Klinische und molekulargenetische Charakterisierung von Phäochromozytomen und Paragangliomen

Pheochromocytoma can occur sporadically or as part of a familial syndrome with specific mutations. Such mutations have been identified in the RET-gene for the MEN 2-syndrome, in the VHL-gene for the VHL-syndrome, in the NF1-gene for the NF1-syndrome, as well as in the SDHB-, SDHC- and SDHD-genes and newly in the SDHAF2- and TMEM127-genes for the hereditary paraganglioma syndromes 1 to 4. The purpose of this dissertation was to assemble and characterise a representative patient population with pheochromocytoma or paraganglioma from Marburg using the available molecular genetic methods. The analysis consisted in testing especially for the RET-gene with its exons 10, 11, 13-16, as well as for the VHL-, SDHB- and SDHD-genes with all their exons. In this dissertation was described in detail a total of 30 patients with pheochromocytoma and/or paraganglioma with their clinical and molecular genetic results. This way it was possible to make a complex genotype-phenotype-analysis of the patients. The whole spectrum of age, gender, production of catecholamines, localisation, number and dignity of the tumours was analysed, as well as the penetrance and the expressivity of the mutations and the variability of the clinical manifestations of the different syndromes. It was also discussed about the indication for a genetic testing of patients with pheochromocytoma and paraganglioma and of their family members, as well as about effective screening algorithms. Of importance is also the genotype-phenotype-analysis regarding the dignity of the tumours. Both benign and malign hereditary pheochromocytomas and paragangliomas were reported in this dissertation. The carriers of SDHB-mutations deserve a closer attention because of their higher risk for malignancy. Mentionable are also the special phenotypes, as those of the ACTH-producing pheochromocytomas, which raise more questions about the tumour pathogenesis of pheochromocytoma and paraganglioma. The importance of the genetic testing of patients with pheochromocytoma or paraganglioma and their family members remains indisputable. The MEN 2-syndrome is among the few hereditary cancer diseases which profit from an early prophylactic operation, in terms of a total thyroidectomy as a curative therapy of the medullary thyroid cancer in young carriers of the specific mutations. The family members without such mutations do not need any regular expensive laboratory and imaging investigations. To sum up, the clinical picture of the various syndrome manifestations of the patients with pheochromocytoma and paraganglioma appears to be as complex and variable as the spectrum of the underlying mutations. However, based on the acquired data from this dissertation, a more efficient molecular genetic testing and optimised patient clinical care, in terms of screening and follow-up examinations, could be achieved.