Abstract-Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, nϭ380) and peripheral (APA, nϭ344; bilateral adrenal hyperplasia, nϭ174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; PϽ10 Ϫ3) and in younger patients (42.1Ϯ1.0 versus 47.6Ϯ0.7 years; PϽ10 Ϫ3 ) and were associated with higher preoperative aldosterone levels (455Ϯ26 versus 376Ϯ17 ng/L; Pϭ0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism. H ypertension is a major cardiovascular risk factor that affects between 10% and 40% of the population in industrialized countries. Detection of secondary forms of hypertension is particularly important because it allows for the targeted management of the underlying disease. Primary aldosteronism (PA) is the most common form of secondary hypertension, with an estimated prevalence between 6% and 12% of hypertensives and as high as 20% in patients with resistant hypertension. 1-5 PA occurs as the result of a dysregulation of the mechanisms controlling adrenal aldosterone production, ultimately leading to hypertension with low plasma renin and elevated aldosterone sometimes associated with hypokalemia. Among subtypes of PA, aldosteroneproducing adenoma (APA) and bilateral adrenal hyperplasia (BAH; also known as idiopathic hyperaldosteronism) together account for Ϸ95% of cases. [1][2][3] Aldosterone production from the adrenal zona glomerulosa is tightly controlled to maintain electrolyte and fluid homeostasis by the kidney. Thus, the two most important physiological stimuli of aldosterone secretion are angiotensin II and serum potassium. Glomerulosa cell membrane depolarization leads to openi...

Abstract-Primary aldosteronism is the most common form of secondary hypertension with hypokalemia and suppressed renin-angiotensin system caused by autonomous aldosterone production. Our aim was to compare zona glomerulosa (ZG) structure and function between control adrenals and the peritumoral tissue from patients operated on for aldosterone-producing adenoma. ZG morphology and CYP11B1, CYP11B2, and disabled 2 expression were studied in 15 control adrenals and 25 adrenals with aldosterone-producing adenoma. A transcriptome analysis was done using publicly available data sets. In control adrenals, ZG was discontinuous, and CYP11B2 expression was focal or partly continuous and localized to 3 structures, foci, megafoci, and aldosterone-producing cell clusters. CYP11B2 expression was restricted to a limited number of ZG cells expressing Dab2 but not CYP11B1; aldosterone-producing cell clusters were composed of cells with an intermediate phenotype expressing CYP11B2 but not disabled 2 or CYP11B1. In peritumoral tissue, large remodeling of the adrenal cortex was observed with increased nodulation and decreased vascularization that were not correlated with CYP11B2 expression. In 17 out of 25 adrenals, hyperplasia of adjacent ZG was observed with persistent expression of CYP11B2 that was extended to the entire ZG. In all of the adrenals from patients with aldosterone-producing adenoma, CYP11B2 expression was present in foci, megafoci, and aldosteroneproducing cell clusters. Transcriptome profiling indicates a close relationship between peritumoral and control adrenal cortex. In conclusion, adrenal cortex remodeling, reduced vascularization, and ZG hyperplasia are major features of adrenals with aldosterone-producing adenoma. Transcriptional phenotyping is not in favor of this being an intermediate step toward the formation of aldosterone-producing adenoma. (Hypertension. 2010;56:885-892.)Key Words: zona glomerulosa hyperplasia Ⅲ aldosterone-producing adenoma Ⅲ secondary hypertension Ⅲ adrenal cortex remodeling Ⅲ aldosterone Ⅲ potassium Ⅲ transcriptome P rimary aldosteronism (PAL) is the most common form of endocrine hypertension with a prevalence of 7% to 10% of hypertensive patients. 1 In PAL, autonomous production of aldosterone is associated with suppressed renin activity, hypokalemia, and hypertension. The two principal forms are unilateral aldosterone-producing adenoma (APA), a benign tumor of the adrenal cortex, and bilateral adrenal hyperplasia, also known as idiopathic hyperaldosteronism. Whereas in APA the adjacent zona glomerulosa (ZG) is believed to be nonfunctional because of negative feedback regulation, bilateral adrenal hyperplasia involves the entire ZG of both adrenal glands. 2 Patients with PAL operated on the basis of an APA, and/or a lateralized aldosterone hypersecretion can be cured by unilateral adrenalectomy. However, only Ϸ70% of patients with lateralized aldosterone secretion are cured by surgery, 3 suggesting that, in some cases, residual aldosterone secretion from the contralateral adrenal g...