title: ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia.
abstract: BACKGROUND
  Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS) and its familial clustering has been described previously. Recent studies identified that ARMC5 mutations occur frequently in BMAH, but the relation between ARMC5 mutation and the expression of aberrant G-protein-coupled receptor has not been examined in detail yet.
  
  
  METHODS
  We studied a large French-Canadian family with BMAH and sub-clinical or overt CS. Screening was performed using the 1-mg dexamethasone suppression test (DST) in 28 family members. Screening for aberrant regulation of cortisol by various hormone receptors were examined in vivo in nine individuals. Sequencing of the coding regions of ARMC5 gene was carried out.
  
  
  RESULTS
  Morning ambulating cortisol post 1 mg DST were >50 nmol/l in 5/8 members in generation II (57-68 years old), 9/22 in generation III (26-46 years old). Adrenal size was enlarged at different degrees. All affected patients increased cortisol following upright posture, insulin-induced hypoglycemia and/or isoproterenol infusion. β-blockers led to the reduction of cortisol secretion in all patients with the exception of two who had adrenalectomies because of β-blockers intolerance. We identified a heterozygous germline variant in the ARMC5 gene c.327_328insC, (p.Ala110Argfs*9) in nine individuals with clinical or subclinical CS, in four out of six individuals with abnormal suppression to dexamethasone at initial investigation and one out of six individuals with current normal clinical screening tests.
  
  
  CONCLUSIONS
  Systematic screening of members of the same family with hereditary BMAH allows the diagnosis of unsuspected subclinical CS associated with early BMAH. The relation between the causative ARMC5 mutation and the reproducible pattern of aberrant β-adrenergic and V1-vasopressin receptors identified in this family remains to be elucidated.
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil isabelle.bourdeau@umontreal.ca.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bourdeau
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Oble
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors.forename: Fabien
authors.initials: F
authors.lastname: Magne
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lévesque
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors.forename: Katia Y
authors.initials: KY
authors.lastname: Cáceres-Gorriti
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors.forename: Serge
authors.initials: S
authors.lastname: Nolet
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors.forename: Pavel
authors.initials: P
authors.lastname: Hamet
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors.forename: Maria Candida Barisson Villares
authors.initials: MC
authors.lastname: Fragoso
authors.affiliation: Division of EndocrinologyDepartment of MedicineDivision of Medical GeneticsDepartment of Medicine, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, CanadaDepartment of PathologyCHUM, Montréal, Quebec, CanadaDepartment of PediatricsCentre de Recherche CHU Sainte-Justine, Université de Montréal, Montréal, Quebec, CanadaUnidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
authors.forename: André
authors.initials: A
authors.lastname: Lacroix
mesh_terms: D000311:Adrenal Glands / Q000473:pathology; D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D000315:Adrenalectomy; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D051186:Armadillo Domain Proteins; D003480:Cushing Syndrome / Q000175:diagnosis / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008875:Middle Aged; D010375:Pedigree; D011187:Posture; D011433:Propranolol / Q000494:pharmacology; D011792:Quebec; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D017483:Receptors, Vasopressin / Q000502:physiology*; D014057:Tomography, X-Ray Computed; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014667:Vasopressins / Q000494:pharmacology
chemical_list: C000590373:ARMC5 protein, human; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D051186:Armadillo Domain Proteins; D007328:Insulin; D011943:Receptors, Adrenergic, beta; D017483:Receptors, Vasopressin; D025521:Tumor Suppressor Proteins; D014667:Vasopressins; D003907:Dexamethasone; D011433:Propranolol; D007545:Isoproterenol; D006854:Hydrocortisone