289 results on '"Stephen J. Marx"'
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2. Distribution of Menin-Occupied Regions in Chromatin Specifies a Broad Role of Menin in Transcriptional Regulation
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Sunita K. Agarwal, Soren Impey, Shannon McWeeney, Peter C. Scacheri, Francis S. Collins, Richard H. Goodman, Allen M. Spiegel, and Stephen J. Marx
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MEN1 ,multiple endocrine neoplasia ,SACO ,chromatin immunoprecipitation ,ChIP ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Menin is the protein product of the MEN1 tumorsuppressor gene; one allele of MEN1 is inactivated in the germ line of patients with “multiple endocrine neoplasia type 1” (MEN1) cancer syndrome. Menin interacts with several proteins involved in transcriptional regulation. RNA expression analyses have identified several menin-regulated genes that could represent proximal or distal interaction sites for menin. This report presents a substantial and unbiased sampling of menin-occupied chromatin regions using Serial Analysis of Chromatin Occupancy; this method combines chromatin immunoprecipitation with Serial Analysis of Gene Expression. Hundreds of menin-occupied genomic sites were identified in promoter regions (32% of menin-occupied loci), near the 3' end of genes (14%), or inside genes (21%), extending other data about menin recruitments to many sites of transcriptional activity. A large number of meninoccupied sites (33%) were located outside known gene regions. Additional annotation of the human genome could help in identifying genes at these loci, or these might be gene-free regions of the genome where menin occupancy could play some structural or regulatory role. Menin occupancy at many intragenic positions distant from the core promoter reveals an unexpected type of menin target region at many loci in the genome. These unbiased data also suggest that menin could play a broad role in transcriptional regulation. more...
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- 2007
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3. FBP1 Is an Interacting Partner of Menin
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Shadia Zaman, Karen Sukhodolets, Patricia Wang, Jun Qin, David Levens, Sunita K. Agarwal, and Stephen J. Marx
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by tumors in multiple endocrine tissues such as the parathyroid glands, the pituitary gland, and the enteropancreatic neuroendocrine tissues. MEN1 is usually caused by mutations in the MEN1 gene that codes for the protein menin. Menin interacts with proteins that regulate transcription, DNA repair and processing, and maintenance of cytoskeletal structure. We describe the identification of FBP1 as an interacting partner of menin in a large-scale pull-down assay that also immunoprecipitated RBBP5, ASH2, and LEDGF, which are members of complex proteins associated with SET1 (COMPASS), a protein complex that methylates histone H3. This interaction was confirmed by coimmunoprecipitation and Flag-pull-down assays. Furthermore, menin localized to the FUSE site on the MYC promoter, a site that is transactivated by FBP1. This investigation therefore places menin in a pathway that regulates MYC gene expression and has important implications for the biological function of menin. more...
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- 2014
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4. Data from Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes
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Settara C. Chandrasekharappa, Francis S. Collins, Stephen J. Marx, Sunita K. Agarwal, Mon-Li Chu, Rui-Zhu Zhang, Yidong Chen, Abdel Elkahloun, Sukhbir Kaur, Elizabeth A. Novotny, Nijaguna B. Prasad, and Youngmi Ji more...
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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized primarily by endocrine tumors of the parathyroids, anterior pituitary, and enteropancreatic endocrine tissues. Affected individuals carry a germ-line loss-of-function mutation of the MEN1 gene, and tumors arise after loss of the second allele. Homozygous loss of Men1 in the germ line of mice results in early embryonic lethality, with defective development of neural tube, heart, liver, and craniofacial structures. We generated immortalized wild-type (WT) and menin-null mouse embryo fibroblast (MEF) cell lines and evaluated their characteristics, including global expression patterns. The WT and menin-null cell lines were aneuploid, and the nulls did not display tumorigenic characteristics in soft agar assay. Expression arrays in menin-null MEFs revealed altered expression of several extracellular matrix proteins that are critical in organogenesis. Specifically, transcripts for fibulin 2 (Fbln2), periostin (Postn), and versican [chondroitin sulfate proteoglycan (Cspg2)], genes critical for the developing heart and known to be induced by transforming growth factor-β (TGF-β), were decreased in their expression in menin-null MEFs. Fbln2 expression was the most affected, and the reduction in menin-null MEFs for Fbln2, Postn, and Cspg2 was 16.18-, 5.37-, and 2.15-fold, respectively. Menin-null MEFs also showed poor response to TGF-β–induced Smad3-mediated transcription in a reporter assay, supporting a role for menin in this pathway. Postn and Cspg2 expression in WT, unlike in null MEFs, increased on TGF-β treatment. The expression changes associated with the loss of the tumor suppressor menin provide insights into the defective organogenesis observed during early embryonic development in Men1-null mouse embryos. (Mol Cancer Res 2007;5(10):1041–51) more...
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- 2023
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5. Supplementary Table S1 from Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes
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Settara C. Chandrasekharappa, Francis S. Collins, Stephen J. Marx, Sunita K. Agarwal, Mon-Li Chu, Rui-Zhu Zhang, Yidong Chen, Abdel Elkahloun, Sukhbir Kaur, Elizabeth A. Novotny, Nijaguna B. Prasad, and Youngmi Ji more...
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Supplementary Table S1 from Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes
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- 2023
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6. Data from Recapitulation of Pancreatic Neuroendocrine Tumors in Human Multiple Endocrine Neoplasia Type I Syndrome via Pdx1-Directed Inactivation of Men1
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Steven K. Libutti, Allen M. Spiegel, Stephen J. Marx, Stephen M. Hewitt, Kris Ylaya, Amelia C. Grover, Charles Heller, Dominique Lorang, Asha Adem, Anathea Powell, Mei He, and H.-C. Jennifer Shen
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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal syndrome caused by mutations in the MEN1 tumor suppressor gene. Whereas the protein product of MEN1, menin, is ubiquitously expressed, somatic loss of the remaining wild-type MEN1 allele results in tumors primarily in parathyroid, pituitary, and endocrine pancreas. To understand the endocrine specificity of the MEN1 syndrome, we evaluated biallelic loss of Men1 by inactivating Men1 in pancreatic progenitor cells using the Cre-lox system. Men1 deletion in progenitor cells that differentiate into exocrine and endocrine pancreas did not affect normal pancreas morphogenesis and development. However, mice having homozygous inactivation of the Men1 in pancreas developed endocrine tumors with no exocrine tumor manifestation, recapitulating phenotypes seen in the MEN1 patients. In the absence of menin, the endocrine pancreas showed increase in cell proliferation, vascularity, and abnormal vascular structures; such changes were lacking in exocrine pancreas. Further analysis revealed that these endocrine manifestations were associated with up-regulation in vascular endothelial growth factor expression in both human and mouse MEN1 pancreatic endocrine tumors. Together, these data suggest the presence of cell-specific factors for menin and a permissive endocrine environment for MEN1 tumorigenesis in endocrine pancreas. Based on our analysis, we propose that menin's ability to maintain cellular and microenvironment integrity might explain the endocrine- restrictive nature of the MEN1 syndrome. [Cancer Res 2009;69(5):1858–66] more...
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- 2023
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7. Supplementary Data from Recapitulation of Pancreatic Neuroendocrine Tumors in Human Multiple Endocrine Neoplasia Type I Syndrome via Pdx1-Directed Inactivation of Men1
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Steven K. Libutti, Allen M. Spiegel, Stephen J. Marx, Stephen M. Hewitt, Kris Ylaya, Amelia C. Grover, Charles Heller, Dominique Lorang, Asha Adem, Anathea Powell, Mei He, and H.-C. Jennifer Shen
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Supplementary Data from Recapitulation of Pancreatic Neuroendocrine Tumors in Human Multiple Endocrine Neoplasia Type I Syndrome via Pdx1-Directed Inactivation of Men1
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- 2023
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8. Supplementary Figures 1-4 from The Tumor Suppressor Protein Menin Inhibits AKT Activation by Regulating Its Cellular Localization
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Stephen J. Marx, Sunita K. Agarwal, Settara C. Chandrasekharappa, Nijaguna B. Prasad, Shadia Zaman, Atsushi Ozawa, and Yan Wang
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Supplementary Figures 1-4 from The Tumor Suppressor Protein Menin Inhibits AKT Activation by Regulating Its Cellular Localization
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- 2023
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9. Neonatal Severe Hyperparathyroidism: Novel Insights From Calcium, PTH, and the CASR Gene
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Ninet Sinaii and Stephen J. Marx
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Male ,Parathyroidectomy ,Heterozygote ,medicine.medical_specialty ,Genotype ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Clinical Biochemistry ,Parathyroid hormone ,Context (language use) ,Biochemistry ,Infant, Newborn, Diseases ,Endocrinology ,Internal medicine ,Calcium flux ,medicine ,Humans ,Hyperparathyroidism ,business.industry ,Homozygote ,Biochemistry (medical) ,Infant, Newborn ,Heterozygote advantage ,Hyperparathyroidism, Primary ,Prognosis ,medicine.disease ,Hypoparathyroidism ,Parathyroid Hormone ,Perspective ,Mutation ,Calcium ,Female ,Secondary hyperparathyroidism ,business ,Receptors, Calcium-Sensing ,Biomarkers - Abstract
Context Neonatal severe hyperparathyroidism (NSHPT) is rare and potentially lethal. It is usually from homozygous or heterozygous germline-inactivating CASR variant(s). NSHPT shows a puzzling range of serum calcium and parathyroid hormone (PTH) levels. Optimal therapy is unclear. Evidence acquisition We categorized genotype/phenotype pairings related to CASRs. For the 2 pairings in NSHPT, each of 57 cases of neonatal severe hyperparathyroidism required calcium, PTH, upper normal PTH, and dosage of a germline pathogenic CASR variant. Evidence synthesis Homozygous and heterozygous NSHPT are 2 among a spectrum of 9 genotype/phenotype pairings relating to CASRs and NSHPT. For the 2 NSHPT pairings, expressions differ in CASR allelic dosage, CASR variant severity, and sufficiency of maternofetal calcium fluxes. Homozygous dosage of CASR variants was generally more aggressive than heterozygous. Among heterozygotes, high-grade CASR variants in vitro were more pathogenic in vivo than low-grade variants. Fetal calcium insufficiency as from maternal hypoparathyroidism caused fetal secondary hyperparathyroidism, which persisted and was reversible in neonates. Among NSHPT pairings, calcium and PTH were higher in CASR homozygotes than in heterozygotes. Extreme hypercalcemia (above 4.5 mM; normal 2.2–2.6 mM) is a robust biomarker, occurring only in homozygotes (83% of that pairing). It could occur during the first week. Conclusions In NSHPT pairings, the homozygotes for pathogenic CASR variants show higher calcium and PTH levels than heterozygotes. Calcium levels above 4.5 mM among NSHPT are frequent and unique only to most homozygotes. This cutoff supports early and robust diagnosis of CASR dosage. Thereby, it promotes definitive total parathyroidectomy in most homozygotes. more...
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- 2019
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10. Long-term remission of disseminated parathyroid cancer following immunotherapy
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Eitan Friedman, Marta Sarquis, Adrian Daly, William F. Simonds, Maria Aparecida Camargos Bicalho, Stephen J. Marx, Arthur R. Bradwell, Luiz De Marco, Daniela Betea, and Albert Beckers
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Oncology ,medicine.medical_specialty ,Poor prognosis ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Article ,Parathyroid Glands ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Humans ,Medicine ,Disseminated disease ,Chemotherapy ,Metastatic Parathyroid Carcinoma ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,Radiation therapy ,Parathyroid Neoplasms ,030220 oncology & carcinogenesis ,Long term remission ,business - Abstract
PURPOSE: Parathyroid cancer is a rare tumor associated with poor prognosis particularly when disseminated. While chemotherapy and/or radiotherapy are of no clinical value in disseminated disease, immunotherapy should be considered. SUBJECT AND RESULTS: A patient with CDC73-associated metastatic parathyroid carcinoma was treated with combined anti-hPTH immunotherapy and surgery. CONCLUSIONS: Following five courses of anti-hPTH immunotherapy and subsequent surgery, a 12-year long remission of disseminated parathyroid cancer is reported. This case further supports the ever-expanding spectrum of cancers that may benefit from immunotherapy. more...
