screening for adrenal masses.
Extracolonic cancers. Several extracolonic cancers occur with a higher incidence in individuals with FAP than in the general population (Table 3) [Burt 2000].
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Site
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Type of Cancer
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Risk of Cancer
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Small bowel: duodenum or periampulla
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Carcinoma
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4-12%
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Small bowel: distal to the duodenum
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Rare
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Stomach
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Adenocarcinoma
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0.5%
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Pancreas
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~2%
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Thyroid
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Papillary thyroid carcinoma
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~2%
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CNS
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Usually medulloblastoma
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<1%
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Liver
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Hepatoblastoma
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1.6% (children <age 5 years)
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Bile ducts
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Adenocarcinoma
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Low, but increased
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Adrenal gland
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Duodenal adenocarcinoma has been reported between ages 17 and 81 years, with the mean age of diagnosis between 45 and 52 years [Wallace & Phillips 1998 , Kadmon et al 2001]. It occurs most commonly in the periampullary area. Small bowel cancer past the duodenum has been reported, but is rare.
Among individuals with FAP, gastric adenocarcinoma occurs in 0.5% living in Western cultures, and with greater frequency in Japanese and Korean cultures [Offerhaus et al 1999]. Gastric adenocarcinoma is believed to arise most often from adenomas, but may also develop from fundic-gland polyps.
Thyroid cancers affected approximately 2% of individuals with FAP with a mean age at diagnosis of 28 years (range: 12-62 years of age) [Cetta et al 2000]. A female preponderance is observed. Papillary histology predominates and may commonly have a cribiform pattern. Familial occurrence has been observed.
Pregnancy/hormone use. Limited information is available on the impact 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 protocolectomy with ileal pouch-anal anastomosis (IPAA) compared to the control population [Olsen et al 2003].
Women who have undergone colectomy are considered to have the same risk of obstetrical 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].
Some studies have suggested that female hormones protect against colorectal cancer development in the general population. A case report in an individual with FAP has shown reduction in polyps after use of oral contraceptives [Giardiello et al 2005].
Gardner 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]. These benign extraintestinal growths occur in about 20% of individuals and families with FAP. When these findings are prominent, many clinicians continue to use the term GS. Osteomas are most commonly found on the mandible and skull, although any bone of the body may be involved. Epidermoid cysts occur on any cutaneous surface and are mainly of cosmetic concern, as they do not appear to have malignant potential. Supernumerary teeth, odontomas, and desmoid tumors were originally described as a part of GS; however, like osteomas and epidermoid cysts, they can occur in any individual with FAP, whether or not other extraintestinal findings are present.
Although GS was once thought to be a distinct clinical entity, it is now known that mutations in the APC gene give rise to both classic FAP and GS. Other manifestations of FAP, such as upper gastrointestinal polyposis, are also found in GS. Some correlation exists between extraintestinal growths and mutation location in APC; see Genotype-Phenotype Correlations .
Turcot syndrome is the association of colonic adenomatous polyposis of classic FAP and CNS tumors, usually medulloblastoma. The risk of CNS tumors is substantially increased in persons with FAP generally, although the absolute risk is only approximately 1%. Families with APC-associated polyposis conditions and multiple individuals with CNS tumors raise the possibility of mutation specificity or modifying genes.
Attenuated FAP (AFAP) is characterized by a significant risk for colon cancer, but fewer colonic polyps (average of 30) than classic FAP. Polyps tend to be found more proximally in the colon than in classic FAP. The average age of colon cancer diagnosis in individuals with AFAP is age 50-55 years — 10-15 years later than in those with classic FAP, but earlier than that seen in individuals with sporadically occurring colon cancer [Spirio et al 1993 , Giardiello et al 1997]. Upper gastrointestinal polyps and cancers may be seen in individuals with AFAP [Burt 2003] and, although the extraintestinal manifestations of FAP may be present, CHRPE lesions and desmoid tumors are rare. For excellent investigations and review of AFAP, see Knudsen et al 2003 and Burt et al 2004 .
Although variation occurs among and within individuals and among and within families with identical mutations in the APC gene [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]; others feel that therapeutic decisions should not be based on genotype [Friedl et al 2001]. While not in routine use at present,f these correlations may become more integral in management decisions in the future.
The penetrance of FAP in terms of colonic adenomatous polyposis and colon cancer is virtually 100% in untreated individuals.
The penetrance of other intestinal and extraintestinal manifestations is less well understood and may depend in part on the mutation location in the APC gene.
Anticipation is not described in this condition.
Other terms used historically for FAP include familial polyposis coli and adenomatous polyposis coli; the latter term is now used for the relevant gene.
The term Gardner syndrome is mainly of historical interest as it is now known to arise from mutations of the APC gene like FAP. Furthermore, subtle extraintestinal manifestations can be found in almost all individuals with FAP with sufficient investigation. Nonetheless individuals and families with particularly prominent extracolonic manifestations will undoubtedly continue to be referred to as having Gardner syndrome.
The risk of CNS tumors is substantially increased in individuals with FAP generally, although the absolute risk is only approximately 1%. In some families with FAP, multiple individuals have CNS tumors, making Turcot syndrome an historical term of uncertain significance as it relates to FAP.
Attenuated FAP (AFAP) appears to be the same as the hereditary flat adenoma syndrome [Lynch et al 1992].
