DÄ internationalArchive10/2010The Differential Diagnosis and Early Detection of Hereditary Gastrointestinal Polyposis Syndromes

Review article

The Differential Diagnosis and Early Detection of Hereditary Gastrointestinal Polyposis Syndromes

Dtsch Arztebl Int 2010; 107(10): 163-73. DOI: 10.3238/arztebl.2010.0163

Aretz, S

Background: Hereditary gastrointestinal polyposis syndromes account for about 1% of all cases of colorectal cancer and are associated with a broad spectrum of extracolonic tumors. The early detection and accurate classification of these syndromes are essential, since effective methods for surveillance and treatment are available.
Methods: This review article is based on a selective literature search, the author’s own work, and evidence-based guidelines and recommendations.
Results and Conclusions: The diagnosis is initially suspected on the basis of the endoscopic findings and polyp histology. Because different syndromes can resemble each other phenotypically, e.g., autosomal dominant familial adenomatous polyposis and autosomal recessive MUTYH-associated polyposis, molecular genetic studies are important for differential diagnosis and for assessing the risk of recurrence. Identification of the familial mutation in an affected patient is a prerequisite for predictive testing in asymptomatic persons at risk and sometimes enables prognostication. In recent years, the rate of detection of mutations has risen by 10% to 30%, and clinically relevant genotype-phenotype correlations have been described for juvenile polyposis syndrome. Except in cases of mild adenomatous polyposis, phenotypic overlap among the hamartomatous polyposes often causes difficulties in differential diagnosis. Thus, in unclear cases, a pathologist with special expertise in gastrointestinal disorders should be consulted for the evaluation of polyp tissue. Aside from the monogenic polyposes, there are many other types of polyposis that are non-hereditary or of unknown cause, including the hyperplastic and mixed polyposis syndromes. Risk-adapted surveillance programs have been established for the more frequently occurring polyposes.
LNSLNS The occurrence of a few isolated colonic polyps is a frequent, age-related phenomenon (e1e3). The number of polyps required for a diagnosis of polyposis has not been clearly defined and depends on the prevalence of the polyp type in the general population, on the location of the polyps, and on the patient’s age.

Gastrointestinal polyposis syndromes include numerous entities, some of which are clinically and genetically well characterized; in the case of others, research into their causes and delineation of their phenotypes has only just begun (Table 1 gif ppt, eTable 1 gif ppt) (15, e4). The known monogenic forms are precancerous and are responsible for approximately 1% of all colorectal carcinomas (CRC); after hereditary nonpolyposis colon cancer (HNPCC, Lynch syndrome) they are the most frequent cause of hereditary cancer of the colon.

Recognition and correct differential diagnosis of the polyposis syndromes is essential, because on the one hand polyposis patients have a high lifetime risk of gastrointestinal and extraintestinal carcinoma and their first-degree relatives a high risk of recurrence of the syndrome; on the other hand, endoscopic screening as an effective instrument in preventing cancer is availabe. Polyposis syndromes may be encountered in patients of any age and can vary greatly in their clinical manifestations, even within a family.

Initial symptoms usually relate to stool abnormalities (blood and/or mucus in the stool, diarrhea, constipation) and nonspecific abdominal complaints. Specialized interdisciplinary centers should be involved in the diagnosis and coordination of surveillance (Box 1 gif ppt).

The Institute for Human Genetics at the University of Bonn has been engaged the molecular genetic diagnostics and research of hereditary gastrointestinal tumor syndrome for 20 years and has access to one of the largest patient cohorts in the world. On the basis of a selective literature search in PubMed and our own work, this review article will summarize the most recent research results and their clinical implications.

Clinical differential diagnosis
Most polyposis syndromes can be confidently distinguished on the basis of the number and distribution of polyps in the gastrointestinal tract, and, especially, on the basis of polyp type (Figures 1 gif ppt and 2 jpg ppt) (5, e5). The initial diagnostic workup is therefore always based on the endoscopic and histological findings, together with any extraintestinal manifestations (eFigure jpg ppt, Box 2 gif ppt) and the family history. Because several polyp types may occur, it is important to examine a large enough number of polyps to get a clear idea of which is the predominant type. The process of classification should be guided by the current histological classification of gastrointestinal polyps (e6). Clinical diagnostic criteria have been developed for most of the hereditary polyposes (Box 3 gif ppt), and these can be accessed at GeneReviews (www.geneclinics.org), for example.

Requirements and role of molecular genetic diagnosis
Demonstration of a causal mutation in leukocyte DNA is essential for the differential diagnosis (e.g. among the various adenomatous polyposis syndromes), assessment of the risk of recurrence (autosomal dominant versus autosomal recessive inheritance), and predictive testing of asymptomatic persons at risk. Using predictive genetic testing allows preventive measures to be restricted to those members of a family who are actually mutation carriers.

The role of molecular genetic findings in treatment decisions, on the other hand, is limited because identification of a germline mutation rarely allows any estimation of the likely course of the disease. Moreover, even if no mutation can be demonstrated, the patient with polyposis still needs to be treated appropriately, so any necessary measures should be initiated even before testing for mutation is complete.

