26 results on '"Espiard S"'
Search Results
2. Purity of islet preparations and 5-year metabolic outcome of allogenic islet transplantation
- Author
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Benomar, K., Chetboun, M., Espiard, S., Jannin, A., Le Mapihan, K., Gmyr, V., Caiazzo, R., Torres, F., Raverdy, V., Bonner, C., D’Herbomez, M., Pigny, P., Noel, C., Kerr-Conte, J., Pattou, F., and Vantyghem, M.C.
- Published
- 2018
- Full Text
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3. Age-dependent effects of Armc5 haploinsufficiency on adrenocortical function
- Author
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Berthon, A., Faucz, F.R., Espiard, S., Drougat, L., Bertherat, J., and Stratakis, C.A.
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- 2017
- Full Text
- View/download PDF
4. Improved Urinary Cortisol Metabolome in Addison Disease : A Prospective Trial of Dual-Release Hydrocortisone
- Author
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Espiard, S, McQueen, J, Sherlock, M, Ragnarsson, O, Bergthorsdottir, R, Burman, P, Dahlqvist, P, Ekman, B, Engström, BE, Skrtic, S, Wahlberg, J, Stewart, PM, and Johannsson, G
- Subjects
11 beta-hydroxysteroid dehydrogenase ,dual-release hydrocortisone ,cortisol metabolism ,primary adrenal insufficiency ,Endokrinologi och diabetes ,Addison disease ,11β-hydroxysteroid dehydrogenase ,hydrocortisone ,Endocrinology and Diabetes - Abstract
CONTEXT: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism. OBJECTIVE: This work aimed to study cortisol metabolism during DR-HC and TID-HC. DESIGN: A randomized, 12-week, crossover study was conducted. INTERVENTION AND PARTICIPANTS: DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls. MAIN OUTCOME MEASURES: Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections. RESULTS: Total cortisol metabolites decreased during DR-HC compared to TID-HC (P Funding: Swedish Research CouncilSwedish Research CouncilEuropean Commission [2015-02561]; Swedish federal government under the LUA/ALF agreement [ALFGBG-719531]; Shire International GmbH [SWE_000991]; FRM (Fondation pour la Recherche Medicale)Fondation pour la Recherche Medicale
- Published
- 2021
5. Diseases associated with calcium-sensing receptor
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Vahe, C., primary, Benomar, K., additional, Espiard, S., additional, Coppin, L., additional, Jannin, A., additional, Odou, M. F., additional, and Vantyghem, M. C., additional
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- 2017
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6. Prevalence of Endocrine Manifestations and GIST in 108 Systematically Screened Patients With Neurofibromatosis Type 1.
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Dupuis H, Chevalier B, Cardot-Bauters C, Jannin A, Do Cao C, Ladsous M, Cortet C, Merlen E, Drouard M, Aubert S, Vidaud D, Espiard S, and Vantyghem MC
- Abstract
Context: In patients with neurofibromatosis type 1 (NF1), guidelines suggest screening for pheochromocytoma by metanephrine measurement and abdominal imaging, which may lead to the discovery of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and their differential diagnosis, gastrointestinal stromal tumors (GISTs). Other endocrine manifestations such as follicular thyroid carcinoma and primary hyperparathyroidism have also been reported in a few cases., Objective: This study aimed to describe prevalence and clinical presentation of these manifestations through systematic screening in a large cohort of patients., Methods: In this monocentric retrospective study, 108 patients with NF1 were included and screened for endocrine manifestations and GISTs. Clinical, laboratory, molecular profile, pathology, and morphologic (abdominal computed tomography scan and/or magnetic resonance imaging) and functional imaging were collected., Results: Twenty-four patients (22.2% of the cohort, 16 female, mean age 42.6 years) presented with pheochromocytomas that were unilateral in 65.5%, benign in 89.7%, and with a ganglioneural component in 20.7%. Three female patients (2.8% of the cohort, aged 42-63 years) presented with well-differentiated GEP-NETs, and 4 (3.7%) with GISTs. One patient had primary hyperparathyroidism, 1 patient had medullary microcarcinoma, and 16 patients had goiter, multinodular in 10 cases. There was no correlation between pheochromocytoma and other NF1 tumoral manifestations, nor correlations between pheochromocytoma and NF1 genotype, despite a familial clustering in one-third of patients., Conclusion: The pheochromocytoma prevalence in this NF1 cohort was higher (>20%) than previously described, confirming the interest of systematic screening, especially in young women. The prevalence of GEP-NETs and GISTs was about 3%, respectively. No phenotype-genotype correlation was observed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2023
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7. Complete pathological response following chemotherapy and radiotherapy in two cases of advanced anaplastic thyroid carcinoma.
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Chevalier B, Karleskind O, Jannin A, Farchi O, Vermaut C, Escande A, Baillet C, Espiard S, Vantyghem MC, Carnaille B, Leteurtre E, and Do Cao C
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- Humans, Prognosis, Thyroid Carcinoma, Anaplastic drug therapy, Thyroid Neoplasms drug therapy, Radiation Oncology
- Abstract
Introduction: Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer with a bleak prognosis. Favorable outcomes are rare but help decipher molecular pathophysiology, investigate prognosis factors, and discover new therapeutic targets., Case Presentation: Two patients were diagnosed with locally advanced nonresectable ATC, one with metastatic extension. Each patient received chemotherapy and radiotherapy, allowing thyroid surgical resection. In both cases, the pathological examination was consistent with complete response with no viable tumor cells. After follow-ups of 48 and 70 months, both patients remain disease-free. Molecular explorations on thyroid biopsies revealed microsatellite instability (MSI) and alterations on mismatch repair-gene complex, also PTEN and ATM variants in both cases. Both also presented with non-classical immune infiltrate composed of equal parts T CD4+ lymphocytes and macrophages., Conclusion: We report two cases of patients cured from advanced ATC and for the first time provide genetic and immunological explorations in this setting. It seems with these two cases that MSI-ATCs may indicate a better prognosis. Our study hypothesizes different responsible mechanisms including increased sensitivity to chemoradiotherapy and/or immune tumor infiltrate modulation.
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- 2022
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8. KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
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Vaczlavik A, Bouys L, Violon F, Giannone G, Jouinot A, Armignacco R, Cavalcante IP, Berthon A, Letouzé E, Vaduva P, Barat M, Bonnet F, Perlemoine K, Ribes C, Sibony M, North MO, Espiard S, Emy P, Haissaguerre M, Tauveron I, Guignat L, Groussin L, Dousset B, Reincke M, Fragoso MC, Stratakis CA, Pasmant E, Libé R, Assié G, Ragazzon B, and Bertherat J
- Subjects
- Armadillo Domain Proteins genetics, Histone Demethylases genetics, Humans, Hyperplasia, Phenotype, Cushing Syndrome diagnosis, Cushing Syndrome genetics, Cushing Syndrome surgery
- Abstract
Purpose: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS., Methods: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing)., Results: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10
-12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS., Conclusion: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.)- Published
- 2022
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9. Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment.
- Author
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Chevalier B, Vantyghem MC, and Espiard S
- Abstract
Bilateral adrenal hyperplasia is a rare cause of Cushing's syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size of the nodules. They both lead to overt or subclinical CS. In the latter case, PPNAD is usually diagnosed after a systematic screening in patients presenting with Carney complex, while for PBMAH, the diagnosis is often incidental on imaging. Identification of causal genes and genetic counseling also help in the diagnoses. This review discusses the last decades' findings on genetic and molecular causes of bilateral adrenal hyperplasia, including the several mechanisms altering the PKA pathway, the recent discovery of ARMC5 , and the role of the adrenal paracrine regulation. Finally, the treatment of bilateral adrenal hyperplasia will be discussed, focusing on current data on unilateral adrenalectomy.
- Published
- 2021
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10. Phakomatoses and Endocrine Gland Tumors: Noteworthy and (Not so) Rare Associations.
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Chevalier B, Dupuis H, Jannin A, Lemaitre M, Do Cao C, Cardot-Bauters C, Espiard S, and Vantyghem MC
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- Humans, Endocrine Gland Neoplasms pathology, Hamartoma Syndrome, Multiple pathology, Neurocutaneous Syndromes pathology, Neurofibromatosis 1 pathology, Tuberous Sclerosis pathology, von Hippel-Lindau Disease pathology
- Abstract
Phakomatoses encompass a group of rare genetic diseases, such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC) and Cowden syndrome (CS). These disorders are due to molecular abnormalities on the RAS-PI3K-Akt-mTOR pathway for NF1, TSC and CS, and to hypoxia sensing for VHL. Phakomatoses share some phenotypic traits such as neurological, ophthalmological and cutaneous features. Patients with these diseases are also predisposed to developing multiple endocrine tissue tumors, e.g., pheochromocytomas/paragangliomas are frequent in VHL and NF1. All forms of phakomatoses except CS may be associated with digestive neuroendocrine tumors. More rarely, thyroid cancer and pituitary or parathyroid adenomas have been reported. These susceptibilities are noteworthy, because their occurrence rate, prognosis and management differ slightly from the sporadic forms. The aim of this review is to summarize current knowledge on endocrine glands tumors associated with VHL, NF1, TSC, and CS, especially neuroendocrine tumors and pheochromocytomas/paragangliomas. We particularly detail recent advances concerning prognosis and management, especially parenchyma-sparing surgery and medical targeted therapies such as mTOR, MEK and HIF-2 α inhibitors, which have shown truly encouraging results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chevalier, Dupuis, Jannin, Lemaitre, Do Cao, Cardot-Bauters, Espiard and Vantyghem.)
