title: A novel PRKAR1A mutation associated with hepatocellular carcinoma in a young patient and a variable Carney complex phenotype in affected subjects in older generations.
abstract: BACKGROUND
  Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia syndrome (OMIM 160980). About 70% of cases are familiar; most have mutations of the PRKAR1A gene on chromosome 17q22-24. There is little phenotype-genotype correlation known to date.
  
  
  OBJECTIVE
  To study the genotype-phenotype correlation in a family with newly diagnosed CNC and three generations of subjects bearing the same PRKAR1A mutation. The proband was diagnosed with hepatocellular carcinoma, a tumour that appears to be associated with CNC.
  
  
  METHODS
  The study consisted of clinical and genetic analysis of a total of 10 individuals belonging to a large Italian family.
  
  
  METHODS
  The index case was referred for PRKAR1A gene mutation analysis because he met the diagnostic criteria for a clinical diagnosis of CNC.
  
  
  RESULTS
  The PRKAR1A-inactivating mutation c.502 +1G > A in the intron 5 splice-donor site was detected after bidirectional sequencing of germline DNA. The mutation causes a frameshift in the transcribed sequence and a nonsense mRNA that was shown to be degraded; this leads to PRKAR1A haploinsufficiency in all tissues. All available relatives were screened first by DNA testing and, if the latter was positive, by clinical, biochemical and imaging means.
  
  
  CONCLUSIONS
  A novel PRKAR1A mutation with an apparently low penetrance and variable expression is reported; the same mutation is also associated with a hepatocellular carcinoma. This is the first time a PRKAR1A mutation is reported in individuals who were diagnosed with CNC after retrospective family screening and following the identification of a proband; the finding has implications for genetic counselling on PRKAR1A and/or CNC.
authors.affiliation: Paediatric Endocrinology, S. Orsola Hospital-University of Bologna, Bologna, Italy. monia.gennari2@unibo.it
authors.forename: Monia
authors.initials: M
authors.lastname: Gennari
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.forename: Anelia
authors.initials: A
authors.lastname: Hovarth
authors.forename: Piero
authors.initials: P
authors.lastname: Pirazzoli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cicognani
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D002648:Child; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005191:Family Characteristics; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D013577:Syndrome
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human