ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences
Year: 2015
Type: article
Study design: Observational Study
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.
DOI: 10.1210/jc.2014-4204
Authors: Stéphanie Espiard, Ludivine Drougat, Rossella Libé, Guillaume Assié, Karine Perlemoine, Laurence Guignat, Gaelle Barrande, Françoise Brucker-Davis, Françoise Doullay, Stephanie Lopez, Emmanuel Sonnet, Florence Torremocha, Denis Pinsard, Nathalie Chabbert-Buffet, Marie-Laure Raffin-Sanson, Lionel Groussin, Françoise Borson-Chazot, Joël Coste, Xavier Bertagna, Constantine A. Stratakis, Felix Beuschlein, Bruno Ragazzon, Jérôme Bertherat
Institutions: Centre National de la Recherche Scientifique, Inserm, Sorbonne Paris Cité, Institut Cochin, Université Paris Descartes, Hôpital Cochin, Assistance Publique – Hôpitaux de Paris, Centre hospitalier universitaire d'Orléans, Assistance Publique Hôpitaux de Marseille, Hôpital Nord, Centre Hospitalier Universitaire de Limoges, Centre Hospitalier Régional Universitaire de Brest, Centre Hospitalier Universitaire de Poitiers, Centre Hospitalier Universitaire de Rennes, Hôpital Tenon, Hôpital Ambroise-Paré, Centre Hospitalier Universitaire de Nice, Hospices Civils de Lyon, Centre de Recherche en Cancérologie de Lyon, Hôtel-Dieu de Paris, Interdisciplinarité en Santé Publique Interventions et Instruments de mesure complexes – Région Est, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, LMU Klinikum, Ludwig-Maximilians-Universität München
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1415267643, G4044507487
OpenAlex ID: W2091277822