Case Report: A Novel ARMC5 Germline Mutation in a Patient with Primary Bilateral Macronodular Adrenal Hyperplasia and Hypogammaglobulinemia

Vena, Walter; Morelli, Valentina; Carrabba, Maria; Elli, Francesca; Fabio, Giovanna; Muller, Ilaria; Lucca, Camilla; Maffini, Maria Antonia; Lania, Andrea; Mantovani, Giovanna; Arosio, Maura

doi:10.3389/fgene.2022.834067

Cited by 3 publications

(1 citation statement)

References 12 publications

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“…Little is known about ARMC5 : it is a cytoplasmic protein and it probably acts as a tumor suppressor gene. ARMC5 mutations are involved in about 25–50% of PBMAH and it seems that genetic forms are characterized by a more severe clinical course (Bouys et al, 2022 ; Cavalcante et al, 2022 ; Faucz et al, 2014 ; Ferreira et al, 2020 ; Vena et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

New pathogenic variants in ARMC5 gene in a series of Italian patients affected by primary bilateral macronodular adrenocortical hyperplasia (PBMAH)

Giacchè

Panarotto

Mori

et al. 2023

Molec Gen & Gen Med

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Background To perform genetic screening for ARMC5 gene germline pathogenic variants in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH). Subjects and Methods In a group of 10 PBMAH patients, we performed complete sequencing of the coding region of the ARMC5 gene and MLPA analysis for large deletion detection. In subjects with the ARMC5 variant, we searched ARMC5 gene somatic variants on tumor samples. Results Among 10 PBMAH patients, we identified four ARMC5 germline variants (40%). One variant, c:174dupC p.Glu59Argfs*44, was already known; one variant p.Gly323Asp, was already reported and classified as likely disease‐causing VUS (class 3–4); two variants p.Leu596Arg and p.Arg811Pro, were never reported before. For p.Gly323Asp and p.Arg811Pro, we identified second deleterious variants at the somatic level, enforcing the possible pathogenic effect of germline variants. Conclusions Our results underscore the importance of performing genetic testing also in sporadic PBMAH patients and broaden the spectrum of molecular variants involved in PBMAH syndrome.

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Section: Introductionmentioning

confidence: 99%

New pathogenic variants in ARMC5 gene in a series of Italian patients affected by primary bilateral macronodular adrenocortical hyperplasia (PBMAH)

Giacchè

Panarotto

Mori

et al. 2023

Molec Gen & Gen Med

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Prevalence and clinical features of armadillo repeat-containing 5 mutations carriers in a single center cohort of patients with bilateral adrenal incidentalomas

Morelli,

Elli,

Frigerio

et al. 2023

European Journal of Endocrinology

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Objective We aimed to evaluate the prevalence of armadillo repeat-containing 5 (ARMC5) genetic defects in our cohort of bilateral adrenal incidentaloma (BAI) patients and to evaluate the possible existence of genotype–phenotype correlations. Design Cross-sectional study. Setting Tertiary care center. Participants 72 BAI patients. Main Outcome Measure(s) The following data have been collected: morning adrenocorticotropic hormone (ACTH) concentrations; cortisol levels after 1 mg overnight dexamethasone suppression test (F-1mgDST); urinary free cortisol (UFC) levels; diameter of the adrenal masses; and the association with overweight/obesity, arterial hypertension, diabetes mellitus, dyslipidemia, cardiovascular events, unrelated neoplasia, osteoporosis, thyroid nodular disease, and primary hyperparathyroidism. A search for ARMC5 germline and somatic pathogenic variants was performed in all patients and in the adrenal tissue of patients operated on, respectively. Results The prevalence of germline ARMC5 pathogenic variants among patients with mild autonomous cortisol secretion (MACS+, defined as F-1mgDST > 1.8 µg/dL) was 18.8%. No germline pathogenic variants were detected in patients without MACS. Moreover, somatic ARMC5 pathogenic variants were also found in the adrenal tissue of six patients without germline ARMC5 variants. The F-1mgDST levels >5 µg/dL predicted with a poor sensitivity but a 90.5% specificity in identifying the presence of ARMC5 germline pathogenic variants. We did not find any clinical parameter predictive of the ARMC5 mutation presence. Conclusions In MACS+ BAI patients, germline ARMC5 gene pathogenic variants are frequent. Further studies are needed to elucidate the pathophysiological role of somatic ARMC5 pathogenic variants on adrenal tumor development in otherwise wild-type (WT) patients.

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Primary bilateral macronodular adrenal hyperplasia: A rare case report of Cushing syndrome and review of literature

Ghanbari Boroujeni,

Meftah,

Zarimeidani

et al. 2024

Medicine

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Rationale: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome (CS), accounting for <2% of CS cases. Diagnosing PBMAH can be difficult and challenging for clinicians. Patient concerns: We report a 52-year-old female, a patient with a history of intermittent fever for 3 years. She presented with nausea, headache, and dizziness for several days, along with fatigue, myalgia, muscle weakness, exertional dyspnea, hoarseness, spontaneous bruising over the past several months, and long-term psychological complaints. Additionally, we observed periorbital and facial edema, right lower quadrant tenderness, and abdominal striae during the examination. Diagnoses: Her laboratory results showed increased cortisol and suppressed ACTH, and an abdominal CT scan revealed 2 heterogeneous masses in the adrenal glands. These findings led us to the diagnosis of PBMAH in this patient. The existence of aberrant receptors was evaluated, and the tests were negative. Interventions: The patient underwent left adrenalectomy and corticosteroid therapy after the surgery. Her clinical complaints improved after the surgery. Outcomes: However, her dependency on corticosteroids was not transient after unilateral adrenalectomy, and she still needs glucocorticoid supplementation 1 year after surgery. Lessons: This patient is a case of PBMAH who presented with fever and CS symptoms and underwent unilateral adrenalectomy. Interestingly, she had suppressed cortisol levels for at least 1 year after the unilateral adrenalectomy. Therefore, we suggest further research on the most effective treatment strategies for PBMAH.

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Case Report: A Novel ARMC5 Germline Mutation in a Patient with Primary Bilateral Macronodular Adrenal Hyperplasia and Hypogammaglobulinemia

Cited by 3 publications

References 12 publications

New pathogenic variants in ARMC5 gene in a series of Italian patients affected by primary bilateral macronodular adrenocortical hyperplasia (PBMAH)

New pathogenic variants in ARMC5 gene in a series of Italian patients affected by primary bilateral macronodular adrenocortical hyperplasia (PBMAH)

Prevalence and clinical features of armadillo repeat-containing 5 mutations carriers in a single center cohort of patients with bilateral adrenal incidentalomas

Primary bilateral macronodular adrenal hyperplasia: A rare case report of Cushing syndrome and review of literature

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