Reference : Molecular and Clinical Evidence for an ARMC5 Tumor Syndrome: Concurrent Inactivating ...
Scientific journals : Article
Human health sciences : Endocrinology, metabolism & nutrition
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
Eibelt, Ulf [> >]
Trovato, Alissa [> >]
Kloth, Michael [> >]
Gentz, Enno [> >]
Finke, Reinhard [> >]
Spranger, Joachim [> >]
Galas, David J. [> >]
Weber, Susanne [> >]
Wolf, Cristina-Alexandra mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
König, Katharina [> >]
Arlt, Wiebke [> >]
Büttner, Reinhard [> >]
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Allolio, Bruno [> >]
Schneider, Jochen mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Journal of Clinical Endocrinology and Metabolism
Endocrine Society
Chevy Chase
[en] Context:Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome (CS), 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 analysed for accompanying somatic mutations in the identified target genes.
Results: PMAH presenting either as overt or subclinical CS 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.
Luxembourg Centre for Systems Biomedicine (LCSB): Medical Translational Research (J. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; University of Luxembourg: High Performance Computing - ULHPC

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