ORIGINAL ARTICLE

Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas

B E Baysal^1,2,3, J E Willett-Brozick², E C Lawrence³, C M Drovdlic³, S A Savul³, D R McLeod⁴, H A Yee⁴, D E Brackmann⁵, W H Slattery, III⁵, E N Myers², R E Ferrell³, W S Rubinstein^3,6

¹ Department of Psychiatry, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA
² Department of Otolaryngology, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA
³ Department of Human Genetics, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA
⁴ Calgary Health Region, Alberta, Canada
⁵ House Ear Institute, Los Angeles, CA, USA
⁶ University of Pittsburgh Cancer Institute, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Correspondence to:
Correspondence to:
Dr B E Baysal, Departments of Psychiatry, Otolaryngology, and Human Genetics, University of Pittsburgh School of Medicine, 3811 O'Hara Street R1445, Pittsburgh, PA 15213, USA;
baysalbe{at}msx.upmc.edu

Background: Paragangliomas are rare and highly heritable tumours of neuroectodermal origin that often develop in the head and neck region. Germline mutations in the mitochondrial complex II genes, SDHB, SDHC, and SDHD, cause hereditary paraganglioma (PGL).

Methods: We assessed the frequency of SDHB, SDHC, and SDHD gene mutations by PCR amplification and sequencing in a set of head and neck paraganglioma patients who were previously managed in two otolaryngology clinics in the USA.

Results: Fifty-five subjects were grouped into 10 families and 37 non-familial cases. Five of the non-familial cases had multiple tumours. Germline SDHD mutations were identified in five of 10 (50%) familial and two of 37 (5%) non-familial cases. R38X, P81L, H102L, Q109X, and L128fsX134 mutations were identified in the familial cases and P81L was identified in the non-familial cases. Both non-familial cases had multiple tumours. P81L and R38X mutations have previously been reported in other PGL families and P81L was suggested as a founder mutation. Allelic analyses of different chromosomes carrying these mutations did not show common disease haplotypes, strongly suggesting that R38X and P81L are potentially recurrent mutations. Germline SDHB mutations were identified in two of 10 (20%) familial and one of 33 (3%) non-familial cases. P131R and M71fsX80 were identified in the familial cases and Q59X was identified in the one non-familial case. The non-familial case had a solitary tumour. No mutations could be identified in the SDHC gene in the remaining four families and 20 sporadic cases.

Conclusions: Mutations in SDHD are the leading cause of head and neck paragangliomas in this clinic patient series. SDHD and SDHB mutations account for 70% of familial cases and 8% of non-familial cases. These results also suggest that the commonness of the SDHD P81L mutation in North America is the result of both a founder effect and recurrent mutations.

Keywords: succinate dehydrogenase; carotid body tumours; 11q23; genomic imprinting

Abbreviations: CB, carotid body; PGL, paraganglioma; STRP, single tandem repeat polymorphism