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- 2019
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11. SUN-366 Neonatal Severe Hyperparathyroidism: Extreme Hypercalcemia as a Robust Marker for Homozygous Dosage of Pathogenic CASR Variants
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Ninet Sinaii and Stephen J. Marx
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medicine.medical_specialty ,Hyperparathyroidism ,business.industry ,Endocrinology, Diabetes and Metabolism ,Internal medicine ,Bone and Mineral Metabolism ,Bone Disease from Bench to Bedside ,medicine ,business ,medicine.disease ,Gastroenterology ,AcademicSubjects/MED00250 - Abstract
Context: Neonatal severe hyperparathyroidism (NSHPT) is a rare and life-threatening emergency. It includes generalized hyperparathyroid bone disease and respiratory distress from combinations among a narrowed thorax, rib fractures, hypotonia, and biochemical disturbances. Successful therapy is compatible with long life and a healthy prognosis. However, neuromotor retardation may persist after otherwise successful therapy. The time and amplitude of hypercalcemia likely correlate with irreversible neuromotor retardation; thus, early intervention seems critical in many cases. NSHPT is usually caused by homozygous or heterozygous pathogenic variant(s) of the CASR; a heterozygous variant of this gene is also the usual cause of familial hypocalciuric hypercalcemia (FHH or FHH1). Homozygotes and heterozygotes with NSHPT are often not distinguished in the current literature. In theory, their management should differ. Optimum treatment in homozygotes is early total parathyroidectomy with induction of postoperative hypoparathyroidism. Optimal management of heterozygotes is more complex. It consists in temporizing measures and varies from careful observation without surgery, to bisphosphonates and/or calcimimetics, and to subtotal parathyroidectomy. The heterozygotes can then develop into healthy babies with asymptomatic FHH1. Evidence Acquisition: Each case met strict criteria for “severe” and neonatal disease. We analyzed the core biochemical parameters of the maximal serum calcium and maximal PTH. To compare different immunoassays, PTH was analyzed as a ratio (thus without units) of the raw data divided by the upper limit of its normal range. Each case also required information about the allelic dosage of the pathogenic or likely pathogenic CASR variant(s). Evidence Synthesis: There were 36 cases with homozygous pathogenic CASR variants and 21 cases with heterozygous pathogenic or likely pathogenic variants. Maximal serum calcium was far higher in homozygotes 5.8 +/- 1.5 versus 3.2 +/- 0.2 (P Conclusions: Extreme hypercalcemia greater than 4.5 mM was newly identified as a conservative cutoff that was 100% predictive of homozygosity for pathogenic CASR variants. Extreme hypercalcemia in NSHPT is an early, facile, rapid, and inexpensive determinant of homozygosity for pathogenic variants of the CASR. It should be sought and used to promote early and definitive total parathyroidectomy, whenever it is identified in NSHPT. more...
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- 2020
12. Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing
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Elisangela P S Quedas, Antonio M. Lerario, Sergio P. A. Toledo, Viviane C. Longuini, Betsaida Urtremari, Delmar M. Lourenço, Fábio Luiz de Menezes Montenegro, Alexander A. L. Jorge, Tomoko Sekiya, Stephen J. Marx, Lucas Santos de Santana, Rodrigo A. Toledo, and Rafael Arrabaça Carvalho more...
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Gene mutation ,Biology ,medicine.disease_cause ,Germline ,Young Adult ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Endocrinology ,Germline mutation ,Proto-Oncogene Proteins ,Internal medicine ,medicine ,Humans ,MEN1 ,Multiplex ligation-dependent probe amplification ,Indel ,Germ-Line Mutation ,Genetics ,Sanger sequencing ,Mutation ,Multiple Endocrine Neoplasia ,Genetic Variation ,Sequence Analysis, DNA ,General Medicine ,Middle Aged ,030220 oncology & carcinogenesis ,symbols ,Female - Abstract
Background Loss-of-function germline MEN1 gene mutations account for 75–95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing. more...
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- 2018
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13. Probability of Positive Genetic Testing Results in Patients with Family History of Primary Hyperparathyroidism
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James Welch, Lee S. Weinstein, Roxanne Merkel, Electron Kebebew, Pavel Nockel, Dhaval Patel, Naris Nilubol, Bin Guan, William F. Simonds, Sunita K. Agarwal, Stephen J. Marx, Mustapha El Lakis, Apostolos Gaitanidis, and Amit Tirosh more...
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Adult ,Male ,Parathyroidectomy ,medicine.medical_specialty ,endocrine system diseases ,medicine.medical_treatment ,Genetic counseling ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Family history ,Germ-Line Mutation ,Probability ,Retrospective Studies ,Genetic testing ,Univariate analysis ,medicine.diagnostic_test ,business.industry ,Age Factors ,Retrospective cohort study ,Middle Aged ,Hyperparathyroidism, Primary ,medicine.disease ,Parathyroid carcinoma ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Surgery ,business ,Primary hyperparathyroidism - Abstract
Background Approximately 10% of patients with primary hyperparathyroidism (PHPT) have hereditary disease. Hereditary PHPT may be syndromic (MEN1, 2, and 4 and hyperparathyroidism-jaw tumor syndrome) or non-syndromic (familial isolated PHPT). There are limited data on the probability of testing positive for genetic mutation based on clinical presentation. The aim of this study was to determine potential associations between clinical and biochemical features and mutation in susceptibility genes for PHPT in patients with a family history of PHPT. Study Design A retrospective analysis of 657 patients who had an initial parathyroidectomy for PHPT at a tertiary referral center. Logistic regression analyses were performed in 205 patients with a family history of PHPT to identify factors associated with a positive genetic test. Results Of 657 patients, 205 (31.2%) had a family history of PHPT. Of those 205 patients, 123 (60%) had a germline mutation detected (91 MEN1 , 14 CDC73 , and 18 GCM2 ). In univariate analysis, younger age (45 years and younger), male sex, multigland disease, and parathyroid carcinoma were associated with positive germline mutation; biochemical cure after an initial parathyroidectomy was less frequent in patients with familial PHPT (96.2% vs 89.2%; p = 0.005). In multivariable analysis, age 45 years and younger, male sex, and multigland disease were independent factors associated with positive genetic testing. Conclusions In addition to a family history of PHPT, male sex, age 45 years and younger, and presence of multigland disease, should prompt physicians to offer the opportunity for genetic counseling and testing, as it could influence the management of patients with PHPT. more...
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- 2018
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14. Recent Topics Around Multiple Endocrine Neoplasia Type 1
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Stephen J. Marx
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Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,030209 endocrinology & metabolism ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Breast cancer ,Proto-Oncogene Proteins ,Internal medicine ,Multiple Endocrine Neoplasia Type 1 ,medicine ,Humans ,MEN1 ,Multiple endocrine neoplasia ,Neuroectodermal tumor ,Insulinoma ,Early Detection of Cancer ,Neuroectoderm ,medicine.diagnostic_test ,business.industry ,Biochemistry (medical) ,Nuclear Proteins ,Foregut ,medicine.disease ,Cell Transformation, Neoplastic ,Positron emission tomography ,030220 oncology & carcinogenesis ,Mutation ,Perspective ,business ,Transcription Factors - Abstract
Introduction Multiple endocrine neoplasia type 1 (MEN1) is complex with regard to clinical expressions, management, and molecular pathways. Advances are being made broadly and in focused aspects. Selected topics are presented for their developments since publication of the most recent MEN1 consensus guidelines 6 years ago. Methods Topics were selected for clinical impact or broad interest or both. For each topic, information was obtained from original reports and reviews. Results The selected topics are as follows: tumor behavior and breast cancer in MEN1; foregut neuroectoderm tumor screening, biomarkers periodically to detect tumor emergence of foregut neuroectoderm tumors, 68Ga dotatate positron emission tomography/computed tomography for pancreatic and duodenal neuroectodermal tumor imaging, and glucagon-like peptide-1 receptor scintigraphy for insulinoma; therapy, the size of pancreatic neuroendocrine tumor (NET) as one criterion for surgery, minimally invasive surgery of pancreatic NETs, and 177Lu dotatate therapy; MEN1 gene, the search for the MEN1/menin pathway and MEN1 or GCM2 mutation in familial isolated hyperparathyroidism, and MEN1 mutation-positive vs mutation-negative cases of MEN1 are different. Conclusions MEN1 topics are a rich and fast-moving area. Important highlights stand out, and major and rapid advances will continue into the near future. more...
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- 2018
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15. Genome-wide analysis of menin binding provides insights into MEN1 tumorigenesis.
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Peter C Scacheri, Sean Davis, Duncan T Odom, Gregory E Crawford, Stacie Perkins, Mohamad J Halawi, Sunita K Agarwal, Stephen J Marx, Allen M Spiegel, Paul S Meltzer, and Francis S Collins
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Genetics ,QH426-470 - Abstract
Multiple endocrine neoplasia type I (MEN1) is a familial cancer syndrome characterized primarily by tumors of multiple endocrine glands. The gene for MEN1 encodes a ubiquitously expressed tumor suppressor protein called menin. Menin was recently shown to interact with several components of a trithorax family histone methyltransferase complex including ASH2, Rbbp5, WDR5, and the leukemia proto-oncoprotein MLL. To elucidate menin's role as a tumor suppressor and gain insights into the endocrine-specific tumor phenotype in MEN1, we mapped the genomic binding sites of menin, MLL1, and Rbbp5, to approximately 20,000 promoters in HeLa S3, HepG2, and pancreatic islet cells using the strategy of chromatin-immunoprecipitation coupled with microarray analysis. We found that menin, MLL1, and Rbbp5 localize to the promoters of thousands of human genes but do not always bind together. These data suggest that menin functions as a general regulator of transcription. We also found that factor occupancy generally correlates with high gene expression but that the loss of menin does not result in significant changes in most transcript levels. One exception is the developmentally programmed transcription factor, HLXB9, which is overexpressed in islets in the absence of menin. Our findings expand the realm of menin-targeted genes several hundred-fold beyond that previously described and provide potential insights to the endocrine tumor bias observed in MEN1 patients. more...
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- 2006
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16. Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism
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Stephen J. Marx
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0301 basic medicine ,Kidney ,medicine.medical_specialty ,endocrine system diseases ,Familial hypocalciuric hypercalcemia ,business.industry ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Parathyroid chief cell ,medicine.disease ,Hypocalciuria ,Subtotal Parathyroidectomy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,Hypoparathyroidism ,Internal medicine ,medicine ,Orthopedics and Sports Medicine ,medicine.symptom ,Calcium-sensing receptor ,business ,Primary hyperparathyroidism - Abstract
Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia with features that overlap with typical primary hyperparathyroidism (PHPT). The incompleteness of this overlap has led to divergent nomenclatures for FHH. I compare two nomenclatures. One sets FHH as an entity distinct from PHPT. The other groups FHH with PHPT but conditions FHH as atypical PHPT. I analyzed selected articles about calcium-sensing receptors, FHH, PHPT, CASR, GNA11, and AP2S1. FHH usually results from a heterozygous germline inactivating mutation of the CASR, and less frequently from mutation of GNA11 or AP2S1. The CASR encodes the calcium-sensing receptors. These are highly expressed on parathyroid cells, where they sense serum calcium concentration and regulate suppression of PTH secretion by serum calcium. Their mutated expression in the kidney in FHH causes increased renal tubular reabsorption of calcium (hypocalciuria). Many FHH features are shared with PHPT and thus support FHH as a form of PHPT. These include a driver mutation expressed mainly in the parathyroid cells. The mutation causes a parathyroid cell insensitivity to extracellular calcium in vivo and in vitro, a right-shift of the set point for suppression of PTH secretion by calcium. Serum PTH is normal or mildly elevated; ie, it is not appropriately suppressed by hypercalcemia. Total parathyroidectomy causes hypoparathyroidism and durable remission of hypercalcemia. Some other features are not shared with PHPT and could support FHH as a distinct entity. These include onset of hypercalcemia in the first week of life, frequent persistence of hypercalcemia after subtotal parathyroidectomy, and hypocalciuria. The features supporting FHH as a form of PHPT are stronger than those favoring FHH as a distinct entity. Classifying FHH as an atypical form of PHPT represents compact nomenclature and supports current concepts of pathophysiology of FHH and PHPT. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. more...
