title: Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes.
abstract: We describe the pathology of 5 patients with germline PRKACA copy number gain and Cushing syndrome: 4 males and 1 female, aged 2 to 43 years, including a mother and son. Imaging showed normal or slightly enlarged adrenal glands in 4 patients and a unilateral mass in the fifth. Biochemically, the patients had corticotropin-independent hypercortisolism. Four underwent bilateral adrenalectomy; unilateral adrenalectomy was performed in the patient with the adrenal mass. Pathologically, 3 patients, including the 1 with the tumor (adenoma), had primary pigmented nodular adrenocortical disease with extranodular cortical atrophy and mild intracapsular and extracapsular extension of cortical cells. The other 2 patients had cortical hyperplasia and prominent capsular and extracapsular micronodular cortical hyperplasia. Immunoperoxidase staining revealed differences for synaptophysin, inhibin-A, and Ki-67 (nuclei) in the atrophic cortices (patients 1, 2, and 3) and hyperplastic cortices (patients 4 and 5) and for Ki-67 (nuclei) and vimentin in the extracortical nodules in the 2 groups of patients. β-Catenin stained the cell membrane, cytoplasm, and nuclei of the adenoma. The patients were well at follow-up (1-23 years); 24-hour urinary cortisol excretion was elevated in the patient who had unilateral adrenalectomy.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: carney.aidan@mayo.edu.
authors.forename: J Aidan
authors.initials: JA
authors.lastname: Carney
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Lyssikatos
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Maya B
authors.initials: MB
authors.lastname: Lodish
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000302:Adrenal Cortex / Q000737:chemistry / Q000000981:diagnostic imaging / Q000473:pathology* / Q000601:surgery; D000315:Adrenalectomy; D000328:Adult; D001284:Atrophy; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D003480:Cushing Syndrome / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D007265:Inhibins / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype; D016708:Synaptophysin / Q000032:analysis; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014746:Vimentin / Q000032:analysis; D055815:Young Adult
chemical_list: D015415:Biomarkers; D019394:Ki-67 Antigen; C569014:SYP protein, human; D016708:Synaptophysin; D014746:Vimentin; C422362:inhibin A; D007265:Inhibins; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human
keywords: Adrenal; Cortical nodules; Cushing syndrome; Genetics; PRKACA