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Genetics of Pheochromocytoma and Paraganglioma in Spanish Patients

Hereditary Endocrine Cancer Group (A.C., I.L., E.L.-J., C.M.-C., S.L., L.J.L.-G., R.L., C.R.-A., M.R.), Genotyping Unit (G.P., A.G.-N.), and Spanish National Cancer Research Centre, Institute de Salud Carlos III Center for Biomedical Research on Rare Diseases (A.C., C.R.-A., M.R.), 28029 Madrid, Spain; Department of Genetics (N.B., A.-P.G.-R.), Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 75908 Paris, France; Department of Endocrinology (J.A.D.), Hospital Universitario Clínico San Carlos, 28013 Madrid, Spain; Hypertension Unit (E.L.-V.), Hospital Universitario Gregorio Marañón, 28007 Madrid, Spain; and Oncologic Pathology Group (A.V., X.M.-G.), Institut de Recerca Biomèdica de Lleida, Institute de Reserca Biomedica de Lleide, 25198 Lleida, Spain

Address all correspondence and requests for reprints to: Mercedes Robledo, Ph.D., Hereditary Endocrine Cancer Group, Human Cancer Genetics Programe, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029 Madrid, Spain. E-mail: mrobledo{at}cnio.es.

Context: The presence of familial history in pheochromocytoma/paraganglioma patients, including syndromic antecedents, leads in the majority of cases to a positive genetic testing for mutations in one of the major susceptibility genes described so far. Furthermore, it has been reported that in the absence of familial antecedents, about 11–24% of patients also carry a mutation in one of these related genes. In these cases, other clinical aspects like bilaterality, multiplicity, location of the tumors, or age at onset can help to recognize the underlying genes involved.

Objective: The objective of the study was to discuss clinical criteria helpful in the genetic diagnosis, placing special emphasis on apparently sporadic cases.

Design: Two hundred thirty-seven nonrelated probands were analyzed for the major susceptibility genes: VHL, RET, SDHB, SDHC, and SDHD. Genetic characterization included both point mutation analysis and gross deletions in the SDH genes performed by multiplex PCR.

Results: As expected, all syndromic probands were genetically diagnosed with a mutation affecting either RET or VHL. A total of 79.1% (19 of 24) and 18.4% (31 of 168) of patients presenting with either nonsyndromic familial antecedents or apparently sporadic presentation were found to carry a mutation in one of the susceptibility genes. Finally, we found a Spanish founder effect for two mutations: SDHB c.166_170delCCTCA and SDHD c.129G>A.

Conclusions: Germline mutations are rare in apparently sporadic probands diagnosed after age 40 yr (3.9% in our series) and mainly involve SDHB. Therefore, we recommend prioritizing SDHB genetic testing in patients developing isolated tumors at any age, especially those with extraadrenal location or malignant behavior.

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