TY - JOUR
T1 - Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice
AU - Xekouki, Paraskevi
AU - Szarek, Eva
AU - Bullova, Petra
AU - Giubellino, Alessio
AU - Quezado, Martha
AU - Mastroyannis, Spyridon A.
AU - Mastorakos, Panagiotis
AU - Wassif, Christopher A.
AU - Raygada, Margarita
AU - Rentia, Nadia
AU - Dye, Louis
AU - Cougnoux, Antony
AU - Koziol, Deloris
AU - De La Luz Sierra, Maria
AU - Lyssikatos, Charalampos
AU - Belyavskaya, Elena
AU - Malchoff, Carl
AU - Moline, Jessica
AU - Eng, Charis
AU - Maher, Louis James
AU - Pacak, Karel
AU - Lodish, Maya
AU - Stratakis, Constantine A.
N1 - Publisher Copyright:
Copyright © 2015 by the Endocrine Society.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - Context: 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. Design: 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. Conclusion: 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.
AB - Context: 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. Design: 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. Conclusion: 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.
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U2 - 10.1210/jc.2014-4297
DO - 10.1210/jc.2014-4297
M3 - Article
C2 - 25695889
AN - SCOPUS:84929347188
SN - 0021-972X
VL - 100
SP - E710-E719
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 5
ER -