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Hao, H.-X., Khalimonchuk, O., Schraders, M., Dephoure, N., Bayley, J.-P., Kunst, H., Devilee, P., Cremers, C. W. R. J., Schiffman, J. D., Bentz, B. G., Gygi, S. P., Winge, D. R., Kremer, H., Rutter, J. (2009). SDH5, a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in Paraganglioma. Science 325: 1139-1142 [Abstract] [Full Text]  
• Park, J. S., Sharma, L. K., Li, H., Xiang, R., Holstein, D., Wu, J., Lechleiter, J., Naylor, S. L., Deng, J. J., Lu, J., Bai, Y. (2009). A heteroplasmic, not homoplasmic, mitochondrial DNA mutation promotes tumorigenesis via alteration in reactive oxygen species generation and apoptosis. Hum Mol Genet 18: 1578-1589 [Abstract] [Full Text]  
• Mannelli, M., Castellano, M., Schiavi, F., Filetti, S., Giacche, M., Mori, L., Pignataro, V., Bernini, G., Giache, V., Bacca, A., Biondi, B., Corona, G., Di Trapani, G., Grossrubatscher, E., Reimondo, G., Arnaldi, G., Giacchetti, G., Veglio, F., Loli, P., Colao, A., Ambrosio, M. R., Terzolo, M., Letizia, C., Ercolino, T., Opocher, G., the Italian Pheochromocytoma/Paraganglioma Network, (2009). Clinically Guided Genetic Screening in a Large Cohort of Italian Patients with Pheochromocytomas and/or Functional or Nonfunctional Paragangliomas. J. Clin. Endocrinol. Metab. 94: 1541-1547 [Abstract] [Full Text]  
• Neumann, H. P.H., Erlic, Z., Boedeker, C. C., Rybicki, L. A., Robledo, M., Hermsen, M., Schiavi, F., Falcioni, M., Kwok, P., Bauters, C., Lampe, K., Fischer, M., Edelman, E., Benn, D. E., Robinson, B. G., Wiegand, S., Rasp, G., Stuck, B. A., Hoffmann, M. M., Sullivan, M., Sevilla, M. A., Weiss, M. M., Peczkowska, M., Kubaszek, A., Pigny, P., Ward, R. L., Learoyd, D., Croxson, M., Zabolotny, D., Yaremchuk, S., Draf, W., Muresan, M., Lorenz, R. R., Knipping, S., Strohm, M., Dyckhoff, G., Matthias, C., Reisch, N., Preuss, S. F., Esser, D., Walter, M. A., Kaftan, H., Stover, T., Fottner, C., Gorgulla, H., Malekpour, M., Zarandy, M. M., Schipper, J., Brase, C., Glien, A., Kuhnemund, M., Koscielny, S., Schwerdtfeger, P., Valimaki, M., Szyfter, W., Finckh, U., Zerres, K., Cascon, A., Opocher, G., Ridder, G. J., Januszewicz, A., Suarez, C., Eng, C. (2009). Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out. Cancer Res. 69: 3650-3656 [Abstract] [Full Text]  
• Joshua, A. M., Ezzat, S., Asa, S. L., Evans, A., Broom, R., Freeman, M., Knox, J. J. (2009). Rationale and Evidence for Sunitinib in the Treatment of Malignant Paraganglioma/Pheochromocytoma. J. Clin. Endocrinol. Metab. 94: 5-9 [Abstract] [Full Text]  
• Peczkowska, M., Erlic, Z., Hoffmann, M. M., Furmanek, M., Cwikla, J., Kubaszek, A., Prejbisz, A., Szutkowski, Z., Kawecki, A., Chojnowski, K., Lewczuk, A., Litwin, M., Szyfter, W., Walter, M. A., Sullivan, M., Eng, C., Januszewicz, A., Neumann, H. P. H. (2008). Impact of Screening Kindreds for SDHD p.Cys11X as a Common Mutation Associated with Paraganglioma Syndrome Type 1. J. Clin. Endocrinol. Metab. 93: 4818-4825 [Abstract] [Full Text]  
• Baysal, B E (2008). Clinical and molecular progress in hereditary paraganglioma. J. Med. Genet. 45: 689-694 [Abstract] [Full Text]  
