Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Elbelt, Ulf UNSPECIFIED UNSPECIFIED UNSPECIFIED Trovato, Alessia UNSPECIFIED UNSPECIFIED UNSPECIFIED Kloth, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Gentz, Enno UNSPECIFIED UNSPECIFIED UNSPECIFIED Finke, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Spranger, Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED Galas, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Cristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Koenig, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Arlt, Wiebke UNSPECIFIED orcid.org/0000-0001-5106-9719 UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED May, Patrick UNSPECIFIED orcid.org/0000-0001-8698-3770 UNSPECIFIED Allolio, Bruno UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Jochen G. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language 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; VASOPRESSIN Multiple languages Endocrinology & Metabolism Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41913