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Clinically Guided Genetic Screening in a Large Cohort of Italian Patients with Pheochromocytomas and/or Functional or Nonfunctional Paragangliomas

2009; Oxford University Press; Volume: 94; Issue: 5 Linguagem: Inglês

10.1210/jc.2008-2419

1945-7197

Massimo Mannelli, Maurizio Castellano, Francesca Schiavi, Sébastiano Filetti, Mara Giacché, Luigi Mori, Viviana Pignataro, Gianpaolo Bernini, Valentino Giaché, Alessandra Bacca, Bernadette Biondi, Giovanni Corona, Giuseppe Di Trapani, Erika Grossrubatscher, Giuseppe Reimondo, Giorgio Arnaldi, Gilberta Giacchetti, Franco Veglio, Paola Loli, Annamaria Colao, Maria Rosaria Ambrosio, Massimo Terzolo, Claudio Letizia, Tonino Ercolino, Giuseppe Opocher,

Cancer, Hypoxia, and Metabolism

The aim of the study was to define the frequency of hereditary forms and the genotype/phenotype correlations in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas.We examined 501 consecutive patients with pheochromocytomas and/or paragangliomas (secreting or nonsecreting). Complete medical and family histories, as well as the results of clinical, laboratory, and imaging studies, were recorded in a database. Patients were divided into different groups according to their family history, the presence of lesions outside adrenals/paraganglia considered syndromic for VHL disease, MEN2, and NF1, and the number and types of pheochromocytomas and/or paragangliomas. Germ-line mutations in known susceptibility genes were investigated by gene sequencing (VHL, RET, SDHB, SDHC, SDHD) or diagnosed according to phenotype (NF1). In 160 patients younger than 50 yr with a wild-type profile, multiplex ligation-dependent probe amplification assays were performed to detect genomic rearrangements.Germline mutations were detected in 32.1% of cases, but frequencies varied widely depending on the classification criteria and ranged from 100% in patients with associated syndromic lesions to 11.6% in patients with a single tumor and a negative family history. The types and number of pheochromocytomas/paragangliomas as well as age at presentation and malignancy suggest which gene should be screened first. Genomic rearrangements were found in two of 160 patients (1.2%).The frequency of the hereditary forms of pheochromocytoma/paraganglioma varies depending on the family history and the clinical presentation. A positive family history and an accurate clinical evaluation of patients are strong indicators of which genes should be screened first.