ECE2014 Oral Communications Adrenal clinical (5 abstracts)
Armadillo repeat containing 5 gene (ARMC5) alterations in a large cohort of 98 ACTH-independant macronodular adrenal hyperplasia (AIMAH) patients: genotype/phenotype correlations.
Rossella Libé 1, , Guillaume Assié 1, , Stéphanie Espiard 1 , Windy Luscap 1 , Laurence Guignat 2 , Gaelle Barrande 3 , Françoise Brucker-Davis 4 , Françoise Doullay 5 , Stephanie Lopez 6 , Emmanuel Sonneta 7 , Florence Torremocha 8 , Denis Pinsard 9 , Nathalie Chabert-Buffet 10 , Marie Laure Raffin Sanson 11 , Lionel Groussin 1, , Françoise Borson-Chazot 12 , Xavier Bertagna 1, , Felix Beuschlein 13 , Bruno Ragazzon 1 & Jérôme Bertherat 1,
1INSERM U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes, Paris, France; 2Department of Endocrinology, Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France; 3Endocrinology Unit, Hôpital La Source, Orléans, France; 4Endocrinology Unit, Centre hospitalier Nice, Nice, France; 5Endocrinology, Avenue Alderic Chave, Istres, France; 6Endocrinology Unit, Hôpital Le Cluzeau, Limoges, France; 7Endocrinology Unit, CHU de Brest, Brest, France; 8Endocrinology Unit, CHU Poitiers, Poitiers, France; 9Endocrinology Unit, CHU Rennes, Rennes, France; 10Endocrinology Unit, Hôpital Tenon, Paris, France; 11Endocrinology Unit, Hôpital Ambroise Paré, Boulogne sur Seine, France; 12Department of Endocrinology Lyon-Est, Groupement hospitalier Est, Bron, France; 13Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munchen, Germany.
Introduction: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is often an incidental finding, but may be diagnosed in patients with Cushing’s syndrome. We have recently identified germline mutations in the armadillo repeat containing 5 gene (ARMC5) in AIMAH patients, associated with somatic second hits specific of each AIMAH nodule ( Assié et al, NEJM, 2013). The aim is to characterize the prevalence of ARMC5 mutations in AIMAH patients and the genotype/phenotype correlations.
Methods: Ninety-eight unrelated patients with AIMAH, defined as a bilateral adrenal enlargement of at least 1 cm, were included. ARMC5 was sequenced by SANGER. Wild type and mutated patients were compared using Student t-tests or Fisher exact tests.).
Results: ARMC5 alterations were found in 24 patients (26%). These alterations included four nonsense mutations, six missense mutations, four frameshift mutations, one inframe small deletion (discarding four aminoacids) and one microdeletion of 1.5 Mb. For four extra-patients, the leukocyte DNA was not available, but two alterations were found in the AIMAH nodule that could be sequenced. Among these four patients, two combined a nonsense mutation and a frameshift mutation, one combined a missense and a frameshift, and one an inframe deletion (one aminoacid) and a missense. None of these mutations were found in public DNA variation databases (dbSNP or 1000 genomes). All the missense mutations were predicted as probably damaging using Polyphen. ARMC5 mutated patients were diagnosed at younger age (49 vs 55, P=0.046). They showed a more severe Cushing syndrome, with higher plasma cortisol after DXM 1 mg (18 vs 9 μg/dl, P<0.001) and a lower ACTH (P=0.003). They also showed bigger adrenals (107 vs 50°g of total adrenal, P=0.001), with more nodules than the non mutated patients (P<0.001). Hypertension was more frequent in the mutated patients group (95% vs 63%, P=0.009). ARMC5 mutated patients were more frequently operated (83% vs 33%, P=0.001).
Conclusion: ARMC5 mutations define a subtype of adrenal hyperplasia characterized by larger adrenals containing multiple nodules, and more prone to overt Cushing’s syndrome.
Volume 35
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Endocrine Abstracts
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