Two tests of peripheral blood by standard methods were negative for Von Hippel-Lindau mutations: A case report

Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the VHL gene causing predisposition to multi-organ benign and malignant neoplasms. Approximately 95-100% of individuals with clinical VHL receive a positive result when they undergo standard genetic testing on DNA extracted from blood. Here, we present the case of an individual with a clinical diagnosis of VHL disease where peripheral blood DNA analysis did not detect a VHL variant.

Our patient is a-38-year-old male whose chief complaints are right shoulder and back pain for almost a year. Cranial Magnetic Resonance Imaging (MRI) showed multiple space occupying lesions in cerebellar hemisphere. Spine MRI showed the formation of intraspinal cavities in cervical 5 to thoracic 10 plane, enhanced lesions in the thoracic 8 vertebral plane. Abdominal MRI showed very weakly enhanced nodules on the left kidney and multiple cystic lesions of pancreas. Our case, without a family history, fulfilled clinical criteria for VHL but initially received negative germline VHL results through multigene panel testing on DNA extracted from peripheral blood leukocytes. One year later, the second peripheral blood send for germline molecular genetic testing was also negative.

Although the patient tested negative for the classic VHL gene, the possibility of somatic mosaicism could not be ruled out. Instead of repeating classic testing, next-generation sequencing, multi-tissue analysis or/and genetic testing of offspring is an efficient tool to identify VHL mosaic mutation.