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Cardiovascular Endocrinology

SAT-274 - Somatic Mutations Vary with Adrenal Lesion Size and Patient Sex in Black Americans with Primary Aldosteronism

Saturday, June 13, 2026
9:30 AM - 4:30 PM CT


Background: Primary aldosteronism (PA), characterized by renin-independent aldosterone production, is the most common cause of secondary hypertension. Excess aldosterone originates from aldosterone synthase (CYP11B2)-expressing adrenal lesions that harbor somatic mutations in genes encoding ion pumps, transporters or channels—most commonly KCNJ5, CACNA1D and ATP1A1. The prevalence of these mutations varies based on sex and race. Black Americans with PA may be particularly sensitive to excess aldosterone, however prevalence studies in this at-risk population are limited. Here, we considered the impact of adrenal lesion size and patient sex on the aldosterone-driver somatic mutations in Black Americans with PA.

Methods: This study included 166 Black Americans with PA who underwent an adrenalectomy for lateralized disease. We used FFPE adrenal tissue sections for CYP11B2 IHC and H&E. CYP11B2 positive lesions were categorized according to the HISTALDO criteria as: aldosterone-producing adenomas (APA, ≥10 mm), aldosterone-producing nodules (APN, < 10 mm, visible with H&E), or subcapsular aldosterone-producing micronodules (APM, < 10 mm, H&E-indistinct). Genomic DNA from CYP11B2-expressing regions was assessed for known aldosterone-driver gene mutations by Sanger and/or targeted next-generation sequencing. Additionally, we compared the transcriptomic profiles of APA and/or APN harboring KCNJ5 (n=8) and CACNA1D (n=10).

Results: Aldosterone-producing lesions identified in 145 Black American patients included 60 APA, 89 APN, and 65 APM. Most APN (67%) harbored CACNA1D mutations, while most APA (67%) harbored KCNJ5 mutations. APN were the most common lesions in men (68%), while APA were most prevalent in women (68%). Within APA, KCNJ5 mutations were most common in women (83%), whereas KCNJ5 and ATP1A1 were equally prevalent in APA from men (31% each). Conversely, in APN, there was no sex difference in mutation distribution. The transcriptomes of mutant KCNJ5 and CACNA1D-bearing lesions showed significant differences: genes associated with the zona glomerulosa were upregulated in mutant CACNA1D lesions, whereas lesions harboring KCNJ5 mutations displayed increased expression of zona fasciculata-related genes.

Conclusion: The distribution of aldosterone-driver somatic mutations in Black American patients with PA varies with adrenal lesion size and patient sex. The most common aldosterone-producing lesion identified in this Black American cohort was CACNA1D-bearing APN. APA, but not APN, exhibited a sexually dimorphic pattern, with mutant KCNJ5 predominating in women. Distinct transcriptional programs in adrenal lesions with KCNJ5 or CACNA1D mutations indicate mutation-specific molecular lesion phenotypes. These findings suggest that adrenal histopathology should be considered in subtyping and genotype-directed therapeutic strategies for PA.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*