Bilateral macronodular and micronodular hyperplasia: Biochemical, radiological and genetic diagnosis.

Abstract

Adrenal-origin Cushing's syndrome (CS) accounts for up to 30 percent of cases, with approximately 10 percent attributable to bilateral adrenal disease. The fifth edition of the WHO classification has redefined the terminology previously referred to as bilateral macronodular and micronodular hyperplasia, now recognising these lesions as independent neoplastic entities and grouping them under the broader concept of "adrenal cortical nodular disease", which includes macronodular (BMACD) and micronodular (miBACD) forms. BMACD is predominantly diagnosed in adults over 50 years of age, typically presenting as an adrenal incidentaloma, although its true prevalence is likely underestimated. In contrast, miBACD presents earlier in life, with a female predominance in primary pigmented nodular adrenocortical disease (PPNAD) and constitutes an infrequent but important cause of ACTH-independent CS, particularly in paediatric and young adult populations. Both entities share a pathogenic mechanism driven by constitutive activation of the cAMP/PKA pathway, although their genetic backgrounds differ. ARMC5 is the most frequently implicated gene in BMACD (up to 80 percent of familial cases), whereas PRKAR1A mutations predominate in miBACD associated with Carney complex. PDE11A and PDE8B may act as modifier genes, particularly in iMAD. Clinical presentation ranges from autonomous cortisol secretion (ACS) to overt CS, with BMACD showing a progressive course and miBACD demonstrating greater variability, including cyclic CS. Diagnosis requires integration of biochemical, imaging and, when indicated, genetic assessments. Early recognition is crucial due to phenotypic heterogeneity and potential association with hereditary syndromes.