The von Hippel-Lindau (VHL) syndrome is an inherited multi-tumor disorder characterized by clinical heterogeneity and high penetrance. Pheochromocytoma (Pheo) is present in 10-15% of cases. It can be isolated or associated with other lesions such as hemangioblastomas, kidney cysts or cancer, and pancreatic lesions. Pheos secrete norepinephrine and are generally located in the adrenals. While performing genetic testing in patients affected by apparently sporadic pheos or PGLs, we found two novel different VHL germline mutations in two patients presenting two uncommon clinical pictures (an adrenal incidentaloma and a neck tumor, respectively).
Coding regions and exon-intron boundaries of RET (exons 10, 11, 13, 14, 15), VHL, SDHD, SDHB and SDHC genes were amplified and sequenced. We identified two novel point mutations: a L198V missense mutation in a 32 yr old female affected by a right adrenal compound and mixed tumor constituted by an epinephrine secreting Pheo, a ganglioneuroma and an adrenocortical adenoma and a T152I missense mutation in a 24 yr old female affected by a left carotid body tumor. An extensive clinical, laboratory and radiological examination of the patients and the mutated relatives did not show any other lesion.
We also analyzed the three-dimensional structure of the wild-type and the mutated VHL protein showing that the mutations are located in functionally relevant sites.
These cases enlarge the list of VHL mutations and add new insights in the clinical variability of VHL disease, thus confirming the importance of genetic testing in patients affected by apparently sporadic Pheos or PGLs.