ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia. Issue 1 (January 2016)

• Record Type: Journal Article
• Authors: Bourdeau, Isabelle; Oble, Sylvie; Magne, Fabien; Lévesque, Isabelle; Cáceres-Gorriti, Katia Y; Nolet, Serge; Awadalla, Philip; Tremblay, Johanne; Hamet, Pavel; Fragoso, Maria Candida Barisson Villares; Lacroix, André
• Is Part Of: European journal of endocrinology. Volume 174:Issue 1(2016)
• Page Start: 85
• Page End: 96
• Publication Date: 2016-01
• Subjects: Endocrinology -- Periodicals; 616.4005
• DOI: 10.1530/EJE-15-0642
• Languages: English
• ISSNs: 0804-4643

Abstract

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.