title: Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype.
abstract: Aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia are important causes of secondary hypertension. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, ATP2B3 and CTNNB1 have been described in APAs.
  
  
  OBJECTIVE
  To characterize clinical-pathological features in APAs and unilateral adrenal hyperplasia, and correlate them with genotypes.
  
  
  METHODS
  Retrospective study.
  
  
  METHODS
  Clinical and pathological characteristics of 90 APAs and seven diffusely or focally hyperplastic adrenal glands were reviewed, and samples were examined for mutations in known disease genes by Sanger or exome sequencing.
  
  
  RESULTS
  Mutation frequencies were as follows: KCNJ5, 37·1%; CACNA1D, 10·3%; ATP1A1, 8·2%; ATP2B3, 3·1%; and CTNNB1, 2·1%. Previously unidentified mutations included I157K, F154C and two insertions (I150_G151insM and I144_E145insAI) in KCNJ5, all close to the selectivity filter, V426G_V427Q_A428_L433del in ATP2B3 and A39Efs*3 in CTNNB1. Mutations in KCNJ5 were associated with female and other mutations with male gender (P = 0·007). On computed tomography, KCNJ5-mutant tumours displayed significantly greater diameter (P = 0·023), calculated area (P = 0·002) and lower precontrast Hounsfield units (P = 0·0002) vs tumours with mutations in other genes. Accordingly, KCNJ5-mutant tumours were predominantly comprised of lipid-rich fasciculata-like clear cells, whereas other tumours were heterogeneous (P = 5 × 10(-6) vs non-KCNJ5 mutant and P = 0·0003 vs wild-type tumours, respectively). CACNA1D mutations were present in two samples with hyperplasia without adenoma.
  
  
  CONCLUSIONS
  KCNJ5-mutant tumours appear to be associated with fasciculata-like clear cell predominant histology and tend to be larger with a characteristic imaging phenotype. Novel somatic KCNJ5 variants likely cause adenomas by loss of potassium selectivity, similar to previously described mutations.
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.|Department of Nephrology, Medical School, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Ute I
authors.initials: UI
authors.lastname: Scholl
authors.affiliation: Department of Surgery and Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Healy
authors.affiliation: Department of Nephrology, Medical School, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Thiel
authors.affiliation: Department of Surgery and Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Annabelle L
authors.initials: AL
authors.lastname: Fonseca
authors.affiliation: Department of Surgery and Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Brown
authors.affiliation: Department of Surgery and Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Kunstman
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Horne
authors.affiliation: Institute of Pathology, University of Bonn, Bonn, Germany.
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
authors.affiliation: Institute of Pathology, Medical School, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Riemer
authors.affiliation: Department of Nephrology, Medical School, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Seher
authors.initials: S
authors.lastname: Kücükköylü
authors.affiliation: Department of Nephrology, Medical School, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Esther N
authors.initials: EN
authors.lastname: Reimer
authors.affiliation: Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anna-Carinna
authors.initials: AC
authors.lastname: Reis
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.affiliation: Institute of Pathology, University of Bonn, Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.affiliation: Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: Department of Surgery and Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Reju
authors.initials: R
authors.lastname: Korah
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Manju L
authors.initials: ML
authors.lastname: Prasad
authors.affiliation: Department of Surgery and Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
mesh_terms: D000328:Adult; D020746:Calcium Channels, L-Type / Q000235:genetics; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics; D006801:Humans; D006929:Hyperaldosteronism / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics; D012189:Retrospective Studies; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C472073:CACNA1D protein, human; C495270:CTNNB1 protein, human; D020746:Calcium Channels, L-Type; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D051176:beta Catenin; C499076:ATP1A1 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases; C506962:ATP2B3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase