Elbelt, Ulf, Trovato, Alessia, Kloth, Michael, Gentz, Enno, Finke, Reinhard, Spranger, Joachim, Galas, David, Weber, Susanne, Wolf, Cristina, Koenig, Katharina, Arlt, Wiebke ORCID: 0000-0001-5106-9719, Buettner, Reinhard, May, Patrick ORCID: 0000-0001-8698-3770, Allolio, Bruno and Schneider, Jochen G. (2015). 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. J. Clin. Endocrinol. Metab., 100 (1). S. E119 - 10. WASHINGTON: ENDOCRINE SOC. ISSN 1945-7197

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Elbelt, UlfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trovato, AlessiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloth, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gentz, EnnoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finke, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spranger, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galas, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, CristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koenig, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arlt, WiebkeUNSPECIFIEDorcid.org/0000-0001-5106-9719UNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, PatrickUNSPECIFIEDorcid.org/0000-0001-8698-3770UNSPECIFIED
Allolio, BrunoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, Jochen G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-419130
DOI: 10.1210/jc.2014-2648
Journal or Publication Title: J. Clin. Endocrinol. Metab.
Volume: 100
Number: 1
Page Range: S. E119 - 10
Date: 2015
Publisher: ENDOCRINE SOC
Place of Publication: WASHINGTON
ISSN: 1945-7197
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INDEPENDENT CUSHINGS-SYNDROME; GASTRIC-INHIBITORY POLYPEPTIDE; PHOSPHODIESTERASE 11A PDE11A; ENDOCRINE NEOPLASIA TYPE-1; ABERRANT HORMONE-RECEPTORS; MCCUNE-ALBRIGHT-SYNDROME; CORTISOL HYPERSECRETION; ADRENOCORTICAL TUMORS; ACTIVATING MUTATIONS; VASOPRESSINMultiple languages
Endocrinology & MetabolismMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/41913

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