• Paraskevi Xekouki, Eva Szarek, Petra Bullova, Alessio Giubellino, Martha Quezado, Spyridon A Mastroyannis, Panagiotis Mastorakos, Christopher A Wassif, Margarita Raygada, Nadia Rentia, Louis Dye, Antony Cougnoux, Deloris Koziol, Maria de La Luz Sierra, Charalampos Lyssikatos, Elena Belyavskaya, Carl Malchoff, Jessica Moline, Charis Eng, Louis James Maher, Karel Pacak, Maya Lodish, and Constantine A Stratakis.
• 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.
• J. Clin. Endocrinol. Metab. 2015 May 1; 100 (5): E710-9.

ContextGermline 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.DesignWe 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.ResultsNo 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.ConclusionThe 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.

27 keywords...

hide…