Uncommon clinical presentations of pheochromocytoma and paraganglioma in two different patients affected by two distinct novel VHL germline mutations

Summary Context The von Hippel-Lindau (VHL) syndrome is an inherited multitumour disorder characterized by clinical heterogeneity and high penetrance. Pheochromocytoma (Pheo) is present in 10%–15% of cases and can be isolated or associated with other lesions such as haemangioblastomas, kidney cysts or cancer and pancreatic lesions. In VHL patients, Pheos generally secrete norepinephrine and are located in the adrenals. Extra-adrenal Pheos (paragangliomas, PGLs) are rare. Objective While performing genetic testing in patients affected by apparently sporadic Pheos or PGLs, we found two novel different VHL germline mutations in two females who presented with two distinct very uncommon clinical pictures. One patient was studied for the presence of an adrenal incidentaloma and the other for the presence of a neck tumour. Methods and results Patients coding regions and exon–intron boundaries of RET (exons 10, 11, 13–15), VHL, SDHD, SDHB and SDHC genes were amplified and sequenced. We identified two novel VHL point mutations: a L198V missense mutation in a 32-year-old female affected by a right adrenal compound and mixed tumour constituted by an epinephrine secreting Pheo, a ganglioneuroma and an adrenocortical adenoma, and a T152I missense mutation in a 24-year-old female affected by a left carotid body tumour. No other lesions were found in the patients or in the VHL mutation positive relatives. Conclusions 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.