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

Department of Clinical Pathophysiology (M.M., T.E., V.G.), University of Florence, 50139 Florence, Italy; Veneto Institute of Oncology (G.O., F.S., V.P.) and Department of Medical and Surgical Sciences (G.O.), University of Padua, 35128 Padua, Italy; Department of Medical and Surgical Sciences (M.C., L.M., M.G.), University of Brescia, 25123 Brescia, Italy; Department of Clinical Sciences (C.L., S.F.), University "La Sapienza," 00161 Rome, Italy; Department of Internal Medicine (G.B., A.B.), University of Pisa, 56100 Pisa, Italy; Department of Molecular and Clinical Endocrinology and Oncology (A.C., B.B.), University "Federico II," 80131 Naples, Italy; Department of Biomedical Sciences and Advanced Therapies (M.R.A.), University of Ferrara, 44100 Ferrara, Italy; Unit of Endocrinology (G.C.), Hospital Maggiore, 40133 Bologna, Italy; Othologic Group (G.D.T.), Clinica "Piacenza," 29100 Piacenza, Italy; Department of Medicine and Experimental Oncology (F.V.), Division of Internal Medicine 4 and Hypertension Unit, University of Turin, 10126 Turin, Italy; Department of Endocrinology (P.L., E.G.), Niguarda Ospedale Ca’ Granda, 20100 Milan, Italy; Department of Clinical and Biological Sciences (M.T., G.R.), Internal Medicine I, University of Turin, 10043 Orbassano, Italy; and Division of Endocrinology, Department of Internal Medicine (G.A., G.G.), University Politecnica delle Marche, 60100 Ancona, Italy

Address all correspondence and requests for reprints to: Massimo Mannelli, M.D., Department Clinical Pathophysiology, University of Florence, Viale Pieraccini 5, 50139 Florence, Italy. E-mail: m.mannelli{at}dfc.unifi.it.

Purpose: 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.

Design: 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.

Results: 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%).

Conclusions: 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.

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