Case report of familial Carney complex due to novel frameshift mutation c.597del C (p.Phe200LeufsX6) in PRKAR1A.

Carney complex is an autosomal dominantly inherited disease characterized by skin pigmentation, myxoma, primary pigmented nodular adrenocortical disease (PPNAD), and acromegaly. However, only a few incidences of PPNAD combined with acromegaly are observed in patients. The type 1alpha regulatory subunit of cAMP-dependent protein kinase (PRKAR1A) has been identified in patients as a causative gene for Carney complex by a positional cloning approach. Here, we report a female patient diagnosed with Cushing's syndrome and a GH-producing pituitary adenoma without otherwise evident acromegaly that could be diagnosed only by specialized endocrinological tests. Based on family history of acromegaly (mother and sister) and the fact that the combination of both diseases is very rare, genetic diagnosis involving Carney complex was considered to be appropriate. The 10 exons and flanking regions of PRKAR1A were screened for mutations by direct DNA sequencing. The patient and her mother and sister were found to have the same, novel frameshift mutation resulting from a single base deletion in exon 6 coding cAMP-binding domain A, denoted c.597delC in PRKAR1A. This single base deletion generated an immature stop codon at the sixth codon (p.Phe200LeufsX6). Even family members with the same mutation can show distinct phenotypes, suggesting that Carney complex is a multifactorial disorder comprising various genetic and environmental factors. Genetic diagnosis makes it possible to prepare more effective therapeutic strategies for patients and gene carriers and to avoid unnecessary tests for non-carriers in the family of the patient.