RESEARCH ARTICLE Gross SDHB Deletions in Patients with Paraganglioma Detected by Multiplex PCR: A Possible Hot Spot? Alberto Casco ´n, 1 Cristina Montero-Conde, 1 Sergio Ruiz-Llorente, 1 Fa ´tima Mercadillo, 1 Rocı ´o Leto ´ n, 1 Cristina Rodrı ´guez-Antona, 1 Beatriz Martı ´nez-Delgado, 2 Manuel Delgado, 3 Alberto Dı ´ez, 3 Adela Rovira, 4 Jose ´A ´ ngel Dı ´az, 5 and Mercedes Robledo 1 * 1 Hereditary Endocrine Cancer Group,Centro Nacional de Investigaciones Oncolo¤ gicas, Madrid, Spain 2 Department of Human Genetics,Centro Nacional de Investigaciones Oncolo¤ gicas, Madrid, Spain 3 Department of Endocrinology, Hospital del Bierzo, Ponferrada, Spain 4 Department of Endocrinology,Fundacio¤ n Jime¤ nez D ı az, Madrid, Spain 5 Department of Endocrinology, Hospital Universitario Cl  ı nico San Carlos, Madrid, Spain Pheochromocytoma and paraganglioma are rare neuroendocrine tumors that arise in the adrenal medulla and the extra-adre- nal paraganglia, respectively. Inheritance of these tumors is mainly a result of mutations affecting the VHL, RET , NF1, and SDH genes. Germ-line mutations of the SDH genes have been found to account for nearly 10% of apparently sporadic cases. Never- theless, alterations other than point mutations have not yet been well characterized. In this study, we investigated the fre- quency of gross SDH deletions in 24 patients who tested negative for point mutations and had at least one of the recom- mended features for genetic testing. For this purpose, we used a technique that is easy to implement in the lab to specifically detect gross deletions affecting SDHB, SDHC, and SDHD. We identified 3 heterozygous SDHB deletions (3/24) in 3 independent cases with paraganglioma: 1 whole SDHB deletion and 2 deletions exclusively affecting exon 1. These latter mutations match the unique gross deletion previously reported, indicating this region could be a hot spot for gross SDHB deletions. It seems likely that these alterations can account for a considerable number of both familial and apparently sporadic paraganglioma cases. Although this is the first report describing the presence of gross deletions in patients with apparently sporadic paragan- gliomas, the extra-adrenal location of the tumor seems to constitute a determining factor for whether to include these patients in genetic testing for gross deletions in the SDHB gene. V V C 2005 Wiley-Liss, Inc. INTRODUCTION Pheochromocytoma (PCC) is a rare catechol- amine-secreting tumor derived from chromaffin cells of the adrenal gland. Tumors that arise outside the adrenal gland are usually termed extra-adrenal PCCs or paragangliomas (PGLs). PGLs are highly vascu- larized and generally benign tumors arising mainly (80% of cases) from neural crest cells of the head and neck or (17% of cases) from intra-abdominal para- ganglia of the sympathoadrenal neuroendocrine system (Lack, 1997). PCC occurs in certain genetic disorders such as von Hippel–Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), neu- rofibromatosis type 1 (NF 1), and SDH syndromes (Schimke, 1990; Anderson and Lynch, 1993; Maher et al., 1996). On the other hand, hereditary PGLs are mainly associated with germ-line mutations in the succinate dehydrogenase (SDH) subunits: SDHB, the iron sulfur protein, associated with PGL type 4; SDHD, the small integral membrane protein, with PGL type 1; and SDHC, the remaining integral protein of the complex, with PGL type 3 (Baysal et al., 2000; Niemann and Muller, 2000; Astuti et al., 2001). To date, large phenotype–genotype studies of SDH mutations have not been conducted, and lit- tle is known about their penetrance and expressiv- ity. Whereas head-and-neck PGLs arise more fre- quently in SDHD mutation carriers, intra-abdomi- nal PGLs and PCCs seem to be associated with SDHB mutations (Neumann et al., 2004). Little is also known about the phenotype of SDHC muta- tion carriers, as only a few families have been described to date. However, genetic testing of the 3 genes is usually performed independently of tumor location. In this sense, more recent studies have pointed to the importance of familial antece- dents, multiplicity, the presence of extra-adrenal tumors, and young age at onset ( 35 years of age) *Correspondence to: Mercedes Robledo, Hereditary Endocrine Cancer Group, Department of Human Genetics, Centro Nacional de Investigaciones Oncolo ´ gicas, Melchor Ferna ´ndez Almagro 3, 28029 Madrid, Spain. E-mail: mrobledo@cnio.es Supported by: Fondo de Investigaciones Sanitarias; Grant num- bers: CP03/00028, PI042154, PI02/0919. Received 22 July 2005; Accepted 27 September 2005 DOI 10.1002/gcc.20283 Published online 28 October 2005 in Wiley InterScience (www.interscience.wiley.com). V V C 2005 Wiley-Liss, Inc. GENES, CHROMOSOMES & CANCER 45:213–219 (2006)