CushieBlog

Objective: Cortisol excess due to adrenal adenomas or hyperplasia causes Cushing’s syndrome. Recent genetic studies have identified a somatic PRKACA^L206R mutation as a cause of cortisol-producing adenomas.

We aimed to compare the clinical features of lesions with PRKACA mutations to those with CTNNB1 mutations and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone.

Design, patients and methods: 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. 36 patients had overt Cushing’s syndrome, the remainder were subclinical. 59 cases were adenomas (three bilateral), one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone.

Results: Among cortisol-secreting unilateral lesions without evidence of co-secretion (n=52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8% and CTNNB1 plus GNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACA^L206R mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing’s syndrome and higher cortisol levels versus non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions.

Conclusions: PRKACA^L206R is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.