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- 2017
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17. Calcimimetic Use in Familial Hypocalciuric Hypercalcemia—A Perspective in Endocrinology
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Stephen J. Marx
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Adult ,medicine.medical_specialty ,Hypercalcaemia ,Adaptor Protein Complex sigma Subunits ,Adolescent ,Calcimimetic ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Adaptor Protein Complex 2 ,030209 endocrinology & metabolism ,Context (language use) ,Calcimimetic Agents ,Biochemistry ,Hypocalciuria ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Child ,Hyperparathyroidism ,Familial hypocalciuric hypercalcemia ,business.industry ,Biochemistry (medical) ,Infant, Newborn ,Infant ,Parathyroid chief cell ,Hyperparathyroidism, Primary ,medicine.disease ,GTP-Binding Protein alpha Subunits ,Child, Preschool ,Hypercalcemia ,medicine.symptom ,Perspectives in Endocrinology ,business ,Receptors, Calcium-Sensing ,Primary hyperparathyroidism - Abstract
Context: Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia that even persists after subtotal parathyroidectomy. Symptoms are usually mild. Past recommendations have often been for monitoring and against surgical or pharmacologic treatments. Methods: Review of publications about FHH, calcium-sensing receptors (CaSRs), and calcimimetics. Results: FHH reflects heterozygous germline mutation of CASR, GNA11, or AP2S1. These mutations inactivate the CaSRs in the parathyroid cell. Thereby, they shift the serum calcium set point to higher values and cause hypercalcemia. Calcimimetic drugs enhance the effects of calcium on the CaSRs and thereby inhibit the parathyroid cell. Calcimimetic drugs are indicated in adults with primary hyperparathyroidism without a good surgical option. Calcimimetic safety and efficacy are not established in children younger than age 18 years. Recent case reports have described treatment of FHH with calcimimetics. Success was classified as combinations of subjective improvements and decreases of serum calcium levels, but not necessarily into the normal range. Treatment was successful in 14 of 16 cases (88%). Conclusion: Deductions based on these case reports have limitations. For example, failures of therapy may not have been reported. Cost of the drug might be rate limiting. Calcimimetics can be offered to adults with FHH and those in whom the serum calcium level is >0.25 mM (1 mg/dL) beyond the upper limit of normal or with possible symptoms of hypercalcemia. Calcimimetics can now be offered to more adults with FHH., Treatment with a calcimimetic was successful in 14 of 16 reported cases of FHH. Calcimimetics can be used in more cases of FHH. more...
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- 2017
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18. Association between neuroendocrine tumors biomarkers and primary tumor site and disease type based on total 68Ga-DOTATATE-Avid tumor volume measurements
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Georgios Z. Papadakis, Stephen J. Marx, Naris Nilubol, Pavel Nockel, Patience Green, Lily Yang, Jasmine Shell, Samira M. Sadowski, Karel Pacak, Dhaval Patel, Amit Tirosh, Corina Millo, Peter Herscovitch, Electron Kebebew, and Xavier M. Keutgen more...
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Adult ,Male ,medicine.medical_specialty ,Databases, Factual ,Endocrinology, Diabetes and Metabolism ,Urinary system ,Vasoactive intestinal peptide ,030209 endocrinology & metabolism ,Neuroendocrine tumors ,Hydroxyindoleacetic Acid/urine ,Multimodal Imaging ,Glucagon ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Biomarkers, Tumor/analysis/metabolism ,Internal medicine ,Organometallic Compounds ,Humans ,Medicine ,Pancreatic polypeptide ,Neoplasm Metastasis ,Retrospective Studies ,Multiple Endocrine Neoplasia/diagnostic imaging/metabolism ,ddc:617 ,biology ,business.industry ,Chromogranin A ,Pancreatic Neoplasms/diagnostic imaging/metabolism ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Primary tumor ,Neuroendocrine Tumors/diagnostic imaging/metabolism ,Positron-Emission Tomography ,030220 oncology & carcinogenesis ,biology.protein ,Biomarker (medicine) ,Female ,Radiopharmaceuticals ,business - Abstract
ObjectiveTo determine the association between neuroendocrine tumor (NET) biomarker levels and the extent of disease as assessed by68Ga DOTATATE PET/CT imaging.DesignA retrospective analysis of a prospective database of patients with NETs.MethodsFasting plasma chromogranin A (CgA), neuron-specific enolase (NSE), gastrin, glucagon, vasoactive intestinal peptide (VIP) and pancreatic polypeptide (PP), and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) levels were measured. Correlation between biomarkers and total68Ga-DOTATATE-avid tumor volume (TV) was analyzed.ResultsThe analysis included 232 patients. In patients with pancreatic NETs (n = 112),68Ga-DOTATATE TV correlated with CgA (r = 0.6,P = 0.001, Spearman). In patients with multiple endocrine neoplasia type 1 (n = 39),68Ga-DOTATATE TV correlated with glucagon (r = 0.5,P = 0.01) and PP levels (r = 0.5,P = 0.049). In patients with von Hippel–Lindau (n = 24), plasma VIP (r = 0.5,P = 0.02) and PP levels (r = 0.7,P 68Ga-DOTATATE TV. In patients with small intestine NET (SINET,n = 74),68Ga-DOTATATE TV correlated with CgA (r = 0.5,P = 0.02) and 5-HIAA levels (r = 0.7,P P = 0.001).68Ga-DOTATATE TV in patients with NET of unknown primary (n = 16) and those with NET of other primary location (n = 30) correlated with 5-HIAA levels (r = 0.8,P = 0.002 andr = 0.7,P = 0.02 respectively).ConclusionsOur data supports the use of specific NET biomarkers based on the site of the primary NET and the presence of hereditary syndrome-associated NET. High urinary 5-HIAA levels indicate the presence of metastatic disease in patients with SINET. more...
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- 2017
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19. Ethnicity of Patients With Germline GCM2-Activating Variants and Primary Hyperparathyroidism
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Yulong Li, Bin Guan, Electron Kebebew, William F. Simonds, Sunita K. Agarwal, Meghana Vemulapalli, James Welch, Stephen J. Marx, and Hua Ling
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medicine.medical_specialty ,sporadic primary hyperparathyroidism ,Parathyroid, Bone, and Mineral Metabolism ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Genetic counseling ,030209 endocrinology & metabolism ,Context (language use) ,Germline ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Ashkenazi Jewish ,Internal medicine ,Diabetes mellitus ,Genotype ,medicine ,parathyroid ,CCID ,Clinical Research Articles ,Sanger sequencing ,GCM2 CCID ,business.industry ,medicine.disease ,030220 oncology & carcinogenesis ,symbols ,familial primary hyperparathyroidism ,business ,Primary hyperparathyroidism ,familial isolated hyperparathyroidism - Abstract
Context: Germline gain-of-function variants in the transcription factor GCM2 were found in 18% of kindreds with familial isolated hyperparathyroidism (FIHP). These variants [c.1136T>A (p.Leu379Gln) and c.1181A>C (p.Tyr394Ser)] were located in a 17-amino acid transcriptional inhibitory domain named C-terminal conserved inhibitory domain (CCID). Objective: We investigated the ethnicity of individuals with germline variants in the GCM2 CCID in our primary hyperparathyroidism (PHPT) patient samples and in the Genome Aggregation Database. Design: Ethnicity information was obtained from an in-house clinical database and genetic counseling. Sanger sequencing of blood DNA was used to determine the genotype of the GCM2 CCID region. Luciferase reporter assays were performed to determine the functional impact of GCM2 variants. Setting and Patients: National Institute of Diabetes and Digestive and Kidney Diseases endocrine clinic is a service that accepts PHPT referral patients. Results: The GCM2 p.Tyr394Ser variant was found in 41% [95% confidence interval (CI), 22% to 64%] of Ashkenazi Jewish (AJ) kindreds with FIHP and in 27% (95% CI, 17% to 40%) of AJ patients with sporadic PHPT. The p.Tyr394Ser variant was also found in sporadic PHPT patients of European ancestry, but at a lower prevalence. The p.Leu379Gln variant was found in 8% (95% CI, 1% to 26%) of European kindreds with FIHP and 0.5% (95% CI, 0% to 3.0%) of sporadic PHPT cases of European ancestry. The sporadic PHPT patients with GCM2-activating variants often had multigland involvement or postoperative recurrent or persistent disease. Conclusions: Specific GCM2-activating variants enriched among various ethnic backgrounds could contribute to a large number of cases with FIHP or sporadic PHPT., Specific GCM2 activating variants enriched in various ethnic backgrounds could contribute to a large number of cases with familial isolated hyperparathyroidism or sporadic primary hyperparathyroidism. more...
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- 2017
20. A patient with MEN1 typical features and MEN2-like features
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William F. Simonds, Sunita K. Agarwal, Diala El-Maouche, Stephen J. Marx, James Welch, and Lee S. Weinstein
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Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Economics and Econometrics ,endocrine system diseases ,030209 endocrinology & metabolism ,Forestry ,Biology ,medicine.disease ,Phenotype ,Article ,Germline ,Frameshift mutation ,Pheochromocytoma ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,Materials Chemistry ,Media Technology ,medicine ,Cancer research ,MEN1 ,CDKN1B ,Multiple endocrine neoplasia - Abstract
Multiple endocrine neoplasia (MEN) type 1 (MEN1) and 2 (MEN2) rarely co-exist in one case. Here we report a patient with features of both syndromes. The patient presented with typical MEN1 features plus pheochromocytoma and thickened corneal nerves. She had a germline 1132delG frameshift mutation in MEN1, no mutation in CDKN1B (p27) and no RET mutation, but had both RET polymorphisms Gly691Ser and Arg982Cys. This is the first case report of a combination of typical clinical findings of MEN1 harboring a germline MEN1 mutation and the MEN2-like phenotype with negative full RET gene analysis of pathogenic variants. Possible explanations include a previously unrecognized phenotype–genotype association or the influence of potential phenotypic modifying RET variants. Furthermore, the combination observed in this patient may point to a single molecular pathway, and supports the possibility of as yet unrecognized connections between the molecular pathways for MEN1/menin protein and MEN2/RET protein. more...
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- 2016
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21. New Concepts About Familial Isolated Hyperparathyroidism
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Stephen J. Marx
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Genetics ,medicine.medical_specialty ,endocrine system diseases ,business.industry ,Endocrinology, Diabetes and Metabolism ,Biochemistry (medical) ,Clinical Biochemistry ,Familial hyperparathyroidism ,Context (language use) ,Biochemistry ,Activating mutation ,Germline ,Parathyroid tumors ,Endocrinology ,Internal medicine ,Mutation (genetic algorithm) ,Perspective ,medicine ,MEN1 ,business ,Evidence synthesis - Abstract
ContextFamilial isolated hyperparathyroidism (FIHP) is defined as familial primary hyperparathyroidism (FH) without a characteristic extraparathyroidal feature of a more complex hyperparathyroid syndrome. New concepts of FIHP have been developed within this definition. FIHP has been difficult to study due to small kindreds and mildly symptomatic cases.Evidence AcquisitionSearches were through PubMed for FIHP, other FH syndromes, and the gene(s) mutated in each.Evidence SynthesisWithin its definition, the current concept of FIHP has clinical and mutational components that can include incomplete expressions of multiple endocrine neoplasia type 1 (MEN1) familial hypocalciuric hypercalcemia, hyperparathyroidism-jaw tumor syndromes, or their mutations. Newest concepts of FIHP focus on kindreds without mutation of the MEN1, CASR, or CDC73 genes; 17% have germline activating mutation of the gene for the GCM2 transcription factor. The FIHP kindreds with or without GCM2 mutation contain a median of only two cases of primary hyperparathyroidism. The small kindred size in both subgroups of FIHP is probably caused by a low rate of screening among relatives. Persons with FIHP and GCM2 mutation present as adults with mild hypercalcemia and multiple parathyroid tumors.ConclusionThe current concept of FIHP led to a focus on small kindreds without mutation of MEN1, CASR, or CDC73. These assisted in identifying germline activating GCM2 mutations in 17% of kindreds. Clinical and mutational characterization in more cases is needed to determine if there are any unique clinical features of FIHP, with or without mutation of GCM2. more...
