• Ulf Elbelt, Alessia Trovato, Michael Kloth, Enno Gentz, Reinhard Finke, Joachim Spranger, David Galas, Susanne Weber, Cristina Wolf, Katharina König, Wiebke Arlt, Reinhard Büttner, Patrick May, Bruno Allolio, and Jochen G Schneider.
• Department of Endocrinology, Diabetes, and Nutrition (U.E., A.T., J.S.), Department of Hepatology and Gastroenterology (E.G.), Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; Institute of Pathology (M.K., K.K., R.B.), University of Cologne, 50937 Cologne, Germany; Praxisgemeinschaft an der Kaisereiche (R.F.), 12159 Berlin, Germany; Luxembourg Centre for Systems Biomedicine (D.G., C.W., P.M., J.G.S.), University of Luxembourg, 4362 Luxembourg, Luxembourg; Pacific Northwest Diabetes Research Institute (D.G.), Seattle, Washington 98122; Department of Internal Medicine II (S.W., C.W.), Saarland University Medical Center, 66421 Homburg/Saar, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom; Family Genomes Group (P.M.), Institute for Systems Biology, Seattle, Washington 98109; and Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany.
• J. Clin. Endocrinol. Metab. 2015 Jan 1; 100 (1): E119-28.

ContextPrimary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, which may present in the context of different familial multitumor syndromes. Heterozygous inactivating germline mutations of armadillo repeat containing 5 (ARMC5) have very recently been described as cause for sporadic PMAH. Whether this genetic condition also causes familial PMAH in association with other neoplasias is unclear.ObjectiveThe aim of the present study was to delineate the molecular cause in a large family with PMAH and other neoplasias.Patients And MethodsWhole-genome sequencing and comprehensive clinical and biochemical phenotyping was performed in members of a PMAH affected family. Nodules derived from adrenal surgery and pancreatic and meningeal tumor tissue were analyzed for accompanying somatic mutations in the identified target genes.ResultsPMAH presenting either as overt or subclinical Cushing's syndrome was accompanied by a heterozygous germline mutation in ARMC5 (p.A110fs*9) located on chromosome 16. Analysis of tumor tissue showed different somatic ARMC5 mutations in adrenal nodules supporting a second hit hypothesis with inactivation of a tumor suppressor gene. A damaging somatic ARMC5 mutation was also found in a concomitant meningioma (p.R502fs) but not in a pancreatic tumor, suggesting biallelic inactivation of ARMC5 as causal also for the intracranial meningioma.ConclusionsOur analysis further confirms inherited inactivating ARMC5 mutations as a cause of familial PMAH and suggests an additional role for the development of concomitant intracranial meningiomas.

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