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Familial Adenomatous Polyposis (familial + adenomatou_polyposi)
Selected AbstractsGenome-wide scan identifies a copy number variable region at 3q26 that regulates PPM1L in APC mutation-negative familial colorectal cancer patientsGENES, CHROMOSOMES AND CANCER, Issue 2 2010L. F. Thean Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited form of colorectal cancer (CRC) caused by mutation in the adenomatous polyposis coli (APC) gene. However, APC mutations are not detected in 10,50% of FAP patients. We searched for a new cancer gene by performing genome-wide genotyping on members of an APC mutation-negative FAP variant family and ethnicity-matched healthy controls. No common copy number change was found in all affected members using the unaffected members and healthy controls as baseline. A 111 kb copy number variable (CNV) region at 3q26.1 was shown to have copy number loss in all eight polyps compared to matched lymphocytes of two affected members. A common region of loss in all polyps, which are precursors to CRC, is likely to harbor disease-causing gene in accordance to Knudsen's "two-hit" hypothesis. There is, however, no gene within the deleted region. A 2-Mb scan of the genomic region encompassing the deleted region identified PPM1L, coding for a novel serine-threonine phosphatase in the TGF-, and BMP signaling pathways. Real-time PCR analyses indicate that the 3,UTR of PPM1L transcript was down-regulated more than two-folds in all six polyps and tumors compared to matched mucosa of the affected member. This down-regulation was not observed in APC mutation-positive FAP patients. Our results suggest that the CNV region at 3q26 harbors an element that regulates the expression of an upstream candidate tumor suppressor, PPM1L, thus providing a novel mechanism for colorectal tumorigenesis in APC mutation-negative familial CRC patients. © 2009 Wiley-Liss, Inc. [source] Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis,,HUMAN MUTATION, Issue 10 2006Sophie Lejeune Abstract Familial adenomatous polyposis has been linked to germline mutations in the APC tumor suppressor gene. However, a number of patients with familial adenomatous polyposis (with either classical or attenuated phenotype) have no APC mutation. Recently, germline mutations in the Wnt pathway component gene AXIN2 have been associated with tooth agenesis-colorectal cancer syndrome. Moreover, biallelic mutations in the base excision repair gene MUTYH have been associated with polyposis and early-onset colorectal cancer. The aim of this study was to further assess the contribution of AXIN2 and MUTYH to hereditary colorectal cancer susceptibility. AXIN2 and MUTYH genes were screened for germline mutations by PCR and direct sequencing in 39 unrelated patients with multiple adenomas or colorectal cancer without evidence of APC mutation nor mismatch repair defect. Two novel AXIN2 variants were detected in one patient with multiple adenomas, but no clearly pathogenic mutation. In contrast, nine different MUTYH mutations were detected in eight patients, including four novel mutations. Biallelic MUTYH mutations were only found in patients with multiple adenomatous polyposis (7 out of 22 (32%)). Interestingly, five MUTYH mutation carriers had a family history consistent with dominant inheritance. Moreover, one patient with biallelic MUTYH mutations presented with multiple adenomas and severe tooth agenesis. Therefore, germline mutations are rare in AXIN2 but frequent in MUTYH in patients with multiple adenomas. Our data suggest that genetic testing of MUTYH may be of interest in patients with pedigrees apparently compatible with autosomal recessive as well as dominant inheritance. © 2006 Wiley-Liss, Inc. [source] Familial adenomatous polyposis patients have high levels of arachidonic acid and docosahexaenoic acid and low levels of linoleic acid and ,-linolenic acid in serum phospholipidsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Kari Almendingen Abstract Familial adenomatous polyposis (FAP) provides a model of APC inactivation as an early genetic event for the ,85% of colorectal cancers that develop from polyps. Abnormal fatty acid composition of tissues and serum phospholipids has been linked to cancer risk. Our aim was to describe the composition of fatty acids in serum phospholipids in 38 colectomized FAP patients as compared to 160 healthy subjects. Mean fatty acid intakes were similar between the groups. Colectomy was done on average 16 years prior to inclusion, and 18% were diagnosed with colorectal cancer at colectomy. The levels (weight %) of linoleic and ,-linolenic acid were higher among the reference subjects (difference: 3.96, 95% confidence interval (CI) = 2.87, 5.04, and difference: 0.06, 95% CI = 0.04, 0.08, respectively), and the levels of arachidonic and docosahexaenoic acid were lower (difference: ,3.70, 95% CI = ,4.35, ,3.06, and difference: ,5.26, 95% CI = ,6.25, ,4.28, respectively) as compared to the FAP patients (all p , 0.0001). The abnormal fatty acid composition was not related to time since colectomy, intestinal reconstruction or history of colorectal cancer for any of the fatty acids assessed. Compositional differences in the fatty acid profile of serum phospholipids have not been described before in FAP patients. Further studies are needed to confirm these findings and assess clinical significances of a possible distorted fatty acid metabolism, including a potentially different dietary need of essential fatty acids. The relevance of these findings for APC induced cancers remains unclear. © 2006 Wiley-Liss, Inc. [source] Psychosocial issues in genetic testing for familial adenomatous polyposis: a review of the literaturePSYCHO-ONCOLOGY, Issue 8 2008K. F. L. Douma Abstract Objectives: Familial adenomatous polyposis (FAP) is characterized by the development of multiple adenomas in the colon that can lead to colorectal cancer. Being a carrier for FAP is hypothesized to have a negative impact on psychosocial well-being. This paper reviews the current literature on the psychosocial aspects of FAP. Methods: Four literature databases were used to identify all papers published between 1986 and 2007 about psychosocial and behavioral issues in FAP related to genetic testing. The following topics were reviewed: uptake and psychosocial impact of genetic testing, endoscopic screening behavior and psychosocial well-being in general. Results: Seventeen papers were identified. Across studies, genetic test uptake varied between 62 and 97%. Two out of three studies showed clinical levels of anxiety and/or depression after genetic testing. A minority of individuals were not reassured by a negative test result, and intended to continue endoscopic surveillance. Well-being (e.g. quality of life, family functioning) was found to be lower in some studies, while comparable to the general population in other studies. The studies had several shortcomings, such as mixed patient population (e.g. colorectal and breast cancer) and small sample sizes, and provided no information on other potentially important issues, such as psychosexual development. Conclusions: Future studies should employ larger sample sizes and standardized measurements. Additionally, future studies should address the long-term consequences of genetic testing for FAP, psychosexual development and consequences of FAP for the family as a whole. Copyright © 2008 John Wiley & Sons, Ltd. [source] Requirement of the tumour suppressor APC for the clustering of PSD-95 and AMPA receptors in hippocampal neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2007Atsushi Shimomura Abstract Mutations in the adenomatous polyposis coli (APC) gene are associated with familial adenomatous polyposis and sporadic colorectal tumours. The APC gene is expressed ubiquitously in various tissues, especially throughout the large intestine and central nervous system (CNS). In the CNS, the expression of the APC protein is highest during embryonic and early postnatal development. APC associates through its C-terminal region with postsynaptic density (PSD)-95, a neuronal protein that participates in synapse development. Here, we examined the involvement of APC in synaptogenesis. In cultured hippocampal neurons, both overexpression of a dominant-negative construct that disrupts the APC,PSD-95 interaction and knockdown of APC expression using small interfering RNA (siRNA) inhibited the clustering of PSD-95 and a glutamate receptor subunit, and reduced alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)-induced activity of AMPA receptors; however, the clustering of an N -methyl- d -aspartate (NMDA) receptor subunit was unaffected. These results are suggestive of APC involvement in the development of glutamatergic synapses. [source] Clinical curiosity: Cribriform-morular variant of papillary thyroid carcinoma,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 5 2006Kimberly M. Dalal MD Abstract Background. There is an increasing awareness of the association of papillary thyroid carcinoma and familial adenomatous polyposis (FAP). Although the incidence is rare, most tend to occur in women. Several authors have described a distinctive histologic variant of papillary thyroid carcinoma, the cribriform-morular variant, which is associated with FAP but also may be encountered in patients with non-FAP. This diagnosis may precede the symptoms of colorectal polyposis. Methods. A healthy 36-year-old woman was seen with a left thyroid nodule, and a 34-year-old woman with FAP was seen with a right thyroid nodule; both masses were suspicious for papillary thyroid carcinoma. Both patients underwent total thyroidectomy. Results. Pathologic examination of both specimens revealed papillary thyroid carcinoma, cribriform-morular variant. The first patient