Mosaicism in von Hippel-Lindau disease: Lessons from kindreds with germline mutations identified in offspring with mosaic parents

von Hippel-Lindau disease (VHL [MIM 193300]) is a heritable autosomal domin ant multiple-neoplastic disorder with high penetrance. It is characterized by brain and spinal-cord hemangioblastomas, retinal angiomas, clear-cell re nal carcinoma, neuroendocrine tumors and cysts of the pancreas, pheochromoc ytomas, endolymphatic-sac tumors, and papillary cystadenomas of the epididy mis and broad ligament. Although most index cases have a positive family hi story of VHL, some do not and may represent de novo cases. Cases without a family history of VHL may or may not have a germline mutation in their VHL tumor-suppressor gene. We present two cases of VHL mosaicism. In each of tw o families, standard testing methods (Southern blot analysis and direct seq uencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysi s of the affected parents' blood detected the VHL-gene mutation in a portio n of their peripheral blood lymphocytes. In one case, detection of the dele ted allele was by FISH, and, in the second case, the 3-bp deletion was dete cted by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Mosaicism in VHL is important to search for and recogni ze when an individual without a family history of VHL has VHL. Patients dia gnosed without family histories of the disease have been reported in as man y as 23% of kindreds with VHL. Identification of individuals potentially mo saic for VHL will affect counseling of families, and these individuals shou ld themselves be included in clinical screening programs for occult disease .