Exp Clin Endocrinol Diabetes 2013; 121 - P25
DOI: 10.1055/s-0033-1336695

Definition of a new algorithm for molecular-genetic testing of patients with hereditary pheochromocytoma and paraganglioma syndromes

C Fottner 1, H Rossmann 2, JK Bickmann 2, S Sollfranck 2, R Hassoun 2, C Neukirch 2, K Papaspyrou 3, WJ Mann 3, B Schneider-Rätzke 4, D Bartsch 4, KJ Lackner 2, MM Weber 1
  • 1I. Medizinische Klinik und Poliklinik der Universitätsmedizin Mainz, Schwerpunkt Endokrinologie und Stoffwechselerkrankungen, Mainz, Germany
  • 2Universitätsmedizin Mainz, Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany
  • 3Universitätsmedizin Mainz, Dept. of Oto-Rhino-Laryngology, Mainz, Germany
  • 4Universitätsmedizin Mainz, Humangenetik, Mainz, Germany

Objective: We intended to optimise routine genetic testing of 110 pheochromocytoma and paraganglioma index patients by extending the usual panel of genes (SDHB, SDHC, SDHD, VHL, RET-protooncogene) by other genes that have been reported to be involved in the pathogenesis of endocrine tumor syndromes and by correlation of molecular-genetic findings with immunohistochemical analysis of SDHx-expression in resected tumors

Design and method: We designed sequencing assays of the genes SDHAF2/SDH5, TMEM127, PHD2 and SDHA. Large rearrangements of the SDH genes were detected by a commercial MLPA (Multiplex Ligation Dependant Probe Assay). Pyrosequencing was applied in the screening of the only known SDHAF2/SDH5 mutation and in evaluating various potential SNPs in a healthy control population. Expression of SDHA and SDHB in tumor samples was evaluated by immunohistochemical staining.

Results and conclusions: Out of 110 index patients 73% suffered from PGLs, 23.6% from Pheos and 2.7% from both tumor types. In 36.4% (40/110) of cases the underlying mutations were identified (familial tumor syndromes). Mutations were found in the following genes (given as percentage of all tested patients): 3.6% RET, 1.8% VHL, 26.5% SDHB, 17.6% SDHC, 52.9% SDHD, and 2.9% SDHA. The overall number of detected mutations (32.8%, 36/110) was 3.6% (36.4%, 40/110) higher corresponding to an increase in the detection rate by 10% compared with the previous diagnostic strategy. There were 6 novel SDH mutations including a large deletion in SDHB and an amino acid exchange in codon 1 of SDHA. Immunohistochemical staining of the tumor samples showed a loss of SDHB-expression in more than 90% of all familial paraganglioma patients with mutations in the SDHA/B/C-and D-genes. Therefore, routine immunohistochemistry of PHEO/PGL's helps to define cost-effective and rapid molecular genetic testing algorithms for patients with PHEO/PGL.