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1. Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients

Author

Lucas Bouys, Anna Vaczlavik, Anne Jouinot, Patricia Vaduva, Stéphanie Espiard, Guillaume Assié, Rossella Libé, Karine Perlemoine, Bruno Ragazzon, Laurence Guignat, Lionel Groussin, Léopoldine Bricaire, Isadora Pontes Cavalcante, Fidéline Bonnet-Serrano, Hervé Lefebvre, Marie-Laure Raffin-Sanson, Nicolas Chevalier, Philippe Touraine, Christel Jublanc, Camille Vatier, Gérald Raverot, Magalie Haissaguerre, Luigi Maione, Matthias Kroiss, Martin Fassnacht, Sophie Christin-Maitre, Eric Pasmant, Françoise Borson-Chazot, Antoine Tabarin, Marie-Christine Vantyghem, Martin Reincke, Peter Kamenicky, Marie-Odile North, Jérôme Bertherat, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], CHU Lille, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Rouen, Normandie Université (NU), Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Hôpital Haut-Lévêque - CHU de Bordeaux (Centre médico chirurgical Magellan), Physiologie et physiopathologie endocriniennes (PHYSENDO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), University Hospital of Würzburg, Klinikum der Universität [München], CHU Saint-Antoine [AP-HP], L B is recipient of research fellowships from the Cancer Research for Personalized Medicine (CARPEM) and the Fondation ARC pour la Recherche contre le Cancer, J B laboratory is supported by the Agence Nationale pour la Recherche grant ANR-18-CE14-0008-01 and the Fondation pour la Recherche Médicale (EQU201903007854). P T, C J, M F, S C M, F B C, M R, P C and J B clinical departments are part the European Reference Network on Rare Endocrine Conditions (Endo-ERN) – Project ID No 739572, and ANR-18-CE14-0008,STEROMICS,Steroïdogénomique de l'hypersécrétion des stéroïdes surrénaliens(2018)

Subjects
Armadillo Domain Proteins, Hyperplasia, Hydrocortisone, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], 71 ARMC5, General Medicine, genetic screening, PBMAH, Endocrinology, Primary Bilateral Macronodular Adrenal Hyperplasia, adrenal tumors, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Adrenal Glands, Humans, Cushing syndrome, tumor suppressor gene, Retrospective Studies
Abstract

Objective Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants. Methods We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively. Results 52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant. Conclusion We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.

Published
2023

2. 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

Eric Van Belle, François Machuron, Marc Hazzan, Marie-Christine Vantyghem, Christian Noel, Thomas Hubert, Robert Caiazzo, Stéphanie Espiard, Julie Kerr-Conte, Arnaud Jannin, Violeta Raverdy, Pascal Pigny, François Pattou, Nathalie Delalleau, Valery Gmyr, Kristell Le Mapihan, Marie Frimat, Mikael Chetboun, Université de Lille, LillOA, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - USR 3290 (MSAP), Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Inserm, CHU Lille, Recherche translationnelle sur le diabète (RTD) - U1190, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE], Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP], Lille Inflammation Research International Center - U 995 [LIRIC], and Recherche translationnelle sur le diabète - U 1190 [RTD]

Subjects
Advanced and Specialized Nursing, Type 1 diabetes, medicine.medical_specialty, geography, geography.geographical_feature_category, business.industry, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], MEDLINE, 030209 endocrinology & metabolism, medicine.disease, Islet, 3. Good health, Islet after kidney, Transplantation, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, 030212 general & internal medicine, business, Cohort study
Abstract

The names of the working groups that collaborated in the study reported in this article were inadvertently omitted from the byline. The corrected byline should … 2019;42

