Header

UZH-Logo

Maintenance Infos

Somatic PRKACA mutations: association with transition from pituitary-dependent to adrenal-dependent Cushing's syndrome


Di Dalmazi, Guido; Timmers, Henri J L M; Arnaldi, Giorgio; Küsters, Benno; Scarpelli, Marina; Bathon, Kerstin; Calebiro, Davide; Beuschlein, Felix; Hermus, Ad; Reincke, Martin (2019). Somatic PRKACA mutations: association with transition from pituitary-dependent to adrenal-dependent Cushing's syndrome. Journal of Clinical Endocrinology & Metabolism, 104(11):5651-5657.

Abstract

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.

Abstract

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.

Statistics

Citations

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Endocrinology and Diabetology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 November 2019
Deposited On:26 Jul 2019 12:53
Last Modified:11 Oct 2019 01:06
Publisher:Oxford University Press
ISSN:0021-972X
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1210/jc.2018-02209
PubMed ID:31276155

Download

Full text not available from this repository.
View at publisher

Get full-text in a library