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- 2018
22. High prevalence of chronic kidney disease in patients with multiple endocrine neoplasia type 1 and improved kidney function after parathyroidectomy ()
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Jonathan Zagzag, Nancy D. Perrier, Patience Green, Jenny E Blau, Electron Kebebew, William F. Simonds, Stephen J. Marx, Dhaval Patel, Naris Nilubol, and Lee S. Weinstein
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Parathyroidectomy ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Population ,Urology ,Renal function ,030230 surgery ,Severity of Illness Index ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Multiple Endocrine Neoplasia Type 1 ,Prevalence ,Medicine ,Humans ,Renal Insufficiency, Chronic ,Multiple endocrine neoplasia ,education ,Child ,Aged ,Retrospective Studies ,Hyperparathyroidism ,education.field_of_study ,business.industry ,Middle Aged ,medicine.disease ,Hyperparathyroidism, Primary ,Comorbidity ,United States ,030220 oncology & carcinogenesis ,Surgery ,Calcium ,Female ,business ,Primary hyperparathyroidism ,Kidney disease ,Glomerular Filtration Rate - Abstract
Background Because chronic kidney disease is an important comorbidity associated with primary hyperparathyroidism, we sought to evaluate the prevalence of chronic kidney disease and effects of parathyroidectomy on kidney function in patients with multiple endocrine neoplasia type 1–associated primary hyperparathyroidism. Methods We performed a retrospective analysis of 112 patients with multiple endocrine neoplasia type 1–associated primary hyperparathyroidism who had at least 1 operation for primary hyperparathyroidism at 2 tertiary referral centers. The preoperative and postoperative estimated glomerular filtration rates were compared. The prevalence of chronic kidney disease stage 3 or worse (estimated glomerular filtration rates less than 60 mL/min/1.73m2) in this cohort was compared to the rates in the US population reported by the Centers for Disease Control and Prevention. Results The median age at the time of parathyroidectomy was 36.5 years (range: 12–76 years). A total of 99 patients had biochemical remission. The rate of chronic kidney disease stage 3 or worse in patients with multiple endocrine neoplasia type 1–associated primary hyperparathyroidism was greater than that observed in the US population for ages 20–39 and 40–59 (5% [n = 2/44] vs 0.39% [n = 18/4565], P = .015 and 10% [n = 4/40] vs 2.31% (n = 89/3848), P = .015, respectively). We observed improved estimated glomerular filtration rates in those with chronic kidney disease stage 3 or worse postoperatively (48 vs 57 mL/min/1.73m2, P = .047). A successful parathyroidectomy normalized all 24-hour urine calcium excretion. Conclusion An indication for early parathyroidectomy should include estimated glomerular filtration rates less than 60mL/min/1.73m2 in patients with multiple endocrine neoplasia type 1–associated primary hyperparathyroidism. more...
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- 2018
23. Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective
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David Goltzman and Stephen J. Marx
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0301 basic medicine ,Proband ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Parathyroid hormone ,030209 endocrinology & metabolism ,Multiple Endocrine Neoplasia Type 2a ,Bioinformatics ,History, 21st Century ,Article ,03 medical and health sciences ,0302 clinical medicine ,CDKN2B ,medicine ,Multiple Endocrine Neoplasia Type 1 ,Humans ,Orthopedics and Sports Medicine ,MEN1 ,Multiple endocrine neoplasia ,Neonatal severe primary hyperparathyroidism ,Familial hypocalciuric hypercalcemia ,business.industry ,Hyperparathyroidism ,Syndrome ,History, 20th Century ,medicine.disease ,Neoplasm Proteins ,030104 developmental biology ,Parathyroid Neoplasms ,Calcitonin ,business - Abstract
We review advancing and overlapping stages for our understanding of the expressions of six hyperparathyroid (HPT) syndromes: multiple endocrine neoplasia type 1 (MEN1) or type 4, multiple endocrine neoplasia type 2A (MEN2A), hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism. During stage 1 (1903 to 1967), the introduction of robust measurement of serum calcium was a milestone that uncovered hypercalcemia as the first sign of dysfunction in many HPT subjects, and inheritability was reported in each syndrome. The earliest reports of HPT syndromes were biased toward severe or striking manifestations. During stage 2 (1959 to 1985), the early formulations of a syndrome were improved. Radioimmunoassays (parathyroid hormone [PTH], gastrin, insulin, prolactin, calcitonin) were breakthroughs. They could identify a syndrome carrier, indicate an emerging tumor, characterize a tumor, or monitor a tumor. During stage 3 (1981 to 2006), the assembly of many cases enabled recognition of further details. For example, hormone non-secreting skin lesions were discovered in MEN1 and MEN2A. During stage 4 (1985 to the present), new genomic tools were a revolution for gene identification. Four principal genes ("principal" implies mutated or deleted in 50% or more probands for its syndrome) (MEN1, RET, CASR, CDC73) were identified for five syndromes. During stage 5 (1993 to the present), seven syndromal genes other than a principal gene were identified (CDKN1B, CDKN2B, CDKN2C, CDKN1A, GNA11, AP2S1, GCM2). Identification of AP2S1 and GCM2 became possible because of whole-exome sequencing. During stages 4 and 5, the newly identified genes enabled many studies, including robust assignment of the carriers and non-carriers of a mutation. Furthermore, molecular pathways of RET and the calcium-sensing receptor were elaborated, thereby facilitating developments in pharmacotherapy. Current findings hold the promise that more genes for HPT syndromes will be identified and studied in the near future. © 2018 American Society for Bone and Mineral Research. more...
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- 2018
24. Limited Parathyroidectomy in Multiple Endocrine Neoplasia Type 1-Associated Primary Hyperparathyroidism: A Setup for Failure
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William F. Simonds, Lee S. Weinstein, Electron Kebebew, Robert T. Jensen, Stephen J. Marx, and Naris Nilubol
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Adult ,Male ,Parathyroidectomy ,medicine.medical_specialty ,Adolescent ,endocrine system diseases ,medicine.medical_treatment ,030230 surgery ,Subtotal Parathyroidectomy ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Multiple Endocrine Neoplasia Type 1 ,medicine ,Humans ,Treatment Failure ,Multiple endocrine neoplasia ,Aged ,Neoplasm Staging ,Retrospective Studies ,Hyperparathyroidism ,business.industry ,Retrospective cohort study ,Middle Aged ,Hyperparathyroidism, Primary ,medicine.disease ,Surgery ,medicine.anatomical_structure ,Oncology ,Hypoparathyroidism ,030220 oncology & carcinogenesis ,Female ,Parathyroid gland ,business ,Primary hyperparathyroidism ,Follow-Up Studies - Abstract
Recently, some surgeons have suggested that minimally invasive parathyroidectomy guided by preoperative localizing studies of patients with multiple endocrine neoplasia type 1 (MEN1)-associated primary hyperparathyroidism (pHPT) provides an acceptable outcome while minimizing the risk of hypoparathyroidism. This study aimed to evaluate the outcome for MEN1 patients who underwent limited parathyroidectomy compared with subtotal parathyroidectomy. The authors performed a retrospective analysis of 99 patients with MEN1-associated pHPT who underwent at least one parathyroid operation at their institution. Preoperative imaging studies, intraoperative findings, and clinical outcomes for patients were compared. A total of 99 patients underwent 146 operations. Persistent pHPT was significantly higher in patients whose initial operations involved removal of 1 or 2 glands (69 %) or 2.5 to 3 glands (20 %) compared with those who had 3.5 or more glands removed (6 %) (P more...
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- 2015
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25. Results of 68Gallium-DOTATATE PET/CT Scanning in Patients with Multiple Endocrine Neoplasia Type 1
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Roxanne Merkel, Electron Kebebew, Karel Pacak, Peter Herscovitch, Corina Millo, Lily Yang, William F. Simonds, Samira M. Sadowski, Stephen J. Marx, and Candice Cottle-Delisle
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medicine.medical_specialty ,PET-CT ,business.industry ,Standardized uptake value ,Neuroendocrine tumors ,medicine.disease ,Medicine ,Somatostatin receptor 2 ,Surgery ,MEN1 ,Tomography ,Radiology ,business ,Multiple endocrine neoplasia ,Nuclear medicine ,Prospective cohort study - Abstract
Background Screening for neuroendocrine tumors (NETs) in patients with multiple endocrine neoplasia type 1 (MEN1) is recommended to detect primary and metastatic tumors, which can result in significant morbidity and mortality. The utility of somatostatin receptor imaging 68 Gallium-DOTATATE PET/CT in patients with MEN1 is not known. The aim of this study was to prospectively determine the accuracy of 68 Gallium-DOTATATE PET/CT vs 111 In- pentetreotide single-photon emission CT (SPECT)/CT and anatomic imaging in patients with MEN1. Study Design We performed a prospective study comparing 68 Gallium-DOTATATE PET/CT, 111 In-pentetreotide SPECT/CT, and triphasic CT scan to clinical, biochemical, and pathologic data in 26 patients with MEN1. Results 68 Gallium-DOTATATE PET/CT detected 107 lesions; 111 In-pentetreotide SPECT/CT detected 33 lesions; and CT scan detected 48 lesions. Lesions detected on 68 Gallium-DOTATATE PET/CT had high standard uptake value (SUV) max (median SUV max = 72.8 [range 19 to 191]). In 7 of the 26 patients (27%), 68 Gallium-DOTATATE PET/CT was positive, with a negative 111 In-pentetreotide SPECT/CT, and in 10 patients (38.5%), additional metastases were detected (range 0.3 cm to 1.5 cm). In 8 of the 26 patients (31%), there was a change in management recommendations as a result of the findings on 68 Gallium-DOTATATE PET/CT that were not seen on 111 In-pentetreotide SPECT/CT and CT scan. Conclusions 68 Gallium-DOTATATE PET/CT is more sensitive for detecting NETs than 111 In-pentetreotide SPECT/CT and CT scan in patients with MEN1. This imaging technique should be integrated into radiologic screening and surveillance of patients with MEN1 because it can significantly alter management recommendations. more...
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- 2015
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26. Familial Hyperparathyroidism - Disorders of Growth and Secretion in Hormone-Secretory Tissue
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Delmar M. Lourenço and Stephen J. Marx
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medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Parathyroid hormone ,030209 endocrinology & metabolism ,Biology ,Biochemistry ,Pheochromocytoma ,Parathyroid Glands ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Humans ,MEN1 ,Genetic Predisposition to Disease ,Multiple endocrine neoplasia ,Neonatal severe primary hyperparathyroidism ,Familial hypocalciuric hypercalcemia ,Biochemistry (medical) ,Medullary thyroid cancer ,General Medicine ,medicine.disease ,Hyperparathyroidism, Primary ,Parathyroid Hormone ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Primary hyperparathyroidism - Abstract
Six syndromes of familial hyperparathyroidism are compared: 1) Familial hypocalciuric hypercalcemia (FHH) expresses primary hyperparathyroidism (PHPT) beginning at birth with lifelong hypercalcemia. There is nonsuppressed PTH secretion from outwardly normal parathyroid glands. It reflects germline heterozygous mutation in CASR, GNA11, or AP2S1. 2) Neonatal severe primary hyperparathyroidism is severest of the six syndromes. It requires urgent total parathyroidectomy in infancy. It usually reflects biallelic inactivation of the CASR. 3) Multiple endocrine neoplasia type 1 (MEN1) is most frequently expressed as PHPT with asymmetric enlargement of 3–4 parathyroids. Benign or malignant tumors may occur among 30 other tissues. It is predisposed by germline inactivation of MEN1 or rarely by inactivation of a cyclin dependent kinase inhibitor, and then termed MEN4. 4) Multiple endocrine neoplasia type 2A from RET activating mutation rarely presents as familial hyperparathyroidism, because medullary thyroid cancer and pheochromocytoma are more prominent. 5) Hyperparathyroidism-jaw tumor syndrome (HPT-JT) has frequent PHPT and benign jaw tumors. Twenty percent develop parathyroid cancer. It is predisposed by inactivating mutation in CDC73. 6) Familial isolated hyperparathyroidism causes multiple parathyroid tumors. It can be an incomplete expression of FHH, MEN1, HPT-JT or even of relatives without a shared driver mutation. However, in 20% of families it reflects GCM2 activating mutation. Five of the PHPT syndromes reflect overgrowth of parathyroid tissue; in contrast, familial hypocalciuric hypercalcemia reflects dysregulation of PTH secretion with little or no parathyroid overgrowth. These differences underlie major differences in clinical expression. more...
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- 2017
27. High Total 68Ga-DOTATATE-Avid Tumor Volume (TV) is associated with low progression-free survival and high disease-specific mortality rate in patients with neuroendocrine tumors
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Naris Nilubol, Jasmine Shell, Dhaval Patel, Xavier M. Keutgen, Patience Green, Samira M. Sadowski, Pavel Nockel, Georgios Z. Papadakis, Stephen J. Marx, Lily Yang, Corina Millo, Karel Pacak, Electron Kebebew, Peter Herscovitch, and Amit Tirosh more...
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Age specific mortality ,Medicine ,In patient ,Progression-free survival ,Neuroendocrine tumors ,68Ga-DOTATATE ,business ,medicine.disease ,Surgery - Published
- 2017
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28. Prognostic Utility of Total
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Amit, Tirosh, Georgios Z, Papadakis, Corina, Millo, Dima, Hammoud, Samira M, Sadowski, Peter, Herscovitch, Karel, Pacak, Stephen J, Marx, Lily, Yang, Pavel, Nockel, Jasmine, Shell, Patience, Green, Xavier M, Keutgen, Dhaval, Patel, Naris, Nilubol, and Electron, Kebebew more...
