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Rajesh V Thakker - One of the best experts on this subject based on the ideXlab platform.
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multiple Endocrine Neoplasia type 1 latest insights
Endocrine Reviews, 2021Co-Authors: Maria Luisa Brandi, Nancy D. Perrier, Gerlof D. Valk, Kate E Lines, Sunita K Agarwal, Rajesh V ThakkerAbstract:Multiple Endocrine Neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroEndocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
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clinical practice guidelines for multiple Endocrine Neoplasia type 1 men1
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Rajesh V Thakker, Henning Dralle, Paul J Newey, Gerard V Walls, John P Bilezikian, Peter R Ebeling, Shlomo Melmed, Akihiro Sakurai, Francesco Tonelli, Maria Luisa BrandiAbstract:Objective: The aim was to provide guidelines for evaluation, treatment, and genetic testing for multiple Endocrine Neoplasia type 1 (MEN1). Participants: The group, which comprised 10 experts, including physicians, surgeons, and geneticists from international centers, received no corporate funding or remuneration. Process: Guidelines were developed by reviews of peer-reviewed publications; a draft was prepared, reviewed, and rigorously revised at several stages; and agreed-upon revisions were incorporated. Conclusions: MEN1 is an autosomal dominant disorder that is due to mutations in the tumor suppressor gene MEN1, which encodes a 610-amino acid protein, menin. Thus, the finding of MEN1 in a patient has important implications for family members because first-degree relatives have a 50% risk of developing the disease and can often be identified by MEN1 mutational analysis. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. Some patients may also develo...
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role of multiple Endocrine Neoplasia type 1 mutational analysis in clinical practice
Endocrine Practice, 2011Co-Authors: Paul J Newey, Rajesh V ThakkerAbstract:ABSTRACT Objective: To review and assess the role of MEN1 mutational analysis in clinical practice. Methods: Articles relevant to MEN1 mutation testing and screening were reviewed. Results: Multiple Endocrine Neoplasia type 1 (MEN 1) is an autosomal dominant disorder characterized by the combined occurrence of tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland. MEN 1 is associated with premature mortality attributable primarily to malignant pancreatic neuroEndocrine tumors and fore-gut carcinoids. The MEN1 gene is located on chromosome 11q13, and germline MEN1 mutations are highly penetrant and lead to tumor development in > 99% of patients by the age of 45 years. Current consensus guidelines recommend an integrated program of mutational analysis of the MEN1 gene and a combination of biochemical and radiologic screening to detect the early development of tumors and thereby reduce the morbidity and mortality associated with MEN 1. Our results reveal that MEN1 mutational analysis helps to confirm the clinical diagnosis, identify asymptomatic family members who have a MEN1 mutation and require screening from an early age, and identify the 50% of family members who do not have the MEN1 mutation and can therefore have the burden of screening and anxiety regarding potential disease removed. Moreover, MEN1 mutational analysis helps to resolve diagnostic challenges due to phenocopies, which occur in 5% to 10% of families with MEN 1. Conclusion: MEN1 mutational analysis facilitates clinical management and provides benefits to patients and families with MEN 1. (Endocr Pract 2011;17[Suppl 3]: 8-17) Abbreviations: HPT-JT = hyperparathyroidism-jaw tumor; MEN 1 = multiple Endocrine Neoplasia type 1; NETs = neuroen-docrine tumors
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Multiple Endocrine Neoplasia type 1 (MEN1).
Best practice & research. Clinical endocrinology & metabolism, 2010Co-Authors: Rajesh V ThakkerAbstract:Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterised by the occurrence of tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene, consists of 10 exons that encode a 610-amino acid protein referred to as Menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division and proliferation. Germ-line mutations usually result in MEN1 or occasionally in an allelic variant referred to as Familial Isolated Hyperparathyroidism (FIHP). MEN1 tumours frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumour suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 Endocrine tumours. To date, over 1300 mutations have been reported, and the majority (>70%) of these are predicted to lead to truncated forms of Menin. The mutations are scattered throughout the >9 kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210-211) have been reported to occur frequently in 4.5%, 2.7%, 2.6% and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype-genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of Menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation.