- Published
- 2021
- Full Text
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11. Improved Urinary Cortisol Metabolome in Addison Disease: A Prospective Trial of Dual-Release Hydrocortisone.
- Author
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Espiard S, McQueen J, Sherlock M, Ragnarsson O, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engström BE, Skrtic S, Wahlberg J, Stewart PM, and Johannsson G
- Subjects
- Adult, Aged, Cortisone metabolism, Cortisone urine, Cross-Over Studies, Delayed-Action Preparations pharmacokinetics, Delayed-Action Preparations therapeutic use, Europe, Female, Humans, Hydrocortisone therapeutic use, Hydrocortisone urine, Male, Metabolome drug effects, Middle Aged, Pregnanes metabolism, Pregnanes urine, Steroids metabolism, Tetrahydrocortisol metabolism, Tetrahydrocortisol urine, Tetrahydrocortisone metabolism, Tetrahydrocortisone urine, Urinalysis, Addison Disease drug therapy, Addison Disease metabolism, Addison Disease urine, Hydrocortisone pharmacokinetics, Steroids urine
- Abstract
Context: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism., Objective: This work aimed to study cortisol metabolism during DR-HC and TID-HC., Design: A randomized, 12-week, crossover study was conducted., Intervention and Participants: DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls., Main Outcome Measures: Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections., Results: Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < .001) and reached control values (P = .089). During DR-HC, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity measured by tetrahydrocortisol + 5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < .05), but remained increased vs controls (P < .001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC vs controls (P < .01) but normalized with DR-HC (P = .358). 5α- and 5β-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5β-reductase activity., Conclusions: The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy, with increased 11β-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change toward normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)
- Published
- 2021
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12. Genomic classification of benign adrenocortical lesions.
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Faillot S, Foulonneau T, Néou M, Espiard S, Garinet S, Vaczlavik A, Jouinot A, Rondof W, Septier A, Drougat L, Hécale-Perlemoine K, Ragazzon B, Rizk-Rabin M, Sibony M, Bonnet-Serrano F, Guibourdenche J, Libé R, Groussin L, Dousset B, de Reyniès A, Bertherat J, and Assié G
- Subjects
- Humans, Adrenocortical Adenoma genetics, Genomics methods
- Abstract
Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays, miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all tumors. Pangenomic analysis identifies four distinct molecular categories: (1) tumors responsible for overt Cushing, gathering distinct tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2) adenomas with mild autonomous cortisol excess and non-functioning adenomas, associated with beta-catenin mutations; (3) primary macronodular hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4) aldosterone-producing adrenocortical adenomas, apart from other benign tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in tumors with no or mild cortisol secretion, miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.
- Published
- 2021
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13. PRKACB variants in skeletal disease or adrenocortical hyperplasia: effects on protein kinase A.
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Espiard S, Drougat L, Settas N, Haydar S, Bathon K, London E, Levy I, Faucz FR, Calebiro D, Bertherat J, Li D, Levine MA, and Stratakis CA
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- Adolescent, Adrenal Gland Neoplasms pathology, Adult, Animals, Female, Humans, Mice, Young Adult, Adrenal Gland Neoplasms genetics, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits metabolism
- Abstract
Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C>T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may be responsible for a novel syndrome, associated with endocrine and skeletal abnormalities.
- Published
- 2020
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14. Genetic predisposition to neural crest-derived tumors: revisiting the role of KIF1B.
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Cardot Bauters C, Leteurtre E, Carnaille B, Do Cao C, Espiard S, Penven M, Destailleur E, Szuster I, Lovecchio T, Leclerc J, Frénois F, Esquivel E, Dahia PLM, Ait-Yahya E, Crépin M, and Pigny P
- Abstract
Objective: We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband's brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis., Design and Methods: Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations., Results: A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband's brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband., Conclusion: In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.
- Published
- 2020
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15. Erratum. Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study. Diabetes Care 2019;42:2042-2049.
