title: Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation.
abstract: BACKGROUND
  Inactivating germline mutations of the probable tumor suppressor gene, armadillo repeat containing 5 (ARMC5), have recently been identified as a genetic cause of macronodular adrenal hyperplasia (MAH).
  
  
  OBJECTIVE
  We searched for ARMC5 mutations in a large cohort of patients with MAH. The clinical phenotype of patients with and without ARMC5 mutations was compared.
  
  
  METHODS
  Blood DNA from 34 MAH patients was genotyped using Sanger sequencing. Diurnal serum cortisol measurements, plasma ACTH levels, urinary steroids, 6-day Liddle's test, adrenal computed tomography, and weight of adrenal glands at adrenalectomy were assessed.
  
  
  RESULTS
  Germline ARMC5 mutations were found in 15 of 34 patients (44.1%). In silico analysis of the mutations indicated that seven (20.6%) predicted major implications for gene function. Late-night cortisol levels were higher in patients with ARMC5-damaging mutations compared with those without and/or with nonpathogenic mutations (14.5 ± 5.6 vs 6.7 ± 4.3, P < .001). All patients carrying a pathogenic ARMC5 mutation had clinical Cushing's syndrome (seven of seven, 100%) compared with 14 of 27 (52%) of those without or with mutations that were predicted to be benign (P = .029). Repeated-measures analysis showed overall higher urinary 17-hydroxycorticosteroids and free cortisol values in the patients with ARMC5-damaging mutations during the 6-day Liddle's test (P = .0002).
  
  
  CONCLUSIONS
  ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with MAH. Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families.
authors.affiliation: Section on Endocrinology and Genetics (F.R.F., M.Z., M.B.L., E.S., G.T., A.B., C.A.S.), Program on Developmental Endocrinology and Genetics, Program on Reproductive and Adult Endocrinology (M.Z.), Biostatistics and Clinical Epidemiology Service (N.S.), Clinical Center, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Group for Advanced Molecular Investigation (F.R.F.), Graduate Program in Health Science, Center for Biological and Sciences, Pontificia Universidade Catolica do Paraná, Curitiba Brazil 80215-901; Department of Endocrinology, Metabolism, and Cancer (R.L., G.A., S.E., L.D., B.R., J.B.), INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, 75014 Paris, France.
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.forename: Mihail
authors.initials: M
authors.lastname: Zilbermint
authors.forename: Maya B
authors.initials: MB
authors.lastname: Lodish
authors.forename: Eva
authors.initials: E
authors.lastname: Szarek
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Trivellin
authors.forename: Ninet
authors.initials: N
authors.lastname: Sinaii
authors.forename: Annabel
authors.initials: A
authors.lastname: Berthon
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Guillaume
authors.initials: G
authors.lastname: Assié
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Espiard
authors.forename: Ludivine
authors.initials: L
authors.lastname: Drougat
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Jerome
authors.initials: J
authors.lastname: Bertherat
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000328:Adult; D051186:Armadillo Domain Proteins / Q000235:genetics*; D015331:Cohort Studies; D003480:Cushing Syndrome / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; 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