Hereditary paragangliomas : clinical characteristics and genotype-phenotype associations

Abstract

The findings of the present thesis can be summarized in the following conclusions: 1. In Leiden, the so-called ‘founder effect’ resulted in genetic clustering with an extremely high prevalence of one single SDHD mutation, the SDHD-c.274G>T (p.Asp92Tyr) mutation. 2. Patients with head-and-neck paragangliomas have a considerable impairment of quality of life. 3. Patients with head-and-neck paragangliomas have serious subjective sleep complaints. 4. Patients with SDHD-associated head-and-neck paragangliomas have an increased risk for development of pheochromocytomas and paragangliomas at other locations and life long, repetitive follow up with protocolized clinical, biochemical and radiological screening is therefore mandatory. 5. The use of [123I]-MIBG for detection of intra- and extra-adrenal paragangliomas combined, revealed a sensitivity and specificity of only 80% and 75%, respectively. The sensitivity is dependent on tumor localization and tumor behavior, with an increase in sensitivity to 92% if (intra-adrenal) pheochromocytomas are investigated separately. 6. The practical clinical implications of non-secreting intra-adrenal paragangliomas are currently uncertain. 7. Patients with SDHD mutations have malignant disease in at least ~2.5% of the cases. 8. Mediastinal paragangliomas are associated with mutations in the succinate dehydrogenase genes (either SDHB or SDHD) and aggressive behavior and might be more prevalent than hitherto appreciated. 9. Although the consequences of missing non-secreting and mediastinal paragangliomas in an SDHD-associated population are currently unclear, their possible presence should be taken into consideration in the development of future screening protocols. 10. In the future, [18F]-FDOPA and/or [18F]-FDA are expected to (at least partly) replace MIBG in diagnostic imaging for pheochromocytoma and paraganglioma.