Heritable and Syndromic Pheochromocytoma and Paraganglioma

  • Peter KoppEmail author
Part of the Contemporary Endocrinology book series (COE)


Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine neoplasias that develop in the adrenal medulla or in the paravertebral extra-adrenal ganglia. Although they are more commonly benign (~75%) than malignant (~25%), they can be associated with a high degree of morbidity and a substantial mortality due to the hypersecretion of catecholamines or mass effects. Although PCC/PGL occur more commonly as sporadic tumors, about 30–40% are inherited and associated with predisposing germline mutations in more than 15 susceptibility genes. Several classic autosomal dominant tumor syndromes (von Hippel-Lindau, neurofibromatosis type 1, multiple endocrine neoplasia type 2) are associated with an increased risk for the development of PCC/PGL. Mutations in the TMEM127, MAX, MDH2, FH, and EPAS1/HIF2A genes, among others, can be associated with PCC/PGL, and mutations in the genes encoding the succinate dehydrogenase (SDH) subunits A, B, C, and D or its cofactor SDHAF2 lead to a predisposition to developing paragangliomas (paraganglioma syndrome types 1–5).

Mutational analysis of these susceptibility genes is of increasing clinical importance for the early identification and treatment of carriers, as well as genetic counseling. Important insights into the oncogenic events have been obtained through the recently completed comprehensive molecular characterization of 173 PCC/PGL in The Cancer Genome Atlas (TCGA) project. It has revealed a broad spectrum of somatic mutations (CSDE1, HRAS, RET, EPAS1, NF1) or rearrangements (MAML3, BRAF, NGFR, NF1) affecting several genes and pathways. A thorough understanding of the genetic susceptibility factors and the oncogenic mechanisms underlying PCC/PGL is essential for clinical management, genetic counseling, the identification of tumors with an aggressive behavior, and the development of novel targeted therapeutic modalities for metastatic tumors.


Pheochromocytoma Paraganglioma Genetics Von Hippel-Lindau syndrome Neurofibromatosis Multiple endocrine neoplasia Succinate dehydrogenase genes Genetics 


  1. 1.
    Fishbein L, Nathanson KL. Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet. 2012;205(1–2):1–11.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Gupta G, Pacak K, AACE Adrenal Scientific Committee. Precision medicine: an update on genotype- biochemical phenotype relationships in Pheochromocytoma/Paraganglioma patients. Endoc Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinologists. 2017;23:690–704.Google Scholar
  3. 3.
    Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366(9486):665–75.PubMedCrossRefGoogle Scholar
  4. 4.
    Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, et al. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab. 2011;96(3):717–25.PubMedCrossRefGoogle Scholar
  5. 5.
    Hescot S, Leboulleux S, Amar L, Vezzosi D, Borget I, Bournaud-Salinas C, et al. One- year progression-free survival of therapy-naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013;98(10):4006–12.PubMedCrossRefGoogle Scholar
  6. 6.
    Pamporaki C, Hamplova B, Peitzsch M, Prejbisz A, Beuschlein F, Timmers H, et al. Characteristics of pediatric vs adult pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2017;102(4):1122–32.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, et al. Germ- line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346(19):1459–66.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Neumann HP, Erlic Z, Boedeker CC, Rybicki LA, Robledo M, Hermsen M, et al. Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res. 2009;69(8):3650–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol. 2015;11(2):101–11.PubMedCrossRefGoogle Scholar
  10. 10.
    Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR, et al. Comprehensive molecular characterization of Pheochromocytoma and Paraganglioma. Cancer Cell. 2017;31(2):181–93.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009;94(8):2817–27.PubMedCrossRefGoogle Scholar
  12. 12.
    Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–42.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Jameson J, Kopp P. Principles of human genetics. In: Braunwald E, Fauci A, Kasper D, Hauser S, Longo D, Jameson J, editors. Harrison’s principles of internal medicine. 19th ed. New York: McGraw-Hill; 2015. p. 425–45.Google Scholar
  14. 14.
    NGS in PPGL (NGSnPPGL) Study Group, Toledo RA, Burnichon N, Cascon A, Benn DE, Bayley JP, et al. Consensus statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol. 2017;13(4):233–47.CrossRefGoogle Scholar
  15. 15.
    Toledo RA, Qin Y, Cheng ZM, Gao Q, Iwata S, Silva GM, et al. Recurrent mutations of chromatin-remodeling genes and kinase receptors in pheochromocytomas and paragangliomas. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(9):2301–10.CrossRefGoogle Scholar
  16. 16.
    Murgia A, Martella M, Vinanzi C, Polli R, Perilongo G, Opocher G. Somatic mosaicism in von Hippel-Lindau disease. Hum Mutat. 2000;15(1):114.PubMedCrossRefGoogle Scholar
  17. 17.
    Santarpia L, Sarlis NJ, Santarpia M, Sherman SI, Trimarchi F, Benvenga S. Mosaicism in von Hippel-Lindau disease: an event important to recognize. J Cell Mol Med. 2007;11(6):1408–15.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Kaplan L, Foster R, Shen Y, Parry DM, McMaster ML, O'Leary MC, et al. Monozygotic twins discordant for neurofibromatosis 1. Am J Med Genet A. 2010;152A(3):601–6.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Vogt J, Kohlhase J, Morlot S, Kluwe L, Mautner VF, