{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T23:32:42Z","timestamp":1772580762490,"version":"3.50.1"},"reference-count":24,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Primary aldosteronism is most often caused by aldosterone-producing adenoma (APA) and bi-lateral adrenal hyperplasia. Most APAs are caused by somatic mutations of various ion channels and pumps, the most common being the inward-rectifying potassium channel KCNJ5. Germ line mutations of KCNJ5 cause familial hyperaldosteronism type 3 (FH3), which is associated with severe hyperaldosteronism and hypertension. We present an unusual case of FH3 in a young woman, first diagnosed with primary aldosteronism at the age of 6 years, with bilateral adrenal hyperplasia, who underwent unilateral adrenalectomy (left adrenal) to alleviate hyperaldosteronism. However, her hyperaldosteronism persisted. At the age of 26 years, tomography of the remaining adrenal revealed two different adrenal tumors, one of which grew substantially in 4 months; therefore, the adrenal gland was removed. A comprehensive histological, immunohistochemical, and molecular evaluation of various sections of the adrenal gland and in situ visualization of aldosterone, using matrix-assisted laser desorption\/ionization imaging mass spectrometry, was performed. Aldosterone synthase (CYP11B2) immunoreactivity was observed in the tumors and adrenal gland. The larger tumor also harbored a somatic \u03b2-catenin activating mutation. Aldosterone visualized in situ was only found in the subcapsular regions of the adrenal and not in the tumors. Collectively, this case of FH3 presented unusual tumor development and histological\/molecular findings.<\/jats:p>","DOI":"10.3390\/cimb44010010","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T02:31:27Z","timestamp":1640745087000},"page":"128-138","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Familial Hyperaldosteronism Type 3 with a Rapidly Growing Adrenal Tumor: An In Situ Aldosterone Imaging Study"],"prefix":"10.3390","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6469-7546","authenticated-orcid":false,"given":"Nae","family":"Takizawa","sequence":"first","affiliation":[{"name":"Department of Urology and Andrology, Kansai Medical University, Osaka 573-1191, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4804-7839","authenticated-orcid":false,"given":"Susumu","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Kansai Medical University, Osaka 573-1191, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koshiro","family":"Nishimoto","sequence":"additional","affiliation":[{"name":"Department of Uro-Oncology, Saitama Medical University, International Medical Center 1397-1 Yamane, Hidaka 350-1298, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Sugiura","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, School of Medicine, Keio University, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Suematsu","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, School of Medicine, Keio University, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chisato","family":"Ohe","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kansai Medical University, Osaka 573-1191, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruyuki","family":"Ohsugi","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, Kansai Medical University, Osaka 573-1191, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosuke","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, Division of Morphological Science, Saitama Medical University, Saitama 350-0495, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9590-5077","authenticated-orcid":false,"given":"Kuniaki","family":"Mukai","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, School of Medicine, Keio University, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsugio","family":"Seki","sequence":"additional","affiliation":[{"name":"Department of Medical Education, California University of Science and Medicine, Colton, CA 92324, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9225-8193","authenticated-orcid":false,"given":"Kenji","family":"Oki","sequence":"additional","affiliation":[{"name":"Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celso E.","family":"Gomez-Sanchez","sequence":"additional","affiliation":[{"name":"Medical Service, G.V. (Sonny) Montgomery VA Medical Center, Department of Pharmacology and Toxicology, Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadashi","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, Kansai Medical University, Osaka 573-1191, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1126\/science.1198785","article-title":"K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension","volume":"331","author":"Choi","year":"2011","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1055\/a-0713-0629","article-title":"Inherited Forms of Primary Hyperaldosteronism: New Genes, New Phenotypes and Proposition of a New Classification","volume":"127","author":"Williams","year":"2019","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1093\/ajh\/hpz172","article-title":"Mosaicism for KCNJ5 causing early-onset primary aldosteronism due to bilateral adrenocortical hyperplasia","volume":"33","author":"Maria","year":"2020","journal-title":"Am. J. Hypertens."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.mce.2016.07.031","article-title":"Somatic KCNJ5 mutation occurring early in adrenal development may cause a novel form of juvenile primary aldosteronism","volume":"441","author":"Tamura","year":"2017","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.1210\/jc.2009-2010","article-title":"Adrenocortical zonation in humans under normal and pathological conditions","volume":"95","author":"Nishimoto","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7834356","DOI":"10.1155\/2016\/7834356","article-title":"Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation","volume":"2016","author":"Nishimoto","year":"2016","journal-title":"Int. J. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"E4591","DOI":"10.1073\/pnas.1505529112","article-title":"Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands","volume":"112","author":"Nishimoto","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.mce.2016.10.025","article-title":"Disordered zonal and cellular CYP11B2 enzyme expression in familial hyperaldosteronism type 3","volume":"439","author":"Qi","year":"2017","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1161\/HYPERTENSIONAHA.118.11243","article-title":"Aldosterone and 18-Oxocortisol Coaccumulation in Aldosterone-Producing Lesions","volume":"72","author":"Sugiura","year":"2018","journal-title":"Hypertension"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1111\/j.1651-2227.2005.tb02098.x","article-title":"Long-term follow-up of a girl with primary aldosteronism: Effect of potassium supplement","volume":"94","author":"Takaya","year":"2005","journal-title":"Acta Paediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1210\/jc.2015-3285","article-title":"Case Report: Nodule Development from Subcapsular Aldosterone-Producing Cell Clusters Causes Hyperaldosteronism","volume":"101","author":"Nishimoto","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/jhg.2016.12","article-title":"Human genetic variation database, a reference database of genetic variations in the Japanese population","volume":"61","author":"Higasa","year":"2016","journal-title":"J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1210\/er.2013-1029","article-title":"Adrenocortical carcinoma","volume":"35","author":"Else","year":"2014","journal-title":"Endocr. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.mce.2015.09.011","article-title":"Potassium channels related to primary aldosteronism: Expression similarities and differences between human and rat adrenals","volume":"417","author":"Chen","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s00428-017-2283-z","article-title":"Correction to: Ki67 labeling index: Assessment and prognostic role in gastroenteropancreatic neuroendocrine neoplasms","volume":"472","year":"2018","journal-title":"Virchows Arch. Int. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1093\/hmg\/ddq029","article-title":"Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development","volume":"19","author":"Berthon","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1210\/jc.2008-0594","article-title":"A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism","volume":"93","author":"Geller","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1073\/pnas.1121407109","article-title":"Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5","volume":"109","author":"Scholl","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1001\/archinte.1996.00440100086010","article-title":"Prevalence of adrenal and extra-adrenal Conn syndrome in hypertensive patients","volume":"156","author":"Abdelhamid","year":"1996","journal-title":"Arch. Intern. Med."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/44\/1\/10\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:54:53Z","timestamp":1760169293000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/44\/1\/10"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,28]]},"references-count":24,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["cimb44010010"],"URL":"https:\/\/doi.org\/10.3390\/cimb44010010","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,28]]}}}