• Fabio R Faucz, Mihail Zilbermint, Maya B Lodish, Eva Szarek, Giampaolo Trivellin, Ninet Sinaii, Annabel Berthon, Rossella Libé, Guillaume Assié, Stéphanie Espiard, Ludivine Drougat, Bruno Ragazzon, Jerome Bertherat, and Constantine A Stratakis.
• Section on Endocrinology and Genetics (F.R.F., M.Z., M.B.L., E.S., G.T., A.B., C.A.S.), Program on Developmental Endocrinology and Genetics, Program on Reproductive and Adult Endocrinology (M.Z.), Biostatistics and Clinical Epidemiology Service (N.S.), Clinical Center, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Group for Advanced Molecular Investigation (F.R.F.), Graduate Program in Health Science, Center for Biological and Sciences, Pontificia Universidade Catolica do Paraná, Curitiba Brazil 80215-901; Department of Endocrinology, Metabolism, and Cancer (R.L., G.A., S.E., L.D., B.R., J.B.), INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, 75014 Paris, France.
• J. Clin. Endocrinol. Metab. 2014 Jun 1; 99 (6): E1113-9.

ContextInactivating 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).ObjectiveWe searched for ARMC5 mutations in a large cohort of patients with MAH. The clinical phenotype of patients with and without ARMC5 mutations was compared.MethodsBlood 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.ResultsGermline 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).ConclusionsARMC5 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.

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