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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

Item Type:Article
Title: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
Creators Name:Elbelt, U., Trovato, A., Kloth, M., Gentz, E., Finke, R., Spranger, J., Galas, D., Weber, S., Wolf, C., Koenig, K., Arlt, W., Buettner, R., May, P., Allolio, B. and Schneider, J.G.
Abstract: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.
Keywords:Adrenal Cortex Diseases, Cushing Syndrome, Germ-Line Mutation, Hyperplasia, Meningeal Neoplasms, Meningioma, Pedigree, Tumor Suppressor Proteins
Source:Journal of Clinical Endocrinology and Metabolism
ISSN:0021-972X
Publisher:Endocrine Society
Volume:100
Number:1
Page Range:E119-E128
Date:January 2015
Official Publication:https://doi.org/10.1210/jc.2014-2648
PubMed:View item in PubMed

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