SUN-241 Comparison of Aldosterone-Producing Adenomas Harboring ATP1A1 and ATP2B3 Aldosterone-Driver Mutations

Abstract Disclosure: Y. Liu: None. C. Lee: None. D. Van Rooyen: None. J. Rege: None. P. Vibhatavata: None. A. Udager: None. W.E. Rainey: None. A. Turcu: None. Background: Over 90% of aldosterone-producing adenomas (APAs) harbor somatic mutations in genes with impact on aldosterone synthesis. These mutations facilitate inappropriate intracellular Ca2+ entrance, which subsequently boosts aldosterone production. Detailed histopathological studies of APAs have shown morphologic and enzymatic heterogeneity across genotypes, which translate into differences in phenotype and steroidogenic potential. Steroid profiling of peripheral blood could serve as a non-invasive method for primary aldosteronism subtyping, and they might offer pre-operative prognostic value. The most prevalent aldosterone-driver mutations are found in KCNJ5 (encodes the potassium channel Kir3.4) and CACNA1D (encodes the voltage-dependent L-type Ca2+ channel subunit 1D). In contrast, mutations in ATP1A1 and ATP2B3, which encode for the Na+/K+ ATPase α-1 subunit and a Ca2+ ATPase 3, respectively, are relatively rare, and because of their lower prevalence, previous studies have clustered these as ATPase mutations. Objective: To compare the clinical phenotype and steroid profiles of patients with APAs harboring ATP1A1 and ATP2B3 mutations. Methods: The study included patients with primary aldosteronism who: 1) underwent adrenal vein sampling-guided adrenalectomy, and 2) were identified to harbor APAs with pathogenic variants in ATP1A1 and ATP2B3 (based on aldosterone synthase immunohistochemistry-guided next-generation sequencing). Clinical data were collected from medical records. Liquid chromatography-tandem mass spectrometry was used to quantify 17 steroids in peripheral and adrenal vein blood, both before and after cosyntropin stimulation. Results: We identified 59 patients with APAs harboring ATPase mutations, including 47 in ATP1A1 and 12 in ATP2B3. Age, sex, and race distribution was similar between the two groups. The groups also displayed similar BMI, blood pressure, aldosterone concentrations, and tumor size. Patients with ATP2B3 mutations had more dramatic lateralization on adrenal vein sampling, both at baseline (lateralization index, LI: 36.8 vs. 8.6, p=0.01) and after cosyntropin stimulation (LI: 32.7 vs. 10.2, p=0.003). Serum for steroid profiling was available in 19 patients with ATP1A1 and 6 patients with ATP2B3. The latter group showed higher concentrations of 18-oxocortisol, aldosterone, and several other steroids. Adrenal vein sampling-guided adrenalectomy led to biochemical cure in all patients with ATP2B3 mutations, but only 74% of those with ATP1A1 mutations. Conclusion: APAs harboring ATP1A1 and ATP2B3 mutations share similarities in demographic distribution and phenotype, but those with ATP2B3 mutations tend to have higher hormonal activity, more profound lateralization, and higher likelihood of post-operative biochemical cure. Presentation: Sunday, July 13, 2025