subsequently underwent colonoscopy, which was negative for polyposis. Conclusions. Patients diagnosed with the cribriform-morular variant of papillary thyroid cancer should be screened for the presence of FAP. © 2006 Wiley Periodicals, Inc. Head Neck28: 471,476, 2006 [source] MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay,HUMAN MUTATION, Issue 2 2010Sara Molatore Abstract MUTYH -associated polyposis (MAP) is a colorectal cancer syndrome, due to biallelic mutations of MUTYH. This Base Excision Repair gene encodes for a DNA glycosylase that specifically mitigates the high mutagenic potential of the 8-hydroxyguanine (8-oxodG) along the DNA. Aim of this study was to characterize the biological effects, in a mammalian cell background, of human MUTYH mutations identified in MAP patients (137insIW [c.411_416dupATGGAT; p.137insIleTrp]; R171W [c.511C>T; p.Arg171Trp]; E466del [c.1395_1397delGGA; p.Glu466del]; Y165C [c.494A>G; p.Tyr165Cys]; and G382D [c.1145G>A; p.Gly382Asp]). We set up a novel assay in which the human proteins were expressed in Mutyh,/, mouse defective cells. Several parameters, including accumulation of 8-oxodG in the genome and hypersensitivity to oxidative stress, were then used to evaluate the consequences of MUTYH expression. Human proteins were also obtained from Escherichia coli and their glycosylase activity was tested in vitro. The cell-based analysis demonstrated that all MUTYH variants we investigated were dysfunctional in Base Excision Repair. In vitro data complemented the in vivo observations, with the exception of the G382D mutant, which showed a glycosylase activity very similar to the wild-type protein. Our cell-based assay can provide useful information on the significance of MUTYH variants, improving molecular diagnosis and genetic counseling in families with mutations of uncertain pathogenicity. Hum Mutat 30:1,8, 2009. © 2009 Wiley-Liss, Inc. [source] Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP),HUMAN MUTATION, Issue 10 2007Stefan Aretz Abstract Somatic mutational mosaicism presents a challenge for both molecular and clinical diagnostics and may contribute to deviations from predicted genotype,phenotype correlations. During APC mutation screening in 1,248 unrelated patients with familial adenomatous polyposis (FAP), we identified 75 cases with an assumed or confirmed de novo mutation. Prescreening methods (protein truncation test [PTT], DHPLC) indicated the presence of somatic mosaicism in eight cases (11%). Sequencing of the corresponding fragments revealed very weak mutation signals, pointing to the presence of either nonsense or frameshift mutations at low level. All mutations were confirmed and quantified by SNaPshot analysis: in leukocyte DNA from the eight patients, the percentage of mosaicism varied between 5.5% and 77%, while the proportion of the mutation in DNA extracted from adenomas of the respective patient was consistently higher. The eight mutations identified as mosaic are localized within codons 216,1464 of the APC gene. According to the known genotype,phenotype correlation, patients with mutations in this region exhibit typical or severe FAP. However, six of the eight patients presented with an attenuated or atypical polyposis phenotype. Our data demonstrate that in a fraction of FAP patients the causative APC mutation may not be detected due to weak signals or somatic mosaicism that is restricted to tissues other than blood. SNaPshot analysis was proven to be an easy, rapid, and reliable method of confirming low-level mutations and evaluating the degree of mosaicism. Some of the deviations from the expected phenotype in FAP can be explained by the presence of somatic mosaicism. Hum Mutat 28(10), 985,992, 2007. © 2007 Wiley-Liss, Inc. [source] Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis,,HUMAN MUTATION, Issue 10 2006Sophie Lejeune Abstract Familial adenomatous polyposis has been linked to germline mutations in the APC tumor suppressor gene. However, a number of patients with familial adenomatous polyposis (with either classical or attenuated phenotype) have no APC mutation. Recently, germline mutations in the Wnt pathway component gene AXIN2 have been associated with tooth agenesis-colorectal cancer syndrome. Moreover, biallelic mutations in the base excision repair gene MUTYH have been associated with polyposis and early-onset colorectal cancer. The aim of this study was to further assess the contribution of AXIN2 and MUTYH to hereditary colorectal cancer susceptibility. AXIN2 and MUTYH genes were screened for germline mutations by PCR and direct sequencing in 39 unrelated patients with multiple adenomas or colorectal cancer without evidence of APC mutation nor mismatch repair defect. Two novel AXIN2 variants were detected in one patient with multiple adenomas, but no clearly pathogenic mutation. In contrast, nine different MUTYH mutations were detected in eight