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Adult ,Male ,Chi-Square Distribution ,Time Factors ,Maryland ,Kaplan-Meier Estimate ,Middle Aged ,Disease-Free Survival ,Article ,Tumor Burden ,Pancreatic Neoplasms ,Neuroendocrine Tumors ,Predictive Value of Tests ,Risk Factors ,Positron Emission Tomography Computed Tomography ,Multivariate Analysis ,Disease Progression ,Organometallic Compounds ,Humans ,Female ,Prospective Studies ,Radiopharmaceuticals ,Aged ,Gastrointestinal Neoplasms ,Proportional Hazards Models - Abstract
BACKGROUND & AIMS: Survival times vary among patients with neuroendocrine tumors (NETs)—even among those with the same site, stage, and grade of primary tumor. This makes it difficult to select treatment for patients with unresectable NETs, because some patients can survive decades without treatment. (68)Gallium-DOTATATE positron emission tomography with computed tomography ((68)Ga-DOTATATE PET/CT) is a sensitive imaging technique for detection of NETs. We investigated the prognostic accuracy of (68)Ga-DOTATATE PET/CT analysis of tumor volume in patients with NETs. METHODS: We performed a prospective study of 184 patients with NETs (128 [69.6%] with metastases and 11 patients [6.0%] with locally advanced disease) at the National Institutes of Health Clinical Center from 2013 through 2017. All patients underwent (68)Ga-DOTATATE PET/CT image analysis and total (68)Ga-DOTATATE-Avid tumor volume ((68)Ga-DOTATATE TV) was determined. We also measured fasting serum chromogranin A, neuron-specific enolase, gastrin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, and 24-hour urinary 5-hydroxyindoleacetic acid levels in all patients. Disease progression was defined as a new lesion or a growth of a known lesion, during the interval between baseline (68)Ga-DOTATATE PET/CT scan and follow-up imaging (14.0±6.1 months; range 1–35 months). The primary outcomes were progression-free survival (PFS) and disease-specific mortality during a median follow-up time of 18 months (range 4–35 months). RESULTS: We found an inverse correlation between quartiles of (68)Ga-DOTATATE TV and PFS (P=.001) and disease-specific survival (P=.002). A (68)Ga-DOTATATE TV of 7.0 mL or more was associated with higher odds of disease progression (hazard ratio, 3.0; P=.04). A (68)Ga-DOTATATE TV of 35.8 mL or more was associated with increased risk of disease-specific death (hazard ratio, 10.6) in multivariable analysis (P=.01), as well as in subgroup analysis of patients with pancreatic NETs. CONCLUSIONS: In a prospective study, we demonstrated the prognostic utility of (68)Ga-DOTATATE TV in a large cohort of patients with NETs, in terms of PFS and disease-specific mortality. more...
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- 2017
29. Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure
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James Welch, Bin Guan, Sunita K. Agarwal, Yulong Li, Stephen J. Marx, Roxanne Merkel, William F. Simonds, Naris Nilubol, Lily Yang, Pavel Nockel, Electron Kebebew, Dhaval Patel, and Mustapha El Lakis
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,endocrine system diseases ,Adolescent ,Parathyroid hormone ,030209 endocrinology & metabolism ,Disease ,Gastroenterology ,Parathyroid Glands ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Germline mutation ,Internal medicine ,medicine ,Humans ,Young adult ,Germ-Line Mutation ,Aged ,Retrospective Studies ,Hyperparathyroidism ,business.industry ,Nuclear Proteins ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Hyperparathyroidism, Primary ,Parathyroid carcinoma ,030220 oncology & carcinogenesis ,Surgery ,Female ,business ,Primary hyperparathyroidism ,Transcription Factors - Abstract
Hereditary primary hyperparathyroidism may be syndromic or nonsyndromic (familial isolated hyperparathyroidism). Recently, germline activating mutations in the GCM2 gene were identified in a subset of familial isolated hyperparathyroidism. This study examined the clinical and biochemical characteristics and the treatment outcomes of GCM2 mutation-positive familial isolated hyperparathyroidism as compared to sporadic primary hyperparathyroidism.We performed a retrospective analysis of clinical features, parathyroid pathology, and operative outcomes in 18 patients with GCM2 germline mutations and 457 patients with sporadic primary hyperparathyroidism.Age at diagnosis, sex distribution, race/ethnicity, and preoperative serum calcium concentrations were similar between the 2 groups. The preoperative serum levels of intact parathyroid hormone was greater in patients with GCM2-associated primary hyperparathyroidism (239 ± 394 vs 136 ± 113, P = .005) as were rates of multigland disease and parathyroid carcinoma in the GCM2 group (78% vs 14.3%, P .001 and 5% vs 0%, P = .04, respectively), but the biochemical cure rate was less in the GCM2 group (86% vs 99%, P .001).GCM2-associated primary hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure, and a substantial risk of parathyroid carcinoma. Knowledge of these clinical characteristics could optimize the surgical management of GCM2-associated familial isolated hyperparathyroidism. more...
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- 2017
30. Hyperparathyroidism-jaw tumor syndrome: Results of operative management
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Dhaval Patel, William F. Simonds, Amit Mehta, Avi Rosenberg, Electron Kebebew, Myriem Boufraqech, Martha Quezado, Ryan J. Ellis, Stephen J. Marx, and Naris Nilubol
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Hyperparathyroidism ,Pathology ,medicine.medical_specialty ,Adenoma ,Tumor suppressor gene ,business.industry ,Parathyroid neoplasm ,Autosomal dominant trait ,medicine.disease ,Hyperparathyroidism-Jaw Tumor Syndrome ,Germline mutation ,Medicine ,Surgery ,business ,Parathyroid disease - Abstract
Background Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant disease secondary to germline inactivating mutations of the tumor suppressor gene HRPT2/CDC73. The aim of the present study is to determine the optimal surgical approach to parathyroid disease in patients with HPT-JT. more...
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- 2014
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31. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome
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Hans Morreau, Catharina Larsson, Sunita K. Agarwal, Stephen J. Marx, E. Gillanders, Raman Sood, Andrea Villablanca, Lars-Ove Farnebo, Silvano Presciuttini, Laura James-Newton, Lars Forsberg, Christiane M. Robbins, G. M. Besser, Bruce G. Robinson, William F. Simonds, Branca M. Cavaco, Joan E. Bailey-Wilson, N.D. Perrier, I.B. Rosen, David Cameron, Rajesh V. Thakker, C. Haven, J.M. Trent, John D. Carpten, Brian Harding, Tracy Moses, Bin Tean Teh, Jindong Chen, H. Heath, Wassif S. Wassif, R.J. Zarbo, A.M. Kennedy, P.D. Leotlela, David Petillo, Peter D. Turnpenny, Maurine R. Hobbs, Anna A.J. Pannett, Mary Pat Jones, Charles E. Jackson, Anders Höög, and Ulf Kristoffersson more...
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Adenoma ,Heterozygote ,Genotype ,Genetic Linkage ,Parafibromin ,Molecular Sequence Data ,Biology ,medicine.disease_cause ,Germline ,Exon ,Open Reading Frames ,Germline mutation ,Genetics ,medicine ,Humans ,Genes, Tumor Suppressor ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Genetic Testing ,Gene ,Germ-Line Mutation ,Expressed Sequence Tags ,Mutation ,Base Sequence ,Hyperparathyroidism ,Tumor Suppressor Proteins ,Proteins ,Exons ,Syndrome ,Hyperparathyroidism-Jaw Tumor Syndrome ,Pedigree ,Parathyroid Neoplasms ,Chromosomes, Human, Pair 1 ,Chromosomal region ,Microsatellite Repeats - Abstract
We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors. more...
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- 2016
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32. GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism
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Yulong Li, Jennifer J. Johnston, Hua Ling, William F. Simonds, Sunita K. Agarwal, Julie C. Sapp, Stephen J. Marx, Leslie G. Biesecker, James Welch, Electron Kebebew, and Bin Guan
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0301 basic medicine ,Adenoma ,Adult ,Male ,endocrine system diseases ,Adolescent ,Parathyroid hormone ,Fibroma ,Biology ,Proto-Oncogene Mas ,Article ,03 medical and health sciences ,Young Adult ,Germline mutation ,Proto-Oncogenes ,Genetics ,medicine ,Multiple Endocrine Neoplasia Type 1 ,Missense mutation ,Humans ,Exome ,Amino Acid Sequence ,Multiple endocrine neoplasia ,Genetics (clinical) ,Exome sequencing ,Germ-Line Mutation ,Aged ,Hyperparathyroidism ,Genetic Variation ,Nuclear Proteins ,Sequence Analysis, DNA ,Middle Aged ,medicine.disease ,Hyperparathyroidism, Primary ,Jaw Neoplasms ,Pedigree ,030104 developmental biology ,Parathyroid Hormone ,Female ,Primary hyperparathyroidism ,Transcription Factors - Abstract
Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP. Selected rare variants were assessed for co-segregation in affected family members and screened for in an additional 32 kindreds with FIHP. In eight kindreds with FIHP, we identified three rare missense variants in GCM2, a gene encoding a transcription factor required for parathyroid development. Functional characterization of the GCM2 variants and deletion analyses revealed a small C-terminal conserved inhibitory domain (CCID) in GCM2. Two of the three rare variants were recurrent, located in the GCM2 CCID, and found in seven of the 40 (18%) kindreds with FIHP. These two rare variants acted as gain-of-function mutations that increased the transcriptional activity of GCM2, suggesting that GCM2 is a parathyroid proto-oncogene. Our results demonstrate that germline-activating mutations affecting the CCID of GCM2 can cause FIHP. more...
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- 2016
33. Contributors
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John C. Achermann, Lloyd P. Aiello, Erik K. Alexander, Rebecca H. Allen, David Altshuler, Mark S. Anderson, Mark A. Atkinson, Rebecca S. Bahn, Jennifer M. Barker, Rosemary Basson, Sarah L. Berga, Shalender Bhasin, Morris J. Birnbaum, Dennis M. Black, Anirban Bose, Andrew J.M. Boulton, Glenn D. Braunstein, William J. Bremner, Gregory A. Brent, F. Richard Bringhurst, Michael Brownlee, Serdar E. Bulun, Charles F. Burant, David A. Bushinsky, Roger D. Cone, David W. Cooke, Mark E. Cooper, Philip E. Cryer, Mehul T. Dattani, Terry F. Davies, Francisco J.A. de Paula, Marie B. Demay, Sara A. DiVall, Joel K. Elmquist, Sebastiano Filetti, Evelien F. Gevers, Ezio Ghigo, Anne C. Goldberg, Ira J. Goldberg, Peter A. Gottlieb, Steven K. Grinspoon, Melvin M. Grumbach, Ian D. Hay, Frances J. Hayes, Martha Hickey, Joel N. Hirschhorn, Ken K.Y. Ho, Ieuan A. Hughes, Ursula Kaiser, Andrew M. Kaunitz, Samuel Klein, David Kleinberg, Henry M. Kronenberg, Steven W.J. Lamberts, Fabio Lanfranco, P. Reed Larsen, Peter Laurberg, Mitchell A. Lazar, Lynn Loriaux, Malcolm J. Low, Amit R. Majithia, Stephen J. Marx, Alvin M. Matsumoto, Shlomo Melmed, Rebeca D. Monk, Robert D. Murray, John D.C. Newell-Price, Joshua F. Nitsche, Kjell Öberg, Jorge Plutzky, Kenneth S. Polonsky, Sally Radovick, Alan G. Robinson, Johannes A. Romijn, Clifford J. Rosen, Domenico Salvatore, Martin-Jean Schlumberger, Clay F. Semenkovich, Patrick M. Sluss, Paul M. Stewart, Christian J. Strasburger, Dennis M. Styne, Annewieke W. van den Beld, Adrian Vella, Joseph G. Verbalis, Aaron I. Vinik, Anthony P. Weetman, Samuel A. Wells, and William F. Young more...
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- 2016
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34. Preoperative Localizing Studies for Initial Parathyroidectomy in MEN1 Syndrome: Is There Any Benefit?