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multiple Endocrine Neoplasia type 1
Endocrine-related Cancer, 1999Co-Authors: Anna A J Pannett, Rajesh V ThakkerAbstract:Combined clinical and laboratory investigations of multiple Endocrine Neoplasia type 1 (MEN1) have resulted in an increased understanding of this disorder which may be inherited as an autosomal dominant condition. Defining the features of each disease manifestation in MEN1 has improved patient management and treatment, and has also facilitated a screening protocol to be instituted. The application of the techniques of molecular biology has enabled the identification of the gene causing MEN1 and the detection of mutations in patients. The function of the protein encoded by the MEN1 gene has been shown to be in the regulation of JunD-mediated transcription but much still remains to be elucidated. However, these recent advances provide for the identification of mutant MEN1 gene carriers who are at a high risk of developing this disorder and thus require regular and biochemical screening to detect the development of Endocrine tumours.
Samuel A. Wells - One of the best experts on this subject based on the ideXlab platform.
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management of the parathyroid glands during preventive thyroidectomy in patients with multiple Endocrine Neoplasia type 2
Annals of Surgery, 2015Co-Authors: Jeffrey F Moley, Terry C. Lairmore, Michael K Skinner, William E Gillanders, Kathryn J Rowland, Amber L Traugott, Samuel A. WellsAbstract:Objectives:Patients with multiple Endocrine Neoplasia type 2 (MEN2) have mutations in the RET protooncogene and virtually all of them will develop medullary thyroid carcinoma. Family members identified by genetic testing are candidates for preventive thyroidectomy. Management of the parathyroids dur
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multiple Endocrine Neoplasia type 2 and familial medullary thyroid carcinoma an update
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Samuel A. Wells, Furio Pacini, Bruce G Robinson, Massimo SantoroAbstract:Context: Over the last decade, our knowledge of the multiple Endocrine Neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded greatly. In this manuscript, we summarize how recent discoveries have enhanced our understanding of the molecular basis of these diseases and led to improvements in the diagnosis and management of affected patients. Evidence Acquisition: We reviewed the English literature through PubMed from 2000 to the present, using the search terms medullary thyroid carcinoma, multiple Endocrine Neoplasia type 2, familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin. Evidence Synthesis: Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent findings from studies of large kindreds with these syndromes have clouded the relationship between genotype and phenotype, primarily because of the varied clinical presentation of different families with the same RET mutation. This clinical variability has also confo...
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the multiple Endocrine Neoplasia syndromes
Annual Review of Medicine, 2007Co-Authors: Vipul T Lakhani, Nancy Y You, Samuel A. WellsAbstract:AbstractMultiple Endocrine Neoplasia (MEN) type 1 and type 2 exhibit an autosomal dominant pattern of inheritance. In the past two decades the germline mutations that cause these inherited syndromes have been identified. The large majority of patients with MEN1 have mutations in the menin gene. Mutations in the REarranged during Transfection (RET) gene cause MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). Specific codon mutations within RET correlate with disease phenotype and severity. Also, children from families with MEN2A, MEN2B, or FMTC, who are found to have inherited a mutated RET allele, can be managed by prophylactic thyroidectomy, thus preventing the development of medullary thyroid carcinoma (MTC), the dominant endocrinopathy in patients with these hereditary syndromes. New insights into the molecular pathway of RET signal transduction are leading to novel targeted therapies in patients with locally advanced or metastatic hereditary MTC.
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predictive dna testing and prophylactic thyroidectomy in patients at risk for multiple Endocrine Neoplasia type 2a
Annals of Surgery, 1994Co-Authors: Samuel A. Wells, William G Dilley, David Chi, Koji Toshima, Louis P Dehner, Cheryl M Coffin, Bruce S Dowton, Jennifer Ivanovich, Mary K Debenedettl, Jeffrey F MoleyAbstract:BackgroundMissense germ-line mutations in the RET protooncogene are associated with multiple Endocrine Neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy.MethodsA polymerase chain reactio
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familial medullary thyroid carcinoma and multiple Endocrine Neoplasia type 2b map to the same region of chromosome 10 as multiple Endocrine Neoplasia type 2a
Genomics, 1991Co-Authors: Terry C. Lairmore, James R. Howe, Samuel A. Wells, Jennifer A Korte, William G Dilley, Liisa Aine, Esko Aine, Helen DoniskellerAbstract:Abstract Medullary thyroid carcinoma (MTC) occurs as a component of three well-described autosomal dominant familial cancer syndromes. Multiple Endocrine Neoplasia type 2A (MEN 2A) is characterized by MTC, pheochromocytomas, and parathyroid hyperplasia. Patients with the rarer multiple Endocrine Neoplasia type 2B (MEN 2B) syndrome develop MTC and pheochromocytomas, as well as mucosal neuromas, ganglioneuromatosis of the gastrointestinal tract, and a characteristic “marfanoid” habitus. Finally, MTC is transmitted in an autosomal dominant pattern in some families without associated pheochromocytomas or parathyroid hyperplasia (familial medullary thyroid carcinoma, MTC1 2 . Sixty-one members of two well-characterized kindreds segregating MTC1 members of six families segregating MEN2B were genotyped using a panel of RFLP probes from the pericentromeric region of chromosome 10 near a locus for MEN 2A. Statistically significant linkage was observed between the chromosome 10 centromere-specific marker D10Z1 and MTC1 (maximum pairwise lod score 5.88 with 0% recombination) and D10Z1 and MEN2B (maximum pairwise lod score 3.58 with 0% recombination). A maximum multipoint lod score of 4.08 was obtained for MEN2B at the position of D10Z1. In addition, 92 members of a previously unreported large MEN 2A kindred were genotyped, and linkage to the pericentromeric region of chromosome 10 is reported (maximum pairwise lod score of 11.33 with 0% recombination between MEN2A and RBP3). These results demonstrate that both a locus for familial MTC and a locus for MEN 2B map to the pericentromeric region of chromosome 10, in the same region as a locus for MEN 2A. The finding that each of these three clinically distinct familial cancer syndromes maps to the same chromosomal region suggests that all are allelic mutations at the same locus or represent a cluster of genes involved in the regulation of neuroEndocrine tissue development.
Piero Ferolla - One of the best experts on this subject based on the ideXlab platform.
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multiple Endocrine Neoplasia syndrome type 1 institution management and data analysis of a nationwide multicenter patient database
Endocrine, 2017Co-Authors: Francesca Giusti, Luisella Cianferotti, Francesca Boaretto, Filomena Cetani, Federica Cioppi, Annamaria Colao, Maria Vittoria Davi, Antongiulio Faggiano, Giuseppe Fanciulli, Piero FerollaAbstract:The aim of this study was to integrate European epidemiological data on patients with multiple Endocrine Neoplasia type 1 by creating an Italian registry of this syndrome, including clinical and genetic characteristics and therapeutic management. Clinical, familial and genetic data of patients with multiple Endocrine Neoplasia type 1, diagnosed, treated, and followed-up for a mean time of 11.3 years, in 14 Italian referral endocrinological centers, were collected, over a 3-year course (2011–2013), to build a national electronic database. The Italian multiple Endocrine Neoplasia type 1 database includes 475 patients (271 women and 204 men), of whom 383 patients (80.6%) were classified as familial cases (from 136 different pedigrees), and 92 (19.4%) patients were sporadic cases. A MEN1 mutation was identified in 92.6% of familial cases and in 48.9% of sporadic cases. Four hundred thirty-six patients were symptomatic, presenting primary hyperparathyroidism, gastroenteropancreatic neuroEndocrine tumors and pituitary tumors in 93, 53, and 41% of cases, respectively. Thirty-nine subjects, belonging to affected pedigrees positive for a MEN1 mutation, were asymptomatic at clinical and biochemical screening. Age at diagnosis of multiple Endocrine Neoplasia type 1 probands was similar for both familial and simplex cases (mean age 47.2 ± 15.3 years). In familial cases, diagnosis of multiple Endocrine Neoplasia type 1 in relatives of affected probands was made more than 10 years in advance (mean age at diagnosis 36.5 ± 17.6 years). The analysis of Italian registry of multiple Endocrine Neoplasia type 1 patients revealed that clinical features of Italian multiple Endocrine Neoplasia type 1 patients are similar to those of other western countries, and confirmed that the genetic test allowed multiple Endocrine Neoplasia type 1 diagnosis 10 years earlier than biochemical or clinical diagnosis.