patients, including four novel mutations. Biallelic MUTYH mutations were only found in patients with multiple adenomatous polyposis (7 out of 22 (32%)). Interestingly, five MUTYH mutation carriers had a family history consistent with dominant inheritance. Moreover, one patient with biallelic MUTYH mutations presented with multiple adenomas and severe tooth agenesis. Therefore, germline mutations are rare in AXIN2 but frequent in MUTYH in patients with multiple adenomas. Our data suggest that genetic testing of MUTYH may be of interest in patients with pedigrees apparently compatible with autosomal recessive as well as dominant inheritance. © 2006 Wiley-Liss, Inc. [source] Disease-associated casein kinase I , mutation may promote adenomatous polyps formation via a Wnt/,-catenin independent mechanismINTERNATIONAL JOURNAL OF CANCER, Issue 5 2007I-Chun Tsai Abstract The Wnt signaling pathway is critical for embryonic development and is dysregulated in multiple cancers. Two closely related isoforms of casein kinase I (CKI, and ,) are positive regulators of this pathway. We speculated that mutations in the autoinhibitory domain of CKI,/, might upregulate CKI,/, activity and hence Wnt signaling and increase the risk of adenomatous polyps and colon cancer. Exons encoding the CKI, and CKI, regulatory domains were sequenced from DNA obtained from individuals with adenomatous polyps and a family history of colon cancer unaffected by familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer (HNPCC). A CKI, missense mutation, changing a highly conserved residue, Arg324, to His (R324H), was found in an individual with large and multiple polyps diagnosed at a relatively young age. Two findings indicate that this mutation is biologically active. First, ectopic ventral expression of CKI,(R324H) in Xenopus embryos results in secondary axis formation with an additional distinctive phenotype (altered morphological movements) similar to that seen with unregulated CKI,. Second, CKI,(R324H) is more potent than wildtype CKI, in transformation of RKO colon cancer cells. Although the R324H mutation does not significantly change CKI, kinase activity in an in vitro kinase assay or Wnt/,-catenin signal transduction as assessed by a ,-catenin reporter assay, it alters morphogenetic movements via a ,-catenin-independent mechanism in early Xenopus development. This novel human CKI, mutation may alter the physiological role and enhance the transforming ability of CKI, through a Wnt/,-catenin independent mechanism and thereby influence colonic adenoma development. © 2006 Wiley-Liss, Inc. [source] Dextran sodium sulfate strongly promotes colorectal carcinogenesis in ApcMin/+ mice: Inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasmsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Takuji Tanaka Abstract The mouse model for familial adenomatous polyposis, ApcMin/+ mouse, contains a truncating mutation in the Apc gene and spontaneously develops numerous adenomas in the small intestine but few in the large bowel. Our study investigated whether dextran sodium sulfate (DSS) treatment promotes the development of colonic neoplasms in ApcMin/+ mice. ApcMin/+ and Apc+/+ mice of both sexes were exposed to 2% dextran sodium sulfate in drinking water for 7 days, followed by no further treatment for 4 weeks. Immunohistochemistry for cyclooxygenase-2, inducible nitric oxide synthase, ,-catenin, p53, and nitrotyrosine, and mutations of ,- catenin and K- ras and loss of wild-type allele of the Apc gene in the colonic lesions were examined. Sequential observation of female ApcMin/+ mice that received DSS was also performed up to week 5. At week 5, numerous colonic neoplasms developed in male and female ApcMin/+ mice but did not develop in Apc+/+ mice. Adenocarcinomas developed in ApcMin/+ mice that received DSS showed loss of heterozygosity of Apc and no mutations in the ,- catenin and K- ras genes. The treatment also significantly increased the number of small intestinal polyps. Sequential observation revealed increase in the incidences of colonic neoplasms and dysplastic crypts in female ApcMin/+ mice given DSS. DSS treatment increased inflammation scores, associated with high intensity staining of ,-catenin, cyclooxygenase-2, inducible nitric oxide synthase and nitrotyrosine. Interestingly, strong nuclear staining of p53 was specifically observed in colonic lesions of ApcMin/+ mice treated with DSS. Our results suggest a strong promotion effect of DSS in the intestinal carcinogenesis of ApcMin/+ mice. The findings also suggest that strong oxidative/nitrosative stress caused by DSS-induced inflammation may contribute to the colonic neoplasms development. © 2005 Wiley-Liss, Inc. [source] Human papillomavirus-negative ileostomal chronic papillomatous dermatitisJOURNAL OF CUTANEOUS PATHOLOGY, Issue 4 2003Christy M. Williams Background:, Papillomatous stoma-related skin lesions may result from irritant reactions or infection with epidermodysplasia verruciformis human papillomavirus (HPV) types. Methods:, ,We report upon a papillomatous lesion at the ileostoma of a 63-year-old male with familial adenomatous polyposis and colorectal adenocarcinoma. We thoroughly tested the lesion for HPV using immunohistochemistry, transmission electron microscopy, and polymerase chain reaction analyses. Results:, ,The lesion was a fleshy, multilobulated, and verrucous plaque, with hyperkeratosis, hypergranulosis, acanthosis and marked papillomatosis. The clinical and light microscopic features were suggestive of a condyloma. However, no HPV was detected. Conclusions:, We suggest that the lesion most likely represents chronic papillomatous dermatitis, a reaction to mechanical and/or chemical irritation usually associated with urostomies and only rarely observed with ileostomies. This case highlights the clinical, diagnostic and therapeutic aspects of an unusual cutaneous morbidity associated with ileostomies. [source] Oral and maxillofacial manifestations of familial adenomatous polyposisORAL DISEASES, Issue 4 2007MA Wijn Patients with familial adenomatous polyposis (FAP) develop multiple premalignant colorectal adenomas. Untreated, one or more of these polyps will progress to colorectal carcinoma in middle-aged adults. Extra-intestinal manifestations of FAP are frequently observed and this combination has been called Gardner's syndrome. Oral and maxillofacial symptoms of FAP include an increased risk of jaw osteomas, odontomas and supernumerary or unerupted teeth. Early diagnosis of FAP is crucial and may be life saving. As oral signs usually precede gastrointestinal symptoms, the dentist may play an important role in the diagnosis of FAP. [source] Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations?,PEDIATRIC BLOOD & CANCER, Issue 6 2006Stefan Aretz MD Abstract Background Hepatoblastoma (HB) is the most frequent liver tumor in childhood, occurring in the first few years of life. Surgery combined with chemotherapy has resulted in dramatic improvements in prognosis. However, even today, about one quarter of affected children do not survive the disease. Compared to the general population, the risk of HB is 750,7,500 times higher in children predisposed to familial adenomatous polyposis (FAP), an autosomal-dominant cancer predispostion syndrome caused by germline mutations in the tumor suppressor gene APC. Only limited data exist about the frequency of APC germline mutations in cases of apparently sporadic HB without a family history of FAP. Procedure In our sample of 1,166 German FAP families, all known cases of HB were registered. In addition, 50 patients with apparently sporadic HB were examined for APC germline mutations. Results In the FAP families, seven unrelated cases of HB are documented; three had been detected at an advanced stage. In patients with apparently sporadic HB, germline mutations in the APC gene were identified in 10%. Conclusions These data raise the issue of the appropriate screening for HB in children of FAP patients. To date, the efficiency of surveillance for HB is unclear. In Beckwith,Wiedemann syndrome (BWS), recent studies suggest an earlier detection of both Wilms tumor and HB by frequent screening. We discuss the rationale and implications of a screening program; besides the examination procedure itself, screening for HB in children of FAP patients would have important consequences for the policy of predictive testing in FAP. In a substantial fraction of sporadic HB, the disease is obviously the first manifestation of a de novo FAP. These patients should be identified by routine APC mutation screening and undergo colorectal surveillance thereafter. Pediatric Blood Cancer 2006;47:811,818. © 2005 Wiley-Liss, Inc. [source] Psychosocial issues in genetic testing for familial adenomatous polyposis: a review of the literaturePSYCHO-ONCOLOGY, Issue 8 2008K. F. L. Douma Abstract Objectives: Familial adenomatous polyposis (FAP) is characterized by the development of multiple adenomas in the colon that can lead to colorectal cancer. Being a carrier for FAP is hypothesized to have a negative impact on psychosocial well-being. This paper reviews the current literature on the psychosocial aspects of FAP. Methods: Four literature databases were used to identify all papers published between 1986 and 2007 about psychosocial and behavioral issues in FAP related to genetic testing. The following topics were reviewed: uptake and psychosocial impact of genetic testing, endoscopic screening behavior and psychosocial well-being in general. Results: Seventeen papers were identified. Across studies, genetic test uptake varied between 62 and 97%. Two out of three studies showed clinical levels of anxiety and/or depression after genetic testing. A minority of individuals were not reassured by a negative test result, and intended to continue