Succinate Dehydrogenase (SDH) D Subunit (SDHD) Inactivation in a Growth-Hormone-Producing Pituitary Tumor: A New Association for SDH?

Abstract

We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis.

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

“…1). This is consistent with Xekouki et al (6) who observed SDHD LOH accompanied by decreased SDH enzymatic activity in one GH-secreting PA and preliminary data concerning another relevant case in the SDH-deficient setting (5) (Supplementary Table 1, see section on supplementary data given at the end of this article). By contrast, the other PA demonstrated retention of SDHD heterozygosity, which is in accordance with the positive SDHB expression (Fig.…”

“…Although familial PGL syndromes were initially thought to predispose only for pheochromocytoma (PCC) and PGL, other tumor types such as gastrointestinal stromal tumors (GISTs) (2,3), renal cell carcinomas (RCCs) (4), and pituitary adenomas (PAs) (5,6) have expanded the SDHx-associated tumor spectrum. Several other neoplasms have been reported in SDHx mutation carriers including papillary thyroid carcinoma (PTC), medullary thyroid carcinoma, pancreatic neuroendocrine tumor, adrenal cortical adenoma, neuroblastoma (NBL), ganglioneuroma (GN), adenomatoid tumor of the adrenal gland, melanoma, lung cancer, breast carcinoma, oesophageal cancer, rectal and ovarian carcinomas, uterine adenocarcinoma, uterine leiomyoma, testicular seminoma, bladder cancer, meningioma, oligodendroglioma, cecal polyps, and hematolymphoid malignancies (7,8,9,10,11,12,13,14,15,16,17,18,19).…”

“…Biallelic inactivation of SDHx genes has only been reported in six RCC cases (8,16,20,21), two PAs (5,6), one NBL (14), and one testicular seminoma (15) but was not identified in a PA (7), PTC (16), or small-cell lung carcinoma (8). Despite the fact that SDHx inactivation may contribute to these particular phenotypes, the significance of this contribution remains unclear given the relative lack of studies displaying an increased lifetime risk for these tumors arising in the context of an SDH-deficient state (22).…”

15 YEARS OF PARAGANGLIOMA: The association of pituitary adenomas and phaeochromocytomas or paragangliomas

“…Following a case report of an SDHB mutation positive family with PGLs and macroprolactinomas in 2009 (Brahma et al 2009), Xekouki et al (2012) demonstrated loss of heterozygosity at the SDHD locus along with reduced SDHD protein expression in a growth hormone (GH)-secreting macroadenoma in a patient with a germline SDHD mutation.…”

“…Converting association into causality has only begun to occur in the last few years due to the identification of the seemingly ever increasing multiple phaeo/PGL and PA-predisposing genes. Using a combination of tumour DNA analysis to look for loss of heterozygosity (LOH) at specific loci and immunohistochemistry for their related gene products, it has been possible to begin to identify causal relationships (Xekouki et al 2012, Papathomas et al 2014, Dénes et al 2015. Indeed, the term '3Pas' representing the association of three tumour types -pituitary, phaeo and PGL -has been coined to identify this clinical scenario .…”