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  • Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene

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Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene
  1. C Cybulski1,2,
  2. K Krzystolik1,3,
  3. A Murgia4,
  4. B Górski1,
  5. T Dębniak1,
  6. A Jakubowska1,
  7. M Martella4,
  8. G Kurzawski1,
  9. M Prost5,
  10. I Kojder6,
  11. J Limon7,
  12. P Nowacki8,
  13. L Sagan6,
  14. B Białas9,
  15. J Kałuża10,
  16. M Zdunek11,
  17. A Omulecka12,
  18. D Jaskólski13,
  19. E Kostyk14,
  20. B Koraszewska-Matuszewska15,
  21. O Haus16,
  22. H Janiszewska16,
  23. K Pecold17,
  24. M Starzycka18,
  25. R Słomski19,
  26. M Ćwirko20,
  27. A Sikorski21,
  28. B Gliniewicz21,
  29. L Cyryłowski22,
  30. Ł Fiszer-Maliszewska23,
  31. J Gronwald1,
  32. A Tołoczko-Grabarek1,
  33. S Zajączek1,
  34. J Lubiński1
  1. 1Department of Genetics and Pathology, Pomeranian Academy of Medicine, Szczecin, Poland
  2. 2I Department of Pediatrics, Pomeranian Academy of Medicine, SzczeciBiaan, Poland
  3. 3I Department of Ophthalmology, Pomeranian Academy of Medicine, Szczecin, Poland
  4. 4Department of Paediatrics, University of Padua, Italy
  5. 5Department of Ophthalmology, Children's Memorial Health Institute, Warsaw, Poland
  6. 6Department of Neurosurgery, Pomeranian Academy of Medicine, Szczecin, Poland
  7. 7Department of Biology and Genetics, Medical University, Gdansk, Poland
  8. 8Department of Neurology, Pomeranian Academy of Medicine, Szczecin, Poland
  9. 9Department of Pathology, The Silesian Medical Academy, Katowice, Poland
  10. 10Department of Neuropathology, Institute of Neurology, Collegium Medicum, Jagilellonian University, Kraków, Poland
  11. 11Department of Pathology, Medical University, Lublin, Poland
  12. 12Department of Pathology, School of Medicine, Lódź, Poland
  13. 13Department of Neurosurgery, Medical Academy of Lódź, Poland
  14. 14Department of Genetics, Polish-American Children's Hospital, Collegium Medicum, Jagilellonian University, Kraków, Poland
  15. 15Department of Ophthalmology, The Silesian Medical Academy, Katowice, Poland
  16. 16Department of Genetics, Medical Academy, Bydgoszcz, Poland
  17. 17Department of Ophthalmology, Medical Academy, Poznań, Poland
  18. 18Department of Ophthalmology, Collegium Medicum, Jagiellonian University, Kraków, Poland
  19. 19Department of Human Genetics, Poznań, Poland
  20. 20Department of Ophthalmology, Medical Academy, Wrocław, Poland
  21. 21Department of Urology, Pomeranian Academy of Medicine, Szczecin, Poland
  22. 22Department of Radiology, Pomeranian Academy of Medicine, Szczecin, Poland
  23. 23Institute of Immunology and Experimental Therapy PAS, Wrocław, Poland
  1. Correspondence to:
 Dr C Cybulski, Department of Genetics and Pathology, Pomeranian Academy of Medicine, Szczecin ul Polabska 4, 70-115 Szczecin, Poland;
 cezaryc{at}priv6.onet.pl

https://doi.org/10.1136/jmg.39.7.e38

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    Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder characterised by a predisposition to haemangioblastomas of the central nervous system (cHAB) and retina (rHAB), renal cell carcinomas (RCC), phaeochromocytomas and paragangliomas, endolymphatic sac tumours (ELST), pancreatic neuroendocrine tumours (PNET), papillary cystadenomas of epididymis, and adnexal papillary tumours of probable mesonephric origin (APMO). Renal, pancreatic, epididymal, and broad ligament cysts also occur frequently.1 It is caused by germline mutations in the VHL tumour suppressor gene on chromosome 3p25-26.2,3 VHL disease occurs with an estimated incidence of 1:36 000 live births and shows variable expression and age dependent penetrance that is almost complete by the age of 65.4 Median actuarial life expectancy of VHL subjects is reduced to 49 years, renal cell carcinoma5 or CNS haemangioblastoma6 being the most common cause of death. At present, early diagnosis and treatment of VHL associated tumours result in improved prognosis for VHL subjects.7

    The disease can be diagnosed on the basis of clinical criteria in the presence of a single haemangioblastoma, phaeochromocytoma, multiple pancreatic cysts, or renal cell carcinoma in a member of a VHL family. For clinical diagnosis of isolated cases of VHL, at least two haemangioblastomas or a single haemangioblastoma in association with a visceral manifestation are required.8 In early studies, using standard Southern analysis and sequencing of the VHL coding region, disease causing mutations were detected in 38-80% of families fulfilling clinical VHL criteria.1 More recently, the development of quantitative Southern analysis (QSA) to detect partial and complete deletions has improved VHL mutation detection. QSA analysis in conjunction with direct sequencing of the coding region showed germline mutations in 100% of 93 families with definite VHL.9 However, the results implying that all cases fulfilling clinical VHL criteria are related to mutations …

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