- Author
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Vantyghem MC, Chetboun M, Gmyr V, Jannin A, Espiard S, Le Mapihan K, Raverdy V, Delalleau N, Machuron F, Hubert T, Frimat M, Van Belle E, Hazzan M, Pigny P, Noel C, Caiazzo R, Kerr-Conte J, and Pattou F
- Published
- 2020
- Full Text
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16. Frequency and Incidence of Carney Complex Manifestations: A Prospective Multicenter Study With a Three-Year Follow-Up.
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Espiard S, Vantyghem MC, Assié G, Cardot-Bauters C, Raverot G, Brucker-Davis F, Archambeaud-Mouveroux F, Lefebvre H, Nunes ML, Tabarin A, Lienhardt A, Chabre O, Houang M, Bottineau M, Stroër S, Groussin L, Guignat L, Cabanes L, Feydy A, Bonnet F, North MO, Dupin N, Grabar S, Duboc D, and Bertherat J
- Subjects
- Adolescent, Adult, Aged, Carney Complex diagnosis, Carney Complex genetics, Child, Child, Preschool, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit genetics, Female, Follow-Up Studies, France epidemiology, Humans, Incidence, Male, Middle Aged, Prevalence, Prospective Studies, Young Adult, Carney Complex epidemiology
- Abstract
Introduction: Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far., Methods: This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation., Results: The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype., Conclusion: This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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17. Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study.
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Vantyghem MC, Chetboun M, Gmyr V, Jannin A, Espiard S, Le Mapihan K, Raverdy V, Delalleau N, Machuron F, Hubert T, Frimat M, Van Belle E, Hazzan M, Pigny P, Noel C, Caiazzo R, Kerr-Conte J, and Pattou F
- Subjects
- Adult, Blood Glucose metabolism, Combined Modality Therapy, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 complications, Female, Glycated Hemoglobin analysis, Humans, Hypoglycemia epidemiology, Hypoglycemia etiology, Hypoglycemic Agents administration & dosage, Immunosuppression Therapy methods, Insulin administration & dosage, Islets of Langerhans Transplantation adverse effects, Kidney Transplantation adverse effects, Male, Middle Aged, Postoperative Complications epidemiology, Postoperative Complications etiology, Prospective Studies, Treatment Outcome, Diabetes Mellitus, Type 1 surgery, Islets of Langerhans Transplantation methods, Kidney Transplantation methods
- Abstract
Objective: The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft., Research Design and Methods: We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median [interquartile range]) 68 days (43-92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function., Results: The primary outcome was met by (Kaplan-Meier estimates [95% CI]) 39% (22-57) and 28% (13-45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62-92) and 78% (57-89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence., Conclusions: Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not., (© 2019 by the American Diabetes Association.)
- Published
- 2019
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18. Systematic thyroid screening in myotonic dystrophy: link between thyroid volume and insulin resistance.
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Ben Hamou A, Espiard S, Do Cao C, Ladsous M, Loyer C, Moerman A, Boury S, Kyheng M, Dhaenens CM, Tiffreau V, Pigny P, Lebuffe G, Caiazzo R, Aubert S, and Vantyghem MC
- Subjects
- Adult, Female, Goiter diagnosis, Goiter etiology, Goiter genetics, Humans, Insulin Resistance genetics, Male, Middle Aged, Myotonic Dystrophy genetics, Thyroid Cancer, Papillary diagnosis, Thyroid Cancer, Papillary etiology, Thyroid Cancer, Papillary genetics, Thyroid Neoplasms etiology, Thyroid Neoplasms genetics, Insulin Resistance physiology, Myotonic Dystrophy diagnosis, Myotonic Dystrophy etiology, Thyroid Gland pathology, Thyroid Neoplasms diagnosis
- Abstract
Background: Myotonic dystrophy (DM1), a neuromuscular disease related to DMPK gene mutations, is associated to endocrine disorders and cancer. A routine endocrine work-up, including thyroid ultrasound (US), was conducted in 115 genetically-proven DM1 patients in a neuromuscular reference center. The aim of this study was to determine the prevalence and the causes of US thyroid abnormalities in DM1., Results: In the whole population (age 45.1 ± 12.2 years, 61.7% female), palpable nodules or goiters were present in 29.2%. The percentage of US goiter (thyroid volume > 18 mL) and US nodules were, respectively, 38.3 and 60.9%. Sixteen of the 115 patients had a thyroidectomy, after 22 fine-needle aspiration cytology guided by thyroid imaging reporting and data system (TIRADS) classification. Six micro- (1/6 pT3) and 3 macro-papillary thyroid carcinoma (PTCs) (2/3 intermediate risk) were diagnosed (7.9% of 115). Thyroid US led to the diagnosis of 4 multifocal and 2 unifocal (including 1 macro-PTC) non-palpable PTCs. Ultrasound thyroid volume was positively correlated to body mass index (BMI) (p = 0.015) and parity (p = 0.036), and was inversely correlated to TSH (p < 0.001) and vitamin D levels (p = 0.023). The BMI, the frequencies of glucose intolerance and PTC were significantly higher in UsGoiter versus non-UsGoiter groups., Conclusion: In this systematically screened DM1 cohort, the frequency of UsGoiter, mainly associated to BMI, was about 40%, US nodules 60%, thyroidectomies 13-14%, and PTCs 8%, two-thirds of them being micro-PTCs with good prognosis. Therefore, a systematic screening remains debatable. A targeted US screening in case of clinical abnormality or high BMI seems more appropriate.
