Familial Cancer

, 8:465 | Cite as

Mutation screening of VHL gene in a family with malignant bilateral pheochromocytoma: from isolated familial pheochromocytoma to von Hippel-Lindau disease

  • Shirin Hasani-Ranjbar
  • Mahsa M. Amoli
  • Azadeh Ebrahim-Habibi
  • Vahid Haghpanah
  • Maryam Hejazi
  • Akbar Soltani
  • Bagher Larijani
Article

Abstract

von Hippel-Lindau (vHL) disease is an inherited, autosomal dominant syndrome manifested by a variety of benign and malignant tumors. More than 300 germline VHL mutations have been identified that are involved in VHL disease. A large family (four generations) was evaluated. In this paper we report the presence of a single nucleotide mutation in exon 3 of VHL gene c499 C>T causing substitution of Arginine by Tryptophan at position 167 (R 167 W). It was detected in a family with bilateral malignant pheochromocytoma who has been followed for at least 9 years as RET negative isolated familial pheochromocytoma, finally diagnosed as von Hipple-Lindau disease according to retinal angioma and VHL gene mutation. VHL type 2 presenting with both pheochromocytoma and retinal angioma in this family found to be associated with the new missense mutation (c499 C>T) of VHL gene.

Keywords

Familial pheochromocytoma von Hippel-Lindau disease Mutation Pheochromocytomas 

Notes

Acknowledgments

We gratefully thank the patients and their family for consenting to the publication of this study. We thank Miss Parvin Amiri for their assistance with the genetic tests and Dr. Ramin Heshmat for his invaluable consult.

