title: ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences.
abstract: BACKGROUND
  Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of primary adrenal Cushing's syndrome (CS). ARMC5 germline mutations have been identified recently in PBMAH.
  
  
  OBJECTIVE
  To determine the prevalence of ARMC5 mutations and analyze genotype-phenotype correlation in a large cohort of unrelated PBMAH patients with subclinical or clinical CS.
  
  
  METHODS
  ARMC5 was sequenced in 98 unrelated PBMAH index cases. PBMAH was identified by bilateral adrenal nodular enlargement on computed tomography scan. The effect on apoptosis of ARMC5 missense mutants was tested in H295R and HeLa cells. Clinical and hormonal data were collected including midnight and urinary free cortisol levels, ACTH, androgens, renin/aldosterone ratio, cortisol after overnight dexamethasone suppression test, cortisol and 17-hydroxyprogesterone after ACTH 1-24 stimulation and illegitimate receptor responses. Computed tomography and histological reports were analyzed.
  
  
  RESULTS
  ARMC5-damaging mutations were identified in 24 patients (26%). The missense mutants and the p.F700del deletion were unable to induce apoptosis in both H295R and HeLa cell lines, unlike the wild-type gene. ARMC5-mutated patients showed an overt CS more frequently, compared to wild-type patients: lower ACTH, higher midnight plasma cortisol, urinary free cortisol, and cortisol after dexamethasone suppression test (P = .003, .019, .006, and <.001, respectively). Adrenals of patients with mutations were bigger and had a higher number of nodules (P = .001 and <.001, respectively).
  
  
  CONCLUSIONS
  ARMC5 germline mutations are common in PBMAH. Index cases of mutation carriers show a more severe hypercortisolism and larger adrenals. ARMC5 genotyping may help to identify clinical forms of PBMAH better and may also allow earlier diagnosis of this disease.
authors: Stéphanie
authors: S
authors: Espiard
authors: Ludivine
authors: L
authors: Drougat
authors: Rossella
authors: R
authors: Libé
authors: Guillaume
authors: G
authors: Assié
authors: Karine
authors: K
authors: Perlemoine
authors: Laurence
authors: L
authors: Guignat
authors: Gaelle
authors: G
authors: Barrande
authors: Françoise
authors: F
authors: Brucker-Davis
authors: Françoise
authors: F
authors: Doullay
authors: Stephanie
authors: S
authors: Lopez
authors: Emmanuel
authors: E
authors: Sonnet
authors: Florence
authors: F
authors: Torremocha
authors: Denis
authors: D
authors: Pinsard
authors: Nathalie
authors: N
authors: Chabbert-Buffet
authors: Marie-Laure
authors: ML
authors: Raffin-Sanson
authors: Lionel
authors: L
authors: Groussin
authors: Françoise
authors: F
authors: Borson-Chazot
authors: Joël
authors: J
authors: Coste
authors: Xavier
authors: X
authors: Bertagna
authors: Constantine A
authors: CA
authors: Stratakis
authors: Felix
authors: F
authors: Beuschlein
authors: Bruno
authors: B
authors: Ragazzon
authors: Jérôme
authors: J
authors: Bertherat
mesh_terms: D000303:Adrenal Cortex Diseases / Q000453:epidemiology / Q000235:genetics*; D000311:Adrenal Glands / Q000473:pathology*; D000328:Adult; D000368:Aged; D051186:Armadillo Domain Proteins; D002478:Cells, Cultured; D015331:Cohort Studies; D003480:Cushing Syndrome / Q000453:epidemiology / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006367:HeLa Cells; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000590373:ARMC5 protein, human; D051186:Armadillo Domain Proteins; D025521:Tumor Suppressor Proteins