- Published
- 2019
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19. Safety and efficacy of thermal ablation (radiofrequency and laser): should we treat all types of thyroid nodules? † .
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Ben Hamou A, Ghanassia E, Espiard S, Abi Rached H, Jannin A, Correas JM, Do Cao C, Kyheng M, Vantyghem MC, and Monpeyssen H
- Subjects
- Abscess etiology, Adult, Cranial Nerve Diseases etiology, Female, Hematoma etiology, Humans, Laryngeal Nerves, Male, Middle Aged, Postoperative Complications, Treatment Outcome, Catheter Ablation adverse effects, Laser Therapy adverse effects, Thyroid Nodule surgery
- Abstract
Background: Thermal ablation is a minimally invasive technique that is gradually acknowledged as an effective alternative to surgery to treat thyroid nodules. Two main techniques have been described: radiofrequency (RFA) and laser ablation. Objective: To evaluate the safety and efficacy of the two main techniques (RFA and laser ablation) for the treatment of benign thyroid nodules. Patients: This bicentric retrospective study included 166 consecutive patients, who received clinical, biological and ultrasound evaluations for thyroid nodules, from October 2013 to November 2017. Methods: One of the two techniques was proposed if a nodule was proven to be benign after fine needle aspiration cytology or micro-biopsy. Adverse events and outcomes (symptoms, nodule reduction) were assessed at 6 weeks and 6, 12, and 18 months after treatment. Results: One hundred and eighty-nine nodules (mean size 17.5 ± 16.9 mL, 86.1% palpable) were treated by RFA (n = 108 (57.1%)) or laser ablation ( n = 81 (42.9%)) in 166 patients (80.1% women, mean age 51.7 years). Two cases of transient recurrent laryngeal nerve palsy, one hematoma, and two successfully drained abscesses (5/166 = 3%) were observed. Clinical symptoms improved significantly in the two groups (anterior cervical discomfort -83.6%, esthetic complaints -84.9% and dysphagia -86.4%). Nodule volume (mL) decreased significantly (baseline vs. 18 months) from 20.4 ± 18.6 to 5.8 ± 6.6 (-75%) in the RFA, and from 13.6 ± 13.3 to 3.4 ± 4.1 (-83.9%) in the laser ablation groups. Conclusions: Transient but potentially serious adverse events were reported in 3% of patients. A significant volumetric reduction was achieved with both techniques, regardless of nodule's characteristics, at 18 months.
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- 2019
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20. Activating PRKACB somatic mutation in cortisol-producing adenomas.
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Espiard S, Knape MJ, Bathon K, Assié G, Rizk-Rabin M, Faillot S, Luscap-Rondof W, Abid D, Guignat L, Calebiro D, Herberg FW, Stratakis CA, and Bertherat J
- Subjects
- Adenoma metabolism, Adrenal Gland Neoplasms diagnostic imaging, Adrenal Gland Neoplasms pathology, Adrenal Gland Neoplasms surgery, Adrenal Insufficiency etiology, Adrenalectomy methods, Adult, Catalytic Domain genetics, Cushing Syndrome pathology, Cushing Syndrome surgery, Cyclic AMP Receptor Protein metabolism, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, Female, Holoenzymes metabolism, Humans, Mutation, Treatment Outcome, Exome Sequencing methods, Adenoma enzymology, Cushing Syndrome diagnostic imaging, Cyclic AMP-Dependent Protein Kinases genetics, Hydrocortisone metabolism
- Abstract
Mutations in the gene encoding the protein kinase A (PKA) catalytic subunit α have been found to be responsible for cortisol-producing adenomas (CPAs). In this study, we identified by whole-exome sequencing the somatic mutation p.S54L in the PRKACB gene, encoding the catalytic subunit β (Cβ) of PKA, in a CPA from a patient with severe Cushing syndrome. Bioluminescence resonance energy transfer and surface plasmon resonance assays revealed that the mutation hampers formation of type I holoenzymes and that these holoenzymes were highly sensitive to cAMP. PKA activity, measured both in cell lysates and with recombinant proteins, based on phosphorylation of a synthetic substrate, was higher under basal conditions for the mutant enzyme compared with the WT, while maximal activity was lower. These data suggest that at baseline the PRKACB p.S54L mutant drove the adenoma cells to higher cAMP signaling activity, probably contributing to their autonomous growth. Although the role of PRKACB in tumorigenesis has been suggested, we demonstrated for the first time to our knowledge that a PRKACB mutation can lead to an adrenal tumor. Moreover, this observation describes another mechanism of PKA pathway activation in CPAs and highlights the particular role of residue Ser54 for the function of PKA.
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- 2018
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21. ARMC5 mutation in a Portuguese family with primary bilateral macronodular adrenal hyperplasia (PBMAH).
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Rego T, Fonseca F, Espiard S, Perlemoine K, Bertherat J, and Agapito A
- Abstract
Summary: PBMAH is a rare etiology of Cushing syndrome (CS). Familial clustering suggested a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 ( ARMC5 ) gene. A 70-year-old female patient was admitted due to left femoral neck fracture in May 2014, in Orthopedics Department. During hospitalization, hypertension (HTA) and hypokalemia were diagnosed. She presented with clinical signs of hypercortisolism and was transferred to the Endocrinology ward for suspected CS. Laboratory workup revealed: ACTH <5 pg/mL; urinary free cortisol (UFC), 532 µg/24 h (normal range: 20-90); failure to suppress the low-dose dexamethasone test (0.5 mg every 6 h for 48 h): cortisol 21 µg/dL. Abdominal magnetic resonance imaging (MRI) showed enlarged nodular adrenals (right, 55 × 54 × 30 mm; left, 85 × 53 × 35 mm), and she was submitted to bilateral adrenalectomy. In 2006, this patient's 39-year-old daughter had been treated by one of the authors. She presented with severe clinical and biological hypercortisolism. Computed tomography (CT) scan showed massively enlarged nodular adrenals with maximal axis of 15 cm for both. Bilateral adrenalectomy was performed. In this familial context of PBMAH, genetic study was performed. Leucocyte DNA genotyping identified in both patients the same germline heterozygous ARMC5 mutation in exon 1 c.172_173insA p.I58Nfs*45. The clinical cases herein described have an identical phenotype with severe hypercortisolism and huge adrenal glands, but different ages at the time of diagnosis. Current knowledge of inheritance of this disease, its insidious nature and the well-known deleterious effect of hypercortisolism favor genetic study to timely identify and treat these patients., Learning Points: PBMAH is a rare etiology of CS, characterized by functioning adrenal macronodules and variable cortisol secretion.The asymmetric/asynchronous involvement of only one adrenal gland can also occur, making disease diagnosis a challenge.Familial clustering suggests a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 ( ARMC5 ) gene.The insidious nature of this disease and the well-known deleterious effect of hypercortisolism favor genetic study of other family members, to diagnose and treat these patients timely.As ARMC5 is expressed in many organs and recent findings suggest an association of PBMAH and meningioma, a watchful follow-up is required.
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- 2017
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22. Reversal of a Blunted Follicle-Stimulating Hormone by Chemotherapy in an Inhibin B-Secreting Adrenocortical Carcinoma.
