title: Case Report: Nodule Development From Subcapsular Aldosterone-Producing Cell Clusters Causes Hyperaldosteronism.
abstract: BACKGROUND
  We previously reported that the human adrenal cortex remodels to form subcapsular aldosterone-producing cell clusters (APCCs). Some APCCs were recently found to carry aldosterone-producing adenoma (APA)-associated somatic mutations in ion channel/pump genes, which implied that APCCs produce aldosterone autonomously and are an origin of APA. However, there has been no report describing an APCC-to-APA transitional lesion.
  
  
  METHODS
  A histological examination revealed unilateral multiple adrenocortical micronodules in the adrenals of two patients with primary aldosteronism (PA). Based on immunohistochemistry for aldosterone synthase, some of the micronodules were identified as possible APCC-to-APA transitional lesions (pAATLs; a tentative term used in this manuscript), which consisted of a subcapsular APCC-like portion and an inner micro-APA-like (mAPA-like) portion without an apparent histological border. Genomic DNA samples prepared from pAATL histological sections were analyzed by next-generation sequencing for the known APA-associated mutations. The mAPA-like portions from two of the three large pAATLs examined harbored mutations (KCNJ5 [p.G151R] in pAATL 3 and ATP1A1 [p.L337M] in pAATL 7), whereas their corresponding APCC-like portions did not, suggesting their role in the formation of mAPA. Another lesion carried novel mutations in ATP1A1 (p.Ile322_Ile325del and p.Ile327Ser) in both the mAPA-like and APCC-like portions, thereby supporting these portions having a clonal origin.
  
  
  CONCLUSIONS
  A novel aldosterone-producing pathology, pAATL that causes unilateral PA, was detected in the adrenals of two patients. Next-generation sequencing analyses of the large pAATLs suggested that the introduction of APA-associated mutations in the ion channel/pump genes may be involved in the development of mAPA from existing APCCs.
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Koshiro
authors.initials: K
authors.lastname: Nishimoto
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Tsugio
authors.initials: T
authors.lastname: Seki
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Isao
authors.initials: I
authors.lastname: Kurihara
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yokota
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Masao
authors.initials: M
authors.lastname: Omura
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Shibata
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kosaka
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.affiliation: Departments of Biochemistry (K.N., M.S., K.M.), Internal Medicine (I.K., K.Y.), and Urology (T.K., M.Oy.), and Medical Education Center (K.M.), Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Urology (K.N.), Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tachikawa, Tokyo 190-8531, Japan; Endocrinology and Diabetes Center (M.Om., T.N.), Yokohama Rosai Hospital, Yokohama 222-0036, Japan; Department of Endocrinology, Metabolism, Rheumatology, and Nephrology (H.S.), Faculty of Medicine, Oita University, Yufu 879-5593, Japan; and Department of Medical Education (T.S.), College of Medicine, California University of Science and Medicine, Colton, California 92324.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Mukai
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics; D018246:Adrenocortical Adenoma / Q000235:genetics; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis*; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D004247:DNA / Q000235:genetics; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics; D006801:Humans; D006929:Hyperaldosteronism / Q000209:etiology* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics; D016606:Thyroid Nodule / Q000150:complications* / Q000235:genetics / Q000473:pathology*
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D000450:Aldosterone; D004247:DNA; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; C499076:ATP1A1 protein, human; D000254:Sodium-Potassium-Exchanging ATPase