Patients with primary bilateral macronodular adrenal hyperplasia, recently reclassified as bilateral macronodular adrenal disease (BMAD) have bilateral benign large adrenocortical nodules and variable cortisol excess. BMAD is considered a rare cause of overt Cushing's syndrome but a more frequent cause of bilateral adrenal incidentalomas. Initially considered a sporadic disease, the bilateral nature of the adrenal nodules and familial aggregation suggested a genetic origin. Indeed, genomic studies have improved our understanding of BMAD pathogenesis and identified several genetic events responsible for BMAD. As rare syndromic presentations were described, non-syndromic etiologies were also identified, suggesting distinct molecular backgrounds among BMAD cases. Firstly, germline heterozygous inactivating mutations of the ARMC5 gene, discovered in 2013, are now known to account for around 20-25% of sporadic cases and most familial cases. A second molecular group was later identified, characterized by germline heterozygous pathogenic variants and loss of heterozygosity of the lysine demethylase 1A gene (KDM1A, or LSD1) in familial and sporadic GIP-dependent BMAD, representing less than 5% of BMAD cases. Similarly to ARMC5, the stepwise inactivation of KDM1A, an epigenetic regulator gene, supports a tumor suppressor model of tumorigenesis. The latter, more heterogeneous, molecular group remains globally unelucidated, with the exception of reports of pathogenic variants in genes involved in the PKA and cAMP signaling pathways. In all cases, genetic counseling should be offered to identify affected members and to screen for BMAD.

Primary bilateral macronodular adrenocortical disease is an uncommon adrenal disorder characterized by bilateral adrenal enlargement with multiple nodules and autonomous steroid hormone production. Although genetic alterations involving ARMC5 have been implicated in its development, individual nodules within the same adrenal gland often show considerable variability in size, morphology, and hormonal activity, and detailed genetic evaluation of each nodule has rarely been performed. We report the case of a 58-year-old man with a long-standing history of hypertension who was found to have bilateral adrenal nodules on imaging studies. Endocrinological evaluation revealed primary aldosteronism with lateralized aldosterone secretion from the left adrenal gland, along with autonomous cortisol secretion from both adrenal glands. The patient underwent laparoscopic left adrenalectomy. Gross and histopathological examination demonstrated multiple macronodular lesions without evidence of malignancy. Genetic analyses conducted separately on individual nodules identified different ARMC5 mutations in each nodule examined, indicating intraglandular genetic heterogeneity. This case illustrates that distinct adrenal nodules within primary bilateral macronodular adrenal disease can arise from genetically independent clonal events. The concomitant presence of cortisol and aldosterone overproduction further underscores the functional diversity of this condition. Careful histopathological sampling combined with nodule-specific molecular analysis may provide important insights into the pathogenesis and biological heterogeneity of this disease.

Bilateral macronodular adrenocortical disease (BMAD) is a rare disorder characterized by bilateral adrenocortical nodules and variable cortisol excess. ARMC5 is a well-established genetic driver of BMAD, but data in East Asian populations are limited. We investigated the prevalence of pathogenic variants and genotype-phenotype correlations in Korean patients with BMAD. A total of 69 patients with BMAD were retrospectively enrolled at Seoul National University Hospital (2009-2023). Whole-exome sequencing was performed for 35 patients. Clinical, biochemical, and imaging data were analyzed. Serum steroid profiling was conducted using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify 18 adrenal-derived steroids. The mean age of the cohort was 66.4 years, and 58% were male. Most had mild autonomous cortisol secretion (79.7%), and 15.9% had overt Cushing syndrome. Among the 35 patients who underwent genetic testing, 22.9% harbored pathogenic/likely pathogenic (P/LP) variants in ARMC5. P/LP ARMC5 variant carriers had lower BMI (25.0 vs 27.4 kg/m2), larger maximal tumor diameter (4.1 vs 2.7 cm), and greater total adrenal volume (19.8 vs 15.3 cm3). LC-MS/MS profiling revealed that P/LP ARMC5 carriers had significantly higher cortisol (153.1 vs 100.6 ng/mL), corticosterone (16.5 vs 1.3 ng/mL), and 18-hydroxycortisol concentrations (1.66 vs .66 ng/mL) (P < .05). This study in a Korean cohort with BMAD showed that P/LP ARMC5 variants were present in 22.9% of the genetically investigated patients and were associated with more severe radiological and steroidogenic features. These findings underscore the importance of closely monitoring patients with BMAD who carry ARMC5 P/LP variants.

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.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare genetic disease mainly associated with Carney complex (CNC), which is caused by germline mutations of the regulatory subunit type I-alpha of the cAMP-dependent protein kinase (PRKAR1A) gene. We report three cases suffering from CNC with unique features in diagnosis and follow-up. All cases had obesity and a cushingoid appearance and exhibited laboratory characteristics of hypercortisolism. However biochemical and radiological examinations initially suggested Cushing’s disease in one case. All of the cases were treated surgically; two of them underwent bilateral adrenalectomy at once, one of them had unilateral adrenalectomy at first but required contralateral adrenalectomy after nine months. Contrary to what is usually known regarding PPNAD, the adrenal glands of two cases (Case 2 and 3) had a macronodular morphology. Genetic analyses revealed pathogenic variants in PRKAR1A (Case 1: c.440+5 G>A, not reported in the literature; cases 2 and 3: c.349G>T, p.V117F). One case developed Hodgkin lymphoma five year after adrenalectomy, this association was not previously reported with CNC. The findings of these families provides important information for a better understanding of the genetic pathogenesis, diagnosis, and clinical management of CNC. Hodgkin lymphoma may be a component of CNC.