Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients

in European Journal of Endocrinology
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  • 1 Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France
  • | 2 Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
  • | 3 Institut Curie, INSERM U900, MINES ParisTech, PSL-Research University, CBIO-Centre for Computational Biology, Paris, France
  • | 4 Department of Endocrinology, Diabetology and Nutrition, CHU Rennes, Rennes, France
  • | 5 Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190, Lille, France
  • | 6 Unit of Hormonology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
  • | 7 Department of Endocrinology, Diabetes and Metabolic Diseases, CHU Rouen, Rouen, France
  • | 8 Department of Endocrinology, Diabetology and Nutrition, Hôpital Ambroise Paré, Assistance Publique Hôpitaux de Paris, Boulogne-Billancourt, France
  • | 9 Department of Endocrinology, Diabetology and Reproduction, CHU Nice, Nice, France
  • | 10 Department of Endocrinology and Reproduction, Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France
  • | 11 Department of Endocrinology and Metabolism, Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France
  • | 12 Department of Endocrinology, Diabetology and Reproduction, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris, Paris, France
  • | 13 Department of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
  • | 14 Department of Endocrinology, Diabetology and Nutrition, Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux, France
  • | 15 Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Department of Endocrinology and Reproduction, Reference Center for Rare Pituitary Diseases, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France
  • | 16 Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, University of Würzburg, Würzburg, Germany
  • | 17 Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
  • | 18 Unit of Oncogenetics, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France

Correspondence should be addressed to J Bertherat; Email: jerome.bertherat@aphp.fr
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Objective

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants.

Methods

We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively.

Results

52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P  < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P  < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P  < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant.

Conclusion

We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.

Supplementary Materials

 

     European Society of Endocrinology

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