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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.
Original language | English |
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Pages (from-to) | E119-28 |
Journal | The Journal of clinical endocrinology and metabolism |
Volume | 100 |
Issue number | 1 |
Early online date | 3 Oct 2014 |
DOIs | |
Publication status | Published - Jan 2015 |
Keywords
- Adrenal Cortex Diseases
- Adult
- Cushing Syndrome
- Female
- Germ-Line Mutation
- Humans
- Hyperplasia
- Male
- Meningeal Neoplasms
- Meningioma
- Pedigree
- Tumor Suppressor Proteins
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Dive into the research topics of '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'. Together they form a unique fingerprint.Projects
- 1 Finished
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Steroid Profiling as a Biomarker Tool in the Diagnosis and Monitoring of Adrenal Tumours
Arlt, W. & Stewart, P.
2/03/09 → 29/02/12
Project: Research Councils