, Volume 59, Issue 1, pp 175–182 | Cite as

Routine genetic screening with a multi-gene panel in patients with pheochromocytomas

  • Emilia Sbardella
  • Treena Cranston
  • Andrea M. Isidori
  • Brian Shine
  • Aparna Pal
  • Bahram Jafar-Mohammadi
  • Greg Sadler
  • Radu Mihai
  • Ashley B. Grossman
Original Article



Several new gene mutations have been reported in recent years to be associated with a risk of familial pheochromocytoma. However, it is unclear as to whether extensive genetic testing is required in all patients.


The clinical data of consecutive patients operated for pheochromocytoma over a decade in a tertiary referral center were reviewed. Genetic screening was performed using a 10-gene panel: RET, VHL, SDHB, SDHD, SDHA, SDHC, SDHAF2, MAX, TMEM127 and FH.


A total of 166 patients were analyzed: 87 of them had genetic screening performed (39 M: 44.8%, 48 F: 55.2%, age range 6–81 years, mean 45±16.8 years). In total, 22/87 (25.3%) patients had germline mutations, while 65/87 (74.7%) patients presented with apparently sporadic tumors. Germline VHL mutations were identified in 11.7% of patients, RET in 6.8% (five MEN2A/MEN2 and one MEN2B/MEN3), SDHD in 2.3%, MAX in 2.3%, SDHB in 1.1%, and TMEM127 in 1.1% of patients. At diagnosis, 15.1% of patients with unilateral non-syndromic pheochromocytoma showed germline mutations. We identified 19.7% of mutations in patients with unilateral-non-recurrent pheochromocytomas within 5 years vs. 50% in the recurrent-bilateral-metastatic group (p = 0.01). Germline mutations were more frequently seen with bilateral pheochromocytomas (p = 0.001): 80% of patients with bilateral disease had germline mutations (4 VHL, 3 RET, 1 MAX).


The advent of rapid genetic screening using a gene-panel makes it feasible to screen large cohorts of patients and provides a valuable tool to contribute to the prediction of bilateral and malignant disease and to screen family members.


Pheochromocytoma Gene Genetic screening Adrenal Sporadic 







Neuroendocrine tumor










Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration, and its later amendments or comparable ethical standards.


  1. 1.
    J.T. Adler et al., Pheochromocytoma: current approaches and future directions. Oncologist 13(7), 779–793 (2008)CrossRefPubMedGoogle Scholar
  2. 2.
    I. Ilias, K. Pacak, A clinical overview of pheochromocytomas/paragangliomas and carcinoid tumors. Nucl. Med. Biol. 35(Suppl 1), S27–S34 (2008)CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    G. Eisenhofer et al., Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin. Chem. 51(4), 735–744 (2005)CrossRefPubMedGoogle Scholar
  4. 4.
    M.M. Walther, H.R. Keiser, W.M. Linehan, Pheochromocytoma: evaluation, diagnosis, and treatment. World J. Urol. 17(1), 35–39 (1999)CrossRefPubMedGoogle Scholar
  5. 5.
    L. Fishbein, K.L. Nathanson, Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet. 205(1-2), 1–11 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    V.L. Martucci, K. Pacak, Pheochromocytoma and paraganglioma: diagnosis, genetics, management, and treatment. Curr. Probl. Cancer 38(1), 7–41 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    L. Amar et al., Genetic testing in pheochromocytoma or functional paraganglioma. J. Clin. Oncol. 23(34), 8812–8818 (2005)CrossRefPubMedGoogle Scholar
  8. 8.
    N. Burnichon et al., The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J. Clin. Endocrinol. Metab. 94(8), 2817–2827 (2009)CrossRefPubMedGoogle Scholar
  9. 9.
    K. Pacak, S.J. Wimalawansa, Pheochromocytoma and paraganglioma. Endocr. Pract. 21(4), 406–412 (2015)CrossRefPubMedGoogle Scholar
  10. 10.
    H.P. Neumann et al., Germ-line mutations in nonsyndromic pheochromocytoma. N. Engl. J. Med. 346(19), 1459–1466 (2002)CrossRefPubMedGoogle Scholar
  11. 11.
    C.H. Lee et al., Genetics of apparently sporadic pheochromocytoma and paraganglioma in a Chinese population. Horm. Metab. Res. 47(11), 833–838 (2015)CrossRefPubMedGoogle Scholar
  12. 12.
    D. Viskochil et al., Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62(1), 187–192 (1990)CrossRefPubMedGoogle Scholar
  13. 13.
    L.M. Mulligan et al., Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363(6428), 458–460 (1993)CrossRefPubMedGoogle Scholar
  14. 14.
    F. Latif et al., Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260(5112), 1317–1320 (1993)CrossRefPubMedGoogle Scholar
  15. 15.
    R.E. Ferrell et al., Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum. Mol. Genet. 7(13), 2073–2078 (1998)CrossRefPubMedGoogle Scholar
  16. 16.
    S. Niemann, U. Muller, Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat. Genet. 26(3), 268–270 (2000)CrossRefPubMedGoogle Scholar
  17. 17.
    D. Astuti et al., Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 69(1), 49–54 (2001)CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    S. Lee et al., Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell. 8(2), 155–167 (2005)CrossRefPubMedGoogle Scholar
  19. 19.
    S. Schlisio et al., The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 22(7), 884–893 (2008)CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    H.X. Hao et al., SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325(5944), 1139–1142 (2009)CrossRefPubMedGoogle Scholar
  21. 21.
    J. Gaal et al., Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. J. Clin. Endocrinol. Metab. 95(3), 1274–1278 (2010)CrossRefPubMedGoogle Scholar
  22. 22.
    Y. Qin et al., Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat. Genet. 42(3), 229–233 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    N. Burnichon et al., SDHA is a tumor suppressor gene causing paraganglioma. Hum. Mol. Genet. 19(15), 3011–3020 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    I. Comino-Mendez et al., Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat. Genet. 43(7), 663–667 (2011)CrossRefPubMedGoogle Scholar
  25. 25.
    C. Yang et al., Somatic mosaicism of EPAS1 mutations in the syndrome of paraganglioma and somatostatinoma associated with polycythemia. Hum. Genome. Var. 2, 15053 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    A. Buffet et al., A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. Horm. Metab. Res. 44(5), 359–366 (2012)CrossRefPubMedGoogle Scholar
  27. 27.
    F.M. Brouwers et al., High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J. Clin. Endocrinol. Metab. 91(11), 4505–4509 (2006)CrossRefPubMedGoogle Scholar
  28. 28.
    D.E. Benn et al., Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J. Clin. Endocrinol. Metab. 91(3), 827–836 (2006)CrossRefPubMedGoogle Scholar
  29. 29.
    J.W. Lenders et al., Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99(6), 1915–1942 (2014)CrossRefPubMedGoogle Scholar
  30. 30.
    P.F. Plouin et al., European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma. Eur. J. Endocrinol. 174(5), G1–G10 (2016)CrossRefPubMedGoogle Scholar
  31. 31.
    M.E. Robson et al., American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J. Clin. Oncol. 28(5), 893–901 (2010)CrossRefPubMedGoogle Scholar
  32. 32.
    R. Martins, M.J. Bugalho, Paragangliomas/Pheochromocytomas: clinically oriented genetic testing. Int. J. Endocrinol. 2014, 794187 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    L. Fishbein et al., Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann. Surg. Oncol. 20(5), 1444–1450 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    J.P. Brito et al., Testing for germline mutations in sporadic pheochromocytoma/paraganglioma: a systematic review. Clin. Endocrinol. 82(3), 338–345 (2015)CrossRefGoogle Scholar
  35. 35.
    E. Rattenberry et al., A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. J. Clin. Endocrinol. Metab. 98(7), E1248–E1256 (2013)CrossRefPubMedGoogle Scholar
  36. 36.
    NGS in PPGL Study Group, R.A. Toledo, N. Burnichon, A. Cascon, D.E. Benn, J.P. Bayley, J. Welander, C.M. Tops, H. Firth, T. Dwight, T. Ercolino, M. Mannelli, G. Opocher, R. Clifton-Bligh, O. Gimm, E.R. Maher, M. Robledo, A.P. Gimenez-Roqueplo, P.L. Dahia, Consensus statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat. Rev. Endocrinol. 13(4), 233–247. doi: 10.1038/nrendo.2016.185
  37. 37.
    M. Curras-Freixes et al., Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. J. Med. Genet. 52(10), 647–656 (2015)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill HospitalUniversity of OxfordOxfordUK
  2. 2.Department of Experimental MedicineSapienza University of RomeRomeItaly
  3. 3.Oxford Medical Genetics Laboratories, Churchill HospitalUniversity of OxfordOxfordUK
  4. 4.Department of Clinical Biochemistry,John Radcliffe HospitalUniversity of OxfordOxfordUK
  5. 5.Department of Endocrine Surgery, Churchill HospitalOxford University Hospitals NHS Foundation TrustOxfordUK

Personalised recommendations