OBJECTIVE: Aldosterone-producing adenoma (APA) is a common curable cause of hypertension. Somatic mutations in five genes (KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1) have been found to cause the excess aldosterone production of two thirds of APAs [1-4]. KCNJ5 mutant APAs, the most common and largest, had explicit genotype-phenotype relationship - a low protein expression of KCNJ5 relative to their peritumoural zona glomerulosa (ZG) and a zona fasciculata-like composition [5-6]. Conversely for the other genes, controversy arises on whether they have the opposite cell phenotype [4,7-8]. This prospective study aim to to characterize the histopathological-specific mutation spectrum of APAs. DESIGN AND METHOD: Targeted sequencing of 'hotspots' for mutations associated with primary aldosteronism were performed on all APAs. Diagnosis of APA was confirmed through CYP11B2 expression as measured by immunohistochemistry. Immunohistochemical staining using KCNJ5 as a ZG cell marker and CYP17A1 as a ZF cell marker was used to characterize the APAs in addition to hematoxylin and eosin staining. The relationship between genotype and phenotype was then compared. RESULTS: APAs with intense staining of KCNJ5 frequently had a mutation in ATP1A1 or CACNA1D. APAs with intense staining of CYP17A1 frequently had a mutation in KCNJ5. In addition to previously reported mutations, a new causal mutation in exon 28 of CACNA1D was identified. CONCLUSIONS: ATP1A1 and CACNA1D mutant APAs comprise of ZG-like cell composition with intense staining of KCNJ5 whereas KCNJ5 mutant APAs comprise of ZF-like cell composition with intense staining of CYP17A1. As ZG-like APAs have been reported to be small [4], diagnosis of an APA in these patients could be made easier through identification of the causal mutation through genotyping the free-circulating ZG-like APA DNA pre-adrenalectomy.

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