Endocrine Abstracts

Introduction: Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) represents <2% of all causes of Cushing’s Syndrome (CS). Clinical course is insidious, with adrenal bilateral macronodules and gradual cortisol excess, only rarely presenting with overt CS. The pathophysiology remains unclear in most cases; however, pathogenic variants in the onco-supressor ARMC5 gene are described in 25-50% of PBMAH and may confer a more severe clinical course.

Objectives: To report a new germline variant in the ARMC5 gene associated with PBMAH.

Case Report: A 34-year-old woman presented with exuberant CS phenotype including progressive weight gain, facial hair growth, plethoric face, dorsocervical and supraclavicular fat pads and easy bruising. She had been diagnosed with prediabetes and hypertension. Serum morning cortisol was 46.1 µg/dl (N: 6.2-18) and ACTH was <1 pg/ml. Morning cortisol after 1 mg overnight dexamethasone suppression test was 37.9 µg/dl, 24 h urinary cortisol was 6825 µg/24 h (N:124-581), while salivary cortisol kept circadian rhythm. Androgen and mineralocorticoid hypersecretion were excluded. Androgen and mineralocorticoid hypersecretion were excluded. Adrenal CT scan documented evident bilateral adrenal enlargement with multiple hypodense macronodules that reached a maximum diameter of 67 mm and 49 mm. No aberrant receptors were identified following a stimulation tests protocol. The patient showed good biochemical response to metyrapone and was submitted to unilateral adrenalectomy of the largest adrenal gland. Histopathologic evaluation revealed adrenal cortex macronodular hyperplasia, compatible with the diagnosis of PBMAH. There was an evident clinical response after surgery, with improved well-being, CS phenotype regression and weight loss. Additionally biochemical response with normalization of cortisol levels was achieved. One year after surgery, hydrocortisone replacement was resumed. Given the clinical diagnosis, a Next Generation Sequencing (NGS) panel including the ARMC5 and KDM1A genes was performed, and identified a novel germline variant in heterozygosity in the ARMC5 gene, c.169G>T p. (Gly57), leading to a premature stop codon. This new variant is classified as likely pathogenic. The recurrence risk for offspring is 50%.

Discussion and Conclusions: We report a case of PBMAH with a new germline variant in the ARMC5 gene, c.169G>T p.(Gly57), diagnosed due to overt CS and successfully treated with unilateral adrenalectomy. Genetic assessment of patients with PBMAH and family members may allow an early diagnosis of CS, minimize complications, and contribute to a better management and follow-up of PBMAH patients.