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Espiard S, Lahlou N, Sibony M, Louiset E, Bienvenu M, Bertherat J, Dousset B, Groussin L, and Libé R
- Abstract
Context: Adrenocortical carcinomas (ACCs) are revealed in 60% of cases by steroid hypersecretion. Alternatively, it is uncommon to observe a paraneoplastic syndrome due to a peptide oversecretion., Case Description: We describe a 60-year-old man with a right adrenal mass. Hormonal evaluation showed an ACTH-independent Cushing syndrome. Surprisingly, follicle-stimulating hormone (FSH) levels were suppressed and blunted during gonadotropin-releasing hormone stimulation, despite normal luteinizing hormone levels. Levels of inhibin B, which negatively regulates the pituitary FSH, were very high. Given the atypical hormonal findings, an adrenal mass biopsy was performed, which allowed the diagnosis of an adrenocortical tumor (positive for steroidogenic factor-1 immunostaining). Moreover, an intense α -inhibin subunit immunostaining was observed. Because of the presence of metastases, the patient received mitotane and chemotherapy (etoposide and cisplatin). After 2 cycles, the inhibin B dropped. After 5 cycles, tumor size was reduced by 15%. Inhibin B levels remained low, and basal and gonadotropin-releasing hormone-stimulated FSH levels normalized. The patient underwent tumor resection, and pathology confirmed the ACC diagnosis (Weiss score of 9). The intensity of the α -inhibin subunit immunostaining was significantly decreased., Conclusions: We report the case of an inhibin B-secreting ACC in which the response to chemotherapy and mitotane was associated with a normalization of inhibin B secretion, allowing the reversal of the blunted FSH secretion. Inhibin B should be measured in case of suppressed FSH levels despite normal luteinizing hormone levels and may be considered a tumoral marker in some ACCs, even during treatment follow-up.
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- 2017
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23. A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone.
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Espiard S, Savagner F, Flamant F, Vlaeminck-Guillem V, Guyot R, Munier M, d'Herbomez M, Bourguet W, Pinto G, Rose C, Rodien P, and Wémeau JL
- Subjects
- Adult, Amino Acid Substitution, Diarrhea complications, Diarrhea genetics, Dwarfism genetics, Female, Humans, Hypercalcemia complications, Hypercalcemia genetics, Musculoskeletal Abnormalities genetics, Phenotype, Genes, erbA, Germ-Line Mutation, Thyroid Hormone Resistance Syndrome genetics
- Abstract
Context: RTHα is a recently discovered resistance to thyroid hormone (RTH) due to mutation of THRA, the gene encoding TRα1, the thyroid hormone receptor. It has been described in a few patients with growth retardation, short stature, and a low free T4/free T3 (FT4/FT3) ratio., Objective: A 27-year-old patient presenting with dwarfism and a low FT4/FT3 ratio was investigated., Design: Clinical, biochemical, and radiological data were collected. Whole exome sequencing was performed in the patient and her relatives., Results: The patient exhibited congenital macrocytic anemia and severe bone malformation with growth retardation, dwarfism, clavicular agenesis, and abnormalities of the fingers, toes, and elbow joints. In adulthood, she presented with active behavior, chronic motor diarrhea, and hypercalcemia. Treatment with T3 led to heart rate acceleration, worsening of diarrhea, and TSH suppression. Low resting energy expenditure normalized on T3. rT3, SHBG, and IGF-1 remained normal. A de novo monoallelic missense mutation in THRA was discovered, the N359Y amino acid substitution (c.1075A>T), which affected both the TRα1 and the non-receptor isoform TRα2. The mutant TRα1 had a decrease in transcriptional activity related to decreased T3 binding and a dominant-negative effect on the wild-type receptor., Conclusions: This patient presents a new phenotype including more significant bone abnormalities, lower TSH, and higher FT3 levels, without certainty of all her symptoms with the TRα1(N359Y) mutation. This case suggests that patients with a low FT4/FT3 ratio should be screened for THRA mutations, even if clinical and biological features differ from previous reported cases of RTHα.
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- 2015
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24. ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences.