A suspected diagnosis based on clinical and histological features is a requirement for rational, targeted testing for mutation, which is always first carried out on a person who is already ill—the so-called index patient. Failure to identify a mutation does not invalidate a clinically definite diagnosis (6), but only demonstration of a mutation makes it possible to perform predictive testing of at-risk relatives who are clinically healthy (Figure 3 gif ppt).

The more typical the clinical and histological features of the polyposis, the more likely it is that a mutation will be identified. When the diagnostic criteria are not fulfilled, the mutation detection rate drops markedly (7, 8). With the introduction of multiplex -ligation-dependent probe amplification (MLPA), it is now possible to identify large genomic deletions affecting the whole gene or individual exons. This has increased the mutation detection rate by 10% to 30% (Table 1).

Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) is the most common colorectal polyposis. With more than 100 colorectal adenomas and early manifestation during adolescence, the classical form is usually not difficult to diagnose. Without treatment, the risk of CRC is almost 100% (9, 10, e7) (Box 3). In about 80% of families a heterozygous germline mutation in the tumor suppressor gene APC is demonstrated. FAP is inherited in an autosomal dominant pattern, so children of a person affected by FAP have a 50% risk of the disease. In some patients a de novo mutation is seen.

In 10% to 15% of de novo mutations a somatic APC mosaicism may be present (11, e8). The clinical significance of mosaicism is that predisposed children may be more severely affected than the parent, and in an apparently new (sporadic) case there may be a clinically normal parent who carries the mutation in mosaic form and may, unnoticed, develop adenomas.

FAP with a mild disease course is usually designated “attenuated FAP” (AFAP) (Box 3), but even here without treatment the risk of CRC is still very high. This patient group is clinically poorly defined and genetically heterogeneous. An APC mutation is found in only 20% to 30% of index patients. The diagnostic criteria are a smaller number of polyps (<100) and manifestation at a later age (12). However, the severity of disease in polyposis can in the end be understood as a biological continuum and the dichotomous classification into classical versus attenuated should be seen more as marking the phenotypic extremes than as distinct nosological entities.

Benign fundic gland polyps develop in over 50% of FAP patients; gastric carcinoma, however, is rare (incidence 0.6%) (e9, e10). The incidence of duodenal adenomas is up to 90%; the lifetime risk of developing duodenal carcinoma is around 5% (e11).

In some patients typical extraintestinal manifestations are seen: in addition to osteomas or epidermoid cysts, about 10% of patients develop desmoids, which can grow aggressively (e12). The benign pigment changes in the retina—so-called congenital hypertrophy of the retinal pigment epithelium (CHRPE)—have largely lost their diagnostic significance. The most frequently described extraintestinal malignant tumors are hepatoblastoma, medulloblastoma, and thyroid carcinoma; because their incidence is very low (1% to 2%), there is no consensus about specific preventative measures (13, e13). Gardner syndrome and Turcot syndrome are phenotypic variants of FAP, not separate syndromes.

Genotype–phenotype correlations regarding the severity of colorectal polyposis and the occurrence of extraintestinal manifestations have been known for a long time (14, e14). However, these are statistical relationships that can give no reliable prediction of the course of the disease in an individual patient. In addition, mosaic findings and splice mutations can lead to deviations from the expected phenotype (11, e15).

MUTYH-associated polyposis
MUTYH-associated polyposis (MAP) is the most important differential diagnosis of APC-associated FAP (e16e18). This autosomal recessive polyposis syndrome is caused by biallelic mutations in the MUTYH gene (previously called the MYH gene). The MUTYH protein is a component of the base excision repair system of the cell, which corrects DNA point mutations caused by oxidative stress. Loss of function of the protein leads to an accumulation of somatic mutations in other genes, e.g. the APC gene, and hence in particular to the development of adenomas.

The colorectal phenotype of MAP resembles that of attenuated FAP (15). Usually from 20 to a few hundred adenomas occur; the mean age at diagnosis is 45 years, with a range between 12 and 68 years. As with attenuated FAP, without treatment the lifetime risk of CRC is up to 100% (e19). According to a current multicenter study of 276 patients with MAP, there is a 17% risk of duodenal polyposis, and the lifetime risk of duodenal carcinoma is around 4%. Extraintestinal malignancies occur significantly more frequently than in the general population and show a certain overlap with HNPCC. However, no dominant tumor type was found (e20). Desmoids were not observed.

Because of the mode of inheritance, the obligate heterozygote children of a patient with MAP and a non-consanguineous partner have only a small risk of developing MAP (about 1%). The CRC risk of heterozygous carriers is still under debate. Recent systematic studies in large patient populations estimate the relative risk at 1.5 to 2.1 in relation to the general population (e19, e21, e22).

Mutation-negative adenomatous polyposis
In about 50% of families the cause of adenomatous polyposis remains unexplained. In these cases milder forms of the disease dominate, and extracolonic manifestations are rare. The family history often shows no abnormalities or is nonspecific. In some patients the failure to find a mutation is explained by diagnostic difficulties or misdiagnoses. In cases where there are fewer than 30 colorectal adenomas, HNPCC should be considered in the differential diagnosis. Besides this, adenomas are also observed in other polyposis syndromes. In the remaining cases, APC mutations that are unidentifiable or uninterpretable by routine diagnostic methods or mutations in yet unknown genes are the probable explanation. In the latter scenario a monogenic or multifactorial etiology is a possibility.

