Familial Isolated Primary Pigmented Nodular Adrenocortical Disease Associated with a Novel Low Penetrance PRKAR1A Gene Splice Site Mutation

BACKGROUND/AIMS: Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating germline protein kinase A regulatory subunit type 1-alpha (PRKAR1A) mutations and loss of heterozygosity at the 17q22-24 locus in approximately 50% patients. PRKAR1A mutations are observed in both isolated PPNAD (iPPNAD) and Carney complex (CNC). Most mutations result in a functionally null-allele and exhibit high penetrance. We genotyped members of an extended family for a novel PRKAR1A mutation and undertook detailed phenotyping for CNC in the affected individuals. METHODS: A 10.5-year-old male was diagnosed with PPNAD; the patient's mother also had iPPNAD. A 13-year-old sibling and 7 other relatives (mean age 58.2, range 29.1-80.2 years) were referred for PRKAR1A mutation analysis. RESULTS: DNA analysis of the index case and parent revealed a novel germline heterozygous PRKAR1A mutation at the +1 position of the acceptor site of intron 3 [c.349 G>T]. The same heterozygous splice site mutation was present in the sibling with no PPNAD or CNC manifestations and 2 other individuals aged 54.9 and 57.1 years who had subclinical Cushing's syndrome but no features of CNC. CONCLUSION: We conclude that c.349 G>T, a novel splice site germline PRKAR1A defect, has low penetrance resulting in incomplete clinical expression in this kindred.