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Espiard S, Drougat L, Libé R, Assié G, Perlemoine K, Guignat L, Barrande G, Brucker-Davis F, Doullay F, Lopez S, Sonnet E, Torremocha F, Pinsard D, Chabbert-Buffet N, Raffin-Sanson ML, Groussin L, Borson-Chazot F, Coste J, Bertagna X, Stratakis CA, Beuschlein F, Ragazzon B, and Bertherat J
- Subjects
- Adrenal Cortex Diseases epidemiology, Adult, Aged, Armadillo Domain Proteins, Cells, Cultured, Cohort Studies, Cushing Syndrome epidemiology, Cushing Syndrome genetics, DNA Mutational Analysis, Female, Genetic Association Studies, HeLa Cells, Humans, Hyperplasia genetics, Hyperplasia pathology, Male, Middle Aged, Adrenal Cortex Diseases genetics, Adrenal Glands pathology, Mutation, Missense, Tumor Suppressor Proteins genetics
- Abstract
Context: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of primary adrenal Cushing's syndrome (CS). ARMC5 germline mutations have been identified recently in PBMAH., Objective: To determine the prevalence of ARMC5 mutations and analyze genotype-phenotype correlation in a large cohort of unrelated PBMAH patients with subclinical or clinical CS., Patients and Methods: ARMC5 was sequenced in 98 unrelated PBMAH index cases. PBMAH was identified by bilateral adrenal nodular enlargement on computed tomography scan. The effect on apoptosis of ARMC5 missense mutants was tested in H295R and HeLa cells. Clinical and hormonal data were collected including midnight and urinary free cortisol levels, ACTH, androgens, renin/aldosterone ratio, cortisol after overnight dexamethasone suppression test, cortisol and 17-hydroxyprogesterone after ACTH 1-24 stimulation and illegitimate receptor responses. Computed tomography and histological reports were analyzed., Results: ARMC5-damaging mutations were identified in 24 patients (26%). The missense mutants and the p.F700del deletion were unable to induce apoptosis in both H295R and HeLa cell lines, unlike the wild-type gene. ARMC5-mutated patients showed an overt CS more frequently, compared to wild-type patients: lower ACTH, higher midnight plasma cortisol, urinary free cortisol, and cortisol after dexamethasone suppression test (P = .003, .019, .006, and <.001, respectively). Adrenals of patients with mutations were bigger and had a higher number of nodules (P = .001 and <.001, respectively)., Conclusions: ARMC5 germline mutations are common in PBMAH. Index cases of mutation carriers show a more severe hypercortisolism and larger adrenals. ARMC5 genotyping may help to identify clinical forms of PBMAH better and may also allow earlier diagnosis of this disease.
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- 2015
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25. Primary Aldosteronism and ARMC5 Variants.
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Zilbermint M, Xekouki P, Faucz FR, Berthon A, Gkourogianni A, Schernthaner-Reiter MH, Batsis M, Sinaii N, Quezado MM, Merino M, Hodes A, Abraham SB, Libé R, Assié G, Espiard S, Drougat L, Ragazzon B, Davis A, Gebreab SY, Neff R, Kebebew E, Bertherat J, Lodish MB, and Stratakis CA
- Subjects
- Adult, Alternative Splicing genetics, Armadillo Domain Proteins, DNA Mutational Analysis, Female, Gene Frequency, Genetic Predisposition to Disease, Glucocorticoids metabolism, Humans, Hyperaldosteronism metabolism, Male, Middle Aged, Mutation, Missense, Retrospective Studies, Germ-Line Mutation, Hyperaldosteronism genetics, Polymorphism, Single Nucleotide, Tumor Suppressor Proteins genetics
- Abstract
Context: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia., Objective: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects., Methods: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods., Results: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023)., Conclusions: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension.
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- 2015
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26. Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation.
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Faucz FR, Zilbermint M, Lodish MB, Szarek E, Trivellin G, Sinaii N, Berthon A, Libé R, Assié G, Espiard S, Drougat L, Ragazzon B, Bertherat J, and Stratakis CA
- Subjects
- Adult, Cohort Studies, Cushing Syndrome diagnosis, Cushing Syndrome epidemiology, DNA Mutational Analysis, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Missense, Armadillo Domain Proteins genetics, Cushing Syndrome genetics, Tumor Suppressor Proteins genetics
- Abstract
Context: Inactivating germline mutations of the probable tumor suppressor gene, armadillo repeat containing 5 (ARMC5), have recently been identified as a genetic cause of macronodular adrenal hyperplasia (MAH)., Objective: We searched for ARMC5 mutations in a large cohort of patients with MAH. The clinical phenotype of patients with and without ARMC5 mutations was compared., Methods: Blood DNA from 34 MAH patients was genotyped using Sanger sequencing. Diurnal serum cortisol measurements, plasma ACTH levels, urinary steroids, 6-day Liddle's test, adrenal computed tomography, and weight of adrenal glands at adrenalectomy were assessed., Results: Germline ARMC5 mutations were found in 15 of 34 patients (44.1%). In silico analysis of the mutations indicated that seven (20.6%) predicted major implications for gene function. Late-night cortisol levels were higher in patients with ARMC5-damaging mutations compared with those without and/or with nonpathogenic mutations (14.5 ± 5.6 vs 6.7 ± 4.3, P < .001). All patients carrying a pathogenic ARMC5 mutation had clinical Cushing's syndrome (seven of seven, 100%) compared with 14 of 27 (52%) of those without or with mutations that were predicted to be benign (P = .029). Repeated-measures analysis showed overall higher urinary 17-hydroxycorticosteroids and free cortisol values in the patients with ARMC5-damaging mutations during the 6-day Liddle's test (P = .0002)., Conclusions: ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with MAH. Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families.
- Published
- 2014
- Full Text
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