Published
2020

3. Non-islet-cell tumour hypoglycaemia (NICTH): About a series of 6 cases

Author

Stéphanie Espiard, Kanza Benomar, Marie-Christine Vantyghem, Henri Porte, Christine Do Cao, Nicolas Penel, Bénédicte Mycinski, Arnaud Jannin, Michèle d’Herbomez, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, Solitary fibrous tumor, Fibrosarcoma, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, Fibroma, Neuroendocrine tumors, Hypoglycemia, Gastroenterology, Asymptomatic, Hospitals, University, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin-Like Growth Factor II, Interquartile range, Internal medicine, Meningeal Neoplasms, medicine, Humans, Magnesium, Retroperitoneal Neoplasms, Insulin-Like Growth Factor I, Aged, Hemangiopericytoma, Human Growth Hormone, business.industry, General Medicine, Prognosis, medicine.disease, Hypokalemia, 3. Good health, Solitary Fibrous Tumor, Pleural, Pleural Solitary Fibrous Tumor, Neuroendocrine Tumors, 030220 oncology & carcinogenesis, Potassium, Female, medicine.symptom, business
Abstract

The purpose of this study was to analyse the characteristics of 6 patients managed in a university hospital between 1996 and 2016 for non-islet cell tumor hypoglycemia (NICTH), a form of hypoglycaemia due to the paraneoplastic secretion of IGF-2 or its related substances. RESULTS: Three of these 6 patients (50%), aged over 69 years, including 2 with acromegaloid phenotype, presented with a pleural solitary fibrous tumor (SFT), with median diameter 20 cm (interquartile range, 12.5-20.5) with a low median SUV (3.3 g/mL (QR, 2-7.5)) on 18F-FDG PET. The other 3 patients presented respectively neuroendocrine carcinoma (NEC) of the palate (70-year-old woman), retroperitoneal myxofibrosarcoma (66-year-old man) and meningeal hemangiopericytoma (36-year-old woman). All 3 were inoperable and did not respond to any therapy other than glucose solution. Corticosteroid therapy was effective in the 3 SFTs and the NEC. One of the SFTs recurred 10 years later with asymptomatic hypoglycemia, which resolved after reintervention. Median (IQR) blood glucose levels of the 6 patients was 0.4g/L (QR, 0.31-0.41), with hypoinsulinemia at 0.7mIU/L (QR 0.7-2.0), undetectable GH, low IGF-1, normal IGF-2 level in 5/6 cases, a high IGF-2:IGF-1 ratio at 26.9 (QR, 20.8-37.8), hypokalemia and hypomagnesemia. CONCLUSION: NICTH is a rare syndrome, which should be considered in the presence of hypoinsulinemic hypoglycemia with low GH and IGF-1, and a IGF-2:IGF-1 ratio>10. Corticosteroid therapy was effective in elderly subjects, particularly with solitary fibrous tumor, which was generally operable. Hemangiopericytoma and myxofibrosarcoma had poor prognosis in younger patients.

Published
2019

4. Activating PRKACB somatic mutation in cortisol-producing adenomas

Author

Guillaume Assié, Kerstin Bathon, Daniel Abid, Jérôme Bertherat, Marthe Rizk-Rabin, Matthias J. Knape, Constantine A. Stratakis, Friedrich W. Herberg, Guignat L, Windy Luscap-Rondof, S. Faillot, Davide Calebiro, Stéphanie Espiard, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), CHU Cochin [AP-HP], Institute of Pharmacology and Toxicology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-University Hospital of Würzburg-Rudolf Virchow Center for Experimental Biomedicine, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Section on Endocrinology and Genetics, National Institutes of Health (NIH)-National Institute of Child Health and Human Development, Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Adenoma, Adult, Cyclic AMP Receptor Protein, Hydrocortisone, Protein subunit, [SDV]Life Sciences [q-bio], Mutant, Adrenal Gland Neoplasms, medicine.disease_cause, 7. Clean energy, 03 medical and health sciences, Germline mutation, Catalytic Domain, Exome Sequencing, PRKACB Gene, medicine, Humans, Protein kinase A, Cushing Syndrome, ComputingMilieux_MISCELLANEOUS, Mutation, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, Chemistry, Adrenalectomy, General Medicine, Molecular biology, Cyclic AMP-Dependent Protein Kinases, 030104 developmental biology, Treatment Outcome, Phosphorylation, Female, Carcinogenesis, Holoenzymes, Adrenal Insufficiency, Research Article
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.

Published
2018

5. Evaluation of the occurrence of the manifestations of Carney complex in a french cohort of 70 patients during a three years standardized follow-up

Author

Herve Lefebvre, Catherine Cardot-Bauters, Marie-Christine Vantyghem, Francoise Archambeaud-Mouveroux, Olivier Chabre, Marie-Laure Nunes, Muriel Houang, Gérald Raverot, Jérôme Bertherat, Françoise Brucker-Davis, Stéphanie Espiard, Anne Lienhardt, Antoine Tabarin, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d’endocrinologie, diabétologie et maladies métaboliques [CHRU LIlle], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), Département d'endocrinologie - Bordeaux 2, Université Bordeaux Segalen - Bordeaux 2, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Service de Pédiatrie médicale - Spécialités médicales [CHU Limoges], CHU Limoges, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Endocrinologie, Diabète et Maladies Métaboliques [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service d'endocrinologie-diabétologie-nutrition [CHU Grenoble-Alpes], Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Service d'Endocrinologie (BORDEAUX - Endocrino), CHU Bordeaux [Bordeaux], CHU Cochin [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Pediatrics, medicine.medical_specialty, business.industry, Cohort, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, business, Carney complex, 3. Good health
Abstract

International audience; IntroductionThe Carney Complex is a multiple endocrine and non endocrine neoplasia mostly due to PRKAR1A mutations. Spectrum of manifestations and genotypephenotype correlations have been previously described by retrospective studies. A prospective study evaluating the occurrence of the different manifestations was needed to precise the optimum follow-up.MethodsMulti-center national prospective study (Clinical Trials NCT00668291) including 70 patients mutated or wild-type for PRKAR1A followed prospectively during 3years with screening of the different manifestations by annual clinical, biological and radiological evaluation.ResultsThe cohort was compound of 50 females and 20 males with a mean age at 35.4years C/K16.7. Prevalence of cardiac myxomas at the end of the follow-up was 22.9% with newly diagnosis during the study period for 3 patients. Fortyfour% of patients with myxomas had related stroke attack and 56% had recurrences. Median delay between recurrences was 3.8years (minimummaximum: 0.8–24). Primary pigmented adrenal nodular disease was diagnosed in 57.1%. Skin manifestations, abnormal somatotroph hormonal tests and thyroid tumors were observed respectively in 58.6, 21.4 and 12.9%. Four% had melanotic shwannomas confirmed by histology. Spinal magnetic resonance imagery revealed lesions for 8.6%. Characteristic multiples calcified tumors on testicular ultrasonography were present in 35% of male patients. Ten% of female patients had surgery for breast myxoma or adenofibroma. Forty% had lesions classified ACR2-3 at mammography. Interestingly, four patients (8%) had breast adenocarcinomas (11.1% of female older than 30years). Eighty-three% of patients had PRKAR1A mutations. Patients carrying the mutation c.709-7del6 (34% of the cohort) had no manifestation or phenotype restricted to adrenal, lentigines and abnormal somatotroph test.ConclusionThe penetrance of the disease is high after screening except for patient carrying the c.709-7del6 mutation. This study highlights the importance of an annual follow-up, with especially annual cardiac imaging for patients with history of cardiac myxomas and earlier and regular senologic evaluation.DOI: 10.1530/endoabs.49.GP120

