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A Personal Experience
a Section of Endocrinology, b Clinical Biochemistry, c Medical Genetic, and d Radiology, Department of Clinical Physiopathology, e Section of Vascular Surgery, Department of Clinical and Surgical Critical Care, and f Department of Human Pathology and Oncology, University of Florence Medical School, Florence, Italy g ICP Istituti Clinici di Perfezionamento, Padiglione Alfieri, Milan, Italy h Internal Medicine 2, Pistoia Hospital, Pistoia, Italy i Department of Internal Medicine, University of Pisa, Pisa, Italy
Key Words: succinate dehydrogenase • founder effect • neural crest–derived tumors
Address for correspondence: Prof. M. Mannelli, Endocrinology Section, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6 50139, Florence, Italy. Voice: ++39-055-4271428; fax: ++39-055-4271413. e-mail: m.mannelli{at}dfc.unifi.it
Mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are frequently involved in the development of neural crest-derived (NCD) tumors, such as pheochromocytomas (PHEOs) or paragangliomas (PGLs). In this study we report the results of sequencing analysis in leukocyte DNA of patients affected by PHEO/PGL who turned out to be SDH mutation carriers. A nonsense germline heterozygous mutation (Q109X) was found in the exon 4 of the SDHD gene in the index cases of six unrelated families affected by PHEO/PGL. Haplotype analysis showed the presence of a founder effect. Affected patients showed high clinical variability, ranging from monolateral to bilateral glomus tumors, variably associated or not with PGLs or PHEOs. A novel missense SDHD variant, T112I, was also found in one of our families. A new missense G106D mutation, involving a highly conserved amino acid, was found in two sisters affected by bilateral glomus tumors. A P81L mutation associated with abdominal and head and neck PGL was detected in three families. A G12S variant of the SDHD gene was found in one patient affected by a PHEO. The finding of this variant in 3 of 100 control subjects suggests that it is a polymorphism and not a mutation. A novel IVS2-1G>T variant was found at intron 2 of SDHD gene in one patient affected by a glomus tumor. All the tumors associated with SDHD mutations were benign. Conversely, the only mutation we found in SDHB gene (IVS3 + 1G>A) was associated with a malignant PHEO.
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