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

  1. Author:
    Sgambati, M. T.
    Stolle, C.
    Choyke, P. L.
    Walther, M. M.
    Zbar, B.
    Linehan, W. M.
    Glenn, G. M.
  2. Author Address

    Glenn GM 6120 Execut Blvd,EPS 7108,MSC 7236 Bethesda, MD 20892 USA NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH Bethesda, MD 20892 USA NCI, Urol Oncol Branch, Div Clin Sci, NIH Bethesda, MD 20892 USA NIH, Warren G Magnuson Clin Ctr, Dept Radiol Bethesda, MD 20892 USA Univ Penn, Sch Med, Genet Diagnost Lab Philadelphia, PA 19104 USA NCI, Immunobiol Lab, Div Basic Sci Frederick, MD 21701 USA
    1. Year: 2000
  1. Journal: American Journal of Human Genetics
    1. 66
    2. 1
    3. Pages: 84-91
  2. Type of Article: Article
  1. Abstract:

    von Hippel-Lindau disease (VHL [MIM 193300]) is a heritable autosomal dominant multiple-neoplastic disorder with high penetrance. It is characterized by brain and spinal-cord hemangioblastomas, retinal angiomas, clear-cell renal carcinoma, neuroendocrine tumors and cysts of the pancreas, pheochromocytomas, endolymphatic-sac tumors, and papillary cystadenomas of the epididymis and broad ligament. Although most index cases have a positive family history 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 two families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL-gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, the 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the disease have been reported in as many as 23% of kindreds with VHL. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult disease. [References: 28]

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