Germline FH mutations presenting with pheochromocytoma

Graeme R. Clark, Marco Sciacovelli, Edoardo Gaude, Diana M. Walsh, Gail Kirby, Michael A. Simpson, Richard C. Trembath, Jonathon N. Berg, Emma R. Woodward, Esther Kinning, Patrick J. Morrison, Christian Frezza, Eamonn R. Maher (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    42 Citations (Scopus)

    Abstract

    CONTEXT: At least a third of the patients with pheochromocytoma (PCC) or paraganglioma (PGL) harbor an underlying germline mutation in a known PCC/PGL gene. Mutations in genes (SDHB, SDHD, SDHC, and SDHA) encoding a component of the tricarboxylic acid cycle, succinate dehydrogenase (SDH), are a major cause of inherited PCC and PGL. SDHB mutations are also, albeit less frequently, associated with inherited renal cell carcinoma. Inactivation of SDH and another tricarboxylic acid cycle component, fumarate hydratase (FH), have both been associated with abnormalities of cellular metabolism, responsible for the activation of hypoxic gene response pathways and epigenetic alterations (eg, DNA methylation). However, the clinical phenotype of germline mutations in SDHx genes and FH is usually distinct, with FH mutations classically associated with hereditary cutaneous and uterine leiomyomatosis and renal cell carcinoma, although recently an association with PCC/PGL has been reported.
    OBJECTIVE AND DESIGN:To identify potential novel PCC/PGL predisposition genes, we initially undertook exome resequencing studies in a case of childhood PCC, and subsequently FH mutation analysis in a further 71 patients with PCC, PGL, or head and neck PGL. RESULTS: After identifying a candidate FH missense mutation in the exome study, we then detected a further candidate missense mutation (p.Glu53Lys) by candidate gene sequencing. In vitro analyses demonstrated that both missense mutations (p.Cys434Tyr and p.Glu53Lys) were catalytically inactive. CONCLUSIONS: These findings 1) confirm that germline FH mutations may present, albeit rarely with PCC or PGL; and 2) extend the clinical phenotype associated with FH mutations to pediatric PCC.
    Original languageEnglish
    Pages (from-to)E2046-E2050
    Number of pages5
    JournalJournal of Clinical Endocrinology and Metabolism
    Volume99
    Issue number10
    Early online date8 Jul 2014
    DOIs
    Publication statusPublished - Oct 2014

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