endoscopic surveillance. Well-being (e.g. quality of life, family functioning) was found to be lower in some studies, while comparable to the general population in other studies. The studies had several shortcomings, such as mixed patient population (e.g. colorectal and breast cancer) and small sample sizes, and provided no information on other potentially important issues, such as psychosexual development. Conclusions: Future studies should employ larger sample sizes and standardized measurements. Additionally, future studies should address the long-term consequences of genetic testing for FAP, psychosexual development and consequences of FAP for the family as a whole. Copyright © 2008 John Wiley & Sons, Ltd. [source] Determination of 3,,4,,5,,5,7-pentamethoxyflavone in the plasma and intestinal mucosa of mice by HPLC with UV detectionBIOMEDICAL CHROMATOGRAPHY, Issue 4 2009Hong Cai Abstract In a preliminary experiment 3,,4,,5,,5,7-pentamethoxyflavone (PMF) inhibited adenoma development in ApcMin mice, a model of the human heritable condition familial adenomatous polyposis. An HPLC method for tricin was modified and validated to permit measurement of PMF in mouse plasma and intestinal mucosa. HPLC analysis was carried out on a Hypersil-BDS C18 column with detection at 324 nm and tricin as internal standard. The assay was linear in the range of 100,2000 ng/mL plasma and 1.0,40 µg/mL mucosa. PMF in plasma was efficiently extracted using solid-phase columns. In the case of mucosa organic solvent protein precipitation displayed satisfactory accuracy and precision. The assay recovery at low, medium and high concentrations was between 85 and 103% for both biomatrices, with a relative standard deviation of <15%. The lower limits of quantitation for plasma and mucosa were 100 ng/mL and 1.0 µg/mL, respectively. This method allowed measurement of PMF steady-state median concentrations in plasma (1.08 nmol/mL, n = 11; 10th and 90th percentiles: 0.633 and 2.385 nmol/mL) and mucosa (108.5 nmol/g, n = 9; 10th and 90th percentiles: 38.9 and 164.4 nmol/g) in mice which had received PMF (0.2%, w/w) with their diet. Copyright © 2008 John Wiley & Sons, Ltd. [source] The concomitant occurrence of multiple epidermal cysts, osteomas and thyroid gland nodules is not diagnostic for Gardner syndrome in the absence of intestinal polyposis: a clinical and genetic reportBRITISH JOURNAL OF DERMATOLOGY, Issue 4 2003S.-M. Herrmann Summary Gardner syndrome, a phenotypic variant of familial adenomatous polyposis, is characterized by the classical clinical triad of skin and soft tissue tumours, osteomas and intestinal polyposis, but disease patterns with pairs of these findings have also been reported. Different mutations in the adenomatous polyposis coli (APC) gene have been shown to be associated with Gardner syndrome disease phenotypes. A 36-year-old patient presented with multiple epidermal cysts on the face, left ear lobe and neck, and the possible diagnosis of Gardner syndrome was based on the additional findings of two classical osteomas in the left radius and ulna and a cold non-malignant nodule of the thyroid gland. Intestinal polyposis was lacking at the time of examination. Major deletions but not microdeletions were excluded by a cytogenetic analysis with 650 chromosomal bands per haploid set. Systematic sequencing of the entire coding region of the APC gene (> 8500 bp) of the patient and five healthy controls was also performed. As a results, new APC gene polymorphisms were identified in exons 13 [A545A (A/G)] and 15 [G1678G (A/G), S1756S (G/T), P1960P (A/G)]. We also detected D1822V (A/T) which has recently been reported to be potentially related to colorectal carcinoma, and genotyped 194 randomly chosen healthy individuals from the Glasgow area for this as well as for the above variants in exons 13 and 15. Interestingly, of the 194 controls, 112 carried the DD (57·7%), 71 the DV (36·6%), and the remaining 11 (5·7%), including our patient, the VV genotype. It is therefore unlikely that APC D1822V serves as an important marker for colorectal carcinoma. In conclusion, we failed to identify obvious germline candidate mutations in >,8500 bp of the coding region of the APC gene in a patient with multiple epidermal cysts, osteomas and a thyroid gland nodule; major chromosomal deletions were excluded. Therefore, we assume that only the presence of intestinal polyposis is a marker for Gardner syndrome. [source] A 10-year review of surgery for desmoid disease associated with familial adenomatous polyposis (Br J Surg 2006; 93; 1258,1264)BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 2 2007T. E. Rix No abstract is available for this article. [source] Causes and outcomes of pouch excision after restorative proctocolectomyBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 1 2006M. Prudhomme Background: Pouch failure occurs in up to 10 per cent of patients after ileal pouch,anal