The mutational landscape of ARMC5 in Primary Bilateral Macronodular Adrenal Hyperplasia: an update.

Ulrich Dischinger, Albain Chansavang, Maria C Fragoso, Annabel Berthon, Florian Violon, Isadora P Cavalcante, Anna Vaczlavik, Lucas Bouys, Antoine Tabarin, Peter Kamenicky, Martin Reincke, Patricia Vaduva, Gérald Raverot, Constantine A Stratakis, Eric Pasmant, Marie-Christine Vantyghem, Jérôme Bertherat, Stéphanie Espiard, Cristina L Ronchi, Anne Jouinot, Karine Perlemoine, Bruno Ragazzon

Journal: Orphanet journal of rare diseases 2025;20(1):51

PMID: 39910635

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Abstract

BACKGROUND

Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare cause of Cushing's syndrome due to bilateral adrenocortical macronodules. Germline inactivating variants of the tumor suppressor gene ARMC5 are responsible for 20-25% of apparently sporadic PBMAH cases and 80% of familial presentations. ARMC5 screening is now routinely performed for PBMAH patients and families. Based on literature review and own observation, this study aims to give an overview of both published and unpublished ARMC5 genetic alterations and to compile the available evidence to discriminate pathogenic from benign variants.

RESULTS

146 different germline variants (110 previously published and 36 novel) are identified, including 46% missense substitutions, 45% truncating variants, 3% affecting splice sites, 4% in-frame variants and 2% large deletions. In addition to the germline events, somatic 16p loss-of-heterozygosity and 104 different somatic events are described. The pathogenicity of ARMC5 variants is established on the basis of their frequency in the general population, in silico predictions, familial segregation and tumor DNA sequencing.

CONCLUSIONS

This is the first extensive review of ARMC5 pathogenic variants. It shows that they are spread on the whole coding sequence. This is a valuable resource for genetic investigations of PBMAH and will help the interpretation of new missense substitutions that are continuously identified.

Address: Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France.; Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France.; Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France.; Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France.; Department of Endocrinology, Diabetology and Nutrition, CHU Rennes, Rennes, France.; Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190, Lille, France.; 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.; Department of Endocrinology, Diabetology and Nutrition, Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux, France.; Department of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.; Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK.; Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, UK.; Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany.; Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.; Department of Endocrinology, Adrenal Unit, University of Sao Paulo, Sao Paulo, Brazil.; Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USA.; Research Institute, ELPEN, Pikermi, Athens, Greece.; Human Genetics and Precision Medicine, IMBB, FORTH, Heraklion, Crete, Greece.; Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France.; Department of Genomic Medicine of Tumors and Cancers, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.; Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France. [email protected].; Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France. [email protected].

DOI: 10.1186/s13023-025-03554-1

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MeSH Terms: Humans, Tumor Suppressor Proteins, Mutation, Armadillo Domain Proteins, Germ-Line Mutation, Cushing Syndrome