The prevalence data reported from national registries include all of the APC-associated polyposis conditions (except possibly some cases of attenuated FAP); reported prevalence is 2.29-3.2 per 100,000 population [Burn et al 1991 , Jarvinen 1992 , Bulow et al 1996]. 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.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
APC-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. Conditions to consider in the differential diagnosis include the following hereditary disorders:
MYH-associated polyposis. The phenotype of MYH-associated polyposis is similar to FAP and attenuated FAP but is inherited in an autosomal recessive manner. Germline mutations in MYH predispose persons to multiple adenoma or polyposis coli. If an APC mutation is not identified in an individual with FAP or attenuated FAP, molecular genetic testing of MYH should be considered [Sieber et al 2003]. Biallelic MYH mutations have also been found in a few individuals diagnosed with colorectal cancer at 50 years of age or younger who have had few or no polyps [Wang et al 2004].
Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant colon cancer syndrome with proximal colonic predominance. Few colonic adenomas are present. Other malignancies include cancer of the endometrium, ovary, stomach, small intestine, and urinary tract. HNPCC is caused by mutations in DNA mismatch repair genes, primarily MLH1 and MSH2, but also MSH6 and PMS2. It may be difficult to distinguish between HNPCC and attenuated FAP in individuals and families who have 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 on a tumor block from a colon cancer may be helpful in deciding which condition to pursue further.
Turcot syndrome is the association of colon cancer or colonic polyposis and CNS tumors, usually medulloblastoma. Two-thirds of persons with Turcot syndrome have a mutation in the APC gene, and one-third have mutations in one of the mismatch repair genes that cause hereditary non-polyposis colon cancer (HNPCC) [Hamilton et al 1995 , Paraf et al 1997]. The CNS tumors in individuals with HNPCC are usually glioblastoma multiforme.
Peutz-Jeghers syndrome (PJS). Inherited in an autosomal dominant manner, PJS is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation. Peutz-Jeghers type hamartomatous polyps are most prevalent in the small intestine (jejenum, ileum, and duodenum, respectively), but can occur elsewhere in the GI tract. Mucocutaneous hyperpigmentation presents in children under the age of five years as dark blue to dark brown mucocutaneous macules around the mouth, eyes, and nostrils, in the perianal area, on the buccal mucosa, and on the fingers. Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries. Males occasionally develop calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia. Individuals with Peutz-Jeghers syndrome are at increased risk for intestinal and extraintestinal malignancies, including colorectal, esophageal, gastric, breast, ovarian, and pancreatic cancers [Giardiello et al 2000]. Molecular genetic testing of the STK11 gene reveals disease-causing mutations in about 70% of familial cases and 30-70% of nonfamilial cases.
PTEN hamartoma tumor syndrome (PHTS) is a syndrome comprising hamartomas and cancer that is characterized by germline PTEN mutations and inherited in an autosomal dominant manner. PHTS includes Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba (BRR) syndrome. CS is a multiple hamartoma syndrome with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium. BRR syndrome is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, and pigmented macules of the glans penis. Approximately 80% of individuals who meet the diagnostic criteria for CS and 60% of individuals with a clinical diagnosis of BRR syndrome have a detectable PTEN gene mutation.
Juvenile polyposis syndrome (JPS) is characterized by predisposition for hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. JPS is diagnosed if any one of the following is present: more than five juvenile polyps of the colorectum OR multiple juvenile polyps throughout the GI tract OR any number of juvenile polyps and a family history of juvenile polyps [Jass et al 1988]. The term "juvenile" refers to the type of polyp, not the age of onset of polyps. Most individuals with JPS have some polyps by 20 years of age. Some individuals may only have four or five polyps over their lifetimes, whereas others in the same family may have over a hundred. Most juvenile polyps are benign; however, malignant transformation can occur. Estimates of developing GI cancers in families with JPS range from 9% to 50%. Two genes are known to be associated with JPS: MADH4 (previously SMAD4) and BMPR1A. Approximately 15% of individuals affected with JPS have mutations in the MADH4 gene; approximately 25% have mutations in the BMPR1A gene. JPS is inherited in an autosomal dominant manner.
Hereditary mixed polyposis syndrome. Mode of inheritance is unknown. The syndrome is characterized by atypical juvenile polyps, polyps containing mixed histology, or multiple polyps of more than one histologic type in an individual.
Neurofibromatosis type 1 (NF1). Individuals with NF1 may exhibit multiple intestinal polypoid neurofibromas or ganglioneuromas in the small bowel, stomach, and colon.
Conditions to be considered in the differential diagnosis include the following acquired disorders:
Cronkite-Canada syndrome is characterized by generalized gastrointestinal hamartomatous polyposis, cutaneous hyperpigmentation, hair loss, and nail atrophy.
Nodular lymphoid hyperplasia is a lymphoproliferative disorder resulting in hyperplastic lymphoid nodules in small bowel, stomach, and colon; may be associated with common variable immunodeficiency syndrome.
Lymphomatous polyposis is characterized by occurrence of primary extranodal lymphomas in the gastrointestinal tract; two types include multiple lymphomatous polyposis and Mediterranean-type lymphoma.
Inflammatory polyposis is charcterized by acquired; non-neoplastic polyps associated with inflammatory bowel disease, most commonly ulcerative colitis.
Sporadic colorectal tumors. The majority of colorectal tumors not known to be familial have been shown to have a somatic mutation in the APC gene [Miyoshi et al 1992 , Powell et al 1992 , Smith et al 1993] that is believed to occur early in colorectal tumorigenesis [Fearon & Vogelstein 1990].
Hyperplastic polyposis (or metaplastic polyposis) comprises multiple non-neoplastic hyperplastic polyps of the gastrointestinal tract; whether it is inherited or acquired is unknown.