X214L
Families with VHL disease type 2A were evaluated for mutations in the VHL gene. In four families, three different coding sequence substitutions causing a 15 amino-acid extension from the original stop codon of the VHL gene were described. Genomic DNA was extracted from peripheral blood lymphocytes using standard procedures. Sequence analysis consisted of polymerase chain reaction (PCR) amplification and automated fluorescence sequencing of all three VHL exons. Patient 1 (family 1), female, presented with a pheochromocytoma at age 11, a pheochromocytoma at age 20, bilateral retinal hemangioblastoma at age 20, and a nodal metastatic pancreatic neuroendocrine tumor at age 20. She had a family history of early onset pheochromocytoma. She was found to have a substitution mutation in the VHL gene causing a loss of the stop codon, and an extension of 14 amino acids on the C-terminal end of the protein c.641G>T (p.*214Lext*14). This mutation is noted as p.*214Lext*15 in the paper due to a difference in nomenclature.) Her mother was found to have the same mutation. Her mother had two pheochromocytomas at age 12, and was found to have bilateral retinal hemangioblastomas at age 40. Her brother was found to have a pheochromocytoma at age 13, but was not sequenced. Her maternal grandfather was noted to have had liver cancer at 72, her great grandfather had unspecified cancer, and her great aunt had Hodgkin's lymphoma at age 38. A second patient (patient 2) from an independent family was found to have the same mutation as patient 1. Patient 2 was also female and presented with bilateral retinal hemangioblastomas. Her last recorded age was 38 years old, and no age of diagnosis was provided.