Download PDF
Horm Metab Res 2012; 44(05): 343-348
DOI: 10.1055/s-0032-1304662
Humans, Clinical
© Georg Thieme Verlag KG Stuttgart · New York

Genetic Screening for von Hippel-Lindau Gene Mutations in Non-syndromic Pheochromocytoma: Low Prevalence and False-positives or Misdiagnosis Indicate a Need for Caution

G. Eisenhofer
1   Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III, University of Dresden, Dresden, Germany
,
C. D. Vocke
2   Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
,
A. Elkahloun
3   Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD, USA
,
T.-T. Huynh
4   Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, Bethesda, MD, USA
,
T. Prodanov
4   Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, Bethesda, MD, USA
,
J.W. M. Lenders
5   Department of Internal Medicine and Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
,
H. J. Timmers
6   Department of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
,
J. N. Benhammou
2   Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
,
W. M. Linehan
2   Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
,
K. Pacak
4   Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, Bethesda, MD, USA
› Author Affiliations
Further Information

Publication History

received 26 September 2011

accepted 31 January 2012

Publication Date:
21 March 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Genetic testing of tumor susceptibility genes is now recommended in most patients with pheochromocytoma or paraganglioma (PPGL), even in the absence of a syndromic presentation. Once a mutation is diagnosed there is rarely follow-up validation to assess the possibility of misdiagnosis. This study prospectively examined the prevalence of von Hippel-Lindau (VHL) gene mutations among 182 patients with non-syndromic PPGLs. Follow-up in positive cases included comparisons of biochemical and tumor gene expression data in 64 established VHL patients, with confirmatory genetic testing in cases with an atypical presentation. VHL mutations were detected by certified laboratory testing in 3 of the 182 patients with non-syndromic PPGLs. Two of the 3 had an unusual presentation of diffuse peritoneal metastases and substantial increases in plasma metanephrine, the metabolite of epinephrine. Tumor gene expression profiles in these 2 patients also differed markedly from those associated with established VHL syndrome. One patient was diagnosed with a partial deletion by Southern blot analysis and the other with a splice site mutation. Quantitative polymerase chain reaction, multiplex ligation-dependent probe amplification, and comparative genomic hybridization failed to confirm the partial deletion indicated by certified laboratory testing. Analysis of tumor DNA in the other patient with a splice site alteration indicated no loss of heterozygosity or second hit point mutation. In conclusion, VHL germline mutations represent a minor cause of non-syndromic PPGLs and misdiagnoses can occur. Caution should therefore be exercised in interpreting positive genetic test results as the cause of disease in patients with non-syndromic PPGLs.

Key words

pheochromocytoma - paraganglioma - von Hippel-Lindau syndrome - mutation testing - germline mutations - loss of heterozygosity
 

  • References

  • 1 Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002; 346: 1459-1466
    CrossrefPubMedGoogle Scholar
  • 2 Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005; 23: 8812-8818
    CrossrefPubMedGoogle Scholar
  • 3 Cascon A, Pita G, Burnichon N, Landa I, Lopez-Jimenez E, Montero-Conde C, Leskela S, Leandro-Garcia LJ, Leton R, Rodriguez-Antona C, Diaz JA, Lopez-Vidriero E, Gonzalez-Neira A, Velasco A, Matias-Guiu X, Gimenez-Roqueplo AP, Robledo M. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab 2009; 94: 1701-1705
    CrossrefPubMedGoogle Scholar
  • 4 Bayley JP, Kunst HP, Cascon A, Sampietro ML, Gaal J, Korpershoek E, Hinojar-Gutierrez A, Timmers HJ, Hoefsloot LH, Hermsen MA, Suarez C, Hussain AK, Vriends AH, Hes FJ, Jansen JC, Tops CM, Corssmit EP, de Knijff P, Lenders JW, Cremers CW, Devilee P, Dinjens WN, de Krijger RR, Robledo M. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 2010; 11: 366-372
    CrossrefPubMedGoogle Scholar
  • 5 Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, Lechleiter JD, Sass M, Aronin N, Schiavi F, Boaretto F, Opocher G, Toledo RA, Toledo SP, Stiles C, Aguiar RC, Dahia PL. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 2010; 42: 229-233
    CrossrefPubMedGoogle Scholar
  • 6 Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, Landa I, Leandro-García LJ, Letón R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gómez-Graña A, de Cubas AA, Inglada-Pérez L, Maliszewska A, Taschin E, Bobisse S, Pica G, Loli P, Hernández-Lavado R, Díaz JA, Gómez-Morales M, González-Neira A, Roncador G, Rodríguez-Antona C, Benítez J, Mannelli M, Opocher G, Robledo M, Cascón A. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 2011; 43: 663-667
    CrossrefPubMedGoogle Scholar
  • 7 Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM, Tischler AS. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. Nat Clin Pract Endocrinol Metab 2007; 3: 92-102
    CrossrefPubMedGoogle Scholar
  • 8 Hattori K, Teranishi J, Stolle C, Yoshida M, Kondo K, Kishida T, Kanno H, Baba M, Kubota Y, Yao M. Detection of germline deletions using real-time quantitative polymerase chain reaction in Japanese patients with von Hippel-Lindau disease. Cancer Sci 2006; 97: 400-405
    CrossrefPubMedGoogle Scholar
  • 9 Eisenhofer G, Pacak K, Huynh TT, Qin N, Bratslavsky G, Linehan WM, Mannelli M, Friberg P, Grebe SK, Timmers HJ, Bornstein SR, Lenders JW. Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer 2011; 18: 97-111
    PubMedGoogle Scholar
  • 10 Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K, Bratslavsky G, Linehan WM, Pacak K. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem 2011; 57: 411-420
    CrossrefPubMedGoogle Scholar
  • 11 Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, Wu X, Korolevich S, Nathanson KL, Stolle CA, Linehan WM. Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dube syndrome. Genes Chromosomes Cancer 2011; 50: 466-477
    CrossrefPubMedGoogle Scholar
  • 12 Brauch H, Hoeppner W, Jahnig H, Wohl T, Engelhardt D, Spelsberg F, Ritter MM. Sporadic pheochromocytomas are rarely associated with germline mutations in the vhl tumor suppressor gene or the ret protooncogene. J Clin Endocrinol Metab 1997; 82: 4101-4104
    CrossrefPubMedGoogle Scholar
  • 13 Pigny P, Cardot-Bauters C, Do Cao C, Vantyghem MC, Carnaille B, Pattou F, Caron P, Wemeau JL, Porchet N. Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation?. Eur J Endocrinol 2009; 160: 227-231
    PubMedGoogle Scholar
  • 14 Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, Mannelli M, Goldstein DS, Linehan WM, Lenders JW, Pacak K. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 2001; 86: 1999-2008
    CrossrefPubMedGoogle Scholar
  • 15 Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore F, Dluhy R, Sosa JA, Ocal IT, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SP, Nose V, Li C, Stiles CD. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 2005; 1: 72-80
    PubMedGoogle Scholar
  • 16 Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS, Elkahloun AG. Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocr Rel Cancer 2004; 11: 897-911
    CrossrefPubMedGoogle Scholar
  • 17 Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HPH, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CHM, Linehan WM, Lerman M. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 1996; 8: 348-357
    CrossrefPubMedGoogle Scholar
  • 18 Young AC, Craven RA, Cohen D, Taylor C, Booth C, Harnden P, Cairns DA, Astuti D, Gregory W, Maher ER, Knowles MA, Joyce A, Selby PJ, Banks RE. Analysis of VHL gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma. Clin Cancer Res 2009; 15: 7582-7592
    CrossrefPubMedGoogle Scholar
  • 19 Ercolino T, Becherini L, Valeri A, Maiello M, Gagliano MS, Parenti G, Ramazzotti M, Piscitelli E, Simi L, Pinzani P, Nesi G, DeglInnocenti D, Console N, Bergamini C, Mannelli M. Uncommon clinical presentations of pheochromocytoma and paraganglioma in two different patients affected by two distinct novel VHL germline mutations. Clin Endocrinol (Oxf) 2008; 68: 762-768
    CrossrefPubMedGoogle Scholar
  • 20 Solano AR, Dourisboure RJ, Weitzel J, Podesta EJ. A cautionary note: false homozygosity for BRCA2 6174delT mutation resulting from a single nucleotide polymorphism masking the wt allele. Eur J Hum Genet 2002; 10: 395-397
    CrossrefPubMedGoogle Scholar
  • 21 Ramus SJ, Harrington PA, Pye C, Peock S, Cook MR, Cox MJ, Jacobs IJ, DiCioccio RA, Whittemore AS, Piver MS, Embrace Easton DF, Ponder BA, Pharoah PD, Gayther SA. Screening for the BRCA1-ins6kbEx13 mutation: potential for misdiagnosis. Mutation in brief #964. Online. Hum Mutat 2007; 28: 525-526
    PubMedGoogle Scholar
  • 22 Choi JH, Velayati A, Stubblefield BK, Orr-Urtreger A, Gan-Or Z, Tayebi N, Sidransky E. False-positive results using a Gaucher diagnostic kit – RecTL and N370S. Mol Genet Metab 2010; 100: 100-102
    CrossrefPubMedGoogle Scholar
  • 23 Miolo G, Crovatto M, Manno M, Pivetta B, Tessitori G, Picci L. Heterozygous variant at nucleotide position 875+11A>T in exon 6A cystic fibrosis transmembrane conductance regulator gene induces 852del22 mutation false-positivity by line probe assay. Fertil Steril 2011; 95 (1121) e1121-e1124
    PubMedGoogle Scholar
  • 24 Cascon A, Lopez-Jimenez E, Landa I, Leskela S, Leandro-Garcia LJ, Maliszewska A, Leton R, de la Vega L, Garcia-Barcina MJ, Sanabria C, Alvarez-Escola C, Rodriguez-Antona C, Robledo M. Rationalization of genetic testing in patients with apparently sporadic pheochromocytoma/paraganglioma. Horm Metab Res 2009; 41: 672-675
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Eisenhofer G, Timmers H, Lenders JW, Bornstein SR, Tiebel O, Mannelli M, King KS, Vocke C, Linehan WM, Bratslavsky G, Pacak K. Age at diagnosis of pheochromocytoma differs according to catecholamine phenotype and tumor location. J Clin Endocrinol Metab 2011; 96: 375-384
    CrossrefPubMedGoogle Scholar