Differences in adiposity in Cushing syndrome caused by PRKAR1A mutations: clues for the role of cyclic AMP signaling in obesity and diagnostic implications.

CONTEXT: The cAMP signaling pathway is implicated in bilateral adrenocortical hyperplasias. Bilateral adrenocortical hyperplasia is often associated with ACTH-independent Cushing syndrome (CS) and may be caused by mutations in genes such as PRKAR1A, which is responsible for primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A regulates cAMP-dependent protein kinase (PKA), an essential enzyme in the regulation of adiposity. Although CS is invariably associated with obesity, its different forms, including those associated with PKA defects, have not been compared. OBJECTIVE: The purpose of this study was to characterize the phenotypic and molecular differences in periadrenal adipose tissue (PAT) between patients with CS with and without PRKAR1A mutations. DESIGN AND SETTING: Samples from adrenalectomies of 51 patients were studied: patients with CS with (n = 13) and without (n = 32) PRKAR1A mutations and a comparison group with aldosterone-producing adenomas (APAs) (n = 6). In addition, clinical data from a larger group of patients with Cushing disease (n = 89) and hyperaldosteronism (n = 26) were used for comparison. METHODS: Body mass index (BMI), abdominal computed tomography scans, and cortisol data were collected preoperatively. PAT was assayed for PKA activity, cAMP levels, and PKA subunit expression. RESULTS: BMI was lower in adult patients with CS with PRKAR1A mutations. cAMP and active PKA levels in PAT were elevated in patients with CS with PRKAR1A mutations. CONCLUSIONS: Increased PKA signaling in PAT was associated with lower BMI in CS. Differences in fat distribution may contribute to phenotypic differences between patients with CS with and without PRKAR1A mutations. The observed differences are in agreement with the known roles of cAMP signaling in regulating adiposity, but this is the first time that germline defects of PKA are linked to variable obesity phenotypes in humans.

Inter-observer variability in the measurement of diffuse intrinsic pontine gliomas.

Diffuse intrinsic pontine glioma (DIPG) is an invasive pediatric brainstem tumor with a poor prognosis. Patients commonly enter investigational trials, many of which use radiographic response as an endpoint for assessing drug efficacy. However, DIPGs are difficult to measure on magnetic resonance imaging (MRI). In this study, we characterized the reproducibility of these commonly performed measurements. Each of four readers measured 50 MRI scans from DIPG patients and inter-observer variability was estimated with descriptive statistics. Results confirmed that there is wide variability in DIPG tumor measurements between readers for all image types. Measurements on FLAIR imaging were most consistent. For patients on clinical trials, measurement of DIPG should be performed by a single reader while comparing prior images side-by-side. Endpoints for clinical trials determining efficacy in this population should also include more objective measures, such as survival, and additional endpoints need to be investigated.