anastomosis (IPAA). The aims of this study were to determine the reasons for pouch excision and to evaluate the outcome of the perineal wound after pouch excision. Methods: Between 1984 and 2002, 91 patients with severe ileal pouch dysfunction were treated. This was a retrospective analysis of data collected prospectively from 24 patients who underwent pouch excision. Results: Patients were grouped according to the final histological diagnosis. Fourteen patients with Crohn's disease developed extensive fistulous disease and/or recurrent abscesses, of whom six had a persistent perineal sinus after pouch excision. Five patients had familial adenomatous polyposis, in three of whom desmoid tumours were the cause of failure. Three patients had chronic ulcerative colitis and developed recurrent pelvic sepsis. Finally, two patients with multiple colorectal adenocarcinoma developed recurrent cancer (one) or sepsis (one). Conclusion: Sepsis was the principal reason for pouch excision and was usually associated with recrudescent Crohn's disease in the pouch. Perineal wound healing was problematic after pouch excision for Crohn's disease. Copyright © 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] A nonsense mutation in exon 8 of the APC gene (Arg283Ter) causes clinically variable FAP in a Malaysian Chinese familyCANCER SCIENCE, Issue 8 2003Zulqarnain Mohamed The present study was carried out to characterize the causative genetic mutation in a medium-sized Malaysian Chinese pedigree of three generations affected with familial adenomatous polyposis (FAP). Clinical data and genetic studies revealed considerable phenotypic variability in affected individuals in this family. Blood was obtained from members of the FAP-01 family and genomic DNA was extracted. Mutation screening of the adenomatous polyposis coli (APC) gene was carried out using the single strand conformation polymorphism (SSCP) technique. The possibility of exon skipping was predicted by splicing motif recognition software (ESEfinder release2.0). SSCP results showed mobility shifts in exon 8 of the APC gene which segregated with affected members of the family. Sequence analysis revealed that the affected individuals are heterozygous for a C847T transition, whilst all the unaffected family members and control individuals are homozygous C at the same position. This nucleotide substitution generates a stop codon at amino acid position 283, in place of the usual arginine (Arg283Ter). We conclude that an Arg283Ter mutation in the APC gene is causative of the FAP phenotype in this family, although there is considerable variation in the presentation of this disease among affected individuals. Computational analysis predicts that this mutation occurs within sequences that may function as splicing signals, so that the sequence change may affect normal splicing. [source] 2463: Phenotype/genotype in Gardner diseaseACTA OPHTHALMOLOGICA, Issue 2010S MILAZZO Purpose Gardner syndrome is a variant of familial adenomatous polyposis and results in the manifestation of external and internal symptoms including gastrointestinal polyps, osteomas, tumors, epidermoid cysts and congenital hypertrophy of retinal pigment epithelium. Methods Three families of Gardner syndrome including 23 patients underwent complete check-up to characterize ocular and general phenotype. Ophthalmologic manifestations are simple, non invasive reliable and very sensitive. The gene responsible for this disorder was localized on the long arm of the fifth chromosome. APC-associated polyposis conditions are caused by mutations in the APC gene. A subset of individuals with clinical features of FAP will instead carry a mutation in the MUTYH gene. Results Of the 23 patients, 13 presented a bilateral congenital hypertrophy of retinal pigment epithelium. In these patients 6 had a positive coloscopic exploration. This inherited autosomal dominant disorder has a marked propensity to malignant transformation, so, it is important to detect affected patients early. Conclusion Currently, there are no specific screening recommendations for Gardner syndrome, but testing following general screening recommendations for extra-colonic malignancies, genetic counseling, and endoscopy are encouraged. [source] Should ileal pouch,anal anastomosis include mucosectomy?COLORECTAL DISEASE, Issue 5 2007W. M. Chambers Abstract Objective, Debate exists as to the benefits of performing mucosectomy as part of pouch surgery for ulcerative colitis (UC) and familial adenomatous polyposis (FAP). Whilst mucosectomy results in a more complete removal of diseased mucosa, this benefit may be at the price of poorer function. We examined these issues. Method, Using Medline, Embase, Ovid and Cochrane database searches papers were identified relating to the outcome following pouch surgery with and without mucosectomy. Potential reasons for functional problems were investigated, as