Key Points
- Characterize the clinical phenotype and evaluate potential founder effects in 12 kindreds harboring an identical PRKAR1A mutation presenting with primary pigmented nodular adrenocortical disease.
- Conducted a multicenter descriptive case series of 12 unrelated kindreds referred to two specialized centers for PRKAR1A mutation screening due to primary pigmented nodular adrenocortical disease.
- Assessed patients and relatives for Carney complex manifestations and genotyped chromosome 17 polymorphic markers to evaluate for a shared ancestral founder effect.
- Identified an identical heterozygous 6-bp polypyrimidine tract deletion (exon 7 IVS del [-7-->-2]) in PRKAR1A across all 12 kindreds.
- Isolated disease presented in nine simplex cases and two kindreds with a positive family history, while only one patient met diagnostic criteria for Carney complex.
- Asymptomatic mutation-positive relatives exhibited no endocrine or skin manifestations, indicating low disease penetrance, and chromosome 17 marker analysis ruled out a common founder.
Structured PICO
PPopulation12 unrelated kindreds referred for PRKAR1A gene mutation analysis because of a diagnosis of apparently isolated primary pigmented nodular adrenocortical disease (iPPNAD)
IInterventionPRKAR1A gene mutation analysis and phenotyping for Carney complex manifestations
OOutcomePhenotypic manifestations of Carney complex (CNC) or PPNAD and presence of a founder effectsurrogate
A small intronic deletion of the PRKAR1A gene is a low-penetrance cause of mainly isolated PPNAD, representing the first PRKAR1A genetic defect associated with a specific phenotype.