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multiple Endocrine Neoplasia syndrome type 1 institution management and data analysis of a nationwide multicenter patient database
Endocrine, 2017Co-Authors: Francesca Giusti, Luisella Cianferotti, Francesca Boaretto, Filomena Cetani, Federica Cioppi, Annamaria Colao, Maria Vittoria Davi, Antongiulio Faggiano, Giuseppe Fanciulli, Piero FerollaAbstract:Objective The aim of this study was to integrate European epidemiological data on patients with multiple Endocrine Neoplasia type 1 by creating an Italian registry of this syndrome, including clinical and genetic characteristics and therapeutic management.
Henning Dralle - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effectiveness of screening for multiple Endocrine Neoplasia type 2a
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Andreas Machens, Henning DralleAbstract:Context: Although technological progress revolutionized detection of genetic predisposition to medullary thyroid cancer (MTC), carriers of mutations of disparate risks may not have benefitted alike from screening. Objective: This investigation aimed at assessing the achievements of screening for multiple Endocrine Neoplasia type 2A (MEN 2A) in Germany and identifying current challenges. Design: This was a retrospective analysis comprising 455 carriers at risk of MEN 2A screened and operated between 1963 and 2014. Setting: The setting was tertiary surgical referral centers. Patients: Included were 175 carriers of American Thyroid Association (ATA) level C mutations (codon 634); 116 carriers of ATA level B mutations (codons 609, 611, 618, 620 and 630); and 164 carriers of ATA level A mutations (codons 768, 790, 791, 804 and 891). Interventions: The intervention was thyroidectomy. Main Outcome Measures: Main outcome measures were percentage of index patients among all carriers and percentage of MTC, node-pos...
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surgical curability of medullary thyroid cancer in multiple Endocrine Neoplasia 2b a changing perspective
Annals of Surgery, 2014Co-Authors: Michael Brauckhoff, Andreas Machens, Kerstin Lorenz, Trine Bjoro, Jan Erik Varhaug, Henning DralleAbstract:Objective:This investigation aimed at exploring the suitability of nonEndocrine manifestations preceding medullary thyroid cancer (MTC) for early diagnosis of multiple Endocrine Neoplasia type 2B (MEN 2B).Background:MEN 2B patients, running a high risk of metastatic MTC, must be diagnosed early for
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clinical practice guidelines for multiple Endocrine Neoplasia type 1 men1
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Rajesh V Thakker, Henning Dralle, Paul J Newey, Gerard V Walls, John P Bilezikian, Peter R Ebeling, Shlomo Melmed, Akihiro Sakurai, Francesco Tonelli, Maria Luisa BrandiAbstract:Objective: The aim was to provide guidelines for evaluation, treatment, and genetic testing for multiple Endocrine Neoplasia type 1 (MEN1). Participants: The group, which comprised 10 experts, including physicians, surgeons, and geneticists from international centers, received no corporate funding or remuneration. Process: Guidelines were developed by reviews of peer-reviewed publications; a draft was prepared, reviewed, and rigorously revised at several stages; and agreed-upon revisions were incorporated. Conclusions: MEN1 is an autosomal dominant disorder that is due to mutations in the tumor suppressor gene MEN1, which encodes a 610-amino acid protein, menin. Thus, the finding of MEN1 in a patient has important implications for family members because first-degree relatives have a 50% risk of developing the disease and can often be identified by MEN1 mutational analysis. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. Some patients may also develo...
