Molecular and Clinical Evidence for an : Concurrent Inactivating Germline and Somatic Mutations Are Associated With Both Primary Macronodular Adrenal Hyperplasia and MeningiomaARMC5: Concurrent Inactivating Germline and Somatic Mutations Are Associated With Both Primary Macronodular Adrenal Hyperplasia and Meningioma Tumor Syndrome: Concurrent Inactivating Germline and Somatic Mutations Are Associated With Both Primary Macronodular Adrenal Hyperplasia and Meningioma

    loading  Checking for direct PDF access through Ovid

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.

Related Topics

    loading  Loading Related Articles