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Giovanni Ponti - One of the best experts on this subject based on the ideXlab platform.
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Muir Torre Syndrome and founder mismatch repair gene mutations a long gone historical genetic challenge
Gene, 2016Co-Authors: Giovanni Ponti, Marco Manfredini, Aldo Tomasi, Giovanni PellacaniAbstract:A "cancer predisposing Syndrome" later labeled as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome, was firstly described by Warthin, about one century ago. An increased predisposition to the development of multiple familial tumors is described as characteristic of this Syndrome where visceral and cutaneous malignancies may appear at an early age namely endometrial, gastric, small bowel, ureteral and renal pelvis, ovarian, hepatobiliary tract, pancreatic, brain (Turcot Syndrome) and sebaceous glands (Muir-Torre Syndrome). The latter, a variant of Lynch Syndrome, is characterized by the presence of sebaceous skin adenomas, carcinomas and/or keratoacanthomas associated with visceral malignancies. Both Lynch Syndrome and Muir-Torre Syndrome have been recognized due to germline mutations in mismatch repair genes MLH1, MSH2 and MSH6. To date, 56 Lynch Syndrome founder mutations dependent on MLH1, MSH2 and, although less frequently found, MSH6 and PMS2 are described. Some of these founder mutations, principally of MSH2 gene, have been described to cause Muir-Torre phenotype and have been traced in large and outbreed Muir-Torre Syndrome families living in different US and European territories. Due to the evidences of highly specific Muir-Torre phenotypes related to the presence of widespread MSH2 founder mutations, preliminary search for these MSH2 common mutations in individuals carrying sebaceous tumors and/or keratoacanthomas, at early age or in association to visceral and familial tumors, permits cost-effective and time-saving diagnostic strategies for Lynch/Muir-Torre Syndromes.
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Muir Torre Syndrome
Lancet Oncology, 2005Co-Authors: Giovanni Ponti, Maurizio Ponz De LeonAbstract:Muir-Torre Syndrome is an autosomal-dominant skin condition of genetic origin, characterised by tumours of the sebaceous gland or keratoacanthoma that are associated with visceral malignant diseases. The cutaneous characteristics of Muir-Torre Syndrome are sebaceous adenoma, epithelioma, carcinoma, or multiple keratoacanthomas, whereas visceral malignant diseases include colorectal, endometrial, urological, and upper gastrointestinal tumours. Although Muir-Torre Syndrome has a striking familial association and features of autosomal-dominant transmission, it can arise in individuals without a family history or any known mutations. Clinical and biomolecular evidence has suggested that there are two types of Muir-Torre Syndrome. The most common is a variant of hereditary non-polyposis colorectal cancer, which is characterised by defects in mismatch repair genes and early-onset tumours. The second type does not show deficiency in mismatch repair and its pathogenesis remains undefined. Diagnosis of these rare sebaceous lesions warrants the search for associated internal malignant diseases: the peculiarity of skin lesions and their biomolecular characterisation with microsatellite instability analysis and immunohistochemistry could be used to identify familial Muir-Torre Syndrome, allowing clinicians to tailor a personalised programme to screen for skin and visceral malignant diseases in high-risk individuals.
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attenuated familial adenomatous polyposis and Muir Torre Syndrome linked to compound biallelic constitutional myh gene mutations
Clinical Genetics, 2005Co-Authors: Giovanni Ponti, Ponz M De Leon, Stefania Maffei, Monica Pedroni, Lorena Losi, C Di Gregorio, Viviana Gismondi, A Scarselli, Piero Benatti, B RoncariAbstract:Attenuated familial adenomatous polyposis and Muir-Torre Syndrome linked to compound biallelic constitutional MYH gene mutations.Peculiar dermatologic manifestations are present in several heritable gastrointestinal disorders. Muir-Torre Syndrome (MTS) is a genodermatosis whose peculiar feature is the presence of sebaceous gland tumors associated with visceral malignancies. We describe one patient in whom multiple sebaceous gland tumors were associated with early onset colon and thyroid cancers and attenuated polyposis coli. Her family history was positive for colonic adenomas. She had a daughter presenting with yellow papules in the forehead region developed in the late infancy. Skin and visceral neoplasms were tested for microsatellite instability and immunohistochemical status of mismatch repair (MMR), APC and MYH proteins. The proband colon and skin tumors were microsatellite stable and showed normal expression of MMR proteins. Cytoplasmic expression of MYH protein was revealed in colonic cancer cells. Compound heterozygosity due to biallelic mutations in MYH, R168H and 379delC, was identified in the proband. The 11-year-old daughter was carrier of the monoallelic constitutional mutation 379delC in the MYH gene; in the sister, the R168H MYH gene mutation was detected. This report presents an interesting case of association between MYH-associated polyposis and sebaceous gland tumors. These findings suggest that patients with MTS phenotype that include colonic polyposis should be screened for MYH gene mutations.
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different phenotypes in Muir Torre Syndrome clinical and biomolecular characterization in two italian families
British Journal of Dermatology, 2005Co-Authors: Giovanni Ponti, Ponz M De Leon, Monica Pedroni, Lorena Losi, C Di Gregorio, A Scarselli, Piero Benatti, G Riegler, L Lembo, Giovanni PellacaniAbstract:The Muir-Torre Syndrome (MTS) is an autosomal dominant genodermatosis characterized by the presence of sebaceous gland tumours, with or without keratoacanthomas, associated with visceral malignancies. We describe and characterize two families in which the ample phenotypic variability of MTS was evident. After clinical evaluation, the skin and visceral tumours of one member of a family with 'classic' MTS and one member of a family with a 'peculiar' MTS phenotype without sebaceous lesions, but with only multiple keratoacanthomas, were analysed for microsatellite instability (MSI) and by immunohistochemistry. Tumours of both individuals showed MSI, with a concomitant lack of MSH2 immunostaining in all evaluated skin and visceral lesions; moreover, in the proband of family 2 a constitutional mutation (C-->T substitution leading to a stop codon) in the MSH2 gene was identified. We conclude that the diagnosis of MTS, which is mainly clinical, should take into account an ample phenotypic variability, which includes both cases with typical cancer aggregation in families and cases characterized by the association of visceral malignancies with multiple keratoacanthomas (without sebaceous lesions), without an apparent family history of cancer.
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identification of Muir Torre Syndrome among patients with sebaceous tumors and keratoacanthomas role of clinical features microsatellite instability and immunohistochemistry
Cancer, 2005Co-Authors: Giovanni Ponti, Giovanni Pellacani, Monica Pedroni, Lorena Losi, A Scarselli, Piero Benatti, Carmela Di Gregorio, Luca Roncucci, Stefania Seidenari, L LemboAbstract:BACKGROUND The Muir–Torre Syndrome (MTS) is an autosomal-dominant genodermatosis characterized by the presence of sebaceous gland tumors, with or without keratoacanthomas, associated with visceral malignancies. A subset of patients with MTS is considered a variant of the hereditary nonpolyposis colorectal carcinoma, which is caused by mutations in mismatch-repair genes. The objective of the current study was to evaluate whether a combined clinical, immunohistochemical, and biomolecular approach could be useful for the identification of Muir–Torre Syndrome among patients with a diagnosis of sebaceous tumors and keratoacanthomas. METHODS The authors collected sebaceous skin lesions and keratoacanthomas recorded in the files of the Pathology Department of the University of Modena during the period 1986–2000. Through interviews and examination of clinical charts, family trees were drawn for 120 patients who were affected by these skin lesions. RESULTS Seven patients also were affected by gastrointestinal tumors, thus meeting the clinical criteria for the diagnosis of MTS. In the MTS families, a wide phenotypic variability was evident, both in the spectrum of visceral tumors and in the type of skin lesions. Microsatellite instability was found in five MTS patients: These patients showed concordance with immunohistochemical analysis; moreover, a constitutional mutation in the MSH2 gene was found in 1 patient. Lack of expression of MSH2/MSH6 or MLH1 proteins was evident in the skin lesions and in the associated internal malignancies of 3 patients and 2 patients with MTS, respectively. CONCLUSIONS The clinical, biomolecular, and immunohistochemical characterization of sebaceous skin lesions and keratoacanthomas may be used as screening for the identification of families at risk of MTS, a disease that is difficult to recognize and diagnose. Cancer 2005. © 2005 American Cancer Society.
Marie-odile Joly - One of the best experts on this subject based on the ideXlab platform.
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A case report of Muir-Torre Syndrome in a woman with breast cancer and MSI-Low skin squamous cell carcinoma
Hereditary Cancer in Clinical Practice, 2017Co-Authors: Caroline Kientz, Marie-odile Joly, Laurence Faivre, Alix Clemenson, Sophie Dalac, Côme Lepage, Caroline Chapusot, Caroline Jacquot, Renaud Schiappa, Marine LebrunAbstract:Background The tumor spectrum in the Lynch Syndrome is well defined, comprising an increased risk of developing colonic and extracolonic malignancies. Muir-Torre Syndrome is a variant with a higher risk of skin disease. Patients have been described carrying mutations in the mismatch repair genes and presenting tumors with unusual histology or affected organ not part of the Lynch Syndrome spectrum. Hence, the real link between Lynch Syndrome, or Muir-Torre Syndrome, and these tumors remains difficult to assess. Case presentation We present the case of a 45-year-old-woman, diagnosed with breast cancer at 39 years of age and skin squamous cell carcinoma (SCC) at 41 years of age, without personal history of colorectal cancer. The microsatellite instability analysis performed on the skin SCC showed a low-level of microsatellite instability (MSI-Low). The immunohistochemical expression analysis of the four DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 showed a partial loss of the expression of MSH2 and MSH6 proteins. Germline deletion was found in MSH2 gene (c.1277-? _1661 + ?del), exon 8 to 10. Then, at 45 years of age, she presented hyperplastic polyps of the colon and a sebaceous adenoma. Conclusion Squamous cell carcinomas have been described in Lynch Syndrome and Muir-Torre Syndrome in two studies and two case reports. This new case further supports a possible relationship between Lynch Syndrome and squamous cell carcinoma.
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a case report of Muir Torre Syndrome in a woman with breast cancer and msi low skin squamous cell carcinoma
Hereditary Cancer in Clinical Practice, 2017Co-Authors: Caroline Kientz, Marie-odile Joly, Laurence Faivre, Alix Clemenson, Sophie Dalac, Côme Lepage, Caroline Chapusot, Caroline Jacquot, Renaud SchiappaAbstract:The tumor spectrum in the Lynch Syndrome is well defined, comprising an increased risk of developing colonic and extracolonic malignancies. Muir-Torre Syndrome is a variant with a higher risk of skin disease. Patients have been described carrying mutations in the mismatch repair genes and presenting tumors with unusual histology or affected organ not part of the Lynch Syndrome spectrum. Hence, the real link between Lynch Syndrome, or Muir-Torre Syndrome, and these tumors remains difficult to assess. We present the case of a 45-year-old-woman, diagnosed with breast cancer at 39 years of age and skin squamous cell carcinoma (SCC) at 41 years of age, without personal history of colorectal cancer. The microsatellite instability analysis performed on the skin SCC showed a low-level of microsatellite instability (MSI-Low). The immunohistochemical expression analysis of the four DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 showed a partial loss of the expression of MSH2 and MSH6 proteins. Germline deletion was found in MSH2 gene (c.1277-? _1661 + ?del), exon 8 to 10. Then, at 45 years of age, she presented hyperplastic polyps of the colon and a sebaceous adenoma. Squamous cell carcinomas have been described in Lynch Syndrome and Muir-Torre Syndrome in two studies and two case reports. This new case further supports a possible relationship between Lynch Syndrome and squamous cell carcinoma.
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somatic mmr gene mutations as a cause for msi h sebaceous neoplasms in Muir Torre Syndrome like patients
Human Mutation, 2015Co-Authors: Marie-odile Joly, Laurence Faivre, Valery Attignon, Jeanchristophe Saurin, Francoise Desseigne, Dominique Leroux, Tanguy Martindenavit, Sophie Giraud, M N Bonnetdupeyron, Jessie AuclairAbstract:Sebaceous neoplasms are a major clinical feature of Muir-Torre Syndrome (MTS) associated with visceral malignancies, especially colorectal and endometrial tumors. The diagnosis of MTS relies largely on the microsatellite instability (MSI) phenotype in tumors, suggesting germline mutations in DNA mismatch repair (MMR) genes responsible for the inherited disease. We hypothesized that in some MSI-H sebaceous tumors, acquired rather than inherited mutations in MMR genes could be involved. Using next-generation sequencing, we screened MMR gene mutations in 18 MSI-H sebaceous tumors. We found mutations in 17 samples (94%). Indeed, 12/17 (71%) were shown to carry acquired somatic mutations and among 12 samples, seven were shown to be associated with additional somatic alterations like loss of heterozygosity or multiple mutations, suggesting somatic second hits. Our findings strongly suggest that somatic MMR deficiency is responsible for a proportion of MSI-H sebaceous tumors.
Jonathan Wright - One of the best experts on this subject based on the ideXlab platform.
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Muir Torre Syndrome case report of a patient with concurrent jejunal and ureteral cancer and a review of the literature
Journal of The American Academy of Dermatology, 1999Co-Authors: Saad Akhtar, Krishna K Oza, Seema A Khan, Jonathan WrightAbstract:Abstract Background: Muir-Torre Syndrome is a rare autosomal dominant genodermatosis, first described in 1967, characterized by the presence of sebaceous tumors and an internal malignancy in the absence of other predisposing factors. Objective: Our purpose was to review and update published literature on Muir-Torre Syndrome. Methods: We describe a 66-year-old white man with a history of sebaceous tumors and newly diagnosed transitional cell cancer of the right ureter and adenocarcinoma of the jejunum. The literature on Muir-Torre Syndrome is reviewed by means of MEDLINE search and available published reports and updated. Results: Only 205 cases of Muir-Torre Syndrome with 399 internal malignancies have been reported. The common presentation is the presence of sebaceous tumors along with a low-grade visceral malignancy. Sebaceous tumors appeared before the internal malignancy in 45 cases (22%), concurrently in 12 (6%), and after the internal malignancy in 114 (56%). In 33 (16%) of 205 patients, a temporal relationship was not reported. The total number of sebaceous gland carcinomas reported is 44; 17 of 44 were neoplasms of the meibomian gland. Keratoacanthomas have been noted in 48 (23%) of 205 patients. Gastrointestinal cancers are the most common internal malignancies (61%), followed by genitourinary (22%). Conclusion: The presence of sebaceous tumors warrants a search for an internal malignancy. In patients with Muir-Torre Syndrome, regular follow-up and search for new malignancy is mandatory. Evaluation and monitoring of the family members of patients are also necessary. Patients and their families should be counseled for genetic testing. Genetic analysis of the primary tumor and skin lesions should be arranged as an added research tool if possible to better understand the disease. (J Am Acad Dermatol 1999;41:681-6.)
Laurence Faivre - One of the best experts on this subject based on the ideXlab platform.
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A case report of Muir-Torre Syndrome in a woman with breast cancer and MSI-Low skin squamous cell carcinoma
Hereditary Cancer in Clinical Practice, 2017Co-Authors: Caroline Kientz, Marie-odile Joly, Laurence Faivre, Alix Clemenson, Sophie Dalac, Côme Lepage, Caroline Chapusot, Caroline Jacquot, Renaud Schiappa, Marine LebrunAbstract:Background The tumor spectrum in the Lynch Syndrome is well defined, comprising an increased risk of developing colonic and extracolonic malignancies. Muir-Torre Syndrome is a variant with a higher risk of skin disease. Patients have been described carrying mutations in the mismatch repair genes and presenting tumors with unusual histology or affected organ not part of the Lynch Syndrome spectrum. Hence, the real link between Lynch Syndrome, or Muir-Torre Syndrome, and these tumors remains difficult to assess. Case presentation We present the case of a 45-year-old-woman, diagnosed with breast cancer at 39 years of age and skin squamous cell carcinoma (SCC) at 41 years of age, without personal history of colorectal cancer. The microsatellite instability analysis performed on the skin SCC showed a low-level of microsatellite instability (MSI-Low). The immunohistochemical expression analysis of the four DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 showed a partial loss of the expression of MSH2 and MSH6 proteins. Germline deletion was found in MSH2 gene (c.1277-? _1661 + ?del), exon 8 to 10. Then, at 45 years of age, she presented hyperplastic polyps of the colon and a sebaceous adenoma. Conclusion Squamous cell carcinomas have been described in Lynch Syndrome and Muir-Torre Syndrome in two studies and two case reports. This new case further supports a possible relationship between Lynch Syndrome and squamous cell carcinoma.
