Primary Bilateral Macronodular Adrenal Hyperplasia Presenting as Mild Autonomous Cortisol Secretion in a Young Man with a Novel ARMC5 Variant   — ASN Events
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Primary Bilateral Macronodular Adrenal Hyperplasia Presenting as Mild Autonomous Cortisol Secretion in a Young Man with a Novel ARMC5 Variant   (#445)

Nik Nur Iman Nik Ghazali 1
  1. Endocrinology and Obstetric Medicine, Cairns Base Hospital, Cairns, QLD, Australia

Introduction:
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of endogenous hypercortisolism, accounting for <2% of Cushing syndrome.1,2 Germline ARMC5 variants are identified in 20–55% of cases and are associated with bilateral adrenal enlargement, progressive cortisol excess and familial disease.1,2 We present a young man with PBMAH manifesting as mild autonomous cortisol secretion (MACS).

Case:
A 36-year-old Torres Strait Islander man with hypertension, obesity (BMI 32 kg/m²), metabolic dysfunction-associated steatotic liver disease and previous radioiodine-treated Graves' disease was referred after incidental bilateral adrenal lesions were detected during investigation of haemoptysis. Imaging demonstrated a 35 mm benign-appearing right adrenal adenoma and a multinodular left adrenal gland, with interval growth of the right lesion to 41 mm over two years. Biochemical evaluation excluded pheochromocytoma and primary aldosteronism but demonstrated persistent ACTH-independent cortisol excess, with three abnormal 1 mg overnight dexamethasone suppression tests (post-dexamethasone cortisol 61–128 nmol/L), suppressed ACTH (6–11 ng/L) and subsequently elevated urinary free cortisol. Despite the absence of overt Cushingoid features, he fulfilled diagnostic criteria for MACS. Following multidisciplinary review, laparoscopic right adrenalectomy was performed. Histopathology confirmed a benign adrenocortical adenoma (Weiss score 0). Endogenous adrenal function remained preserved postoperatively. Genetic testing subsequently identified a novel ARMC5 variant, supporting a diagnosis within the PBMAH spectrum.

Discussion:
PBMAH frequently presents with MACS, where biochemical abnormalities may be mild, intermittent and discordant, necessitating repeated testing. In selected patients, unilateral adrenalectomy of the dominant gland can improve cortisol excess while preserving endogenous adrenal function.1 Identification of an ARMC5 variant has important implications for genetic counselling, family screening and lifelong surveillance.1-3

Conclusion:
PBMAH should be considered in younger patients with bilateral adrenal incidentalomas and suppressed ACTH, even without overt Cushing syndrome. Recognition of MACS, multidisciplinary management and ARMC5 testing facilitate personalised treatment while preserving adrenal function.

  1. Jérôme Bertherat, Isabelle Bourdeau, Lucas Bouys, Fanny Chasseloup, Peter Kamenický, André Lacroix, Clinical, Pathophysiologic, Genetic, and Therapeutic Progress in Primary Bilateral Macronodular Adrenal Hyperplasia, Endocrine Reviews, Volume 44, Issue 4, August 2023, Pages 567–628
  2. Cavalcante IP, Berthon A, Fragoso MC, Reincke M, Stratakis CA, Ragazzon B, Bertherat J. Primary bilateral macronodular adrenal hyperplasia: definitely a genetic disease. Nat Rev Endocrinol. 2022 Nov;18(11):699-711. doi: 10.1038/s41574-022-00718-y. Epub 2022 Aug 3.
  3. Bouys L, Chiodini I, Arlt W, Reincke M, Bertherat J. Update on primary bilateral macronodular adrenal hyperplasia (PBMAH). Endocrine. 2021 Mar;71(3):595-603. doi: 10.1007/s12020-021-02645-w. Epub 2021 Feb 15. PMID: 33587256.