Additional succinate dehydrogenase (SDH) mutations in patients with pituitary adenoma and pheochromocytomas/paragangliomas:pituitary pathology and hormonal findings from the Sdhb heterozygous mouse model (Sdhb+/- -)

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 164-196-Pituitary
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-181
Paraskevi Xekouki*1, Eva Szarek1, Alessio Giubellino1, Maria V Nesterova1, Nadia Rentia1, Louis Dye1, Edra London1, Alex Spyridon Mastroyannis1, Panagiotis Mastorakos1, Maria De La Luz Sierra1, Evgenia Gourgari1, Charalampos Lyssikatos1, Louis Maher2, Karel Pacak1, Charis Eng3 and Constantine A Stratakis1
1National Institutes of Health (NIH), Bethesda, MD, 2Mayo Clinic College of Medicine, Rochester, MN, 3Genomic Medicine Institute, Cleveland, OH
Background: We previously described mutations in Succinate Dehydrogenase (SDHx) that may be involved in pituitary tumor development (1,2). The pathogenetic mechanism remains elusive but aberrant hypoxia signaling may be involved (1). Aim of the study: We looked for new patients with Pheochromocytomas (PHEOs)/Paragangliomas (PGLs) and pituitary tumors with germline SDHx mutations and studied pituitary pathology in parallel with the hormonal profile in Sdhb+/- mice. Subjects and methods: Two new unrelated patients (one sporadic and one familial) seen for a pituitary adenoma and PHEO/PGLs were screened for SDHA, SDHB, SDHC and SDHD germline mutations. Pituitaries (n=3 per group) were collected from 12 month-old Sdhb+/- and age-matched male wild-type (WT) mice and were examined histologically  (H&E staining). Pituitary cells were identified by labeling pituitary sections with antisera against the six pituitary hormones (ACTH, LH, FSH, GH, TSH and PRL) and the proportions of each pituitary cell type were determined. Pituitary ultrastructure was observed by electron microscopy (EM). Serum IGF-1 and prolactin (PRL) levels in Sdhb+/- 6-18 months old (n=10) and WT (n=6) aged-matched mice were determined using an Enzyme-Linked Immunosorbent Assay (ELISA). Results: The sporadic case was a 57 year old (yo) female with bilateral head-neck PGLs and a non-functional pituitary adenoma positive for a known deleterious SDHD exon 3 (c.242C>T/ p. P81L) mutation. The familial case was a 72 yo man with vagal body PGL and a GH-secreting pituitary microadenoma, positive for germline SDHB exon 7 (c.689G>A, p.Arg230His) mutation. Family members presented with the same phenotype and were positive for the same mutation. Mouse data revealed hypercellularity in all Sdhb+/- murine pituitary glands. The proportions of pituitary cells expressing PRL were significantly higher in Sdhb+/- mice, than in WT; GH expressing cells were markedly increased, as well. All other pituitary cells remained unchanged. EM revealed mitochondrial abnormalities, including swelling, elongation and destruction of cristae only in older Sdhb+/- mice. Cells with abnormal morphology tended to be chromophobic, a classical feature of PRL-producing adenomas. IGF-1 and PRL levels were elevated in older Sdhb+/- mice. Conclusions: New cases of this new syndromic association were identified. Pathology and hormonal findings in Sdhb+/-  mice provide strong evidence for the involvement of SDHx in pituitary tumorigenesis.

(1) Xekouki et al.,  J Clin Endocrinol Metab. 2012 97:E357-66. (2) Xekouki et al. Presented in  94th Endocrine Society Annual meeting, Houston, Texas, 2012 (OR41-1)

Nothing to Disclose: PX, ES, AG, MVN, NR, LD, EL, ASM, PM, MDLLS, EG, CL, LM, KP, CE, CAS

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