{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:09:10Z","timestamp":1790255350270,"version":"4.1.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The concurrent presence of primary aldosteronism (PA) and mild autonomous cortisol secretion (MACS) caused by adrenal lesions of a solitary cortisol-producing adenoma, accompanied by multiple aldosterone-producing micronodules (MAPM), is exceptionally rare. Moreover, there is a notable paucity of data regarding the molecular pathogenesis of this disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      We report a unique case of a somatic\n                      <jats:italic>GNAS<\/jats:italic>\n                      \/\n                      <jats:italic>CACNA1D<\/jats:italic>\n                      -mutant cortisol-producing adenoma accompanied by MAPM and an aldosterone-producing nodule (APN) in the adjacent adrenal cortex. The patient was a 63-year-old woman with a 25-year history of hypertension and had a mass in the right adrenal gland. Detailed endocrine examinations revealed the concomitant occurrence of PA and MACS. Histologically, the main tumor was a well-circumscribed, encapsulated mass composed of neoplastic cells arranged in trabecular and nested patterns, exhibiting eosinophilic to vacuolated cytoplasm with uniformly round nuclei. Adjacent to the main tumor, a histologically similar 0.4\u2005cm cortical nodule rich in clear cells was observed. Immunohistochemical analysis revealed diffuse CYP11B1 staining in the main tumor, whereas adjacent scattered cortical cell clusters and nodules exhibited distinctively diffuse CYP11B2 positivity. Next-generation sequencing results revealed missense mutations in the\n                      <jats:italic>GNAS<\/jats:italic>\n                      (p.R201H) and\n                      <jats:italic>CACNA1D<\/jats:italic>\n                      genes (p.F1131L).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our molecular findings from bulk tissue analysis identified somatic mutations in the\n                      <jats:italic>GNAS<\/jats:italic>\n                      and\n                      <jats:italic>CACNA1D<\/jats:italic>\n                      genes. Although the lack of microdissection precludes definitively assigning each variant to a specific pathological component, we hypothesize that these mutations may serve as key drivers for concurrent PA and MACS associated with cortisol-producing adenoma and adjacent MAPM\/APN. Furthermore, our data support the emerging concept that primary aldosteronism can originate from MAPM rather than just from conventional adrenal cortical adenomas.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1949358","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:48:02Z","timestamp":1790254082000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Somatic GNAS and CACNA1D mutations responsible for adrenal cortisol-producing adenoma with multiple aldosterone-producing micronodules\u2014concurrence of primary aldosteronism and mild autonomous cortisol secretion"],"prefix":"10.3389","volume":"13","author":[{"given":"Lingna","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]},{"name":"Department of Pathology, The Affiliated Qingyuan Hospital (Qingyuan People\u2019s Hospital), Guangzhou Medical University","place":["Qingyuan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinchun","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haimin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1161\/01.HYP.0000079505.25750.11","article-title":"Primary aldosteronism and hypertensive disease","volume":"42","author":"Mosso","year":"2003","journal-title":"Hypertension"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1016\/j.jacc.2020.02.052","article-title":"Primary aldosteronism in patients in China with recently detected hypertension","volume":"75","author":"Xu","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1111\/joim.12831","article-title":"Diagnosis and treatment of primary aldosteronism: practical clinical perspectives","volume":"285","author":"Young","year":"2019","journal-title":"J Intern Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1161\/HYPERTENSIONAHA.118.11086","article-title":"Cellular and genetic causes of idiopathic hyperaldosteronism","volume":"72","author":"Omata","year":"2018","journal-title":"Hypertension"},{"key":"B5","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1055\/s-0043-122238","article-title":"Disordered CYP11B2 expression in primary aldosteronism","volume":"49","author":"Gomez-Sanchez","year":"2017","journal-title":"Horm Metab Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"631848","DOI":"10.3389\/fendo.2021.631848","article-title":"Functional characteristic and significance of aldosterone-producing cell clusters in primary aldosteronism and age-related hypertension","volume":"12","author":"Pauzi","year":"2021","journal-title":"Front Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1161\/HYPERTENSIONAHA.120.15328","article-title":"Presence of subclinical hypercortisolism in clinical aldosterone-producing adenomas predicts lower clinical success","volume":"76","author":"Peng","year":"2020","journal-title":"Hypertension"},{"key":"B8","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1007\/s42000-019-00114-8","article-title":"The relevance of cortisol co-secretion from aldosterone-producing adenomas","volume":"18","author":"Bhatt","year":"2019","journal-title":"Hormones"},{"key":"B9","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/s10157-006-0413-z","article-title":"Coexistence of three distinct adrenal tumors in the same adrenal gland in a patient with primary aldosteronism and preclinical Cushing\u2019s syndrome","volume":"10","author":"Okura","year":"2006","journal-title":"Clin Exp Nephrol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1507\/endocrj.K06-180","article-title":"Possibly simultaneous primary aldosteronism and preclinical Cushing\u2019s syndrome in a patient with double adenomas of right adrenal gland","volume":"54","author":"Saito","year":"2007","journal-title":"Endocr J"},{"key":"B11","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1186\/s12902-019-0395-y","article-title":"Hypercortisolism and primary aldosteronism caused by bilateral adrenocortical adenomas: a case report","volume":"19","author":"Ren","year":"2019","journal-title":"BMC Endocr Disord"},{"key":"B12","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1186\/s12902-023-01454-8","article-title":"Bilateral co-secretory lesions presenting with coexisting Cushing syndrome and primary aldosteronism: a case report","volume":"23","author":"Gao","year":"2023","journal-title":"BMC Endocr Disord"},{"key":"B13","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s12902-024-01645-x","article-title":"Rare correlation of somatic PRKACA mutations with pregnancy-associated aldosterone- and cortisol-producing adenomas: a case report and literature review","volume":"24","author":"Lin","year":"2024","journal-title":"BMC Endocr Disord"},{"key":"B14","doi-asserted-by":"publisher","first-page":"911333","DOI":"10.3389\/fcvm.2022.911333","article-title":"Case report: primary aldosteronism and subclinical Cushing syndrome in a 49-year-old woman with hypertension plus hypokalaemia","volume":"9","author":"Hu","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"R67","DOI":"10.1530\/JOE-19-0193","article-title":"Molecular mechanisms in primary aldosteronism","volume":"242","author":"De Sousa","year":"2019","journal-title":"J Mol Endocrinol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e594","DOI":"10.1210\/clinem\/dgab682","article-title":"Targeted mutational analysis of cortisol-producing adenomas","volume":"107","author":"Rege","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e92759","DOI":"10.7759\/cureus.92759","article-title":"Mixed aldosterone and cortisol secretion in patients with adrenal incidentalomas: different faces of the old concept of Connshing syndrome","volume":"17","author":"Kamenova","year":"2025","journal-title":"Cureus"},{"key":"B18","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1291\/hypres.24.723","article-title":"Combined primary aldosteronism and preclinical Cushing\u2019s syndrome: an unusual case presentation of adrenal adenoma","volume":"24","author":"Honda","year":"2001","journal-title":"Hypertens Res"},{"key":"B19","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1007\/s10157-008-0064-3","article-title":"Primary aldosteronism and hypercortisolism due to bilateral functioning adrenocortical adenomas","volume":"12","author":"Oki","year":"2008","journal-title":"Clin Exp Nephrol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.1111\/jch.14374","article-title":"Hypertension with unilateral adrenal aldosterone and cortisol cosecreting adenoma: a case report","volume":"23","author":"Hu","year":"2021","journal-title":"J Clin Hypertens"},{"key":"B21","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1186\/s12902-021-00818-2","article-title":"Concurrence of overt Cushing\u2019s syndrome and primary aldosteronism accompanied by aldosterone-producing cell cluster in adjacent adrenal cortex: case report","volume":"21","author":"Fushimi","year":"2021","journal-title":"BMC Endocr Disord"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.12998\/wjcc.v9.i5.1119","article-title":"Primary aldosteronism due to bilateral micronodular hyperplasia and concomitant subclinical Cushing\u2019s syndrome: a case report","volume":"9","author":"Teragawa","year":"2021","journal-title":"World J Clin Cases"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1068335","DOI":"10.3389\/fendo.2023.1068335","article-title":"Different cell compositions and a novel somatic KCNJ5 variant found in a patient with bilateral adrenocortical adenomas secreting aldosterone and cortisol","volume":"14","author":"Zhao","year":"2023","journal-title":"Front Endocrinol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s13256-020-2353-8","article-title":"Primary aldosteronism concurrent with subclinical Cushing\u2019s syndrome: a case report and review of the literature","volume":"14","author":"Zhang","year":"2020","journal-title":"J Med Case Rep"},{"key":"B25","doi-asserted-by":"publisher","first-page":"K1","DOI":"10.1530\/EJE-16-0262","article-title":"Double adrenocortical adenomas harboring independent KCNJ5 and PRKACA somatic mutations","volume":"175","author":"Nanba","year":"2016","journal-title":"Eur J Endocrinol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"101428","DOI":"10.1016\/j.beem.2020.101428","article-title":"Adrenocortical tumorigenesis: lessons from genetics","volume":"34","author":"Kamilaris","year":"2020","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.3390\/biomedicines10051041","article-title":"Genetic alterations in benign adrenal tumors","volume":"10","author":"Pitsava","year":"2022","journal-title":"Biomedicines"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e151","DOI":"10.1016\/j.lpm.2018.07.006","article-title":"Molecular genetics of conn adenomas in the era of exome analysis","volume":"47","author":"El Zein","year":"2018","journal-title":"Presse Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1210\/js.2017-00134","article-title":"Aldosterone-producing cell clusters frequently harbor somatic mutations and accumulate with age in normal adrenals","volume":"1","author":"Omata","year":"2017","journal-title":"J Endocr Soc"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1210\/jc.2012-3726","article-title":"Histopathological diagnosis of primary aldosteronism using CYP11B2 immunohistochemistry","volume":"98","author":"Nanba","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B31","doi-asserted-by":"publisher","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 U S A"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1210\/jc.2016-2986","article-title":"Histopathological classification of cross-sectional image-negative hyperaldosteronism","volume":"102","author":"Yamazaki","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"B33","doi-asserted-by":"publisher","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":"B34","doi-asserted-by":"publisher","first-page":"9042","DOI":"10.3390\/ijms23169042","article-title":"Clinical translationality of KCNJ5 mutation in aldosterone producing adenoma","volume":"23","author":"Kitamoto","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B35","doi-asserted-by":"publisher","first-page":"927669","DOI":"10.3389\/fendo.2022.927669","article-title":"Pathogenesis of primary aldosteronism: impact on clinical outcome","volume":"13","author":"Santana","year":"2022","journal-title":"Front Endocrinol"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1949358\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:48:05Z","timestamp":1790254085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1949358\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":35,"alternative-id":["10.3389\/fmed.2026.1949358"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1949358","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,24]]},"article-number":"1949358"}}