Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas.
OBJECTIVE
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.


METHODS
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.
Mannelli
Massimo
M
Department Clinical Pathophysiology, University of Florence, Viale Pieraccini 5, 50139 Florence, Italy. m.mannelli@dfc.unifi.it
Castellano
Maurizio
M
Schiavi
Francesca
F
Filetti
Sebastiano
S
Giacchè
Mara
M
Mori
Luigi
L
Pignataro
Viviana
V
Bernini
Gianpaolo
G
Giachè
Valentino
V
Bacca
Alessandra
A
Biondi
Bernadette
B
Corona
Giovanni
G
Di Trapani
Giuseppe
G
Grossrubatscher
Erika
E
Reimondo
Giuseppe
G
Arnaldi
Giorgio
G
Giacchetti
Gilberta
G
Veglio
Franco
F
Loli
Paola
P
Colao
Annamaria
A
Ambrosio
Maria Rosaria
MR
Terzolo
Massimo
M
Letizia
Claudio
C
Ercolino
Tonino
T
Opocher
Giuseppe
G
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005784:Gene Amplification; D005787:Gene Frequency; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010235:Paraganglioma / Q000453:epidemiology / Q000235:genetics*; D010673:Pheochromocytoma / Q000453:epidemiology / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D004247:DNA