Published
2017

6. A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone

Author

Jean-Louis Wémeau, Patrice Rodien, William Bourguet, Stéphanie Espiard, C. S. Rose, Romain Guyot, Michèle d’Herbomez, Virginie Vlaeminck-Guillem, Mathilde Munier, Frédérique Savagner, Frédéric Flamant, Graziella Pinto, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Universitaire de Lille (CHU de Lille), UMR1048, Inst Malad Metab & Cardiovasc, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, École normale supérieure - Lyon (ENS Lyon), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Université d'Angers (UA), Université Montpellier 1 (UM1), CHU Necker - Enfants Malades [AP-HP], Hôpital Saint-Vincent de Paul, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
Adult, Diarrhea, Thyroid Hormone Resistance Syndrome, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Dwarfism, Biology, Biochemistry, Short stature, CLASSIFICATION, Endocrinology, Germline mutation, Internal medicine, medicine, POSTNATAL-DEVELOPMENT, Humans, [INFO]Computer Science [cs], ALPHA-GENE, Germ-Line Mutation, Exome sequencing, TR-ALPHA-2, ComputingMilieux_MISCELLANEOUS, Thyroid hormone receptor, MITOCHONDRIAL T3 RECEPTOR, Genes, erbA, Biochemistry (medical), Thyroid, DEFECTS, medicine.disease, Musculoskeletal Abnormalities, 3. Good health, FEMALE, CLEIDOCRANIAL DYSPLASIA, MICE, Phenotype, medicine.anatomical_structure, DIFFERENTIATION, Amino Acid Substitution, Hypercalcemia, Macrocytic anemia, medicine.symptom, hormones, hormone substitutes, and hormone antagonists, Hormone
Abstract

Context: RTH alpha is a recently discovered resistance to thyroid hormone (RTH) due to mutation of THRA, the gene encoding TR alpha 1, the thyroid hormone receptor. It has been described in a few patients with growth retardation, short stature, and a low free T-4/free T-3 (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 T-3. rT(3), 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 TR alpha 1 and the non-receptor isoform TR alpha 2. The mutant TR alpha 1 had a decrease in transcriptional activity related to decreased T-3 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 TR alpha 1(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 RTH alpha

Published
2015

7. ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences

Author

Xavier Bertagna, Francoise Doullay, Ludivine Drougat, E. Sonnet, Jérôme Bertherat, Joël Coste, Lionel Groussin, Rossella Libé, Françoise Borson-Chazot, Stéphanie Espiard, F. Brucker-Davis, Florence Torremocha, Guillaume Assié, Felix Beuschlein, Constantine A. Stratakis, Bruno Ragazzon, Marie-Laure Raffin-Sanson, G. Barrande, Stephanie Lopez, Karine Perlemoine, Nathalie Chabbert-Buffet, Denis Pinsard, Laurence Guignat, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional d'Orléans (CHRO), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Diabétologie-Endocrinologie (NICE - Endocrino), Centre Hospitalier Universitaire de Nice (CHU Nice), Endocrinologie, diabète, maladies métaboliques (CHU Marseille, AP-HM), Assistance Publique - Hôpitaux de Marseille (APHM), Service de Médecine interne B, Endocrinologie, Diabète, Maladies métaboliques [CHU Limoges], CHU Limoges, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Service Endocrinologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'endocrinologie diabétologie et nutrition [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, Gynécologie-obstétrique et médecine de la reproduction - Maternité [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’endocrinologie et nutrition [AP-HP Ambroise-Paré], Hôpital Ambroise Paré [AP-HP], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupement hospitalier lyon Est (Hospices Civils de Lyon), Hospices Civils de Lyon (HCL), Unité d’Epidémiologie et de Biostatistiques [APHP Cochin-Broca-Hôtel Dieu], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Klinikum der Universitat Munchen, Ludwig-Maximilians-Universität München (LMU), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de référence des maladies rares de la surrénale [Cochin], Centre Hospitalier Régional d'Orléans ( CHR ), Centre méditérannéen de médecine moléculaire ( C3M ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Diabétologie-Endocrinologie ( NICE - Endocrino ), CHU Nice, Assistance Publique - Hôpitaux de Marseille ( APHM ), Hôpital de la Cavale Blanche - CHRU Brest ( CHU - BREST ), CHU de Poitiers, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, Service d'obstétrique gynécologie et médecine reproductive [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Service d’endocrinologie et nutrition [AP-HP Hôpital Ambroise-Paré], AP-HP Hôpital Ambroise-Paré [Boulogne-Billancourt], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Groupement hospitalier lyon Est ( Hospices Civils de Lyon ), Hospices Civils de Lyon ( HCL ), Maladies chroniques, santé perçue, et processus d'adaptation. Approches épidémiologiques et psychologiques. ( APEMAC - EA 4360 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Université de Lorraine ( UL ), Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ), Klinikum Grosshadern, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), CHU Cochin [AP-HP], Centre Hospitalier Régional d'Orléans (CHR), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, DNA Mutational Analysis, MESH : Aged, MESH : Adrenal Cortex Diseases, Biochemistry, Cohort Studies, MESH: Cushing Syndrome, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Adrenal Glands, Missense mutation, MESH : Female, MESH: Adrenal Glands, MESH: DNA Mutational Analysis, Cushing Syndrome, MESH: Cohort Studies, Cells, Cultured, MESH : Cushing Syndrome, Subclinical infection, MESH: Genetic Association Studies, MESH: Aged, 0303 health sciences, Aldosterone, MESH: Middle Aged, JCEM Online: Advances in Genetics, MESH : Tumor Suppressor Proteins, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Middle Aged, MESH : Adult, 3. Good health, Dexamethasone suppression test, Female, MESH: Cells, Cultured, Adrenal Cortex Diseases, Adult, medicine.medical_specialty, endocrine system, MESH : Male, Mutation, Missense, MESH : Cohort Studies, 030209 endocrinology & metabolism, Context (language use), MESH : DNA Mutational Analysis, Biology, MESH : Adrenal Glands, 03 medical and health sciences, Germline mutation, Internal medicine, MESH : Hyperplasia, Renin–angiotensin system, MESH : Cells, Cultured, medicine, Humans, MESH : HeLa Cells, MESH : Middle Aged, MESH: Tumor Suppressor Proteins, Genetic Association Studies, 030304 developmental biology, Aged, Armadillo Domain Proteins, MESH: Mutation, Missense, Hyperplasia, MESH: Humans, MESH: Hyperplasia, Tumor Suppressor Proteins, MESH: Adrenal Cortex Diseases, Biochemistry (medical), MESH : Humans, MESH: Adult, MESH : Genetic Association Studies, MESH: Male, chemistry, Macronodular Adrenal Hyperplasia, MESH: HeLa Cells, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Female, MESH : Mutation, Missense, HeLa Cells
Abstract

