Molecular and Clinical Evidence for an ARMC5 Tumor Syndrome: Concurrent Inactivating Germline and Somatic Mutations Are Associated With Both Primary Macronodular Adrenal Hyperplasia and Meningioma

• Published in: The journal of clinical endocrinology and metabolism Vol. 100; no. 1; pp. E119 - E128
• Main Authors: Elbelt, Ulf, Trovato, Alessia, Kloth, Michael, Gentz, Enno, Finke, Reinhard, Spranger, Joachim, Galas, David, Weber, Susanne, Wolf, Cristina, König, Katharina, Arlt, Wiebke, Büttner, Reinhard, May, Patrick, Allolio, Bruno, Schneider, Jochen G
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.01.2015; Copyright by The Endocrine Society
• Subjects: Adrenal Cortex Diseases - genetics; Adrenal Cortex Diseases - pathology; Adult; Armadillo Domain Proteins; Cushing Syndrome - genetics; Cushing Syndrome - pathology; Female; Germ-Line Mutation; Humans; Hyperplasia - genetics; Hyperplasia - pathology; JCEM Online: Advances in Genetics; Male; Meningeal Neoplasms - genetics; Meningeal Neoplasms - pathology; Meningioma - genetics; Meningioma - pathology; Pedigree; Tumor Suppressor Proteins - genetics
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2014-2648

Context: Primary 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. Objective: The aim of the present study was to delineate the molecular cause in a large family with PMAH and other neoplasias. Patients and Methods: Whole-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. Results: PMAH 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. Conclusions: Our 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.