Alpha Omega Alpha Honor Medical Society

2012 Research Abstract

Are Mutations in Succinate Dehydrogenase complex II (SDHx) involved in pituitary tumorigenesis?

Investigators: Spyridon Mastroyannis, George Washington School of Medicine and Health Sciences and Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD); Paraskevi Xekouki, NICHD; Panagiotis Mastorakos, NICHD; Dimitris Avgeropoulos, NICHD; Aristides Lytras, Joslin Diabetes Center, Harvard Medical School; Monalisa Ferreira Azevedo, NICHD; Anelia Horvath, NICHD; Carl Malcoff, University of Connecticut Health Center; Constantine A. Stratakis, NICHD

Mentor: Constantine Stratakis, MD, NICHD

We recently reported a potentially new syndromic association, that of a GH-secreting pituitary adenoma and pheochromocytoma/paraganglioma (PHEO/PGL)1. Prompted by this observation, we interrogated our International Registry of mostly pediatric sporadic pituitary adenomas, as well as adult and pediatric syndromic pituitary tumors for the occurrence of pituitary adenomas with PHEO/PGL. A total of 161 cases were investigated: 16 were identified as familial/syndromic and 145 as sporadic. Among the syndromic cases 4 were diagnosed with Cushing’s disease and 12 with GH-and PRL-secreting adenomas. Among the sporadic cases 117 were diagnosed with Cushing’s disease, 8 with GH-secreting adenomas, 5 with prolactinomas, 5 with non-secreting tumors, 1 with craniopharyngioma and 9 with hormonal syndromes and no obvious tumor. Out of the 145 sporadic cases 2 presented with the new syndromic association; 1 case had a GH/PRL pituitary adenoma and PHEO/PGL, and the other one an ACTH-producing adenoma and PGLs. In the second case, mutation screening for SDHB, SDHC, SDHD, and SDHAF2 genes was negative, whereas mutation screening for the first case is pending. None of the syndromic cases had any PHEO/PGL association, and all were due to other mutations including 2 in AIP and 3 in MEN1 genes or were due to yet unknown molecular defects. In addition to the two kindreds with pituitary adenomas and PHEO/PGLs and the previously reported family with acromegaly and PHEO/PGLs, we also identified four previously reported polymorphisms, including His50Arg and Gly12Ser in SDHD, as well as, 170A>G,p.His57Arg and 163Ser>Pro in SDHB in the sporadic adenoma population. This represents an unexpectedly higher frequency from what has been reported in the general population for these variants; screening of our own control group is ongoing. Both SDHB 163Ser>Pro and SDHD His50Arg have been associated with mitochondrial dysfunction in a subset of PTEN mutation-negative Cowden and Cowden-like syndrome individuals2. We conclude that as we speculated first, when we described the SDHD mutation in connection with a pituitary tumor and PHEO/PGL, there might be an association of these tumors that may constitute a new syndrome. However, it is rare among sporadic pituitary adenomas, although functional SDHx variants may play a role there, too. This discovery may lead to new therapies targeting mitochondrial oxidation in aggressive pituitary tumors.

1. Xekouki et al. J Clin Endocrinol Metab 2011
2. Ni et al. Am J Hum Genet. 2008

Updated on September 4, 2013.

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