Peutz–Jeghers syndrome
Peutz–Jeghers syndrome (PJS) is a rare hamartomatous polyposis (Box 3). Peutz–Jeghers polyps occur particularly in the small intestine and have characteristic histological features. The frequent synchronous occurrence of adenomas can, however, lead to misidentification. The typical perioral pigmentations are rarely present at birth, but usually present before the 5th birthday; they often fade in the course of life (3, e23) and are nonspecific. The differential diagnosis includes in particular the Carney complex and Laugier–Hunziker syndrome (e24).

Age at manifestation is very variable; some patients develop symptoms as early as in the first year of life. Complications in children include acute abdomen due to invaginations or obstructive ileus, and chronic bleeding with secondary anemia. Up to 30% of patients have undergone laparotomy before their 10th birthday (e25).

PJS predisposes not only to CRC but to a broad spectrum of benign and malignant extracolonic tumors which include breast cancer, pancreatic cancer, and endocrinologically active benign sex cord tumors with annular tubules (SCTAT) in the ovaries. The cumulative lifetime risk of developing carcinoma is estimated at 70% to 90% (1).

PJS is caused by germline mutations in the STK11 gene (LKB1 gene). In about 30% of families there is a large deletion of the gene; the mutation detection rate in clinically confirmed PJS has now risen to over 90% (7).

Juvenile polyposis syndrome
Solitary juvenile polyps are the most frequent polyps seen in children and adolescents, and are usually harmless (3, e26). The rare juvenile polyposis syndrome (JPS) only comes under consideration when certain clinical criteria are fulfilled (Box 3). This is often a sporadic disease entity. In about 60% of families with a clinically confirmed diagnosis, mutations of the SMAD4 or BMPRIA genes can be identified (8).

The disease can become manifest even during early childhood with chronic gastrointestinal bleeding or exudative enteropathy accompanied by delayed development. In case of early onset and severe manifestation, the rare juvenile polyposis of infancy should be considered, which is caused by large microdeletions that include the BMPR1A and PTEN genes (e27).

Recently, significant genotype–phenotype relationships were described: gastric polyposis, gastric carcinoma, and clinical symptoms of hereditary hemorrhagic telangiectasia (Osler–Rendu–Weber disease) occur almost exclusively in carriers of an SMAD4 mutation (8, e28).

Correct diagnosis of juvenile polyps is challenging, because of morphological similarities with hyperplastic polyps, lymphocytic infiltrates, and dysplastic components; for this reason, in a sizeable proportion of cases in which JPS is later genetically confirmed, it is initially wrongly identified as ulcerative colitis or hyperplastic polyposis (1, e29). In doubtful cases, therefore, a second opinion from a pathologist specializing in gastroenterology is decisive (8) (Box 1). The delineation of JPS from Cowden and Cronkhite–Canada syndrome can be difficult and is usually done on the basis not of histology but of the extraintestinal tumor spectrum and molecular genetics (2, 4) (Table 1, eTable). Cowden syndrome, which is due to mutations in the PTEN gene, is usually grouped together with its allelic variant, Bannayan–Ruvalcaba–Riley syndrome, which manifests in childhood, under the name PTEN hamartoma tumor syndrome (PHTS). However, colorectal polyps are not the main symptom of PHTS and have at worst a low potential for malignancy (16).

Hereditary mixed polyposis syndromes
The vague term ‘hereditary mixed polyposis syndrome’ (HMPS) unites a collection of polyposis syndromes showing a mixture of various types of polyp. In some patients mutations of the PTEN or the BMPR1A gene are demonstrated. These cases should be seen respectively as variants of Cowden syndrome and JPS and treated accordingly (4).

The nosological status of the remaining cases remains unclear. Misinterpretation of histological findings is a possibility, but on the other hand, in five families an association with a locus on chromosome 15 has been described, indicating a possible new genetic disposition (e30).

Hyperplastic polyposis
Small hyperplastic polyps are the most frequent type of polyp and have no potential for malignancy. Hyperplastic polyposis (HP), by contrast, is a rare, usually sporadic disease entity that remains poorly defined, and little is known about its genetic basis (17, 18). Diagnostic criteria are taken to be more than 20 to 30 colorectal hyperplastic polyps, more than 1 cm in size and with a pronounced proximal localization (eTable, Box 3).

So far the only published data relate to a few large, clinically heterogeneous patient groups, some of whom had a markedly increased risk of CRC. The data vary between studies by anything from 0 to more than 50% and are likely to be strongly biased. In 84% of patients various types of polyp were diagnosed. As to pathogenesis a sequence of HP—serrated adenoma—CRC has been postulated. Larger case numbers and consistent inclusion criteria will be needed for clarification of the etiology of this polyposis.

Other gastrointestinal forms of polyposis
Alongside those already mentioned, there exist numerous rare syndromes that accompany the development of multiple polyps in the gastrointestinal tract (18, 19) (Table 2 gif ppt). Some are probably not heritable, while in the case of others the genetic aspects have not yet been elucidated, as for instance the various intestinal ganglioneuromatoses, which appear in isolation or as an accompanying symptom of known genetic syndromes. Lymphoproliferative diseases and intestinal angiomatoses can usually be easily identified (e31); other forms require a more comprehensive workup and interdisciplinary collaboration between specialists. Since some entities are associated with severe complications and a poor prognosis, and since the treatment options can be different for different syndromes, the outcome of the differential diagnosis has clinical consequences.

