title: Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice.
abstract: BACKGROUND
  Germline mutations in genes coding succinate dehydrogenase (SDH) subunits A, B, C, and D have been identified in familial paragangliomas (PGLs)/pheochromocytomas (PHEOs) and other tumors. We described a GH-secreting pituitary adenoma (PA) caused by SDHD mutation in a patient with familial PGLs. Additional patients with PAs and SDHx defects have since been reported.
  
  
  METHODS
  We studied 168 patients with unselected sporadic PA and with the association of PAs, PGLs, and/or pheochromocytomas, a condition we named the 3P association (3PAs) for SDHx germline mutations. We also studied the pituitary gland and hormonal profile of Sdhb(+/-) mice and their wild-type littermates at different ages.
  
  
  RESULTS
  No SDHx mutations were detected among sporadic PA, whereas three of four familial cases were positive for a mutation (75%). Most of the SDHx-deficient PAs were either prolactinomas or somatotropinomas. Pituitaries of Sdhb(+/-) mice older than 12 months had an increased number mainly of prolactin-secreting cells and several ultrastructural abnormalities such as intranuclear inclusions, altered chromatin nuclear pattern, and abnormal mitochondria. Igf-1 levels of mutant mice tended to be higher across age groups, whereas Prl and Gh levels varied according to age and sex.
  
  
  CONCLUSIONS
  The present study confirms the existence of a new association that we termed 3PAs. It is due mostly to germline SDHx defects, although sporadic cases of 3PAs without SDHx defects also exist. Using Sdhb(+/-) mice, we provide evidence that pituitary hyperplasia in SDHx-deficient cells may be the initial abnormality in the cascade of events leading to PA formation.
authors.affiliation: Section on Endocrinology and Genetics (P.X., E.S., S.A.M., P.M., M.R., N.R., M.d.L.L.S., C.L., E.B., M.L., C.A.S.), Program on Developmental Endocrinology and Genetics, Section on Medical Neuroendocrinology (P.B., A.G.), Program in Reproductive and Adult Endocrinology, Section on Molecular Dysmorphology (C.A.W., A.C.), Program in Developmental Endocrinology and Genetics, Microscopy and Imaging Core (L.D.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Laboratory of Pathology (A.G., M.Q., K.P.), National Cancer Institute, and Biostatistics and Clinical Epidemiology Service (D.K.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; Department of Endocrinology (C.M.), University of Connecticut Health Center, Farmington, Connecticut 06030; Genomic Medicine Institute (J.M., C.E.), Cleveland Clinic, Cleveland, Ohio 44195; Department of Biochemistry and Molecular Biology (L.J.M.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; and Department of Molecular Medicine (P.B.), Institute of Virology, Slovak Academy of Sciences, 833 06 Bratislava, Slovakia.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Xekouki
authors.forename: Eva
authors.initials: E
authors.lastname: Szarek
authors.forename: Petra
authors.initials: P
authors.lastname: Bullova
authors.forename: Alessio
authors.initials: A
authors.lastname: Giubellino
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.forename: Spyridon A
authors.initials: SA
authors.lastname: Mastroyannis
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Mastorakos
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.forename: Margarita
authors.initials: M
authors.lastname: Raygada
authors.forename: Nadia
authors.initials: N
authors.lastname: Rentia
authors.forename: Louis
authors.initials: L
authors.lastname: Dye
authors.forename: Antony
authors.initials: A
authors.lastname: Cougnoux
authors.forename: Deloris
authors.initials: D
authors.lastname: Koziol
authors.forename: Maria de La Luz
authors.initials: Mde L
authors.lastname: Sierra
authors.forename: Charalampos
authors.initials: C
authors.lastname: Lyssikatos
authors.forename: Elena
authors.initials: E
authors.lastname: Belyavskaya
authors.forename: Carl
authors.initials: C
authors.lastname: Malchoff
authors.forename: Jessica
authors.initials: J
authors.lastname: Moline
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Louis James
authors.initials: LJ
authors.lastname: Maher
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Maya
authors.initials: M
authors.lastname: Lodish
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*; D055815:Young Adult
chemical_list: D013385:Succinate Dehydrogenase