A Global Approach to the Long-Term Follow-Up of 17 Families With Bilateral Macronodular Adrenal Disease.

Abstract

Bilateral macronodular adrenocortical disease (BMAD) is a rare and often underdiagnosed cause of adrenal Cushing syndrome (CS), with manifestations ranging from mild autonomous cortisol secretion (MACS) to overt CS. ARMC5 and KDM1A are the most frequently implicated genes in familial BMAD; however, long-term follow-up data on affected patients remain limited. This retrospective study assessed the clinical and hormonal variability, genetic profiles, treatment approaches, and outcomes of 17 familial and 9 sporadic BMAD cases over a follow-up period ranging from 8 to 410 months at a Brazilian tertiary center. A total of 250 individuals (50 index cases and 200 relatives) were included. Clinical, hormonal, and imaging data, along with histological and genetic analyses of ARMC5 and KDM1A, were evaluated. Among 250 individuals, 104 (26 index and 78 relatives) carried germline pathogenic/likely pathogenic ARMC5 variants. No KDM1A (likely) pathogenic variants were identified in ARMC5-wild-type patients. ARMC5-positive index cases exhibited severe clinical manifestations, evidenced by elevated cortisol levels (urinary, salivary, and post-dexamethasone suppression test) and reduced ACTH and DHEAS levels (P = .005, P = .042, P = .005, P = .041, and P = .007, respectively). Index cases had larger adrenal nodules (P < .0001). Adrenal-sparing surgery achieved 100% remission vs a 40% remission rate for unilateral adrenalectomy. Central nervous system meningiomas were observed in BMAD patients independent of ARMC5 status. Interestingly, malignant neoplasms were notably prevalent among ARMC5-altered individuals. The proposed management flowchart highlights the importance of genetic screening and continuous monitoring to mitigate the adrenal insufficiency, MACS recurrence, and tumor risk, while underscoring the need for tailored therapeutic strategies in BMAD, adapted to genetic alterations and ARMC5 status.