Somatic PRKACA Mutations: Association With Transition From Pituitary-Dependent to Adrenal-Dependent Cushing Syndrome

Di Dalmazi, Guido; Timmers, Henri J. L. M.; Arnaldi, Giorgio; Kusters, Benno; Scarpelli, Marina; Bathon, Kerstin; Calebiro, Davide; Beuschlein, Felix; Hermus, Ad und Reincke, Martin (2019): Somatic PRKACA Mutations: Association With Transition From Pituitary-Dependent to Adrenal-Dependent Cushing Syndrome. In: Journal of Clinical Endocrinology & Metabolism, Bd. 104, Nr. 11: S. 5651-5657

Abstract

Context: Prolonged adrenal stimulation by corticotropin, as in long-standing Cushing disease (CD), leads to diffuse to nodular hyperplasia. Adrenal functional autonomy has been described in a subset of patients with CD, leading to the hypothesis of transition from ACTH-dependent to ACTH-independent hypercortisolism. Objective: With the consideration that the catalytic a subunit of protein kinase A (PKA;PRKACA) somatic mutations are the most common finding in adrenal adenomas associated with ACTH-independent Cushing syndrome, our aim was to analyze PRKACA mutations in adrenals of patients with persistent/long-standing CD. Design: Cross-sectional. Setting: University hospital. Patients: Two patients with long-standing CD and suspicion of coexistence of autonomous adrenal hyperfunction, according to pre and postoperative evaluations, were selected for this study, following an intensive literature search and patient-chart reviewing. Intervention: Clinical data were analyzed. DNA was extracted from adrenal tissue for PRKACA sequencing. PKA activity was assayed. Main Outcome Measure: PRKACA somatic mutations. Results: Both patients showed mutations of PRKACA in the macronodule in the context of micronodular adrenal hyperplasia. One patient harbored the previously described p.Leu206Arg substitution, whereas a p.Ser213Arg missense variation was detected in the adrenal nodule of the second patient. No mutations were detected in the adjacent adrenal cortex of the second patient. In silico analysis predicts that p.Ser213Arg can interfere with the interaction between the regulatory and catalytic subunits of PKA. Conclusions: Our study shows that PRKACA somatic mutations can be found in adrenal nodules of patients with CD. These genetic alterations could represent a possible mechanism underlying adrenal nodule formation and autonomous cortisol hyperproduction in a subgroup of patients with long-standing CD.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0021-972X
• Sprache: Englisch