학술논문
Somatic PRKACA Mutations: Association With Transition From Pituitary-Dependent to Adrenal-Dependent Cushing Syndrome
CLINICAL RESEARCH ARTICLE
CLINICAL RESEARCH ARTICLE
Document Type
Academic Journal
Author
Source
Journal of Clinical Endocrinology & Metabolism. November 2019, Vol. 104 Issue 11, p5651, 7 p.
Subject
Language
English
ISSN
0021-972X
Abstract
Prolonged hyperstimulation by ACTH results in alterations of adrenal gland architecture that range from diffuse hyperplasia to micro- and macronodules (1, 2), driven by the trophic effects of corticotropin. Those [...]
Context: Prolonged adrenal stimulation by corticotropin, as in long-standing Cushing disease (CD), leadsto diffuse tonodular hyperplasia. Adrenal functional autonomy has been described in asubset 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 ofpatients with long-standing CD. (J Clin Endocrinol Metab 104: 5651-5657, 2019)
Context: Prolonged adrenal stimulation by corticotropin, as in long-standing Cushing disease (CD), leadsto diffuse tonodular hyperplasia. Adrenal functional autonomy has been described in asubset 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 ofpatients with long-standing CD. (J Clin Endocrinol Metab 104: 5651-5657, 2019)