First Somatic PRKAR1A Defect Associated With Mosaicism for Another PRKAR1A Mutation in a Patient With Cushing Syndrome.

Context: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome (CS) associated mostly with Carney complex (CNC), a rare autosomal dominant multiple neoplasia syndrome. More than two-thirds of familial cases and approximately one-third of sporadic cases of CNC harbor germline inactivating PRKAR1A defects. Increasingly sensitive technologies for the detection of genetic defects such as next-generation sequencing (NGS) have further highlighted the importance of mosaicism in human disease.
Case Description: A 33-year-old woman was diagnosed with ACTH-independent CS with abdominal computed tomography showing bilateral micronodular adrenal hyperplasia with a left adrenal adenoma. She underwent left adrenalectomy with pathology demonstrating PPNAD with a 1.5-cm pigmented adenoma. DNA analysis by Sanger sequencing revealed 2 different PRKAR1A variants in the adenoma that were absent from DNA extracted from blood and saliva: c.682C > T and c.974-2A > G. "Deep" NGS revealed that 0.31% of DNA copies extracted from blood and saliva did in fact carry the c.682C > T variant, suggesting low-level mosaicism for this defect.
Conclusions: We present a case of PPNAD due to low-level mosaicism for a PRKAR1A defect which led to the formation of an adenoma due to a second, adrenal-specific, somatic PRKAR1A mutation. The identification of mosaicism for PRKAR1A , depending on the number and distribution of cells affected has implications for genetic counseling and tumor surveillance. This is the first recorded case of a patient with PRKAR1A mosaicism, PPNAD, and an adenoma forming due to complete inactivation of PRKAR1A in adrenal tissue from a second, somatic-only, PRKAR1A coding sequence mutation.
(Published by Oxford University Press on behalf of the Endocrine Society 2021.)