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Comorbid VHL and SCA2 mutations in a large kindred: confounding diagnosis of neurological dysfunction caused by CNS VHL vascular tumours versus SCA2 atrophic neurodegeneration
  1. D E McNeil1,
  2. W M Linehan2,
  3. G M Glenn1
  1. 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  2. 2Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  1. Correspondence to:
 Dr G M Glenn, Division of Cancer Epidemiology and Genetics, NCI/NIH/EPS/Room 7108, 6120 Executive Boulevard, MSC 7236, Bethesda, MD 20892-7236, USA;

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Von Hippel-Lindau disease (VHL, MIM 193300) is an autosomal dominant heritable neoplastic disorder resulting from any one of 1631 or more non-polymorphic mutations2 found in the VHL tumour suppressor gene on chromosome 3p25.3 Inheritance of a mutated VHL gene predisposes to development of specific types of tumours, including brain and spinal cord haemangioblastoma, renal clear cell carcinoma, phaeochromocytoma, retinal angioma, pancreatic neuroendocrine tumour/islet cell carcinoma, endolymphatic sac tumour, and epididymal and broad ligament papillary cystadenoma.4–8

The spinocerebellar ataxias, also referred to as olivopontocerebellar atrophy, are a diverse group of neurodegenerative disorders associated with atrophy and dysfunction of the cerebellum and brain stem. Varying degrees of extracerebellar manifestations including neuropathy and oculomotor disorders, such as slow saccades and/or ophthalmoplegia, have been described.9

We present clinical and genetic findings for members of a large kindred with a history of both von Hippel-Lindau disease (VHL) and spinocerebellar ataxia type 2 (SCA2, MIM 183090). It is noteworthy that the combined stresses of these two afflictions weakened a number of the nuclear family units of this kindred resulting in separations of parents, children, and sibs.


We studied a multigenerational family with SCA2 and VHL (fig 1). Index family members contacted the National Cancer Institute for screening. They were enrolled in an institutional review board (IRB) approved study of von Hippel-Lindau disease, after reviewing and signing informed consents as well as receiving counselling. Through efforts of the first family members screened, other family members were contacted and informed of our programme for clinical and genetic diagnostic screening. Some members of the extended family had died before the initiation of these efforts. We gathered information on those persons who had died through histories given by living family members as well as information from death certificates.

Figure 1

Family pedigree. VHL is represented by …

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