Prevention
In patients with fewer than 10 colorectal adenomas and no relevant family history, the extent of risk-adjusted colonoscopic surveillance should be guided by the current ‘Colorectal carcinoma’ S3 guideline of the German Society for Digestive and Metabolic Diseases (Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten) (20) or the US recommendations (21, e32) (Table 2).

For the more frequent polyposis syndromes, specific surveillance programs have been established (Table 3 gif ppt) (www.nccn.org). Some of the recommendations disagree, however, and for very rare syndromes it is difficult to validate effectiveness (2, 13, e33, e34).

The efficiency of early and frequent colonoscopy to prevent CRC is well proven in FAP (e35). Besides that, endoscopic surveillance of the upper gastrointestinal tract and appropriate treatment of desmoids is decisive for the prognosis (e12). A European team of experts recently proposed recommendations for prevention of MAP (13). In respect of extraintestinal malignancies, specific preventive measures do not seem to be justified (e20).

In juvenile polyposis syndrome, because of the significant genotype–phenotype relationships, gastric endoscopies could perhaps be reduced in future in patients with a BMPR1A mutation. In carriers of the SMAD4 mutation, however, the occurence of symptoms of hereditary hemorrhagic telangiectasia must be considered. For PJS, the start and extent of a surveillance program have yet to be validated. In the end, it comes down to protocols agreed with the affected individuals.

Future research
In mutation-negative polyposis, a genetic cause is probable because the occurrence of numerous polyps cannot be satisfactorily explained by exogenous factors. Knowledge of the underlying hereditary factors has major significance for our understanding of how gastrointestinal tumors arise and for counseling of the affected families. In addition to modern chip-based methods (SNP arrays), close collaboration between human geneticists, pathologists and gastroenterologists will be necessary for new genetic dispositions to be identified.

Practical diagnostic procedure
Colonoscopy is used to elucidate the cause of stool abnormalities, a suggestive family history, or specific extraintestinal findings. Referral for molecular genetic testing should be done in a targeted manner after appropriate endoscopic and histological workup has been carried out. If nosological doubt remains, obtaining a second opinion on the polyps from a pathologist with gastroenterological expertise is recommended, along with looking for extraintestinal symptoms and consulting with the testing laboratory, in order to rule out unnecessary investigations. Mutation testing requires about 10 mL uncooled EDTA blood (6). Detailed clinical information is important in order to determine the examination strategy and interpret the findings.

Diagnosis of a polyposis syndrome, and especially predictive testing, should always be accompanied by the offer of genetic counseling (22, e36). Predictive testing of minors should not be done until the results could lead to treatment or preventive measures such as screening in the immediate future (23, e37). The address of the nearest genetic counseling center will be found on the internet (24). National self-help groups exist for FAP and MAP (25).

Acknowledgements
The Hereditary Polyposis Syndromes Working Group at the Institute for Human Genetics, Bonn University Hospital, has long been supported, and still is supported, by the German Cancer Society (Deutsche Krebshilfe e.V.), project no. 108421.

Conflict of interest statement
The author declares that no conflict of interest exists according to the guidelines of the International Committee of Medical Journal Editors.

Manuscript submitted on 28 April 2009, revised version accepted on
15 July 2009.

Translated from the original German by Kersti Wagstaff, MA


Corresponding author
PD Dr. med. Stefan Aretz
Institut für Humangenetik
Biomedizinisches Zentrum (BMZ)
Universitätsklinikum Bonn
Siegmund-Freud-Str. 25
53127 Bonn, Germany
Stefan.Aretz@uni-bonn.de


