Xekouki Paraskevi, Szarek Eva, Bullova Petra, Giubellino Alessio, Quezado Martha, Mastroyannis Spyridon A, Mastorakos Panagiotis, Wassif Christopher A, Raygada Margarita, Rentia Nadia, Dye Louis, Cougnoux Antony, Koziol Deloris, Sierra Maria de La Luz, Lyssikatos Charalampos, Belyavskaya Elena, Malchoff Carl, Moline Jessica, Eng Charis, Maher Louis James, Pacak Karel, Lodish Maya, Stratakis Constantine A
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;100(5):E710-9. doi: 10.1210/jc.2014-4297. Epub 2015 Feb 19.
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.
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.
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.
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.
在家族性副神经节瘤（PGL）/嗜铬细胞瘤（PHEO）及其他肿瘤中已发现编码琥珀酸脱氢酶（SDH）亚基A、B、C和D的基因种系突变。我们描述了1例患有家族性PGL的患者，其垂体生长激素分泌型腺瘤（PA）由SDHD突变引起。此后又有其他患有PA和SDHx缺陷的患者被报道。
我们研究了168例未经选择的散发性PA患者，以及PA、PGL和/或嗜铬细胞瘤相关患者，我们将这种情况命名为3P关联（3PA）以研究SDHx种系突变。我们还研究了不同年龄的Sdhb(+/-)小鼠及其野生型同窝小鼠的垂体和激素谱。
在散发性PA中未检测到SDHx突变，而4例家族性病例中有3例突变呈阳性（75%）。大多数SDHx缺陷型PA为泌乳素瘤或生长激素瘤。12个月以上的Sdhb(+/-)小鼠垂体中，主要是泌乳素分泌细胞数量增加，并且存在一些超微结构异常，如核内包涵体、染色质核型改变和线粒体异常。突变小鼠的Igf-1水平在各年龄组中往往较高，而Prl和Gh水平则随年龄和性别而变化。
本研究证实了一种我们称为3PA的新关联的存在。这主要是由于种系SDHx缺陷，尽管也存在无SDHx缺陷的散发性3PA病例。通过使用Sdhb(+/-)小鼠，我们提供了证据表明SDHx缺陷细胞中的垂体增生可能是导致PA形成的一系列事件中的初始异常。