References

  1. 1.
    Stein PP, Black HR (1991) A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution’s experience. Medicine (Baltimore) 70:46–66Google Scholar
  2. 2.
    Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS (2001) Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 134:315–329PubMedGoogle Scholar
  3. 3.
    Neumann HP, Bausch B, McWhinney SR et al (2002) Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466CrossRefPubMedGoogle Scholar
  4. 4.
    Young WF Jr, Abboud AL (2006) Editorial: Paraganglioma—all in the family. J Clin Endocrinol Metab 91:790–792CrossRefPubMedGoogle Scholar
  5. 5.
    Neumann HP, Pawlu C, Peczkowska M et al (2004) Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292:943–951CrossRefPubMedGoogle Scholar
  6. 6.
    Erlic Z, Neumann HP (2009) Familial pheochromocytoma. Hormones (Athens) 8:29–38Google Scholar
  7. 7.
    Maher ER, Yates JR, Harries R et al (1990) Clinical features and natural history of von Hippel-Lindau disease. Q J Med 77:1151–1163PubMedGoogle Scholar
  8. 8.
    Lonser RR, Glenn GM, Walther M et al (2003) von Hippel-Lindau disease. Lancet 361:2059–2067CrossRefPubMedGoogle Scholar
  9. 9.
    Maher ER, Kaelin WG Jr (1997) von Hippel-Lindau disease. Medicine (Baltimore) 76:381–391CrossRefGoogle Scholar
  10. 10.
    Patocs A, Gergics P, Balogh K et al (2008) Ser80Ile mutation and a concurrent Pro25Leu variant of the VHL gene in an extended Hungarian von Hippel-Lindau family. BMC Med Genet 9:29CrossRefPubMedGoogle Scholar
  11. 11.
    Zbar B, Kishida T, Chen F et al (1996) Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 8:348–357CrossRefPubMedGoogle Scholar
  12. 12.
    Schreinemakers JM, Zonnenberg BA, Höppener JW, Hes FJ, Rinkes IH, Lips CJ (2007) A patient with bilateral pheochromocytoma as part of a Von Hippel-Lindau (VHL) syndrome type 2C. World J Surg Oncol 5:112CrossRefPubMedGoogle Scholar
  13. 13.
    Latif F, Tory K, Gnarra J, Yao M et al (1993) Identification of the von Hippel-Lindau Disease tumor suppressor gene. Science 260:1317–1320CrossRefPubMedGoogle Scholar
  14. 14.
    Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22:4991–5004CrossRefPubMedGoogle Scholar
  15. 15.
    Cruz JB, Fernandes LP, Clara SA et al (2007) Molecular analysis of the Von Hippel-Lindau (VHL) gene in a family with non-syndromic pheochromocytoma: the importance of genetic testing. Arq Bras Endocrinol Metabol 51:1463–1467PubMedGoogle Scholar
  16. 16.
    Alvandi E, Pedram M, Soroush AR, Naier BN, Akrami SM (2007) Detection of RET Proto-oncogene Cys634Arg mutation, the cause of medullary thyroid carcinoma, in an Iranian child. Iran J Pediatr 17(Suppl 2):301–305Google Scholar
  17. 17.
    Lindahl E, Azuara C, Koehl P, Delarue M (2006) NOMAD-Ref: visualization, deformation and refinement of macromolecular structures based on all-atom normal mode analysis. Nucleic Acids Res 34:W52–W56CrossRefPubMedGoogle Scholar
  18. 18.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38CrossRefPubMedGoogle Scholar
  19. 19.
    Duan DR, Pause A, Burgess WH et al (1995) Inhibition of transcription elongation by the VHL tumor suppressor protein. Science 269:1402–1406CrossRefPubMedGoogle Scholar
  20. 20.
    Kishida T, Stackhouse TM, Chen F, Lerman MI, Zbar B (1995) Cellular proteins that bind the von Hippel-Lindau disease gene product: mapping of binding domains and the effect of missense mutations. Cancer Res 55:4544–4548PubMedGoogle Scholar
  21. 21.
    Stebbins CE, Kaelin WG, Pavlevitch NP (1999) Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 284:455–461CrossRefPubMedGoogle Scholar
  22. 22.
    Opocher G, Schiavi F, Iacobone M et al (2006) Familial nonsyndromic pheochromocytoma. Ann N Y Acad Sci 1073:149–155CrossRefPubMedGoogle Scholar
  23. 23.
    Gimenez-Roqueplo AP, Lehnert H, Mannelli M, Neumann H, Opocher G, Maher ER, Plouin PF, European Network for the Study of Adrenal Tumours (ENS@T) Pheochromocytoma Working Group (2006) Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf) 65:699–705CrossRefGoogle Scholar
  24. 24.
    Kaelin WG Jr (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682CrossRefPubMedGoogle Scholar
  25. 25.
    Ritter MM, Frilling A, Crossey PA et al (1996) Isolated familial pheochromocytoma as a variant of von Hippel-Lindau disease. J Clin Endocrinol Metab 81:1035–1037CrossRefPubMedGoogle Scholar
  26. 26.
    Tong AL, Zeng ZP, Li HZ et al (2006) von Hippel-Lindau gene mutation in non-syndromic familial pheochromocytomas. Ann N Y Acad Sci 1073:203–207CrossRefPubMedGoogle Scholar
  27. 27.
    Eng C, Crossey PA, Mulligan LM et al (1995) Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. J Med Genet 32:934–937CrossRefPubMedGoogle Scholar
  28. 28.
    Stolle C, Glenn G, Zbar B et al (1998) Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 12:417–423CrossRefPubMedGoogle Scholar
  29. 29.
    Korpershoek E, Petri BJ, van Nederveen FH et al (2007) Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma. Endocr Relat Cancer 14:453–462CrossRefPubMedGoogle Scholar
  30. 30.
    Dollfus H, Massin P, Taupin P et al (2002) Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study. Invest Ophthalmol Vis Sci 43:3067–3074PubMedGoogle Scholar
  31. 31.
    Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Shirin Hasani-Ranjbar
    • 1
  • Mahsa M. Amoli
    • 1
  • Azadeh Ebrahim-Habibi
    • 1
  • Vahid Haghpanah
    • 1
  • Maryam Hejazi
    • 1
  • Akbar Soltani
    • 1
  • Bagher Larijani
    • 1
  1. 1.Endocrinology and Metabolism Research Centre, Shariati HospitalTehran University of Medical SciencesTehranIran

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