@For e-references please refer to:
www.aerzteblatt-international.de/ref1010
eFigure and eTable available at:
www.aerzteblatt-international.de/article10m0163
1.
Schulmann K, Pox C, Tannapfel A, Schmiegel W: The patient with multiple intestinal polyps. Best Pract Res Clin Gastroenterol 2007; 21: 409–26. MEDLINE
2.
Bronner MP: Gastrointestinal polyposis syndromes. Am J Med Genet A 2003; 122A: 335–41. MEDLINE
3.
Friedl W, Kruse R, Jungck M, et al.: Hamartomatöse Polyposis-Syndrome. Dtsch Arztebl 1999; 96: A 2285–91. VOLLTEXT
4.
Zbuk KM, Eng C: Hamartomatous polyposis syndromes. Nat Clin Pract Gastroenterol Hepatol 2007; 4: 492–502. MEDLINE
5.
Jass JR: Colorectal polyposes: from phenotype to diagnosis. Pathol Res Pract 2008; 204: 431–47. MEDLINE
6.
Aretz S, Propping P, Noethen M: Indikationen zur molekulargenetischen Diagnostik bei erblichen Krankheiten. Dtsch Arztebl 2006; 103: A 550–8. VOLLTEXT
7.
Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 2005; 26: 513–9. MEDLINE
8.
Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet 2007; 44: 702–9. MEDLINE
9.
Friedl W, Lamberti C: Familiäre Adenomatöse Polyposis. In: Ganten D, Ruckpaul K (eds.): Molekularmedizinische Grundlagen von hereditären Tumorerkrankungen. Berlin, Heidelberg, New York: Springer 2001: 303–29.
10.
Galiatsatos P, Foulkes WD: Familial adenomatous polyposis. Am J Gastroenterol 2006; 101: 385–98. MEDLINE
11.
Aretz S, Stienen D, Friedrichs N, et al.: Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP). Hum Mutat 2007; 28: 985–92. MEDLINE
12.
Knudsen AL, Bisgaard ML, Bulow S: Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer 2003; 2: 43–55. MEDLINE
13.
Vasen HF, Moslein G, Alonso A, Aretz S, Bernstein I, Bertario L, et al.: Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008; 57: 704–13. MEDLINE
14.
Friedl W, Caspari R, Sengteller M, et al.: Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut 2001; 48: 515–21. MEDLINE
15.
Aretz S, Uhlhaas S, Goergens H, et al.: MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer 2006; 119: 807–14. MEDLINE
16.
Gustafson S, Zbuk KM, Scacheri C, Eng C: Cowden syndrome. Semin Oncol 2007; 34: 428–34. MEDLINE
17.
Chow E, Lipton L, Lynch E, et al.: Hyperplastic polyposis syndrome: phenotypic presentations and the role of MBD4 and MYH. Gastroenterology 2006; 131: 30–9. MEDLINE
18.
Ward EM, Wolfsen HC: Review article: the non-inherited gastrointestinal polyposis syndromes. Aliment Pharmacol Ther 2002; 16: 333–42. MEDLINE
19.
Chan OT, Haghighi P: Hamartomatous polyps of the colon: ganglioneuromatous, stromal, and lipomatous. Arch Pathol Lab Med 2006; 130: 1561–6. MEDLINE
20.
Schmiegel W, Reinacher-Schick A, Arnold D, et al.: Aktualisierte S3-Leitlinie Kolorektales Karzinom. Z Gastroenterol 2008; 46: 799–840. MEDLINE
21.
Levin B, Lieberman DA, McFarland B, et al.: Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology 2008; 134: 1570–95. MEDLINE
22.
Bundes­ärzte­kammer: Richtlinien zur Diagnostik der genetischen Disposition für Krebserkrankungen. Dtsch Arztebl 1998; 95: A 1396–403. VOLLTEXT
23.
Bundes­ärzte­kammer. Richtlinien zur prädiktiven genetischen Diagnostik. Dtsch Arztebl 2003; 100: A 1297–305. VOLLTEXT
24.
Deutsche Gesellschaft für Humangenetik (GfH): Genetische Beratungsstellen.
e1.
Clark JC, Collan Y, Eide TJ, et al.: Prevalence of polyps in an autopsy series from areas with varying incidence of large-bowel cancer. Int J Cancer 1985; 36: 179–86. MEDLINE
e2.
Ransohoff DF, Lang CA: Screening for colorectal cancer. N Engl J Med 1991; 325: 37–41. MEDLINE
e3.
Rex DK, Lehman GA, Ulbright TM, et al.: Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am J Gastroenterol 1993; 88: 825–31. MEDLINE
e4.
Lowichik A, Jackson WD, Coffin CM: Gastrointestinal polyposis in childhood: clinicopathologic and genetic features. Pediatr Dev Pathol 2003; 6: 371–91. MEDLINE
e5.
Gatalica Z, Torlakovic E: Pathology of the hereditary colorectal carcinoma. Fam Cancer 2008; 7: 15–26. MEDLINE
e6.
Snover DC, Jass JR, Fenoglio-Preiser C, Batts KP: Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol 2005; 124: 380–91. MEDLINE
e7.
Bülow S: Results of national registration of familial adenomatous polyposis. Gut 2003; 52: 742–6. MEDLINE
e8.
Hes FJ, Nielsen M, Bik EC, et al.: Somatic APC mosaicism: An underestimated cause of polyposis coli. Gut 2008; 57: 71–76. MEDLINE
e9.
Offerhaus GJ, Giardiello FM, Krush AJ, et al.: The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology 1992; 102: 1980–2. MEDLINE
e10.
Will OC, Man RF, Phillips RK, Tomlinson IP, Clark SK: Familial adenomatous polyposis and the small bowel: a loco-regional review and current management strategies. Pathol Res Pract 2008; 204: 449–58. MEDLINE
