title: Somatic GNAS mutation causes widespread and diffuse pituitary disease in acromegalic patients with McCune-Albright syndrome.
abstract: BACKGROUND
  McCune-Albright syndrome (MAS) is caused by sporadic mutations of the GNAS. Patients exhibit features of acromegaly. In most patients, GH-secreting pituitary adenomas have been held responsible for this presentation. However, surgical adenomectomy rarely eliminates excess GH production.
  
  
  OBJECTIVE
  The aim of this study was to elucidate pituitary pathology in patients with MAS and to explain the basis of failure of adenomectomy to eliminate GH hypersecretion.
  
  
  METHODS
  We conducted a case series at the National Institutes of Health.
  
  
  METHODS
  Interventions included medical therapy and transsphenoidal surgery.
  
  
  METHODS
  We studied clinical and imaging features and the histology and molecular features of the pituitary of four acromegalic MAS patients.
  
  
  RESULTS
  We identified widespread and diffuse pituitary gland disease. The primary pathological changes were characterized by hyperplastic and neoplastic change, associated with overrepresentation of somatotroph cells in structurally intact tissue areas. Genetic analysis of multiple microdissected samples of any type of histological area consistently revealed identical GNAS mutations in individual patients. The only patient with remission after surgery received complete hypophysectomy in addition to removal of multiple GH-secreting tumors.
  
  
  CONCLUSIONS
  These findings indicate developmental effects of GNAS mutation on the entire anterior pituitary gland. The pituitary of individual cases contains a spectrum of changes with regions of normal appearing gland, hyperplasia, and areas of fully developed adenoma formation, as well as transitional stages between these entities. The primary change underlying acromegaly in MAS patients is somatotroph hyperplasia involving the entire pituitary gland, with or without development of somatotroph adenoma. Thus, successful clinical management, whether it is medical, surgical, or via irradiation, must target the entire pituitary, not just the adenomas evident on imaging.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
authors.forename: Sven
authors.initials: S
authors.lastname: Gläsker
authors.forename: Gautam U
authors.initials: GU
authors.lastname: Mehta
authors.forename: Mones S
authors.initials: MS
authors.lastname: Abu-Asab
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Smith
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
authors.forename: Edward H
authors.initials: EH
authors.lastname: Oldfield
mesh_terms: D000172:Acromegaly / Q000097:blood / Q000150:complications / Q000209:etiology / Q000235:genetics*; D000236:Adenoma / Q000097:blood / Q000150:complications / Q000235:genetics; D000328:Adult; D002864:Chromogranins; D004252:DNA Mutational Analysis; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000097:blood / Q000150:complications / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000502:physiology; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000097:blood / Q000150:complications / Q000235:genetics; D019382:Human Growth Hormone / Q000032:analysis / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D020125:Mutation, Missense / Q000502:physiology; D010900:Pituitary Diseases / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
chemical_list: D002864:Chromogranins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs