LAUSR

Abstract Background. Transition from ACTH-dependent to ACTH-independent hypercortisolism has been described in patients with long-standing Cushing´s disease (CD). The underlying molecular mechanisms are unknown. Clinical case.Case 1. A 41-years old woman was referred for Cushing’s syndrome (cortisol after 1-mg dexamethasone suppression test (DST) 410 nmol/L, urinary free cortisol (UFC) 2xULN, midnight cortisol 440 nmol/L). High-dose DST: no suppression. CRH test: no ACTH/cortisol increase. Basal ACTH: 18 pmol/L. Pituitary MRI showed a 7-mm adenoma. The inferior petrosal sinus sampling showed central source of ACTH. She was treated by trans-sphenoidal surgery (pituitary adenoma confirmed histologically) followed by clinical remission. Cushing’s syndrome recurred 1 year after. ACTH was undetectable and pituitary MRI normal. Abdominal CT-scan showed a left adrenal macronodule. Left adrenalectomy was performed, followed by glucocorticoid replacement therapy (1 year) and clinical/biochemical remission at last follow-up (15 years). Histopathology showed a 35-mm adrenal nodule and micronodular hyperplasia. We found a p.L206R missense mutation of PRKACA in the adrenal nodule. The functional implication of the mutation has been described (1). Case 2. A 31-years old woman was referred for Cushing´s syndrome (cortisol after 1-mg DST 579 nmol/L, UFC 4xULN, midnight cortisol 773 nmol/L). Basal ACTH: 18 pmol/L. CRH and desmopressin tests: indicative of CD. High-dose DST: no suppression. A pituitary MRI revealed a microadenoma, treated by trans-sphenoidal surgery (confirmed by histology). She had persistence of Cushing’s syndrome, undetectable basal ACTH and negative pituitary MRI. An abdominal CT-scan showed bilateral adrenal enlargement with a left nodule, treated by bilateral adrenalectomy. Histology showed a macronodule in micronodular hyperplasia. We found a p.S213R somatic missense mutation of PRKACA in the adrenal macronodule. Functional analyses showed that mutant cells had higher cAMP-independent PKA activity than wild-type, and similar to the L206R mutation. Conclusion. This is the first evidence showing that PRKACA somatic mutations can be found in adrenal nodules of patients with CD, possibly explaining the mechanism underlying transition from ACTH-dependent to ACTH-independent hypercortisolism. References. 1. Calebiro D et al. PKA catalytic subunit mutations in adrenocortical Cushing's adenoma impair association with the regulatory subunit. Nat Commun. 2014;5:5680.