PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases

Eur J Endocrinol. 2015 Jun;172(6):677-85. doi: 10.1530/EJE-14-1113. Epub 2015 Mar 6.


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 PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone.

Design, patients, and methods: In this study, 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. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and 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+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 vs 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Neoplasms / genetics*
  • Adrenal Hyperplasia, Congenital / genetics*
  • Adrenalectomy
  • Adrenocortical Adenoma / genetics*
  • Adult
  • Age Factors
  • Aged
  • Aldosterone / metabolism*
  • Cushing Syndrome / genetics*
  • Cushing Syndrome / surgery
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / genetics*
  • Female
  • Humans
  • Hydrocortisone / metabolism*
  • Male
  • Middle Aged
  • Mutation / genetics
  • Phenotype
  • beta Catenin / genetics*


  • CTNNB1 protein, human
  • beta Catenin
  • Aldosterone
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • PRKACA protein, human
  • Hydrocortisone