cad a22 4500 569329892 20191012044303.0 cr unu---uuuuu 190727e20191101xx s 000 0 eng 10.1210/jc.2018-02209 doi (ZORA)oai:www.zora.uzh.ch:172039 610 ddc 31276155 pmid Somatic PRKACA mutations: association with transition from pituitary-dependent to adrenal-dependent Cushing's syndrome [Elektronische Daten] [Guido Di Dalmazi, Henri J L M Timmers, Giorgio Arnaldi, Benno Küsters, Marina Scarpelli, Kerstin Bathon, Davide Calebiro, Felix Beuschlein, Ad Hermus, Martin Reincke] closedAccess eu-repo CONTEXT Prolonged adrenal stimulation by corticotropin, as in long-standing Cushing´s 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 Considering that PRKACA somatic mutations are the most common finding in adrenal adenomas associated with ACTH-independent Cushing´s 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 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 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. Clinic for Endocrinology and Diabetology zora Di Dalmazi Guido joint author Timmers Henri J L M. joint author Arnaldi Giorgio joint author Küsters Benno joint author Scarpelli Marina joint author Bathon Kerstin joint author Calebiro Davide joint author Beuschlein Felix joint author Hermus Ad joint author Reincke Martin joint author Journal of Clinical Endocrinology & Metabolism 104(11):5651-5657 https://www.zora.uzh.ch/172039 text/html WWW-Backlink auf das Repository 1 Journal Article PeerReviewed zora ZORA 856 40 https://www.zora.uzh.ch/172039 text/html WWW-Backlink auf das Repository ZORA 700 1- Di Dalmazi Guido joint author ZORA 700 1- Timmers Henri J L M. joint author ZORA 700 1- Arnaldi Giorgio joint author ZORA 700 1- Küsters Benno joint author ZORA 700 1- Scarpelli Marina joint author ZORA 700 1- Bathon Kerstin joint author ZORA 700 1- Calebiro Davide joint author ZORA 700 1- Beuschlein Felix joint author ZORA 700 1- Hermus Ad joint author ZORA 700 1- Reincke Martin joint author ZORA 773 0- Journal of Clinical Endocrinology & Metabolism 104(11):5651-5657 BK010053 XK010053 XK010000 ZORA ZORA ZORA Journal Article closedAccess