International audience; 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

Published
2015

8. ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing's Syndrome

Author

Jérôme Bertherat, Guillaume Assié, Lucile Lefèvre, Karine Perlemoine, W. Luscap, Stéphanie Rodriguez, Marthe Rizk-Rabin, Stéphanie Espiard, Bruno Ragazzon, Fernande René-Corail, Françoise Borson-Chazot, Mathilde Sibony, Rossella Libé, Constantine A. Stratakis, Anne Guimier, Alix Poussier, Lionel Groussin, Xavier Bertagna, Olivia Barreau, Bilal Trabulsi, Laurence Guignat, Nathalie Chabbert-Buffet, Franck Letourneur, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), CHU Cochin [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [APHP], Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de médecine nucléaire, Fédération d'endocrinologie-Groupement hospitalier Lyon-Est, Section on Endocrinology and Genetics, National Institutes of Health (NIH)-National Institute of Child Health and Human Development, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Fédération d'endocrinologie, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Adult, Male, Genotyping Techniques, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Polymorphism, Single Nucleotide, Article, Germline, Loss of heterozygosity, 03 medical and health sciences, symbols.namesake, Cushing syndrome, 0302 clinical medicine, Adrenal Glands, medicine, Humans, Genes, Tumor Suppressor, Allele, Gene, Cushing Syndrome, 030304 developmental biology, Genetic testing, Aged, Sanger sequencing, Armadillo Domain Proteins, 0303 health sciences, medicine.diagnostic_test, Tumor Suppressor Proteins, General Medicine, Sequence Analysis, DNA, Middle Aged, medicine.disease, 3. Good health, Macronodular Adrenal Hyperplasia, Cancer research, symbols, Female, Transcriptome
Abstract

Background Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing’s syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition. Methods We genotyped blood and tumor DNA obtained from 33 patients with corticotropinindependent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models. Results The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival. Conclusions Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumorsuppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.)

Published
2013

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