• Greenberger, L. M., Horak, I. D., Filpula, D., Sapra, P., Westergaard, M., Frydenlund, H. F., Albaek, C., Schroder, H., Orum, H. (2008). A RNA antagonist of hypoxia-inducible factor-1{alpha}, EZN-2968, inhibits tumor cell growth. Molecular Cancer Therapeutics 7: 3598-3608 [Abstract] [Full Text]  
• Eng, C. (2008). SDHB--A Gene for All Tumors?. JNCI J Natl Cancer Inst 100: 1193-1195 [Full Text]  
• Koopmans, K. P., Jager, P. L., Kema, I. P., Kerstens, M. N., Albers, F., Dullaart, R. P.F. (2008). 111In-Octreotide Is Superior to 123I-Metaiodobenzylguanidine for Scintigraphic Detection of Head and Neck Paragangliomas. JNM 49: 1232-1237 [Abstract] [Full Text]  
• Pigny, P., Vincent, A., Cardot Bauters, C., Bertrand, M., de Montpreville, V. T., Crepin, M., Porchet, N., Caron, P. (2008). Paraganglioma after Maternal Transmission of a Succinate Dehydrogenase Gene Mutation. J. Clin. Endocrinol. Metab. 93: 1609-1615 [Abstract] [Full Text]  
• Weber, F., Eng, C. (2008). Update on the Molecular Diagnosis of Endocrine Tumors: Toward -omics-Based Personalized Healthcare?. J. Clin. Endocrinol. Metab. 93: 1097-1104 [Abstract] [Full Text]  
• Karagiannis, A., Mikhailidis, D. P, Athyros, V. G, Harsoulis, F. (2007). Pheochromocytoma: an update on genetics and management. Endocr Relat Cancer 14: 935-956 [Abstract] [Full Text]  
• Lima, J., Feijao, T., Ferreira da Silva, A., Pereira-Castro, I., Fernandez-Ballester, G., Maximo, V., Herrero, A., Serrano, L., Sobrinho-Simoes, M., Garcia-Rostan, G. (2007). High Frequency of Germline Succinate Dehydrogenase Mutations in Sporadic Cervical Paragangliomas in Northern Spain: Mitochondrial Succinate Dehydrogenase Structure-Function Relationships and Clinical-Pathological Correlations. J. Clin. Endocrinol. Metab. 92: 4853-4864 [Abstract] [Full Text]  
• Szeto, S. S. W., Reinke, S. N., Sykes, B. D., Lemire, B. D. (2007). Ubiquinone-binding Site Mutations in the Saccharomyces cerevisiae Succinate Dehydrogenase Generate Superoxide and Lead to the Accumulation of Succinate. J. Biol. Chem. 282: 27518-27526 [Abstract] [Full Text]  
• Pasini, B., Matyakhina, L., Bei, T., Muchow, M., Boikos, S., Ferrando, B., Carney, J. A., Stratakis, C. A. (2007). Multiple Gastrointestinal Stromal and Other Tumors Caused by Platelet-Derived Growth Factor Receptor {alpha} Gene Mutations: A Case Associated with a Germline V561D Defect. J. Clin. Endocrinol. Metab. 92: 3728-3732 [Abstract] [Full Text]  
• Korpershoek, E., Petri, B.-J., van Nederveen, F. H, Dinjens, W. N M, Verhofstad, A. A, de Herder, W. W, Schmid, S., Perren, A., Komminoth, P., de Krijger, R. R (2007). Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma. Endocr Relat Cancer 14: 453-462 [Abstract] [Full Text]  
• Timmers, H. J.L.M., Kozupa, A., Chen, C. C., Carrasquillo, J. A., Ling, A., Eisenhofer, G., Adams, K. T., Solis, D., Lenders, J. W.M., Pacak, K. (2007). Superiority of Fluorodeoxyglucose Positron Emission Tomography to Other Functional Imaging Techniques in the Evaluation of Metastatic SDHB-Associated Pheochromocytoma and Paraganglioma. JCO 25: 2262-2269 [Abstract] [Full Text]  
• Timmers, H. J. L. M., Kozupa, A., Eisenhofer, G., Raygada, M., Adams, K. T., Solis, D., Lenders, J. W. M., Pacak, K. (2007). Clinical Presentations, Biochemical Phenotypes, and Genotype-Phenotype Correlations in Patients with Succinate Dehydrogenase Subunit B-Associated Pheochromocytomas and Paragangliomas. J. Clin. Endocrinol. Metab. 92: 779-786 [Abstract] [Full Text]  
