T Dekkers1, M ter Meer, J W M Lenders, A R M Hermus, L Schultze Kool, J F Langenhuijsen, K Nishimoto, T Ogishima, K Mukai, E A B Azizan, B Tops, J Deinum, B Küsters. 1. Departments of Internal Medicine (T.D., J.W.M.L., J.D.), Pathology (M.t.M., B.T., B.K.), Endocrinology (A.R.M.H.), Radiology (L.S.K.), and Urology (J.F.L.), Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Departments of Urology (K.N.) and Biochemistry (K.M.), School of Medicine, Keio University, Tokyo 160-8582, Japan; Department of Chemistry (T.O.), Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan; Clinical Pharmacology Unit (E.A.B.A.), Department of Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, Cambridge DB2 2OO, United Kingdom; and Department of Pathology (B.K.), Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands.
Abstract
CONTEXT: Somatic mutations in genes that influence cell entry of calcium have been identified in aldosterone-producing adenomas (APAs) of adrenal cortex in primary aldosteronism (PA). Many adrenal glands removed for suspicion of APA do not contain a single adenoma but nodular hyperplasia. OBJECTIVE: The objective of the study was to assess multinodularity and phenotypic and genotypic characteristics of adrenals removed because of the suspicion of APAs. DESIGN AND METHODS: We assessed the adrenals of 53 PA patients for histopathological characteristics and immunohistochemistry for aldosterone (P450C18) and cortisol (P450C11) synthesis and for KCNJ5, ATP1A1, ATP2B3, and CACNA1D mutations in microdissected nodi. RESULTS: Glands contained a solitary adenoma in 43% and nodular hyperplasia in 53% of cases. Most adrenal glands contained only one nodule positive for P450C18 expression, with all other nodules negative. KCNJ5 mutations were present in 22 of 53 adrenals (13 adenoma and nine multinodular adrenals). An ATP1A1 and a CACNA1D mutation were found in one multinodular gland each and an ATP2B3 mutation in five APA-containing glands. Mutations were always located in the P450C18-positive nodule. In one gland two nodules containing two different KCNJ5 mutations were present. Zona fasciculata-like cells were more typical for KCNJ5 mutation-containing nodules and zona glomerulosa-like cells for the other three genes. CONCLUSIONS: Somatic mutations in KCNJ5, ATP1A1, or CACNA1D genes are not limited to APAs but are also found in the more frequent multinodular adrenals. In multinodular glands, only one nodule harbors a mutation. This suggests that the occurrence of a mutation and nodule formation are independent processes. The implications for clinical management remain to be determined.
CONTEXT: Somatic mutations in genes that influence cell entry of calcium have been identified in aldosterone-producing adenomas (APAs) of adrenal cortex in primary aldosteronism (PA). Many adrenal glands removed for suspicion of APA do not contain a single adenoma but nodular hyperplasia. OBJECTIVE: The objective of the study was to assess multinodularity and phenotypic and genotypic characteristics of adrenals removed because of the suspicion of APAs. DESIGN AND METHODS: We assessed the adrenals of 53 PA patients for histopathological characteristics and immunohistochemistry for aldosterone (P450C18) and cortisol (P450C11) synthesis and for KCNJ5, ATP1A1, ATP2B3, and CACNA1D mutations in microdissected nodi. RESULTS: Glands contained a solitary adenoma in 43% and nodular hyperplasia in 53% of cases. Most adrenal glands contained only one nodule positive for P450C18 expression, with all other nodules negative. KCNJ5 mutations were present in 22 of 53 adrenals (13 adenoma and nine multinodular adrenals). An ATP1A1 and a CACNA1D mutation were found in one multinodular gland each and an ATP2B3 mutation in five APA-containing glands. Mutations were always located in the P450C18-positive nodule. In one gland two nodules containing two different KCNJ5 mutations were present. Zona fasciculata-like cells were more typical for KCNJ5 mutation-containing nodules and zona glomerulosa-like cells for the other three genes. CONCLUSIONS: Somatic mutations in KCNJ5, ATP1A1, or CACNA1D genes are not limited to APAs but are also found in the more frequent multinodular adrenals. In multinodular glands, only one nodule harbors a mutation. This suggests that the occurrence of a mutation and nodule formation are independent processes. The implications for clinical management remain to be determined.
Authors: Yuhong Yang; Celso E Gomez-Sanchez; Diana Jaquin; Elke Tatjana Aristizabal Prada; Lucie S Meyer; Thomas Knösel; Holger Schneider; Felix Beuschlein; Martin Reincke; Tracy Ann Williams Journal: Hypertension Date: 2019-08-26 Impact factor: 10.190
Authors: Kazutaka Nanba; Kei Omata; Celso E Gomez-Sanchez; Constantine A Stratakis; Andrew P Demidowich; Mari Suzuki; Lester D R Thompson; Debbie L Cohen; James M Luther; Lan Gellert; Anand Vaidya; Justine A Barletta; Tobias Else; Thomas J Giordano; Scott A Tomlins; William E Rainey Journal: Hypertension Date: 2019-04 Impact factor: 10.190
Authors: Teresa M Seccia; Brasilina Caroccia; Elise P Gomez-Sanchez; Paul-Emmanuel Vanderriele; Celso E Gomez-Sanchez; Gian Paolo Rossi Journal: Hypertension Date: 2017-09-25 Impact factor: 10.190