Genetic Characterization of GnRH/LH-Responsive Primary Aldosteronism

Abstract Background Recently, somatic β-catenin mutations (CTNNB1) identified in aldosterone-producing adenomas (APAs) from three women were suggested to be responsible for the aberrant overexpression of luteinizing hormone/choriogonadotropin receptor and gonadotropin-releasing hormone receptor in the APA. Objective To genetically characterize patients with primary aldosteronism (PA) evaluated in vivo for gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH)-responsive aldosterone secretion. Method Patients with PA were evaluated in vivo to determine the possible regulation of aldosterone secretion by GnRH or LH. Genetic analysis of the CTNNB1, KCNJ5, ATP1A1, ATP2B3, CACNA1D, and GNAS genes were performed in this cohort and a control cohort of PA not tested in vivo for GnRH response. Results We studied 50 patients with confirmed PA, including 36 APAs, 12 bilateral macronodular adrenal hyperplasias, 1 oncocytoma, and 1 bilateral hyperplasia with cosecretion of cortisol. Among 23 patients tested in vivo for GnRH response of aldosterone, 7 (30.4%) had a positive response, 4 (17.4%) a partial response, and 12 (52.2%) no response. No somatic CTNNB1 mutations were identified, but the disease-causing c.451G>C KCNJ5 mutation was found in two individuals with partial and no GnRH responses and an individual showing a positive response to LH. Two additional somatic pathogenic mutations, CACNA1D c.776T>A and ATP1A1 c.311T>G, were identified in two patients with no GnRH responses. In the 26 patients not tested for GnRH response, we identified 2 CTNNB1 (7.7%), 13 KCNJ5 (50%), and 1 CACNA1D (3.8%) mutations. Conclusion Aberrant regulation of aldosterone by GnRH is frequent in PA, but is not often associated with somatic CTNNB1, although it may be found with somatic KCNJ5 mutations. We studied the prevalence of somatic CTNNB1, KCNJ5, ATP1A1, ATP2B3, CACNA1D, and GNAS mutations in a cohort of patients with PA characterized in vivo for GnRH/LH-responsive aldosterone secretion.