Mosaic PRKACA duplication causing a novel and distinct phenotype of early-onset Cushing syndrome and acral cutaneous mucinosis.

Genetic alterations within the cAMP/PKA pathway result in a spectrum of adrenocortical disorders. Implicated genes include GNAS, PDE8, PDE11A, PRKAR1A/B, and PRKACA. To date, somatic PRKACA mutations and germline PRKACA copy number gain have been associated with the development of cortisol-secreting adrenocortical adenomas and bilateral adrenal hyperplasia, respectively. While perturbations within the PRKAR1A gene are known to cause Carney complex, PKRACA mutations are rarely associated with an extra-adrenal phenotype. We describe a mosaic PRKACA duplication in an infant who presented with a Carney-like complex at the age of three months with bilateral non-pigmented micronodular adrenal hyperplasia, severe early-onset Cushing syndrome, and distinct acral soft tissue overgrowth due to cutaneous mucinosis. This represents a novel manifestation of PRKACA disruption and broadens its extra-adrenal phenotype. It suggests that the Cushing syndrome phenotypes arising from somatic and germline PRKACA abnormalities likely exist on a spectrum. We emphasise the importance of ascertaining a genetic diagnosis for PRKACA-mediated disease.