title: Infantile adrenocortical tumor with an activating GNAS1 mutation.
abstract: BACKGROUND
  Pediatric adrenocortical tumors (ACTs) are rare and are frequently associated with tumor predisposition syndromes. Somatic GNAS1 mutations are associated with adrenocortical hyperplasia, but have not typically been reported in ACTs.
  
  
  OBJECTIVE
  We report on genetic and histopathological findings in a 3-month-old infant presenting with a unilateral cortisol-producing ACT with malignant features.
  
  
  METHODS
  We performed a detailed clinical evaluation of the patient along with molecular genetic testing of genes associated with ACTs in both tumor tissue and peripheral lymphocytes. We also performed a histopathological analysis of the tumor tissue.
  
  
  RESULTS
  The patient was found to have a p.R201C-activating mutation in exon 8 of the GNAS1 gene in adrenocortical tumor tissue but not peripheral lymphocytes. This mutation is the characteristic genetic change in McCune-Albright syndrome. In contrast to previously reported GNAS1-positive tumors characterized by bimodal diffuse and nodular adrenocortical hypertrophy, our patient had a single adrenocortical mass that showed features of malignancy, including areas of necrosis, microcystic degeneration, and venous and capsular microinvasion-changes that have been seen previously in Beckwith-Wiedemann syndrome. However, our patient did not have clinical features of Beckwith-Wiedemann syndrome. Further analysis revealed abnormal allele-specific hypomethylation of the KCNQ1OT1 gene in the tumor sample but not peripheral lymphocytes.
  
  
  CONCLUSIONS
  This is a novel case of an activating GNAS1 mutation associated with an epigenetic alteration that may be related to adrenocortical tumorigenesis. Our findings may have implications in the molecular pathogenesis of pediatric ACTs.
authors.affiliation: Children's Hospital of Michigan, Department of Pediatrics, Division of Genetic and Metabolic Disorders, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: Alpa
authors.initials: A
authors.lastname: Sidhu
authors.forename: Larisa
authors.initials: L
authors.lastname: Debelenko
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Misra
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000175:diagnosis / Q000235:genetics*; D018246:Adrenocortical Adenoma / Q000175:diagnosis / Q000235:genetics*; D000367:Age Factors; D001483:Base Sequence; D002864:Chromogranins; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense / Q000502:physiology
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs