Means, Motive, and Opportunity: SDH Mutations Are Suspects in Pituitary Tumors

Abstract

These are heady times in endocrinology, with the application of new techniques revolutionizing our understanding of the genetic pathophysiology of many syndromes of endocrine deficiency and excess. It seems that not a month goes by without a new genetic discovery, and last year’s teaching slides are already looking out of date. This ferocious pace of progress is uncovering pathways and potential targets for treatment in many rare conditions. Some discoveries are entirely new genetic causes, whereas others are known genes in new disease settings. This situation is analogous to the work of criminologists using the selfsame genetic techniques to link unsolved “cold” cases to known culprits via studies of archived evidence. In the medical setting, similar good clinical detective work is leading to known genetic culprits in other neuroendocrine tumors being hauled in for interrogation in connection with their links to pituitary tumors. In this issue of the JCEM, Dwight et al (1) describe the occurrence of a pituitary adenoma in the setting of a familial succinate dehydrogenase subunit A (SDHA) gene mutation associated with paraganglioma in a first-degree relative. This finding expands the field of the tumor features associated with succinate dehydrogenase subunit (SDHx) mutations into the pituitary, joining the first report from the Stratakis group (2) that definitively linked a succinate dehydrogenase subunit D (SDHD) germline mutation to acromegaly. Also, a case from Spain associated with a succinate dehydrogenase subunit C (SDHC) germline mutation was reported, although without pituitary tumoral DNA confirmation (3). Data from the literature back to 1952 that were reviewed by Xekouki and Stratakis (4) have included 29 instances of coexisting pituitary adenomas and pheochromocytomas/paragangliomas. Some modern cases that were negative for existing causative gene mutations appear to be persuasive for further investigation of SDHx status (4). Indeed, the clinical impact of these mitochondrial protein abnormalities already encompasses a remarkably wide range of tumors from renal cell cancers to sporadic and syndromic gastrointestinal stromal tumors (Carney triad and Carney-Stratakis syndrome) and beyond (5–9). The addition of pituitary adenomas to the expanding phenotype related to inheritable pheochromocytoma/paraganglioma syndromes is intriguing and represents both an opportunity and a challenge. An important area for future study will be to define whether SDHx mutation-associated pituitary adenomas have particular features that differentiate them from the general sporadic population. Clinically relevant pituitary adenomas occur is about 1 in 1000 people in the general population, and prolactinomas account for up to twothirds of these (10). Pituitary adenomas that occur in recognized genetic or familial settings account for about 5% of cases in our experience (11). Most occur in the setting of familial isolated pituitary adenoma—either with or without a germline aryl hydrocarbon receptor interacting protein (AIP) gene mutation—and multiple endocrine neoplasia (MEN) 1 (11–13). Rarer syndromes like that of Carney complex due to protein kinase A regulatory subunit 1A (PRKAR1A) mutations or MEN4 due to cyclindependent kinase inhibitor 1B (CDKN1B) gene mutations also feature pituitary adenomas as part of the described clinical spectrum (14, 15). Large collaborative studies of pituitary adenomas that occur against these known genetic backgrounds have revealed features related to more aggressive behavior, which are useful pointers when determining which patients to offer genetic testing to. AIP