e11.
Bülow S, Bjork J, Christensen IJ, et al.: Duodenal adenomatosis in familial adenomatous polyposis. Gut 2004; 53: 381–6. MEDLINE
e12.
Peterschulte G, Lickfeld T, Moslein G: Das Desmoid-Problem. Chirurg 2000; 71: 894–903. MEDLINE
e13.
Aretz S, Koch A, Uhlhaas S, et al.: Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations? Pediatr Blood Cancer 2006; 47: 811–8. MEDLINE
e14.
Nieuwenhuis MH, Vasen HF: Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol 2007; 61: 153–61. MEDLINE
e15.
Aretz S, Uhlhaas S, Sun Y, et al.: Familial adenomatous polyposis: aberrant splicing due to missense or silent mutations in the APC gene. Hum Mutat 2004; 24: 370–80. MEDLINE
e16.
Al-Tassan N, Chmiel NH, Maynard J, et al.: Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat Genet 2002; 30: 227–32. MEDLINE
e17.
Sampson JR, Dolwani S, Jones S, et al.: Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 2003; 362: 39–41. MEDLINE
e18.
Sieber OM, Lipton L, Crabtree M, et al.: Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003; 348: 791–9. MEDLINE
e19.
Farrington SM, Tenesa A, Barnetson R, et al.: Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet 2005; 77: 112–9. MEDLINE
e20.
Vogt S, Jones N, Christian D, et al.: Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 2009; 137: 1976–85. MEDLINE
e21.
Cleary SP, Cotterchio M, Jenkins MA, et al.: Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology 2009; 136: 1251–60. MEDLINE
e22.
Jones N, Vogt S, Nielsen M, et al.: Cancer risks in MUTYH heterozygotes: increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology 2009; 137: 489–94. MEDLINE
e23.
Back W, Loff S, Dippel E, Friedl W, Jenne D, Bleyl U: Die labialen und oralen Pigmentflecken des Peutz-Jeghers-Syndroms. Aktuelle Dermatologie 2002; 28: 156–60.
e24.
Moore RT, Chae KA, Rhodes AR: Laugier and Hunziker pigmentation: a lentiginous proliferation of melanocytes. J Am Acad Dermatol 2004; 50(5 Suppl): 70–4. MEDLINE
e25.
Hinds R, Philp C, Hyer W, Fell JM: Complications of childhood Peutz-Jeghers syndrome: implications for pediatric screening. J Pediatr Gastroenterol Nutr 2004; 39: 219–20. MEDLINE
e26.
Doxey BW, Kuwada SK, Burt RW: Inherited polyposis syndromes: molecular mechanisms, clinicopathology, and genetic testing. Clin Gastroenterol Hepatol 2005; 3: 633–41. MEDLINE
e27.
Delnatte C, Sanlaville D, Mougenot JF, et al.: Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes. Am J Hum Genet 2006; 78: 1066–74. MEDLINE
e28.
Gallione CJ, Repetto GM, Legius E, et al.: A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004; 363: 852–9. MEDLINE
e29.
Sweet K, Willis J, Zhou XP, et al.: Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 2005; 294: 2465–73. MEDLINE
e30.
Jaeger E, Webb E, Howarth K, et al.: Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet 2008; 40: 26–8. MEDLINE
e31.
Banks PM: Gastrointestinal lymphoproliferative disorders. Histopathology 2007; 50: 42–54. MEDLINE
e32.
Levine JS, Ahnen DJ: Clinical practice. Adenomatous polyps of the colon. N Engl J Med 2006; 355: 2551–7. MEDLINE
e33.
Giardiello FM, Brensinger JD, Petersen GM: AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001; 121: 198–213. MEDLINE
e34.
Schmiegel W, Pox C, Adler G, et al.: S3-Leitlinienkonferenz „Kolorektales Karzinom“ 2004. Z Gastroenterol 2004; 42: 1129–77. MEDLINE
e35.
Jarvinen HJ: Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival. Gut 1992; 33: 357–60. MEDLINE
e36.
Deutsche Gesellschaft für Humangenetik (GfH). Leitlinien zur genetischen Beratung. medgen 2007; 19: 452–3.
e37.
Deutsche Gesellschaft für Humangenetik (GfH). Genetische Diagnostik bei Kindern und Jugendlichen. medgen 2007; 19: 454–5.
e38.
Toro JR, Glenn G, Duray P, et al.: Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia. Arch Dermatol 1999; 135: 1195–202. MEDLINE
e39.
Zbar B, Alvord WG, Glenn G, et al.: Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev 2002; 11: 393–400. MEDLINE
e40.
Howe JR, Mitros FA, Summers RW: The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 1998; 5: 751–6. MEDLINE
e41.
McGarrity TJ, Amos C: Peutz-Jeghers syndrome: clinicopathology and molecular alterations. Cell Mol Life Sci 2006; 63: 2135–44. MEDLINE
e42.
Padberg BC, Emmermann A, Zornig C, Germer M, Schröder S: Leiomyomatose des Rektums. Fallbericht und Literaturübersicht. Pathologe 2007; 28: 161–5. MEDLINE
e43.
Goel A, Tiwari B, Kujur S, Ganguly PK: Pneumatosis cystoides intestinalis. Surgery 2005; 137: 659–60. MEDLINE
e44.
Mills CS, Lloyd TV, van Aman ME, Lucas J: Diffuse hemangiomatosis of the colon. J Clin Gastroenterol 1985; 7: 416–21. MEDLINE
