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A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype

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Abstract

ARMC5 mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5 germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5 gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients’ clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5 mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5 mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p = 0.062), and more severe hypertension and diabetes (p < 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (p < 0.01). No correlation emerged between type of mutation and clinical parameters. ARMC5 mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.

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Acknowledgments

The authors would like to thank the following people for all their help in patients’ collection and characterization during this study: Dr Laura Trementino, Dr Paola Sartorato, Dr Mattia Barbot, Dr Marialuisa Zilio, Dr Margherita Rizzato, and Prof Franco Mantero.

Funding

This work was funded by the Italian Ministry of University and Research (MIUR) through the FIRB project no. RBAP1153LS.

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    Authors and Affiliations

    1. Endocrinology Unit, Department of Medicine DIMED, Padova University Hospital, Padua, Italy

      N. M. Albiger, D. Regazzo, B. Rubin, F. Ceccato, M. Boscaro & C. Scaroni

    2. Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padua, Italy

      A. M. Ferrara, S. Rizzati & E. Taschin

    3. Division of Endocrinology, Ancona University Hospital, Polytechnic University of Marche, Ancona, Italy

      G. Arnaldi

    4. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

      F. Pecori Giraldi

    5. Neuroendocrinology Research Laboratory, Istituto Auxologico Italiano IRCCS, Milan, Italy

      F. Pecori Giraldi

    6. Endocrinology, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University of Roma, Rome, Italy

      A. Stigliano & L. Cerquetti

    7. Endocrinology and Metabolism Unit, S. Maria della Misericordia University Hospital, Udine, Italy

      F. Grimaldi

    8. Department of Internal Medicine, General Hospital, Montebelluna, Treviso, Italy

      E. De Menis

    9. Minimally Invasive Endocrine Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy

      M. Iacobone

    10. Department of Biology, University of Padova, Via U. Bassi 58/B, 35128, Padua, Italy

      G. Occhi

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    1. N. M. Albiger
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    The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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    N. M. Albiger, D. Regazzo, G. Occhi and C. Scaroni have equally contributed to this work.

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    Albiger, N.M., Regazzo, D., Rubin, B. et al. A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype. Endocrine 55, 959–968 (2017). https://doi.org/10.1007/s12020-016-0956-z

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