were rates of ,cuffitis', dysplasia, polyposis and cancer in the ileal pouch and anal canal. Results, The available evidence suggests that performing a mucosectomy leads to a worse functional outcome. Meta-analysis suggested that nighttime seepage of stool and resting and squeeze pressure were worse after mucosectomy. The most likely reason for functional impairment following pouch surgery was the degree of anal manipulation. Mucosectomy does seem to confer benefit in terms of disease control but this benefit does not reach statistical significance. Conclusion, Stapled anastomosis avoiding mucosectomy is the approach of choice for ileal pouch anal anastomosis because this leads to superior functional outcome. Performing mucosectomy results in some clinical benefits in terms of lower rates of inflammation and dysplasia in the retained mucosa in UC patients and lower rates of cuff polyposis in FAP patients. However, on the basis of available evidence mucosectomy is only indicated in those cases where the patient is at a high risk of disease in the retained rectal cuff. [source] Ileostomy carcinomas a review: the latent risk after colectomy for ulcerative colitis and familial adenomatous polyposisCOLORECTAL DISEASE, Issue 6 2005H. M. Quah Abstract Background, Ileostomy carcinoma after colectomy for ulcerative colitis and familial adenomatous polyposis is rare. Methods, Forty-three case reports from the literature and a case of ours are reviewed. Results, The risk of malignancy following ileostomy formation appears to be increased compared to the very low incidence of primary small bowel carcinoma. Chronic physical or chemical irritation of the stoma may predispose the ileal mucosa to colonic metaplasia with subsequent adenoma formation, dysplasia and invasive malignant change. This is particularly so where ileostomies are fashioned for familial adenomatous polyposis and ulcerative colitis. Conclusion, Routine surveillance of patients who have had an ileostomy for 15 years or longer may lead to earlier detection of this complication. [source] The ileo neo rectal anastomosis (INRA) in patients with familial adenomatous polyposis: clinical results at two yearsCOLORECTAL DISEASE, Issue 4 2005S. A. M. Strijbos Abstract Background, Ileo neo rectal anastomosis (INRA) is a promising alternative for patients with familial adenomatous polyposis (FAP) to restorative proctocolectomy with its morbidity and unpredictable functional outcome to colectomy with ileo rectal anastomosis (IRA) with the continuing risk of rectal cancer. The aims of the present study were to evaluate the function of the neorectum, to assess the morbidity and complications of the operation and to determine the incidence of neorectal polyps. Methods, Data of all patients having INRA, including bowel function and complications, were prospectively recorded. The reservoir capacity was determined repeatedly by physiologic tests. The anal sphincter complex was assessed by manometry and ultrasound examination. Evaluation of the neorectal mucosa was performed by endoscopy. Results, Six patients underwent the INRA procedure for FAP. Median defaecation frequency two years postoperatively was 5.5/24 h (range 4,7) including 1/night (range 0,2). Endoscopic examination showed normal mucosa and no evidence of polyp formation in all patients. Conclusion, INRA affords a good functional reservoir and is accompanied by few reservoir-related complications. At a minimum follow up period of two years, no growth of polyps in the neorectum occurred. [source] Colorectal cancer in the young: a 12-year review of patients 30 years or lessCOLORECTAL DISEASE, Issue 3 2004M. H. Kam Abstract Objectives As the incidence of young colorectal cancer is rising, a review of the characteristics of such malignancy in those under 30 years of age is timely at this stage. Patients and methods Thirty-nine patients (21 M, 18 F) were operated upon over a 12-year period in a single centre. The mean age was 25 years and median follow-up was 20 months. Results Rectal bleeding, change in bowel habit and abdominal pain were the commonest symptoms. Six patients had a positive family history, while four others were diagnosed as index cases of familial adenomatous polyposis. Rectal tumours made up 43% of all colorectal cancers diagnosed. Seventy percent of patients presented at an advanced stage, but curative resection was attempted for 29 patients. Eight underwent palliative resections, 1 had an ileostomy while another underwent a bypass procedure. Eleven patients have died, 14 had no evidence of recurrent disease while 3 were still alive with recurrent disease. Conclusion Age does not affect survival, and early endoscopy is recommended for all with persistent symptoms. Early diagnosis, radical resection and adjuvant therapy still form the cornerstone in management of colorectal cancer in this age group. [source] | ||||||||||||||||||||||||||||