title: A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer.
abstract: BACKGROUND
  Most tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, we describe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-α (RIα) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC.
  
  
  OBJECTIVE
  We studied the genotype-phenotype correlation in CNC.
  
  
  METHODS
  We reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center.
  
  
  METHODS
  Twenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations.
  
  
  RESULTS
  Cushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did not have PPNAD. A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism. Unlike in other RIα defects, loss of heterozygosity was not observed in AC. The S147G mutation was compared to other expressed PRKAR1A mutations; it led to decreased cAMP and catalytic subunit binding by RIα and increased protein kinase A activity in vitro.
  
  
  CONCLUSIONS
  In a large family with CNC, one amino acid substitution caused a spectrum of adrenal disease that ranged from lack of manifestations to cancer. PPNAD and AC were the only manifestations of CNC in these patients, in addition to lentigines. These data have implications for counseling patients with CNC and are significant in documenting the first case of AC in the context of PPNAD.
authors: Serviço de Endocrinologia e Nutriço, Ponta Delgada, São Miguel 9500, Azores, Portugal.
authors: João
authors: J
authors: Anselmo
authors: Sandra
authors: S
authors: Medeiros
authors: Victor
authors: V
authors: Carneiro
authors: Elizabeth
authors: E
authors: Greene
authors: Isaac
authors: I
authors: Levy
authors: Maria
authors: M
authors: Nesterova
authors: Charalampos
authors: C
authors: Lyssikatos
authors: Anelia
authors: A
authors: Horvath
authors: J Aidan
authors: JA
authors: Carney
authors: Constantine A
authors: CA
authors: Stratakis
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000150:complications / Q000235:genetics*; D000307:Adrenal Gland Diseases / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D018268:Adrenocortical Carcinoma / Q000150:complications / Q000235:genetics*; D000328:Adult; D019943:Amino Acid Substitution / Q000502:physiology; D056733:Carney Complex / Q000150:complications / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D005190:Family; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000502:physiology; D012694:Serine / Q000235:genetics; D055815:Young Adult
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D012694:Serine; D005998:Glycine