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codon specific development of pheochromocytoma in multiple Endocrine Neoplasia type 2
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Andreas Machens, Michael Brauckhoff, H J Holzhausen, Phuong Nguyen Thanh, Hendrik Lehnert, Henning DralleAbstract:Context: Recent data suggest a codon-specific, age-related development of multiple Endocrine Neoplasia type 2. Objective: The objective of this study was to delineate the codon-specific, age-related development of multiple Endocrine Neoplasia type 2-associated pheochromocytoma. Design: We describe a cohort study with a mean observation period of 26.9 yr. Setting: The study took place in a tertiary referral center at a university hospital. Patients: Included in this study were 206 consecutive carriers (74 index, 132 nonindex) operated on at this institution who harbored point mutations in the RET (rearranged during transfection) protooncogene. Intervention: The intervention was adrenalectomy for clinically confirmed pheochromocytoma. Main Outcome Measure: The main outcome measure was time to histopathological diagnosis of pheochromocytoma. Results: Pheochromocytomas developed in 28% (five of 18) of carriers with mutations in codon 918, 29% (20 of 68) of carriers with mutations in codon 634, 14% (three of 2...
Filomena Cetani - One of the best experts on this subject based on the ideXlab platform.
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multiple Endocrine Neoplasia syndrome type 1 institution management and data analysis of a nationwide multicenter patient database
Endocrine, 2017Co-Authors: Francesca Giusti, Luisella Cianferotti, Francesca Boaretto, Filomena Cetani, Federica Cioppi, Annamaria Colao, Maria Vittoria Davi, Antongiulio Faggiano, Giuseppe Fanciulli, Piero FerollaAbstract:The aim of this study was to integrate European epidemiological data on patients with multiple Endocrine Neoplasia type 1 by creating an Italian registry of this syndrome, including clinical and genetic characteristics and therapeutic management. Clinical, familial and genetic data of patients with multiple Endocrine Neoplasia type 1, diagnosed, treated, and followed-up for a mean time of 11.3 years, in 14 Italian referral endocrinological centers, were collected, over a 3-year course (2011–2013), to build a national electronic database. The Italian multiple Endocrine Neoplasia type 1 database includes 475 patients (271 women and 204 men), of whom 383 patients (80.6%) were classified as familial cases (from 136 different pedigrees), and 92 (19.4%) patients were sporadic cases. A MEN1 mutation was identified in 92.6% of familial cases and in 48.9% of sporadic cases. Four hundred thirty-six patients were symptomatic, presenting primary hyperparathyroidism, gastroenteropancreatic neuroEndocrine tumors and pituitary tumors in 93, 53, and 41% of cases, respectively. Thirty-nine subjects, belonging to affected pedigrees positive for a MEN1 mutation, were asymptomatic at clinical and biochemical screening. Age at diagnosis of multiple Endocrine Neoplasia type 1 probands was similar for both familial and simplex cases (mean age 47.2 ± 15.3 years). In familial cases, diagnosis of multiple Endocrine Neoplasia type 1 in relatives of affected probands was made more than 10 years in advance (mean age at diagnosis 36.5 ± 17.6 years). The analysis of Italian registry of multiple Endocrine Neoplasia type 1 patients revealed that clinical features of Italian multiple Endocrine Neoplasia type 1 patients are similar to those of other western countries, and confirmed that the genetic test allowed multiple Endocrine Neoplasia type 1 diagnosis 10 years earlier than biochemical or clinical diagnosis.
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multiple Endocrine Neoplasia syndrome type 1 institution management and data analysis of a nationwide multicenter patient database
Endocrine, 2017Co-Authors: Francesca Giusti, Luisella Cianferotti, Francesca Boaretto, Filomena Cetani, Federica Cioppi, Annamaria Colao, Maria Vittoria Davi, Antongiulio Faggiano, Giuseppe Fanciulli, Piero FerollaAbstract:Objective The aim of this study was to integrate European epidemiological data on patients with multiple Endocrine Neoplasia type 1 by creating an Italian registry of this syndrome, including clinical and genetic characteristics and therapeutic management.
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functioning glucagonoma associated with primary hyperparathyroidism multiple Endocrine Neoplasia type 1 or incidental association
BMC Cancer, 2012Co-Authors: Enrico Erdas, Filomena Cetani, Nicola Aste, Luca Pilloni, Angelo Nicolosi, S Licheri, A Cappai, Marco Mastinu, Elena Pardi, Stefano MariottiAbstract:Background Diagnosis of multiple Endocrine Neoplasia type 1 (MEN1) is commonly based on clinical criteria, and confirmed by genetic testing. In patients without known MEN1-related germline mutations, the possibility of a casual association between two or more Endocrine tumors cannot be excluded and subsequent management may be difficult to plan. We describe a very uncommon case of functioning glucagonoma associated with primary hyperparathyroidism (pHPT) in which genetic testing failed to detect germline mutations of MEN-1 and other known genes responsible for MEN1.
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genetic and clinical features of multiple Endocrine Neoplasia types 1 and 2
Journal of Oncology, 2012Co-Authors: C. Romei, Filomena Cetani, Elena Pardi, R. EliseiAbstract:Multiple Endocrine Neoplasia (MEN) are clinical inherited syndromes affecting different Endocrine glands. Three different patterns of MEN syndromes can occur (MEN 1, MEN 2A, and MEN 2B). MEN syndromes are very rare, affect all ages and both sexes are equally affected. MEN 1 is characterized by the neoplastic transformation of the parathyroid glands, pancreatic islets, anterior pituitary, and gastrointestinal tract. Heterozygous MEN 1 germline mutations have been detected in about 70-80% of patients with MEN 1. The mutations are scattered throughout the entire genomic sequence of the gene. MEN 1 patients are characterized by variable clinical features, thus suggesting the lack of a genotype-phenotype correlation. Therapeutical approaches are different according to the different endocrinopathies. The prognosis is generally good if adequate treatment is provided. In MEN 2 syndromes, the medullary thyroid cancer (MTC) is almost invariably present and can be associated with pheochromocytoma (PHEO) and/or multiple adenomatosis of parathyroid glands with hyperparathyroidism (PHPT). The different combination of the Endocrine Neoplasia gives origin to 3 syndromes: MEN 2A, MEN 2B, and FMTC. The clinical course of MTC varies considerably in the three syndromes. It is very aggressive in MEN 2B, almost indolent in the majority of patients with FMTC and with variable degrees of aggressiveness in patients with MEN 2A. Activating germline point mutations of the RET protooncogene are present in 98% of MEN 2 families. A strong genotype-phenotype correlation has been observed and a specific RET mutation may be responsible for a more or less aggressive clinical course. The treatment of choice for primary MTC is total thyroidectomy with central neck lymph nodes dissection. Nevertheless, 30% of MTC patients, especially in MEN 2B and 2A, are not cured by surgery. Recently, developed molecular therapeutics that target the RET pathway have shown very promising activity in clinical trials of patients with advanced MTC. MEN 2 prognosis is strictly dependent on the MTC aggressiveness and thus on the success of the initial treatment.