Exp Clin Endocrinol Diabetes 2006; 114 - P05_060
DOI: 10.1055/s-2006-932946

A novel succinate dehydrogenase subunit D (SDHD) gene mutation, F136frameshift, causes familial malignant extraadrenal paragangliomas

C Fottner 1, H Rossmann 2, B Schamberger 1, B Bausch 3, HPH Neumann 3, A Helisch 4, M Schreckenberger 4, TJ Musholt 5, T Bartenstein 4, K Lackner 2, MM Weber 1
  • 1I. Medizinische Klinik und Poliklinik, Klinikum der Johannes Gutenberg Universität, Schwerpunkt Endokrinologie, Mainz, Germany
  • 2Institut für Klinische Chemie, Klinikum der Johannes Gutenberg Universität, Mainz, Germany
  • 3Abtl. Innere Medizin IV, Universitätsklinikum, Freiburg, Germany
  • 4Klinik und Poliklinik für Nuklearmedizin, Klinikum der Johannes Gutenberg Universität, Mainz, Germany
  • 5Klinik und Poliklinik für Allgemein – und Viszeralchirurgie, Endokrine Chirurgie, Mainz, Germany

Objective: Germline mutations of the gene encoding SDHD predispose to paraganglioma syndrome type 1, a dominantly inherited disorder characterized by the development of usually benign pheochromocytomas (PHEO) as well as extraadrenal paragangliomas (PGL). In contrast to SDHB mutation carriers who have more frequently malignant tumors, PGL-1 individuals are less likely to develop malignant disease. However, in this study we report for the first time a family with malignant metastatic PGL, exhibiting a novel germline mutation in the SDHD gene.

Results: The 42-year-old female index patient was diagnosed with an extraadrenal PGL after excision of a tumor of the 8th vertebra. The medical history was negative besides an operation of bilateral carotid body tumors and a positive family history for head and neck tumors of the father and the sister. Further biochemical testing and functional imaging revealed PGL-suspect lesions in the spine, the lungs, the liver and in cervical lymph nodes/paraganglia. Biopsy of the liver showed metastases of a malignant neuroendocrine tumor similar to that excised from the vertebra, thus confirming the diagnosis of a malignant metastatic paraganglioma. Analysis of the patients germline DNA revealed a novel mutation (c.408 del T / F136frameshift) in exon 4 of the SDHD gene, whereas no germline mutations in the SDHC/B, VHL, and RET genes could be identified. Genetic screening of 6 asymptomatic first degree family members identified 3 mutation-positive relatives. While the mutation positive daughter and the niece of the index patient did not show any pathological findings on further diagnosis, the asymptomatic sister showed recurrent bilateral cervical head and neck PGL and a large mediastinal PGL in the aortic arch.

Conclusion: These findings indicate that even if SDHD mutation carriers usually develop benign tumors, in some cases malignant and metastatic PGL can occur, implying the necessity of a close follow-up of affected familiy members and, to allow early treatment with low morbidity, adequate genetic testing and counseling.