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Allelic Variants of ARMC5 in Patients With Adrenal Incidentalomas and in Patients With Cushing's Syndrome Associated With Bilateral Adrenal Nodules.

ABSTRACT: Objective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluated germline allelic variants of ARMC5 in patients with bilateral and unilateral AI and in patients with overt CS associated with bilateral adrenal nodules. Methods: We performed a retrospective multicenter study involving 123 patients with AI (64 bilateral; 59 unilateral). We also analyzed 20 patients with ACTH pituitary independent overt CS associated with bilateral adrenal nodules. All patients underwent germline genotyping analysis of ARMC5; abdominal CT and were classified as normal, possible or autonomous cortisol secretion, according to the low doses of dexamethasone suppression test. Results: We identified only one pathogenic allelic variant among the patients with bilateral AI. We did not identify any pathogenic allelic variants of ARMC5 in patients with unilateral AI. Thirteen out of 20 patients (65%) with overt CS and bilateral adrenal nodules were carriers of pathogenic germline ARMC5 allelic variants, all previously described. The germline ARMC5 mutation was observed in only one patient with bilateral AI; it was associated with autonomous cortisol secretion and showed to be a familial form. Conclusion: The rarity of germline ARMC5 mutations in AI points to other molecular mechanisms involved in this common adrenal disorder and should be investigated. In contrast, patients with overt Cushing's syndrome and bilateral adrenal nodules had the presence of ARMC5 mutations that were with high prevalence and similar to the literature. Therefore, we recommend the genetic analysis of ARMC5 for patients with established Cushing's syndrome and bilateral adrenal nodules rather than patients with unilateral AI.

SUBMITTER: Mariani BMP

PROVIDER: S-EPMC7019100 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Allelic Variants of ARMC5 in Patients With Adrenal Incidentalomas and in Patients With Cushing's Syndrome Associated With Bilateral Adrenal Nodules.

Mariani Beatriz Marinho de Paula BMP Nishi Mirian Yumie MY Wanichi Ingrid Quevedo IQ Brondani Vania Balderrama VB Lacombe Amanda Meneses Ferreira AMF Charchar Helaine H Pereira Maria Adelaide Albergaria MAA Srougi Victor V Tanno Fabio Yoshiaki FY Ceccato Filippo F Regazzo Daniela D Barbot Mattia M Occhi Gianluca G Albiger Nora Maria Elvira NME Vieira-Corrêa Marcelo M Kater Claudio Elias CE Scaroni Carla C Chambô José Luis JL Zerbini Maria Claudia Nogueira MCN Mendonca Berenice B BB Almeida Madson Q MQ Fragoso Maria Candida Barisson Villares MCBV

Frontiers in endocrinology 20200207

Objective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluate ...[more]

PMID: 32117062

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Project description:BackgroundAutonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of endogenous SIOP cannot be explained by cortisol excess alone, and how other steroid metabolites affect bone status is unclear.MethodsACS was diagnosed as serum cortisol ≥1.8 μg/dL after the 1-mg dexamethasone suppression test (DST-cortisol). Using liquid chromatography tandem mass spectrometry, 21 plasma steroid metabolites were measured in 73 patients with ACS and 85 patients with non-functioning adrenal tumors (NFAT). Expression of steroidogenic enzymes and relevant steroid metabolites were analyzed in some of CPA tissues.FindingsDiscriminant and principal component analyses distinguished steroid profiles between the ACS and NFAT groups in premenopausal women. Premenopausal women with ACS exhibited higher levels of a mineralocorticoid metabolite, 11-deoxycorticosterone (11-DOC), and lower levels of androgen metabolites, dehydroepiandrosterone-sulfate, and androsterone-glucuronide. In premenopausal women with ACS, DST-cortisol negatively correlated with trabecular bone score (TBS). Additionally, 11-DOC negatively correlated with lumbar spine-bone mineral density, whereas androsterone-glucuronide positively correlated with TBS. The CPA tissues showed increased 11-DOC levels with increased expression of CYP21A2, essential for 11-DOC synthesis. Adrenal non-tumor tissues were atrophied with reduced expression of CYB5A, required for androgen synthesis.InterpretationThis study demonstrates that unbalanced production of adrenal steroid metabolites, derived from both adrenal tumor and non-tumor tissues, contributes to the pathogenesis of endogenous SIOP in premenopausal women with ACS.FundingJSPS KAKENHI, Secom Science and Technology Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology, AMED-CREST, JSTA-STEP, JST-Moonshot, and Ono Medical Research Foundation.

Dataset Information

Allelic Variants of ARMC5 in Patients With Adrenal Incidentalomas and in Patients With Cushing's Syndrome Associated With Bilateral Adrenal Nodules.

Publications

Allelic Variants of <i>ARMC5</i> in Patients With Adrenal Incidentalomas and in Patients With Cushing's Syndrome Associated With Bilateral Adrenal Nodules.

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