• Pollard, P. J., El-Bahrawy, M., Poulsom, R., Elia, G., Killick, P., Kelly, G., Hunt, T., Jeffery, R., Seedhar, P., Barwell, J., Latif, F., Gleeson, M. J., Hodgson, S. V., Stamp, G. W., Tomlinson, I. P. M., Maher, E. R. (2006). Expression of HIF-1{alpha}, HIF-2{alpha} (EPAS1), and Their Target Genes in Paraganglioma and Pheochromocytoma with VHL and SDH Mutations. J. Clin. Endocrinol. Metab. 91: 4593-4598 [Abstract] [Full Text]  
• Jimenez, C., Cote, G., Arnold, A., Gagel, R. F. (2006). Should Patients with Apparently Sporadic Pheochromocytomas or Paragangliomas be Screened for Hereditary Syndromes?. J. Clin. Endocrinol. Metab. 91: 2851-2858 [Abstract] [Full Text]  
• Iliopoulos, O., Chan-Smutko, G., Gonzalez, R. G., Louis, D. N., Stone, J. R. (2006). Case records of the Massachusetts General Hospital. Case 23-2006. A 36-year-old man with numbness in the right hand and hypertension.. NEJM 355: 394-402 [Full Text]  
• Huang, L.-s., Sun, G., Cobessi, D., Wang, A. C., Shen, J. T., Tung, E. Y., Anderson, V. E., Berry, E. A. (2006). 3-Nitropropionic Acid Is a Suicide Inhibitor of Mitochondrial Respiration That, upon Oxidation by Complex II, Forms a Covalent Adduct with a Catalytic Base Arginine in the Active Site of the Enzyme. J. Biol. Chem. 281: 5965-5972 [Abstract] [Full Text]  
• Schiavi, F., Boedeker, C. C., Bausch, B., Peczkowska, M., Gomez, C. F., Strassburg, T., Pawlu, C., Buchta, M., Salzmann, M., Hoffmann, M. M., Berlis, A., Brink, I., Cybulla, M., Muresan, M., Walter, M. A., Forrer, F., Valimaki, M., Kawecki, A., Szutkowski, Z., Schipper, J., Walz, M. K., Pigny, P., Bauters, C., Willet-Brozick, J. E., Baysal, B. E., Januszewicz, A., Eng, C., Opocher, G., Neumann, H. P. H., for the European-American Paraganglioma Study Grou, (2005). Predictors and Prevalence of Paraganglioma Syndrome Associated With Mutations of the SDHC Gene. JAMA 294: 2057-2063 [Abstract] [Full Text]  
• Simi, L, Sestini, R, Ferruzzi, P, Gagliano, M S, Gensini, F, Mascalchi, M, Guerrini, L, Pratesi, C, Pinzani, P, Nesi, G, Ercolino, T, Genuardi, M, Mannelli, M (2005). Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X. J. Med. Genet. 42: e52-e52 [Abstract] [Full Text]  
• Dannenberg, H., van Nederveen, F. H., Abbou, M., Verhofstad, A. A., Komminoth, P., de Krijger, R. R., Dinjens, W. N.M. (2005). Clinical Characteristics of Pheochromocytoma Patients With Germline Mutations in SDHD. JCO 23: 1894-1901 [Abstract] [Full Text]  
• McWhinney, S. R., Pilarski, R. T., Forrester, S. R., Schneider, M. C., Sarquis, M. M., Dias, E. P., Eng, C. (2004). Large Germline Deletions of Mitochondrial Complex II Subunits SDHB and SDHD in Hereditary Paraganglioma. J. Clin. Endocrinol. Metab. 89: 5694-5699 [Abstract] [Full Text]  
• Zeviani, M., Di Donato, S. (2004). Mitochondrial disorders. Brain 127: 2153-2172 [Abstract] [Full Text]  
• Baysal, B E, Willett-Brozick, J E, Filho, P A A, Lawrence, E C, Myers, E N, Ferrell, R E (2004). An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma. J. Med. Genet. 41: 703-709 [Full Text]  
