Review

. 2025 Feb 5;20(1):51.

doi: 10.1186/s13023-025-03554-1.

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

Lucas Bouys^#^{1

2}, Anna Vaczlavik^#^{1

2}, Isadora P Cavalcante¹, Florian Violon¹, Anne Jouinot^{1

2}, Annabel Berthon¹, Patricia Vaduva^{1

3}, Stéphanie Espiard⁴, Karine Perlemoine¹, Peter Kamenicky⁵, Marie-Christine Vantyghem⁴, Antoine Tabarin⁶, Gérald Raverot⁷, Cristina L Ronchi^{8

9}, Ulrich Dischinger¹⁰, Martin Reincke¹¹, Maria C Fragoso¹², Constantine A Stratakis^{13

14

15}, Albain Chansavang^{1

16}, Eric Pasmant^{1

16}, Bruno Ragazzon¹, Jérôme Bertherat^{17

18}; COMETE and ENSAT Networks

Affiliations

¹ Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France.
² 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.
³ Department of Endocrinology, Diabetology and Nutrition, CHU Rennes, Rennes, France.
⁴ Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190, Lille, France.
⁵ 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.
⁶ Department of Endocrinology, Diabetology and Nutrition, Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux, France.
⁷ Department of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
⁸ Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK.
⁹ Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, UK.
¹⁰ Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany.
¹¹ Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
¹² Department of Endocrinology, Adrenal Unit, University of Sao Paulo, Sao Paulo, Brazil.
¹³ Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USA.
¹⁴ Research Institute, ELPEN, Pikermi, Athens, Greece.
¹⁵ Human Genetics and Precision Medicine, IMBB, FORTH, Heraklion, Crete, Greece.
¹⁶ Department of Genomic Medicine of Tumors and Cancers, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
¹⁷ Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France. jerome.bertherat@aphp.fr.
¹⁸ 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. jerome.bertherat@aphp.fr.

^# Contributed equally.

PMID: 39910635
PMCID: PMC11796173
DOI: 10.1186/s13023-025-03554-1

Review

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

Lucas Bouys et al. Orphanet J Rare Dis. 2025.

. 2025 Feb 5;20(1):51.

doi: 10.1186/s13023-025-03554-1.

Authors

Affiliations

¹ Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France.
² 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.
³ Department of Endocrinology, Diabetology and Nutrition, CHU Rennes, Rennes, France.
⁴ Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190, Lille, France.
⁵ 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.
⁶ Department of Endocrinology, Diabetology and Nutrition, Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux, France.
⁷ Department of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
⁸ Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK.
⁹ Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, UK.
¹⁰ Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany.
¹¹ Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
¹² Department of Endocrinology, Adrenal Unit, University of Sao Paulo, Sao Paulo, Brazil.
¹³ Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, USA.
¹⁴ Research Institute, ELPEN, Pikermi, Athens, Greece.
¹⁵ Human Genetics and Precision Medicine, IMBB, FORTH, Heraklion, Crete, Greece.
¹⁶ Department of Genomic Medicine of Tumors and Cancers, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
¹⁷ Université Paris-Cité, Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France. jerome.bertherat@aphp.fr.
¹⁸ 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. jerome.bertherat@aphp.fr.

^# Contributed equally.

PMID: 39910635
PMCID: PMC11796173
DOI: 10.1186/s13023-025-03554-1

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.

Keywords: ACTH; ARMC5; Adrenal gland; Cortisol; Cushing’s syndrome; Genetics; Primary Bilateral Macronodular Adrenal Hyperplasia.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: Written informed consent was obtained from all patients for which a new ARMC5 variant is reported in this work. The study was approved by the local ethic committee of Ile de France I, Paris. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests.

Figures

**Fig. 1**
Germline *ARMC5* variants. *ARMC5* variants are shown on a graphical representation of ARMC5 protein from 1 to 935 amino acids (NM_001105247.1 canonical transcript). Both Armadillo and BTB/POZ domains appear respectively as pink and green regions. The class 4 (likely pathogenic) and class 5 (pathogenic) variants are displayed in colors: non-sense (red), frameshift (orange), splice sites (purple), missense (blue) and in frame deletions or insertions (green). The class 2 (likely benign) and class 3 (uncertain significance) variants are represented in grey. Tail size of the lollipops represents the recurrence of each protein alteration from 1 to 10

**Fig. 2**
Proportions of protein change categories in germline (panel A) and somatic (panel B) *ARMC5* likely pathogenic and pathogenic variants

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources