Key result
A germline PRKAR1A mutation was identified as a novel cause of Cushing disease in a 15-year-old male with a corticotropinoma, though it was absent in 97 other pediatric cases.
Case Report (n=98)
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Germline PRKAR1A mutations are a novel, albeit infrequent, cause of Cushing disease and can present as a corticotropinoma associated with Carney complex.
Known germline gene abnormalities cause one-fifth of the pituitary adenomas in children and adolescents, but, in contrast with other pituitary tumor types, the genetic causes of corticotropinomas are largely unknown. In this study, we report a case of Cushing disease (CD) due to a loss-of-function mutation in PRKAR1A, providing evidence for association of this gene with a corticotropinoma. A 15-year-old male presenting with hypercortisolemia was diagnosed with CD. Remission was achieved after surgical resection of a corticotropin (ACTH)-producing pituitary microadenoma, but recurrence 3 years later prompted reoperation and radiotherapy. Five years after the original diagnosis, the patient developed ACTH-independent Cushing syndrome, and a diagnosis of primary pigmented nodular adrenocortical disease was confirmed. A PRKAR1A mutation (c.671delG, p.G225Afs*16) was detected in a germline DNA sample from the patient, which displayed loss of heterozygosity in the corticotropinoma. No other germline or somatic mutations of interest were found. As corticotropinomas are not a known component of Carney complex (CNC), we performed loss of heterozygosity and messenger RNA stability studies in the patient’s tissues, and analyzed the effect of Prkar1a silencing on AtT-20/D16v-F2 mouse corticotropinoma cells. No PRKAR1A defects were found among 97 other pediatric CD patients studied. Our clinical case and experimental data support a role for PRKAR1A in the pathogenesis of a corticotroph cell tumor. This is a molecularly confirmed report of a corticotropinoma presenting in association with CNC. We conclude that germline PRKAR1A mutations are a novel, albeit apparently infrequent, cause of CD.
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Hernández‐Ramírez et al. (2017) conducted a case report in Cushing disease (corticotropinoma) (n=98). PRKAR1A mutation was evaluated on Presence of PRKAR1A mutation. A germline PRKAR1A mutation was identified as a novel cause of Cushing disease in a 15-year-old male with a corticotropinoma, though it was absent in 97 other pediatric cases.
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