• Neumann, H. P. H., Pawlu, C., Peczkowska, M., Bausch, B., McWhinney, S. R., Muresan, M., Buchta, M., Franke, G., Klisch, J., Bley, T. A., Hoegerle, S., Boedeker, C. C., Opocher, G., Schipper, J., Januszewicz, A., Eng, C., for the European-American Paraganglioma Study Grou, (2004). Distinct Clinical Features of Paraganglioma Syndromes Associated With SDHB and SDHD Gene Mutations. JAMA 292: 943-951 [Abstract] [Full Text]  
• Badenhop, R F, Jansen, J C, Fagan, P A, Lord, R S A, Wang, Z G, Foster, W J, Schofield, P R (2004). The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. J. Med. Genet. 41: e99-e99 [Full Text]  
• Choong, N. W. W., Miles, J. M. (2004). Bilateral Carotid Body Paraganglioma. Mayo Clin Proc. 79: 681-681  
• Oyedotun, K. S., Yau, P. F., Lemire, B. D. (2004). Identification of the Heme Axial Ligands in the Cytochrome b562 of the Saccharomyces cerevisiae Succinate Dehydrogenase. J. Biol. Chem. 279: 9432-9439 [Abstract] [Full Text]  
• Maier-Woelfle, M., Brandle, M., Komminoth, P., Saremaslani, P., Schmid, S., Locher, T., Heitz, P. U., Krull, I., Galeazzi, R. L., Schmid, C., Perren, A. (2004). A Novel Succinate Dehydrogenase Subunit B Gene Mutation, H132P, Causes Familial Malignant Sympathetic Extraadrenal Paragangliomas. J. Clin. Endocrinol. Metab. 89: 362-367 [Abstract] [Full Text]  
• Lehtonen, R., Kiuru, M., Vanharanta, S., Sjoberg, J., Aaltonen, L.-M., Aittomaki, K., Arola, J., Butzow, R., Eng, C., Husgafvel-Pursiainen, K., Isola, J., Jarvinen, H., Koivisto, P., Mecklin, J.-P., Peltomaki, P., Salovaara, R., Wasenius, V.-M., Karhu, A., Launonen, V., Nupponen, N. N., Aaltonen, L. A. (2004). Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors. Am. J. Pathol. 164: 17-22 [Abstract] [Full Text]  
• Guo, J., Lemire, B. D. (2003). The Ubiquinone-binding Site of the Saccharomyces cerevisiae Succinate-Ubiquinone Oxidoreductase Is a Source of Superoxide. J. Biol. Chem. 278: 47629-47635 [Abstract] [Full Text]  
• Bryant, J., Farmer, J., Kessler, L. J., Townsend, R. R., Nathanson, K. L. (2003). Pheochromocytoma: The Expanding Genetic Differential Diagnosis. JNCI J Natl Cancer Inst 95: 1196-1204 [Abstract] [Full Text]  
• Bauters, C, Vantyghem, M-C, Leteurtre, E, Odou, M-F, Mouton, C, Porchet, N, Wemeau, J-L, Proye, C, Pigny, P (2003). Hereditary phaeochromocytomas and paragangliomas: a study of five susceptibility genes. J. Med. Genet. 40: e75-75 [Full Text]  
• Lehtonen, R, Kiuru, M, Rokman, A, Ikonen, T, Cunningham, J M, Schaid, D J, Matikainen, M, Nupponen, N N, Karhu, A, Kallioniemi, O-P, Thibodeau, S N, Schleutker, J, Aaltonen, L A (2003). No fumarate hydratase (FH) mutations in hereditary prostate cancer. J. Med. Genet. 40: e19-19 [Full Text]  
• Maher, E. R., Eng, C. (2002). The pressure rises: update on the genetics of phaeochromocytoma. Hum Mol Genet 11: 2347-2354 [Abstract] [Full Text]  
• Cascon, A, Cebrian, A, Ruiz-Llorente, S, Telleria, D, Benitez, J, Robledo, M (2002). SDHB mutation analysis in familial and sporadic phaeochromocytoma identifies a novel mutation. J. Med. Genet. 39: e64-64 [Full Text]  
• Young, A. L., Baysal, B. E., Deb, A., Young, W. F. Jr. (2002). Familial Malignant Catecholamine-Secreting Paraganglioma with Prolonged Survival Associated with Mutation in the Succinate Dehydrogenase B Gene. J. Clin. Endocrinol. Metab. 87: 4101-4105 [Abstract] [Full Text]  
• Baysal, B E (2002). Hereditary paraganglioma targets diverse paraganglia. J. Med. Genet. 39: 617-622 [Abstract] [Full Text]