Abstract: Objective This is a case report of family with VHL disease caused by a rare synonymous mutation of VHL gene and then the frequency of the mutation in pheochromocytoma/paraganglioma (PPGL) was investigated. Methods Genomic DNA was extracted from the peripheral blood of proband and his families. The whole exome sequencing was performed to examine the potential pathogenic variations in proband and the Sanger sequencing was used to verify the mutations detected above. Results The proband was a 15-year-old male with episodic palpitations, profuse sweating and elevated blood pressure. Biochemical tests showed that 24 h urinary norepinephrine was significantly increased. CT scanning found masses in bilateral adrenal glands. The masses were removed by surgical operation and pathologically diagnosed as pheochromocytoma. In the proband's family, only the aunt of his mother suffered from pheochromocytoma, and the tumor had been surgically removed. A total of 4 family members were found to be carrier of VHL synonymous mutation c.414A＞G (p.Pro138Pro). No one else in the family had other clinical manifestations of VHL disease. In addition, one patient with the same germ line mutation was also found in another 107 cases of PPGL. Conclusions The VHL synonymous mutation is firstly reported in Chinese families. The frequency of the mutation in the PPGL cohort is about 1%.

Key words: bilateral pheochromocytoma, VHL gene, synonymous mutation