Mannelli, M. et al. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or non-functional paragangliomas. J. Clin. Endocrinol. Metab. doi:10.1210/jc.2008-2419

In patients with pheochromocytomas or paragangliomas (neural-crest-derived neuroendocrine tumors), family history and clinical presentation can help establish whether genetic screening is indicated and which genes should be screened first.

In the past decade, researchers have identified a number of germ-line mutations involved in the development of pheochromocytomas and paragangliomas. As systematic screening for all currently known susceptibility mutations is costly, some experts recommend this to be performed only in patients who are most likely to carry such mutations. To identify clinical characteristics that indicate genetic screening, Massimo Mannelli and colleagues assessed the frequency and distribution of hereditary pheochromocytomas and paragangliomas in a large, Italian cohort.

The study included 501 patients (age 5–93 years, 288 females) with pheochromocytomas and/or paragangliomas. Clinical data were obtained from 17 centers; genetic analysis was carried out with use of the same standardized methodology in four laboratories. “We decided to adopt this approach to better understand the genotype–phenotype correlation in the genetic forms and to have clinical indications on which genes to screen for first in our patients,” explains Mannelli (Department of Clinical Pathophysiology, University of Florence, Italy).

The overall prevalence of germ-line mutations was 32.1%—similar to previously reported data. However, researchers found that the frequency of mutations varies greatly depending on the patient's family history and clinical presentation, from 11.6% in patients with a single tumor and negative family history to 100% in patients with a syndromic lesion. In addition, correlations were found between the type, number and malignancy of tumors, age at presentation and the type of mutation. Interestingly, some patients who had first-degree relatives with pheochromocytomas or paragangliomas had an 'apparently normal' genotype, which suggests that not all mutations that heighten susceptibility have been discovered.

Besides looking for additional susceptibility genes, future research should aim to investigate the molecular mechanisms that lead from a mutation to tumor formation, and search for an effective therapy for malignant pheochromocytomas and paragangliomas.