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Robert T. Jensen, Electron Kebebew, Giao Q. Phan, William F. Simonds, Lee S. Weinstein, Stephen J. Marx, Michael S. Hughes, Naris Nilubol, and Steven K. Libutti
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Adult ,Male ,Technetium Tc 99m Sestamibi ,Parathyroidectomy ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Choristoma ,Multimodal Imaging ,Subtotal Parathyroidectomy ,Parathyroid Glands ,Young Adult ,Preoperative Care ,Ectopic parathyroid ,Multiple Endocrine Neoplasia Type 1 ,medicine ,Humans ,Supernumerary ,Aged ,Retrospective Studies ,Ultrasonography ,Tomography, Emission-Computed, Single-Photon ,business.industry ,Mediastinum ,Middle Aged ,Hyperparathyroidism, Primary ,Magnetic Resonance Imaging ,Surgery ,Sestamibi Scan ,Thymectomy ,Parathyroid Neoplasms ,Treatment Outcome ,medicine.anatomical_structure ,Positron-Emission Tomography ,Female ,Radiopharmaceuticals ,Tomography, X-Ray Computed ,business ,Neck ,Abdominal surgery - Abstract
The objective of the present study was to evaluate the utility of preoperative localizing studies in patients with MEN1 undergoing initial bilateral neck exploration (BNE) and parathyroidectomy for pHPT. We performed a retrospective analysis of patients diagnosed with MEN1 who underwent initial parathyroidectomy between December 1993 and December 2010. Results of preoperative localizing studies were compared with intraoperative findings and outcome. Sixty patients with MEN1 (32 females and 28 males) underwent initial subtotal parathyroidectomy. The median age at the time of surgery was 33 years (range: 13–78 years). Fifty-three patients had one or more positive localizing study results. Neck ultrasonography, sestamibi scan, parathyroid protocol computed tomography scan, and neck and mediastinum magnetic resonance imaging were performed in 93, 91, 32, and 19% of patients, respectively. Fifty-three patients (88%) had cervical thymectomy. Twenty patients had 24 ectopic parathyroid glands; 18 glands were in the thymus (75%). Preoperative localizing studies identified 9 of 24 ectopic parathyroid glands (38%), including 4 ectopic glands outside the thymus in 4 patients (7%); 3 were detected by ultrasonography. There were no supernumerary glands identified on preoperative localizing studies. In patients with MEN1, preoperative localizing studies identified a subset of ectopic glands (38%). Preoperative localizing studies may alter the operative approach in 7% of patients. Ultrasonography can detect most ectopic parathyroid glands outside thymus. This suggests that routine preoperative localizing studies to identify ectopic and supernumerary enlarged parathyroid glands is not useful in the majority of patients with MEN1 undergoing bilateral neck exploration and subtotal parathyroidectomy with cervical thymectomy. more...
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- 2012
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35. Cushing’s syndrome in multiple endocrine neoplasia type 1
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Sarah Varghese, Lynnette K. Nieman, William F. Simonds, and Stephen J. Marx
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congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,medicine.medical_specialty ,endocrine system diseases ,business.industry ,Endocrinology, Diabetes and Metabolism ,Cancer ,Retrospective cohort study ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,Anterior pituitary ,Internal medicine ,medicine ,Endocrine system ,Adrenocortical carcinoma ,Adrenal adenoma ,MEN1 ,Multiple endocrine neoplasia ,business - Abstract
Summary Objective In patients with multiple endocrine neoplasia type 1 (MEN1), Cushing’s syndrome (CS) from endogenous hypercortisolism can result from pituitary, adrenal or other endocrine tumours. The purpose of this study was to characterize the range of presentations of CS in a large series of MEN1 patients. Design Retrospective review of NIH Clinical Center inpatient records over an approximately 40-year period. Patients Nineteen patients (eight males, 11 females) with CS and MEN1. Measurements Biochemical, imaging, surgical and pathological findings. Results An aetiology was determined for 14 of the 19 patients with CS and MEN1: 11 (79%) had Cushing’s disease (CD) and three (21%) had ACTH-independent CS owing to adrenal tumours, frequencies indistinguishable from sporadic CS. Three of 11 MEN1 patients with CD (27%) had additional non-ACTH-secreting pituitary microadenomas identified at surgery, an incidence 10-fold higher than in sporadic CD. Ninety-one per cent of MEN1 patients with CD were cured after surgery. Two of three MEN1 patients with ACTH-independent CS (67%) had adrenocortical carcinoma. One patient with adrenal cancer and another with adrenal adenoma were cured by unilateral adrenalectomy. No case of ectopic ACTH secretion was identified in our patient cohort. The aetiology of CS could not be defined in five patients; in three of these, hypercortisolism appeared to resolve spontaneously. Conclusions The tumour multiplicity of MEN1 can be reflected in the anterior pituitary, MEN1-associated ACTH-independent CS may be associated with aggressive adrenocortical disease and an aetiology for CS in MEN1 may be elusive in a substantial minority of patients. more...
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- 2012
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36. Prognostic Utility of Total 68Ga-DOTATATE-Avid Tumor Volume in Patients With Neuroendocrine Tumors
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Georgios Z. Papadakis, Electron Kebebew, Pavel Nockel, Jasmine Shell, Peter Herscovitch, Corina Millo, Dhaval Patel, Karel Pacak, Samira M. Sadowski, Patience Green, Naris Nilubol, Lily Yang, Xavier M. Keutgen, Dima A. Hammoud, Stephen J. Marx, and Amit Tirosh more...
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medicine.medical_specialty ,Survival ,Subgroup analysis ,Neuroendocrine tumors ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Progression-free survival ,Stage (cooking) ,Prospective cohort study ,Pancreas ,ddc:617 ,Hepatology ,medicine.diagnostic_test ,business.industry ,Hazard ratio ,Gastroenterology ,Tumor size ,medicine.disease ,Primary tumor ,Positron emission tomography ,030220 oncology & carcinogenesis ,Radiology ,business - Abstract
Background & Aims Survival times vary among patients with neuroendocrine tumors (NETs)—even among those with the same site, stage, and grade of primary tumor. This makes it difficult to select treatment for patients with unresectable NETs, because some patients can survive decades without treatment. 68 Gallium-DOTATATE positron emission tomography with computed tomography ( 68 Ga-DOTATATE PET/CT) is a sensitive imaging technique for detection of NETs. We investigated the prognostic accuracy of 68 Ga-DOTATATE PET/CT analysis of tumor volume in patients with NETs. Methods We performed a prospective study of 184 patients with NETs (128 [69.6%] with metastases and 11 patients [6.0%] with locally advanced disease) at the National Institutes of Health Clinical Center from 2013 through 2017. All patients underwent 68 Ga-DOTATATE PET/CT image analysis and total 68 Ga-DOTATATE-Avid tumor volume ( 68 Ga-DOTATATE TV) was determined. We also measured fasting serum chromogranin A, neuron-specific enolase, gastrin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, and 24-hour urinary 5-hydroxyindoleacetic acid levels in all patients. Disease progression was defined as a new lesion or a growth of a known lesion, during the interval between baseline 68 Ga-DOTATATE PET/CT scan and follow-up imaging (14.0±6.1 months; range 1–35 months). The primary outcomes were progression-free survival (PFS) and disease-specific mortality during a median follow-up time of 18 months (range 4–35 months). Results We found an inverse correlation between quartiles of 68 Ga-DOTATATE TV and PFS ( P =.001) and disease-specific survival ( P =.002). A 68 Ga-DOTATATE TV of 7.0 mL or more was associated with higher odds of disease progression (hazard ratio, 3.0; P =.04). A 68 Ga-DOTATATE TV of 35.8 mL or more was associated with increased risk of disease-specific death (hazard ratio, 10.6) in multivariable analysis ( P =.01), as well as in subgroup analysis of patients with pancreatic NETs. Conclusions In a prospective study, we demonstrated the prognostic utility of 68 Ga-DOTATATE TV in a large cohort of patients with NETs, in terms of PFS and disease-specific mortality. more...
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- 2018
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37. Recapitulation of Pancreatic Neuroendocrine Tumors in Human Multiple Endocrine Neoplasia Type I Syndrome via Pdx1-Directed Inactivation of Men1
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Steven K. Libutti, Amelia C. Grover, Mei He, Kris Ylaya, Stephen M. Hewitt, Allen M. Spiegel, Stephen J. Marx, H.-C. Jennifer Shen, Charles K. Heller, Asha Adem, Dominique Lorang, and Anathea C. Powell more...
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congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Cancer Research ,Pancreatic disease ,endocrine system diseases ,Biology ,Neuroendocrine tumors ,medicine.disease ,medicine.anatomical_structure ,Oncology ,Pancreatic tumor ,Cancer research ,medicine ,PDX1 ,Endocrine system ,MEN1 ,Multiple endocrine neoplasia ,Pancreas - Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal syndrome caused by mutations in the MEN1 tumor suppressor gene. Whereas the protein product of MEN1, menin, is ubiquitously expressed, somatic loss of the remaining wild-type MEN1 allele results in tumors primarily in parathyroid, pituitary, and endocrine pancreas. To understand the endocrine specificity of the MEN1 syndrome, we evaluated biallelic loss of Men1 by inactivating Men1 in pancreatic progenitor cells using the Cre-lox system. Men1 deletion in progenitor cells that differentiate into exocrine and endocrine pancreas did not affect normal pancreas morphogenesis and development. However, mice having homozygous inactivation of the Men1 in pancreas developed endocrine tumors with no exocrine tumor manifestation, recapitulating phenotypes seen in the MEN1 patients. In the absence of menin, the endocrine pancreas showed increase in cell proliferation, vascularity, and abnormal vascular structures; such changes were lacking in exocrine pancreas. Further analysis revealed that these endocrine manifestations were associated with up-regulation in vascular endothelial growth factor expression in both human and mouse MEN1 pancreatic endocrine tumors. Together, these data suggest the presence of cell-specific factors for menin and a permissive endocrine environment for MEN1 tumorigenesis in endocrine pancreas. Based on our analysis, we propose that menin's ability to maintain cellular and microenvironment integrity might explain the endocrine- restrictive nature of the MEN1 syndrome. [Cancer Res 2009;69(5):1858–66] more...
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- 2009
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38. Presentation of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Third International Workshop
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Lis Mosekilde, Munro Peacock, M. L. Brandi, Andrew Arnold, D. Sudhaker Rao, Mishaela R. Rubin, Edward M. Brown, David A. Hanley, David Goltzman, Richard Eastell, Pierre D’Amour, E. M. Lewiecki, Roger Bouillon, Shonni J. Silverberg, and Stephen J. Marx more...
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medicine.medical_specialty ,Consensus ,endocrine system diseases ,Bone density ,Endocrinology, Diabetes and Metabolism ,education ,Hypercalciuria ,Clinical Biochemistry ,MEDLINE ,Disease ,Biochemistry ,Asymptomatic ,Radius bone ,The Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism ,Endocrinology ,Bone Density ,Internal medicine ,medicine ,Humans ,Asymptomatic Diseases ,Parathyroidectomy ,business.industry ,Biochemistry (medical) ,Hyperparathyroidism, Primary ,medicine.disease ,Natural history ,medicine.anatomical_structure ,Cardiovascular Diseases ,Creatinine ,Calcium ,medicine.symptom ,Cognition Disorders ,business ,Primary hyperparathyroidism - Abstract
Background: At the Third International Workshop on Asymptomatic Primary Hyperparathyroidism (PHPT) in May 2008, recent data on the disease were reviewed. We present the results of a literature review on issues arising from the clinical presentation and natural history of PHPT. Methods: Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was reviewed, and the questions of the International Task Force were addressed by the Consensus Panel. Conclusions: 1) Data on the extent and nature of cardiovascular involvement in those with mild disease are too limited to provide a complete picture. 2) Patients with mild PHPT have neuropsychological complaints. Although some symptoms may improve with surgery, available data remain inconsistent on their precise nature and reversibility. 3) Surgery leads to long-term gains in spine, hip, and radius bone mineral density (BMD). Because some patients have early disease progression and others lose BMD after 8–10 yr, regular monitoring (serum calcium and three-site BMD) is essential in those followed without surgery. Patients may present with normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism). Data on the incidence and natural history of this phenotype are limited. 4) In the absence of kidney stones, data do not support the use of marked hypercalciuria (>10 mmol/d or 400 mg/d) as an indication for surgery for patients. 5) Patients with bone density T-score −2.5 or less at the lumbar spine, hip, or distal one third radius should have surgery. more...
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- 2009
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39. The MEN1 Gene and Pituitary Tumours
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Sunita K. Agarwal, Stephen J. Marx, Atsushi Ozawa, and Carmen M. Mateo
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congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Gastrinoma ,endocrine system diseases ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.disease ,Endocrinology ,Pediatrics, Perinatology and Child Health ,Gene Knockout Techniques ,Cancer research ,Medicine ,Endocrine system ,MEN1 ,business ,Multiple endocrine neoplasia ,Insulinoma ,Prolactinoma ,Parathyroid adenoma - Abstract
Sporadic multiple endocrine neoplasia type 1 (MEN1) is defined as the occurrence of tumours in two of three main endocrine tissue types: parathyroid, pituitary and pancreaticoduodenal. A prolactinoma variant or Burin variant of MEN1 was found to occur in three large kindreds, with more prolactinomas and fewer gastrinomas than typical MEN1. MEN1 tumours differ from common tumours by showing features from the MEN1 gene (e.g. larger pituitary tumours). They also show various expressions of tumour multiplicity; however, pituitary tumour in MEN1 is usually solitary. Diagnosis in MEN1 carriers during childhood is not directed at cancers but at benign morbid tumours. Morbid prolactinoma occurred at the age of 5 years in one MEN1 individual; hence, this is the earliest age at which to recommend tumour surveillance in carriers. The MEN1 gene shows biallelic inactivation in 30% of some types of common variety endocrine tumours (e.g. parathyroid adenoma, gastrinoma, insulinoma and bronchial carcinoid), but in only 1–5% of common pituitary tumours. Heterozygous knockout of MEN1 in mice provides a robust model of MEN1 and has been found to support further research on anti-angiogenesis therapy for pituitary tumours. The rarity of MEN1 mutations in some MEN1-like states aids the identification of other mutated genes, such as AIP, HRPT2 and p27Kip1. We present recent clinical and basic findings about the MEN1 gene, particularly concerning hereditary vs. common variety pituitary tumours. more...
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- 2009
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40. The utility of routine transcervical thymectomy for multiple endocrine neoplasia 1-related hyperparathyroidism
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David L. Bartlett, Sunita K. Agarwal, Stephen J. Marx, Monica C. Skarulis, James F. Pingpank, Robert T. Jensen, G. Seidel, H. Richard Alexander, Douglas L. Fraker, Anathea C. Powell, Michael S. Hughes, Craig Cochran, Seth M. Steinberg, and Steven K. Libutti more...
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Adult ,Male ,Hyperparathyroidism ,medicine.medical_specialty ,business.industry ,Multiple endocrine neoplasia 1 ,medicine.medical_treatment ,Thymectomy ,medicine.disease ,Article ,Surgery ,Resection ,Neck exploration ,Transcervical thymectomy ,Multiple Endocrine Neoplasia Type 1 ,medicine ,Humans ,Female ,MEN1 ,Multiple endocrine neoplasia ,business ,Neck - Abstract
Operation for multiple endocrine neoplasia (MEN)1-related hyperparathyroidism (HPT) includes a neck exploration with resection of 3.5 or 4 parathyroid glands and transcervical thymectomy (TCT). We reviewed our experience with initial operation for primary HPT to determine the outcome and utility of routine TCT.All patients with MEN1 who underwent initial neck exploration from 1993 to 2007 under an institutional review board-approved protocol were reviewed.We identified 66 patients with initial operation for HPT in MEN1. In 34 patients, 4 glands were found; in 32 patients,4 glands were found. In 2 of the 34 (6%) and 17 of the 32 (53%), intrathymic parathyroid tissue was found on permanent pathology. No thymic carcinoid tissue was found in any specimen.These data highlight the importance of performing TCT when4 entopic parathyroid glands are found at first operation. more...
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- 2008
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41. Dermatoglyphic and radiographic findings in a mother and daughter with pseudohypoparathyroidism
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Beverly J. White and Stephen J. Marx
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Adult ,musculoskeletal diseases ,media_common.quotation_subject ,Radiography ,Turner Syndrome ,Turner syndrome ,Genetics ,medicine ,Humans ,Dermatoglyphics ,Child ,Genetics (clinical) ,Pseudohypoparathyroidism ,media_common ,Daughter ,business.industry ,Anatomy ,medicine.disease ,body regions ,Diaphysis ,Carpal bones ,medicine.anatomical_structure ,Female ,Palmar crease ,business - Abstract
The dermatoglyphic features of a mother and daughter with pseudohypoparathyroidism were compared with those of 19 other reported PHP cases and with findings typical of 45,X Turner syndrome. Our observations included large patterns with a predominance of whorls, unusual accidental patterns on the third fingers, elevated total and absolute finger ridge counts, extralimital digital triradii, intermediately placed axial triradii, and a single complete transverse palmar crease. With barium-coated hand radiographs, the positions of the palmar digital triradii were compared with those of the underlying metacarpal and carpal bones. Normally, the fourth digital triradii (c) are superficial to the epiphyseal region of the proximal phalanx, near the fourth M-P joint. In our cases, the c triradii were distal to the proximal phalanx, near the fourth M-P joint. In our cases, the c triradii were distal to the M-P joint, adjacent to the diaphysis of the proximal phalanx. These findings, related to post-natal differences in growth potential of osseous structures and overlying dermal ridge tissues in this disease, may also be relevant to other syndromes with abnormal development of the hand. The need for further delineation of PHP dermatoglyphics and comparison of findings with data from Turner syndrome and normals is stressed. more...
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- 2008
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42. Prospective Study of Surgery for Primary Hyperparathyroidism (HPT) in Multiple Endocrine Neoplasia-Type 1 and Zollinger-Ellison Syndrome
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Jeffrey A. Norton, Fathia Gibril, Marc J. Berna, Stephen K. Libutti, Robert T. Jensen, Douglas L. Fraker, Stephen J. Marx, David Venzon, and H. R. Alexander
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Parathyroidectomy ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,medicine.medical_specialty ,Gastrinoma ,Hyperparathyroidism ,endocrine system diseases ,business.industry ,medicine.medical_treatment ,Hyperplasia ,medicine.disease ,Zollinger-Ellison syndrome ,Surgery ,medicine ,MEN1 ,Multiple endocrine neoplasia ,business ,hormones, hormone substitutes, and hormone antagonists ,Primary hyperparathyroidism - Abstract
Background:Primary hyperparathyroidism (HPT) in multiple endocrine neoplasia type 1 (MEN1) patients with Zollinger-Ellison syndrome (ZES) is caused by parathyroid hyperplasia. Surgery for parathyroid hyperplasia is tricky and difficult. Long-term outcome in ZES/MEN1/HPT is not well known.Methods:Eig more...
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- 2008
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43. Parathyroid tumor development involves deregulation of homeobox genes
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Sharon A. Savage, Lauren M Yang, Settara C. Chandrasekharappa, Sunita K. Agarwal, Stephen J. Marx, A. Lee Burns, Carmen M. Mateo, Jennifer E. Rosen, Francis S. Collins, H-C Jennifer Shen, Allen M. Spiegel, and Steven K. Libutti more...
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Cancer Research ,Adolescent ,endocrine system diseases ,Tumor suppressor gene ,Endocrinology, Diabetes and Metabolism ,Cellular differentiation ,Biology ,Article ,Endocrinology ,Proto-Oncogene Proteins ,Multiple Endocrine Neoplasia Type 1 ,medicine ,Humans ,Genetic Predisposition to Disease ,MEN1 ,RNA, Messenger ,Multiple endocrine neoplasia ,Hox gene ,Gene ,Aged ,Reverse Transcriptase Polymerase Chain Reaction ,Genes, Homeobox ,Cancer ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Parathyroid Neoplasms ,Oncology ,Mutation ,Cancer research ,Homeobox ,Female - Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome caused by mutations in the MEN1 tumor suppressor gene. Loss of the functional second copy of the MEN1 gene causes individuals to develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and pancreas. While it is clear that the protein encoded by MEN1, menin, suppresses endocrine tumors, its biochemical functions and direct downstream targets remain unclear. Recent studies have suggested that menin may act as a scaffold protein to coordinate gene transcription, and that menin is an oncogenic cofactor for homeobox (HOX) gene expression in hematopoietic cancer. The role of HOX genes in adult cell differentiation is still obscure, but growing evidence suggests that they may play important roles in the development of cancer. Therefore, we hypothesized that specific HOX genes were regulated by menin in parathyroid tumor development. Utilizing quantitative TaqMan RT-PCR, we compared expression profiles of the 39 HOX genes in human familial MEN1 (fMEN1) parathyroid tumors and sporadic parathyroid adenomas with normal samples. We identified a large set of 23 HOX genes whose deregulation is specific for fMEN1 parathyroid tumors, and only 5 HOX genes whose misexpression are specific for sporadic parathyroid tumor development. These findings provide the first evidence that loss of the MEN1 tumor suppressor gene is associated with deregulation of specific HOX gene expression in the development of familial human parathyroid tumors. Our results strongly reinforce the idea that abnormal expression of developmental HOX genes can be critical in human cancer progression. more...
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- 2008
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44. Calcium Disorders : Butterworths International Medical Reviews: Clinical Endocrinology
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David Heath, Stephen J. Marx, David Heath, and Stephen J. Marx
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- Calcium--Metabolism--Disorders
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Clinical Endocrinology 2: Calcium Disorders presents an extensive examination of the treatment of postmenopausal and senile osteoporosis. It discusses the acquired disorders of vitamin D metabolism. It addresses the prevention of osteoporosis. Some of the topics covered in the book are the classification of rickets; mechanisms of homeostasis; transepithelial transport of phosphate anion; definition of mendelian rickets; treatment of; classification of androgens and synthetic anabolic agents; and assessment of parathyroid function. The measurement of parathyroid hormone is fully covered. An in-depth account of the indirect assessment of parathyroid activity is provided. The acquired disorders of Vitamin D metabolism are completely presented. A chapter is devoted to the aetiological views of rickets and osteomalacia. Another section focuses on the treatment and prevention of rickets and osteomalacia. The analysis of renal osteodystrophy, hypercalcemia, and familial hypocalciuric hypercalcemia are briefly covered. The book can provide useful information to doctors, endocrinologists, students, and researchers. more...
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- 2014
45. Mouse Embryo Fibroblasts Lacking the Tumor Suppressor Menin Show Altered Expression of Extracellular Matrix Protein Genes
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Nijaguna B. Prasad, Abdel G. Elkahloun, Rui Zhu Zhang, Francis S. Collins, Settara C. Chandrasekharappa, Sukhbir Kaur, Elizabeth A. Novotny, Youngmi Ji, Yi Chen, Sunita K. Agarwal, Stephen J. Marx, and Mon-Li Chu more...
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congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Cancer Research ,endocrine system diseases ,Organogenesis ,Periostin ,Mice ,chemistry.chemical_compound ,Transforming Growth Factor beta ,Proto-Oncogene Proteins ,medicine ,Animals ,MEN1 ,Multiple endocrine neoplasia ,Fibroblast ,Molecular Biology ,Regulation of gene expression ,Extracellular Matrix Proteins ,biology ,Tumor Suppressor Proteins ,Gene Expression Regulation, Developmental ,Fibroblasts ,Embryo, Mammalian ,medicine.disease ,Molecular biology ,Fibulin ,medicine.anatomical_structure ,Oncology ,chemistry ,Chondroitin sulfate proteoglycan ,biology.protein ,Versican - Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized primarily by endocrine tumors of the parathyroids, anterior pituitary, and enteropancreatic endocrine tissues. Affected individuals carry a germ-line loss-of-function mutation of the MEN1 gene, and tumors arise after loss of the second allele. Homozygous loss of Men1 in the germ line of mice results in early embryonic lethality, with defective development of neural tube, heart, liver, and craniofacial structures. We generated immortalized wild-type (WT) and menin-null mouse embryo fibroblast (MEF) cell lines and evaluated their characteristics, including global expression patterns. The WT and menin-null cell lines were aneuploid, and the nulls did not display tumorigenic characteristics in soft agar assay. Expression arrays in menin-null MEFs revealed altered expression of several extracellular matrix proteins that are critical in organogenesis. Specifically, transcripts for fibulin 2 (Fbln2), periostin (Postn), and versican [chondroitin sulfate proteoglycan (Cspg2)], genes critical for the developing heart and known to be induced by transforming growth factor-β (TGF-β), were decreased in their expression in menin-null MEFs. Fbln2 expression was the most affected, and the reduction in menin-null MEFs for Fbln2, Postn, and Cspg2 was 16.18-, 5.37-, and 2.15-fold, respectively. Menin-null MEFs also showed poor response to TGF-β–induced Smad3-mediated transcription in a reporter assay, supporting a role for menin in this pathway. Postn and Cspg2 expression in WT, unlike in null MEFs, increased on TGF-β treatment. The expression changes associated with the loss of the tumor suppressor menin provide insights into the defective organogenesis observed during early embryonic development in Men1-null mouse embryos. (Mol Cancer Res 2007;5(10):1041–51) more...