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a case report of Muir Torre Syndrome in a woman with breast cancer and msi low skin squamous cell carcinoma
Hereditary Cancer in Clinical Practice, 2017Co-Authors: Caroline Kientz, Marie-odile Joly, Laurence Faivre, Alix Clemenson, Sophie Dalac, Côme Lepage, Caroline Chapusot, Caroline Jacquot, Renaud SchiappaAbstract:The tumor spectrum in the Lynch Syndrome is well defined, comprising an increased risk of developing colonic and extracolonic malignancies. Muir-Torre Syndrome is a variant with a higher risk of skin disease. Patients have been described carrying mutations in the mismatch repair genes and presenting tumors with unusual histology or affected organ not part of the Lynch Syndrome spectrum. Hence, the real link between Lynch Syndrome, or Muir-Torre Syndrome, and these tumors remains difficult to assess. We present the case of a 45-year-old-woman, diagnosed with breast cancer at 39 years of age and skin squamous cell carcinoma (SCC) at 41 years of age, without personal history of colorectal cancer. The microsatellite instability analysis performed on the skin SCC showed a low-level of microsatellite instability (MSI-Low). The immunohistochemical expression analysis of the four DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 showed a partial loss of the expression of MSH2 and MSH6 proteins. Germline deletion was found in MSH2 gene (c.1277-? _1661 + ?del), exon 8 to 10. Then, at 45 years of age, she presented hyperplastic polyps of the colon and a sebaceous adenoma. Squamous cell carcinomas have been described in Lynch Syndrome and Muir-Torre Syndrome in two studies and two case reports. This new case further supports a possible relationship between Lynch Syndrome and squamous cell carcinoma.
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somatic mmr gene mutations as a cause for msi h sebaceous neoplasms in Muir Torre Syndrome like patients
Human Mutation, 2015Co-Authors: Marie-odile Joly, Laurence Faivre, Valery Attignon, Jeanchristophe Saurin, Francoise Desseigne, Dominique Leroux, Tanguy Martindenavit, Sophie Giraud, M N Bonnetdupeyron, Jessie AuclairAbstract:Sebaceous neoplasms are a major clinical feature of Muir-Torre Syndrome (MTS) associated with visceral malignancies, especially colorectal and endometrial tumors. The diagnosis of MTS relies largely on the microsatellite instability (MSI) phenotype in tumors, suggesting germline mutations in DNA mismatch repair (MMR) genes responsible for the inherited disease. We hypothesized that in some MSI-H sebaceous tumors, acquired rather than inherited mutations in MMR genes could be involved. Using next-generation sequencing, we screened MMR gene mutations in 18 MSI-H sebaceous tumors. We found mutations in 17 samples (94%). Indeed, 12/17 (71%) were shown to carry acquired somatic mutations and among 12 samples, seven were shown to be associated with additional somatic alterations like loss of heterozygosity or multiple mutations, suggesting somatic second hits. Our findings strongly suggest that somatic MMR deficiency is responsible for a proportion of MSI-H sebaceous tumors.
Timothy J Sullivan - One of the best experts on this subject based on the ideXlab platform.
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the significance of dna mismatch repair genes in the diagnosis and management of periocular sebaceous cell carcinoma and Muir Torre Syndrome
British Journal of Ophthalmology, 2011Co-Authors: Brent Gaskin, Bertie Fernando, Charlotte Anne Sullivan, Kevin Whitehead, Timothy J SullivanAbstract:Objective The aims of this study were to determine the significance of expression of DNA mismatch repair proteins in detecting systemic malignancies in a series of patients with periocular sebaceous cell carcinoma and to determine the clinical characteristics and frequency of Muir–Torre Syndrome in this cohort. Design The study was a retrospective non-comparative interventional case series. Participants 31 patients with histologically proven sebaceous cell carcinoma of the eyelid participated in the study. Methods The authors made use of retrospective chart review and immunohistochemical staining of specimens. Main outcome measures The main outcome measures are as follows: location, tumour size, sites of origin, growth patterns, management, histopathological and immunohistochemical findings, metastasis, other visceral malignancies and mortality. Results The median age of presentation of the 31 patients in this study was 71 years (range 35–92 years). There was a near-equal gender distribution (M:F—14:17). The average follow-up was 72 months. Seventeen patients had tumours arising from the upper lid, 13 from the lower lid and 1 from the caruncle. Nine patients had clinical Muir–Torre Syndrome. Four patients were positive for microsatellite instability complexes and four were negative. Histologically, 14 patients had a high-grade tumour, 13 were intermediate grade and 4 were low grade. Based on the in situ pattern, six patients had a bowenoid pattern, five had both bowenoid and pagetoid patterns and two had a pagetoid pattern. Eighteen patients had no in situ disease detected. Twenty-one patients were alive without disease, and two were alive with disease. Six patients had died, five from other causes and one from the disease. Conclusions Visceral malignancies are common in patients with periocular sebaceous cell carcinoma. Approximately one in eight demonstrated a heritable risk for further visceral malignancy through failure to express DNA mismatch repair proteins. Diagnosis of periocular sebaceous cell carcinoma should prompt physicians to search for other associated malignancies. Immunohistochemical characterisation of these sebaceous lesions is useful in identifying increased risk in affected patients and family members.