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J Clin Endocrinol Metab. 2014 Oct;99(10):E2046-50. doi: 10.1210/jc.2014-1659. Epub 2014 Jul 8.

Germline FH mutations presenting with pheochromocytoma.

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Department of Medical Genetics (G.R.C., E.R.M.), University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, United Kingdom; Medical Research Council (MRC) Cancer Unit (M.S., E.G., C.F.), University of Cambridge, Hutchison/MRC Research Centre, Cambridge CB2 0XZ, United Kingdom; Centre for Rare Diseases and Personalized Medicine (D.M.W., G.K., E.R.W.), University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; West Midlands Regional Genetics Service (G.K., E.R.W.), Birmingham Women's Hospital, Birmingham B15 2TG, United Kingdom; Division of Genetics and Molecular Medicine (M.A.S., R.C.T.), King's College London School of Medicine, Guy's Hospital, London WC2R 2LS, United Kingdom; Department of Clinical Genetics (J.N.B.), University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom; Department of Clinical Genetics (E.K.), Royal Hospital for Sick Children (Yorkhill), Glasgow G3 8SJ, United Kingdom; and Department of Medical Genetics (P.J.M.), Queen's University Belfast, Belfast Health and Social Care Trust, Belfast BT9 7AB, United Kingdom.



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.


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.


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.


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.

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