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. 2015 Jan;100(1):E119-28. doi: 10.1210/jc.2014-2648.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Diseases / genetics*
  • Adrenal Cortex Diseases / pathology
  • Adult
  • Armadillo Domain Proteins
  • Cushing Syndrome / genetics*
  • Cushing Syndrome / pathology
  • Female
  • Germ-Line Mutation*
  • Humans
  • Hyperplasia / genetics
  • Hyperplasia / pathology
  • Male
  • Meningeal Neoplasms / genetics*
  • Meningeal Neoplasms / pathology
  • Meningioma / genetics*
  • Meningioma / pathology
  • Pedigree
  • Tumor Suppressor Proteins / genetics*

Substances

  • ARMC5 protein, human
  • Armadillo Domain Proteins
  • Tumor Suppressor Proteins