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- 2007
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46. Distribution of Menin-Occupied Regions in Chromatin Specifies a Broad Role of Menin in Transcriptional Regulation
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Francis S. Collins, Soren Impey, Peter C. Scacheri, Richard H. Goodman, Sunita K. Agarwal, Stephen J. Marx, Shannon K. McWeeney, and Allen M. Spiegel
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Cancer Research ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,Transcription, Genetic ,Brief Article ,endocrine system diseases ,ChIP ,chromatin immunoprecipitation ,Biology ,Polymerase Chain Reaction ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Proto-Oncogene Proteins ,Multiple Endocrine Neoplasia Type 1 ,Humans ,Immunoprecipitation ,MEN1 ,multiple endocrine neoplasia ,Promoter Regions, Genetic ,Gene ,3' Untranslated Regions ,030304 developmental biology ,Gene Library ,Regulation of gene expression ,Genetics ,0303 health sciences ,Gene Expression Profiling ,Promoter ,DNA ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Chromatin ,Gene expression profiling ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Human genome ,SACO ,5' Untranslated Regions ,Chromatin immunoprecipitation ,HeLa Cells ,Plasmids ,Protein Binding - Abstract
Menin is the protein product of the MEN1 tumorsuppressor gene; one allele of MEN1 is inactivated in the germ line of patients with “multiple endocrine neoplasia type 1” (MEN1) cancer syndrome. Menin interacts with several proteins involved in transcriptional regulation. RNA expression analyses have identified several menin-regulated genes that could represent proximal or distal interaction sites for menin. This report presents a substantial and unbiased sampling of menin-occupied chromatin regions using Serial Analysis of Chromatin Occupancy; this method combines chromatin immunoprecipitation with Serial Analysis of Gene Expression. Hundreds of menin-occupied genomic sites were identified in promoter regions (32% of menin-occupied loci), near the 3' end of genes (14%), or inside genes (21%), extending other data about menin recruitments to many sites of transcriptional activity. A large number of meninoccupied sites (33%) were located outside known gene regions. Additional annotation of the human genome could help in identifying genes at these loci, or these might be gene-free regions of the genome where menin occupancy could play some structural or regulatory role. Menin occupancy at many intragenic positions distant from the core promoter reveals an unexpected type of menin target region at many loci in the genome. These unbiased data also suggest that menin could play a broad role in transcriptional regulation. more...
- Published
- 2007
47. Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites
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Joanna Shih, Vladimir Neychev, Samira M. Sadowski, Stephen J. Marx, Karel Pacak, Electron Kebebew, Naris Nilubol, Peter Herscovitch, and Corina Millo
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Male ,Cancer Research ,Neuroendocrine tumors ,Multimodal Imaging ,030218 nuclear medicine & medical imaging ,0302 clinical medicine ,Prospective Studies ,Prospective cohort study ,Aged, 80 and over ,medicine.diagnostic_test ,Liver Neoplasms ,ORIGINAL REPORTS ,Hydroxyindoleacetic Acid ,Middle Aged ,Magnetic Resonance Imaging ,Neuroendocrine Tumors ,Oncology ,Positron emission tomography ,030220 oncology & carcinogenesis ,Lymphatic Metastasis ,Unknown primary ,Female ,Radiology ,68Ga-DOTATATE ,Somatostatin ,Vasoactive Intestinal Peptide ,Adult ,medicine.medical_specialty ,Gastro entero pancreatic ,Pancreatic Polypeptide ,03 medical and health sciences ,Young Adult ,Stomach Neoplasms ,Intestinal Neoplasms ,medicine ,Organometallic Compounds ,Humans ,Aged ,Tomography, Emission-Computed, Single-Photon ,business.industry ,Magnetic resonance imaging ,medicine.disease ,Pancreatic Neoplasms ,Phosphopyruvate Hydratase ,Positron-Emission Tomography ,Chromogranin A ,Neoplasms, Unknown Primary ,business ,Nuclear medicine ,Tomography, X-Ray Computed ,Emission computed tomography - Abstract
Purpose Gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) are increasing in incidence, and accurate staging is important for selecting the appropriate treatment. 68Ga-DOTATATE imaging is a promising approach for detecting GEPNETs and could help in selecting optimal therapeutic strategies. The aim of this study was to prospectively determine the clinical utility of 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) in detecting unknown primary and metastatic GEPNETs. Patients and Methods One hundred thirty-one patients were enrolled in a prospective study of patients undergoing 68Ga-DOTATATE PET/CT, 111In-pentetreotide single-photon emission computed tomography (SPECT)/CT and multiphasic CT scan, and/or magnetic resonance imaging in a blinded fashion with comprehensive biochemical testing. The primary outcome measure was the detection of lesions by each imaging study. Results 68Ga-DOTATATE PET/CT imaging detected 95.1% of lesions (95% CI, 92.4% to 96.8%) with an average maximum standardized uptake value of 65.4 ± 47 (range, 6.9 to 244), anatomic imaging detected 45.3% of lesions (95% CI, 37.9% to 52.9%), and 111In-pentetreotide SPECT/CT detected 30.9% of lesions (95% CI, 25.0% to 37.5%), with a significant difference between imaging modalities (P < .001). In four of 14 patients (28.6%), 68Ga-DOTATATE PET/CT found a previously unknown primary tumor, and detected primary GEPNET, lymph node, and distant metastases correctly in 72 of 113 lesions (63.7%) when compared with histopathology, with 22.1% and 38.9% detected by using 111In-pentetreotide SPECT/CT and anatomic imaging, respectively. On the basis of findings with 68Ga-DOTATATE PET/CT, 43 of 131 patients (32.8%) had a change in management recommendation. In patients with carcinoid symptoms but negative biochemical testing, 68Ga-DOTATATE PET/CT detected lesions in 65.2% of patients, 40% of which were detected neither by anatomic imaging nor by 111In-pentetreotide SPECT/CT. Conclusion 68Ga-DOTATATE PET/CT imaging provides important information for accurate staging of GEPNETs and selection of appropriate treatment interventions even in the absence of biochemical evidence of disease in symptomatic patients. more...
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- 2015
48. Hyperplasia in a Gland With Hormone Excess
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Stephen J. Marx
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0301 basic medicine ,Adenoma ,Adult ,Male ,Cancer Research ,Familial hyperaldosteronism ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Puberty, Precocious ,030209 endocrinology & metabolism ,Hyperthyroidism ,Article ,Parathyroid Glands ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Pregnancy ,Internal medicine ,Endocrine Glands ,medicine ,Precocious puberty ,Humans ,Child ,Neonatal severe primary hyperparathyroidism ,Hyperplasia ,business.industry ,Thyroid ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Parathyroid Neoplasms ,Oncology ,Hormones, Ectopic ,Female ,business ,Endocrine gland ,Hormone - Abstract
Five syndromes share predominantly hyperplastic glands with a primary excess of hormones: neonatal severe primary hyperparathyroidism, from homozygous mutatedCASR, begins severelyin utero; congenital non-autoimmune thyrotoxicosis, from mutatedTSHR, varies from severe with fetal onset to mild with adult onset; familial male-limited precocious puberty, from mutatedLHR, expresses testosterone oversecretion in young boys; hereditary ovarian hyperstimulation syndrome, from mutatedFSHR, expresses symptomatic systemic vascular permeabilities during pregnancy; and familial hyperaldosteronism type IIIA, from mutatedKCNJ5, presents in young children with hypertension and hypokalemia. The grouping of these five syndromes highlights predominant hyperplasia as a stable tissue endpoint and as their tissue stage for all of the hormone excess. Comparisons were made among this and two other groups of syndromes, forming a continuum of gland staging: predominant oversecretions express little or no hyperplasia; predominant hyperplasias express little or no neoplasia; and predominant neoplasias express nodules, adenomas, or cancers. Hyperplasias may progress (5 of 5) to neoplastic stages while predominant oversecretions rarely do (1 of 6; frequencies differPPP more...
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- 2015
49. Familial Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism
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Martin R. Pollak, David E. C. Cole, Beat Steinmann, Maria Luisa Brandi, Yah-Huei Wu Chou, Geoffrey N. Hendy, Stephen J. Marx, Fred H. Menko, Christine E. Seidman, Edward M. Brown, Jonathan G. Seidman, and Socrates E. Papapoulos more...
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Nephrology ,medicine.medical_specialty ,Hyperparathyroidism ,Familial hypocalciuric hypercalcemia ,business.industry ,Compound heterozygosity ,medicine.disease ,Hypocalciuria ,Endocrinology ,Internal medicine ,Chromosome 19 ,Medicine ,Parathyroid disorder ,Calcium-sensing receptor ,medicine.symptom ,business - Abstract
The past six decades have witnessed the initial clinical descriptions of neonatal severe hyperparathyroidism (NSHPT) and familial hypocalciuric hypercalcemia (FHH), biochemical and physiologic studies suggesting abnormal calcium sensing by parathyroid glands and kidneys, and finally the description of three distinct molecular causes of FHH. FHH1 results from heterozygous inactivating mutations in the extracellular calcium-sensing receptor (CaSR), usually manifesting as mild to moderate resistance of parathyroid and kidney to calcium, mild PTH-dependent hypercalcemia, and relative hypocalciuria. NSHPT is caused by more severe calcium resistance owing to heterozygous, compound heterozygous, or homozygous CaSR mutations. Recent studies have identified the molecular bases for two additional forms of FHH linked to chromosome 19, FHH2 and FHH3, caused by mutations in downstream proteins in the CaSR signaling pathway. Further studies will likely further expand the range of clinical presentations of FHH, enhance our diagnosis of these conditions, and improve therapies for treating NSHPT and the occasional FHH patients requiring medical or surgical therapy. more...
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- 2015
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50. Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia
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Geoffrey N. Hendy, Lucie Canaff, Svetlana Pidasheva, Stephen J. Marx, and William F. Simonds
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Adult ,Male ,Signal peptide ,Glycosylation ,Molecular Sequence Data ,Mutation, Missense ,Protein Sorting Signals ,Biology ,Kidney ,Transfection ,Microsomes ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,Child ,Molecular Biology ,Genetics (clinical) ,Secretory pathway ,Mitogen-Activated Protein Kinase Kinases ,Calcium metabolism ,chemistry.chemical_classification ,Sequence Homology, Amino Acid ,Familial hypocalciuric hypercalcemia ,Hyperparathyroidism ,Endoplasmic reticulum ,General Medicine ,medicine.disease ,Pedigree ,Cell biology ,Protein Transport ,Biochemistry ,chemistry ,Hypercalcemia ,Mutagenesis, Site-Directed ,Calcium ,Female ,Calcium-sensing receptor ,Signal transduction ,Glycoprotein ,Protein Processing, Post-Translational ,Receptors, Calcium-Sensing - Abstract
The CASR, a cell surface glycoprotein expressed in parathyroid gland and kidney, is critical for maintaining extracellular calcium homeostasis. The inherited disorders, familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), are caused by inactivating mutations in the CASR gene. The CASR has an N-terminal, 19 amino acid signal peptide that is predicted to direct the nascent polypeptide chain, as it emerges from the ribosome, into the endoplasmic reticulum (ER). Here, we report the functional characterization of three CASR mutations identified in hypercalcemic/hyperparathyroid patients. The mutations, L11S, L13P and T14A, lie within the signal peptide hydrophobic core. When transiently transfected into kidney cells, L11S and L13P mutants demonstrated reduced intracellular and plasma membrane expression and signaling to the mitogen-activated protein kinase pathway in response to extracellular calcium relative to wild-type CASR and the T14A mutant. All mutant CASR RNAs translated into protein normally. In cotranslational processing assays, which test the functionality of the signal peptide in the early secretory pathway, the wild-type CASR and mutant T14A nascent polypeptides were targeted to microsomal vesicles, representing the ER, translocated into the vesicular lumen and underwent core N-glycosylation. In contrast, the L11S and L13P mutants failed to be inserted in the microsomes and undergo glycosylation. This is the first study examining the function of the CASR signal sequence and reveals that both L11S and L13P mutants are markedly impaired with respect to cotranslational processing, accounting for the observed parathyroid dysfunction. more...
- Published
- 2005
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