Institut für Humangenetik, Universitätsklinikum Bonn: PD Dr. med. Aretz
1. Schulmann K, Pox C, Tannapfel A, Schmiegel W: The patient with multiple intestinal polyps. Best Pract Res Clin Gastroenterol 2007; 21: 409–26. MEDLINE
2. Bronner MP: Gastrointestinal polyposis syndromes. Am J Med Genet A 2003; 122A: 335–41. MEDLINE
3. Friedl W, Kruse R, Jungck M, et al.: Hamartomatöse Polyposis-Syndrome. Dtsch Arztebl 1999; 96: A 2285–91. VOLLTEXT
4. Zbuk KM, Eng C: Hamartomatous polyposis syndromes. Nat Clin Pract Gastroenterol Hepatol 2007; 4: 492–502. MEDLINE
5. Jass JR: Colorectal polyposes: from phenotype to diagnosis. Pathol Res Pract 2008; 204: 431–47. MEDLINE
6. Aretz S, Propping P, Noethen M: Indikationen zur molekulargenetischen Diagnostik bei erblichen Krankheiten. Dtsch Arztebl 2006; 103: A 550–8. VOLLTEXT
7. Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 2005; 26: 513–9. MEDLINE
8. Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet 2007; 44: 702–9. MEDLINE
9. Friedl W, Lamberti C: Familiäre Adenomatöse Polyposis. In: Ganten D, Ruckpaul K (eds.): Molekularmedizinische Grundlagen von hereditären Tumorerkrankungen. Berlin, Heidelberg, New York: Springer 2001: 303–29.
10. Galiatsatos P, Foulkes WD: Familial adenomatous polyposis. Am J Gastroenterol 2006; 101: 385–98. MEDLINE
11. Aretz S, Stienen D, Friedrichs N, et al.: Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP). Hum Mutat 2007; 28: 985–92. MEDLINE
12. Knudsen AL, Bisgaard ML, Bulow S: Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer 2003; 2: 43–55. MEDLINE
13. Vasen HF, Moslein G, Alonso A, Aretz S, Bernstein I, Bertario L, et al.: Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008; 57: 704–13. MEDLINE
14. Friedl W, Caspari R, Sengteller M, et al.: Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut 2001; 48: 515–21. MEDLINE
15. Aretz S, Uhlhaas S, Goergens H, et al.: MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer 2006; 119: 807–14. MEDLINE
16. Gustafson S, Zbuk KM, Scacheri C, Eng C: Cowden syndrome. Semin Oncol 2007; 34: 428–34. MEDLINE
17. Chow E, Lipton L, Lynch E, et al.: Hyperplastic polyposis syndrome: phenotypic presentations and the role of MBD4 and MYH. Gastroenterology 2006; 131: 30–9. MEDLINE
18. Ward EM, Wolfsen HC: Review article: the non-inherited gastrointestinal polyposis syndromes. Aliment Pharmacol Ther 2002; 16: 333–42. MEDLINE
19. Chan OT, Haghighi P: Hamartomatous polyps of the colon: ganglioneuromatous, stromal, and lipomatous. Arch Pathol Lab Med 2006; 130: 1561–6. MEDLINE
20. Schmiegel W, Reinacher-Schick A, Arnold D, et al.: Aktualisierte S3-Leitlinie Kolorektales Karzinom. Z Gastroenterol 2008; 46: 799–840. MEDLINE
21. Levin B, Lieberman DA, McFarland B, et al.: Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology 2008; 134: 1570–95. MEDLINE
22. Bundes­ärzte­kammer: Richtlinien zur Diagnostik der genetischen Disposition für Krebserkrankungen. Dtsch Arztebl 1998; 95: A 1396–403. VOLLTEXT
23. Bundes­ärzte­kammer. Richtlinien zur prädiktiven genetischen Diagnostik. Dtsch Arztebl 2003; 100: A 1297–305. VOLLTEXT
24. Deutsche Gesellschaft für Humangenetik (GfH): Genetische Beratungsstellen.
25. Familienhilfe Polyposis Coli e.V.
e1. Clark JC, Collan Y, Eide TJ, et al.: Prevalence of polyps in an autopsy series from areas with varying incidence of large-bowel cancer. Int J Cancer 1985; 36: 179–86. MEDLINE
e2. Ransohoff DF, Lang CA: Screening for colorectal cancer. N Engl J Med 1991; 325: 37–41. MEDLINE
e3. Rex DK, Lehman GA, Ulbright TM, et al.: Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am J Gastroenterol 1993; 88: 825–31. MEDLINE
e4. Lowichik A, Jackson WD, Coffin CM: Gastrointestinal polyposis in childhood: clinicopathologic and genetic features. Pediatr Dev Pathol 2003; 6: 371–91. MEDLINE
e5. Gatalica Z, Torlakovic E: Pathology of the hereditary colorectal carcinoma. Fam Cancer 2008; 7: 15–26. MEDLINE
e6. Snover DC, Jass JR, Fenoglio-Preiser C, Batts KP: Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol 2005; 124: 380–91. MEDLINE
e7. Bülow S: Results of national registration of familial adenomatous polyposis. Gut 2003; 52: 742–6. MEDLINE
e8. Hes FJ, Nielsen M, Bik EC, et al.: Somatic APC mosaicism: An underestimated cause of polyposis coli. Gut 2008; 57: 71–76. MEDLINE
e9. Offerhaus GJ, Giardiello FM, Krush AJ, et al.: The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology 1992; 102: 1980–2. MEDLINE
e10. Will OC, Man RF, Phillips RK, Tomlinson IP, Clark SK: Familial adenomatous polyposis and the small bowel: a loco-regional review and current management strategies. Pathol Res Pract 2008; 204: 449–58. MEDLINE
