Introduction: Germline inactivating mutations of the protein kinase A (PKA) regulatory subunit RIα (the PRKAR1A gene) cause primary pigmented nodular adrenocortical disease (PPNAD); other cyclic AMP (cAMP) signalling defects have been associated with bilateral adrenocortical hyperplasia (BAH), cortisol-producing adenoma (CPA) and related lesions. Recently, PRKACA somatic mutations were detected in single, sporadic CPAs in approximately 40% of patients with ACTH-independent Cushing syndrome (AICS) whereas germline copy-number gain (CNG) of the 19p13 PRKACA-locus was associated with micronodular BAH (iMAD) and PPNAD.
Methods: We studied 68 patients with AICS, 24 patients with CPA and 44 patients with BAH that did not have known germline PRKAR1A defects. The clinical characteristics of the patients were evaluated with genetic analysis.
Results: The hotspot somatic mutation (p.Leu206Arg, c.617T>G) in the PRKACA gene was identified in 3 of 25 CPAs. Ten of 44 patients with BAH had germline CNGat the 19p13 PRKACA-locus. In one of these cases, AICS with combined androgen production due to a PPNAD-like BAH that became clinically apparent during pregnancy, there was familial inheritance of the 19p13 CNG, which segregated with AICS in the affected members. There were specific dexamethasone-responses and histological features of the patients with somatic PRKACA defects; BAH due to 19p13 CNG was mostly micronodular but was not consistently PPNAD-like.
Conclusions: We conclude that both germline and somatic PRKACA defects are associated with specific clinical and histologic phenotypes. Their recognition may help in the earlier identification of these patients with AICS and in the case of hereditary BAH, the earlier recognition of carriers with 19p13 CNG may result in better patient outcome.
Disclosure: This research was supported in part by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Clinical trial registration number: NCT00005927).