Predictors and Prevalence of Paraganglioma Syndrome Associated With Mutations of the SDHC Gene

• Published in: JAMA : the journal of the American Medical Association Vol. 294; no. 16; pp. 2057 - 2063
• Main Authors: Schiavi, Francesca, Boedeker, Carsten C, Bausch, Birke, Peçzkowska, Mariola, Gomez, Clara Fuentes, Strassburg, Thomas, Pawlu, Christian, Buchta, Mary, Salzmann, Maren, Hoffmann, Michael M, Berlis, Ansgar, Brink, Ingo, Cybulla, Markus, Muresan, Mihaela, Walter, Martin A, Forrer, Flavio, Välimäki, Matti, Kawecki, Andrzej, Szutkowski, Zbigniew, Schipper, Jörg, Walz, Martin K, Pigny, Pascal, Bauters, Catherine, Willet-Brozick, Joan E, Baysal, Bora E, Januszewicz, Andrzej, Eng, Charis, Opocher, Giuseppe, Neumann, Hartmut P. H, European-American Paraganglioma Study Group, for the
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 26-10-2005
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Deoxyribonucleic acid; Disease; DNA; Europe - epidemiology; General aspects; Genes; Germ-Line Mutation; Head; Head and Neck Neoplasms - epidemiology; Head and Neck Neoplasms - genetics; Heterozygote; Humans; Iron-Sulfur Proteins - genetics; Medical sciences; Membrane Proteins - genetics; Middle Aged; Mutation; Neck; Neoplastic Syndromes, Hereditary - epidemiology; Neoplastic Syndromes, Hereditary - genetics; Neurology; Nucleic Acid Amplification Techniques; Paraganglioma - epidemiology; Paraganglioma - genetics; Pheochromocytoma - epidemiology; Pheochromocytoma - genetics; Prevalence; Prognosis; Protein Subunits - genetics; Registries; Succinate Dehydrogenase - genetics; Tumors of the nervous system. Phacomatoses; Europe; Nervous system diseases; Prevalence; Prediction; Paraganglioma; Epidemiology; Syndrome; Medicine; Association; Gene; Diseases of the autonomic nervous system; Tumor; Genetics; Mutation; Predictive factor; Public health
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.294.16.2057

CONTEXT Paraganglioma syndrome includes inherited head and neck paragangliomas
(HNPs) and adrenal or extra-adrenal pheochromocytomas and are classified according
to the susceptibility genes SDHB, SDHC, and SDHD. In contrast with those with
germline mutations of the SDHB and SDHD genes, clinical and genetic data on patients with mutations of SDHC are scarce. OBJECTIVE To determine the prevalence and clinical characteristics of SDHC mutation carriers compared with patients with SDHB and SDHD mutations and with sporadic
cases. DESIGN, SETTING, AND PATIENTS Genetic screening for SDHC mutations in an
international HNP registry of 121 unrelated index cases and in 371 sporadic
cases from a pheochromocytoma registry, conducted January 1, 2001, until December
31, 2004. Identified index cases and affected relatives were clinically evaluated. MAIN OUTCOME MEASURES Prevalence of and clinical findings for SDHC mutation–associated
HNPs vs those with SDHB and SDHD mutations. RESULTS The prevalence of SDHC carriers was 4% in HNP
but 0% in pheochromocytoma index cases. None of the SDHC mutation carriers had signs of pheochromocytoma. We compared HNPs
in 22 SDHC mutation carriers with the HNPs of SDHB (n = 15) and SDHD (n = 42)
mutation carriers and with 90 patients with sporadic HNPs. Location, number
of tumors, malignancy, and age were different: more carotid body tumors were
found in SDHC (13/22 [59%]) than in sporadic HNPs
(29/90 [32%], P = .03), as well as fewer
instances of multiple tumors in SDHC (2/22) than
in SDHD (24/42; P<.001),
0 malignant tumors in SDHC vs 6/15 in SDHB (P = .002), and younger age
at diagnosis in SDHC than in sporadic HNPs (45 vs
52 years; P = .03). CONCLUSIONS Patients with HNP, but not those with pheochromocytoma, harbor SDHC mutations in addition to those in SDHB and SDHD. In total, more than one quarter
of HNP patients carry a mutation in 1 of these 3 genes. Head and neck paragangliomas
associated with SDHC mutations are virtually exclusively
benign and seldom multifocal. Analysis for germline mutations of SDHC is recommended in apparently sporadic HNP to identify risk of
inheritance.