e11. Bülow S, Bjork J, Christensen IJ, et al.: Duodenal adenomatosis in familial adenomatous polyposis. Gut 2004; 53: 381–6. MEDLINE
e12. Peterschulte G, Lickfeld T, Moslein G: Das Desmoid-Problem. Chirurg 2000; 71: 894–903. MEDLINE
e13. Aretz S, Koch A, Uhlhaas S, et al.: Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations? Pediatr Blood Cancer 2006; 47: 811–8. MEDLINE
e14. Nieuwenhuis MH, Vasen HF: Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol 2007; 61: 153–61. MEDLINE
e15. Aretz S, Uhlhaas S, Sun Y, et al.: Familial adenomatous polyposis: aberrant splicing due to missense or silent mutations in the APC gene. Hum Mutat 2004; 24: 370–80. MEDLINE
e16. Al-Tassan N, Chmiel NH, Maynard J, et al.: Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat Genet 2002; 30: 227–32. MEDLINE
e17. Sampson JR, Dolwani S, Jones S, et al.: Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 2003; 362: 39–41. MEDLINE
e18. Sieber OM, Lipton L, Crabtree M, et al.: Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003; 348: 791–9. MEDLINE
e19. Farrington SM, Tenesa A, Barnetson R, et al.: Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet 2005; 77: 112–9. MEDLINE
e20. Vogt S, Jones N, Christian D, et al.: Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 2009; 137: 1976–85. MEDLINE
e21. Cleary SP, Cotterchio M, Jenkins MA, et al.: Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology 2009; 136: 1251–60. MEDLINE
e22. Jones N, Vogt S, Nielsen M, et al.: Cancer risks in MUTYH heterozygotes: increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology 2009; 137: 489–94. MEDLINE
e23. Back W, Loff S, Dippel E, Friedl W, Jenne D, Bleyl U: Die labialen und oralen Pigmentflecken des Peutz-Jeghers-Syndroms. Aktuelle Dermatologie 2002; 28: 156–60.
e24. Moore RT, Chae KA, Rhodes AR: Laugier and Hunziker pigmentation: a lentiginous proliferation of melanocytes. J Am Acad Dermatol 2004; 50(5 Suppl): 70–4. MEDLINE
e25. Hinds R, Philp C, Hyer W, Fell JM: Complications of childhood Peutz-Jeghers syndrome: implications for pediatric screening. J Pediatr Gastroenterol Nutr 2004; 39: 219–20. MEDLINE
e26. Doxey BW, Kuwada SK, Burt RW: Inherited polyposis syndromes: molecular mechanisms, clinicopathology, and genetic testing. Clin Gastroenterol Hepatol 2005; 3: 633–41. MEDLINE
e27. Delnatte C, Sanlaville D, Mougenot JF, et al.: Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes. Am J Hum Genet 2006; 78: 1066–74. MEDLINE
e28. Gallione CJ, Repetto GM, Legius E, et al.: A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004; 363: 852–9. MEDLINE
e29. Sweet K, Willis J, Zhou XP, et al.: Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 2005; 294: 2465–73. MEDLINE
e30. Jaeger E, Webb E, Howarth K, et al.: Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet 2008; 40: 26–8. MEDLINE
e31. Banks PM: Gastrointestinal lymphoproliferative disorders. Histopathology 2007; 50: 42–54. MEDLINE
e32. Levine JS, Ahnen DJ: Clinical practice. Adenomatous polyps of the colon. N Engl J Med 2006; 355: 2551–7. MEDLINE
e33. Giardiello FM, Brensinger JD, Petersen GM: AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001; 121: 198–213. MEDLINE
e34. Schmiegel W, Pox C, Adler G, et al.: S3-Leitlinienkonferenz „Kolorektales Karzinom“ 2004. Z Gastroenterol 2004; 42: 1129–77. MEDLINE
e35. Jarvinen HJ: Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival. Gut 1992; 33: 357–60. MEDLINE
e36. Deutsche Gesellschaft für Humangenetik (GfH). Leitlinien zur genetischen Beratung. medgen 2007; 19: 452–3.
e37. Deutsche Gesellschaft für Humangenetik (GfH). Genetische Diagnostik bei Kindern und Jugendlichen. medgen 2007; 19: 454–5.
e38. Toro JR, Glenn G, Duray P, et al.: Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia. Arch Dermatol 1999; 135: 1195–202. MEDLINE
e39. Zbar B, Alvord WG, Glenn G, et al.: Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev 2002; 11: 393–400. MEDLINE
e40. Howe JR, Mitros FA, Summers RW: The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 1998; 5: 751–6. MEDLINE
e41. McGarrity TJ, Amos C: Peutz-Jeghers syndrome: clinicopathology and molecular alterations. Cell Mol Life Sci 2006; 63: 2135–44. MEDLINE
e42. Padberg BC, Emmermann A, Zornig C, Germer M, Schröder S: Leiomyomatose des Rektums. Fallbericht und Literaturübersicht. Pathologe 2007; 28: 161–5. MEDLINE
e43. Goel A, Tiwari B, Kujur S, Ganguly PK: Pneumatosis cystoides intestinalis. Surgery 2005; 137: 659–60. MEDLINE
e44. Mills CS, Lloyd TV, van Aman ME, Lucas J: Diffuse hemangiomatosis of the colon. J Clin Gastroenterol 1985; 7: 416–21. MEDLINE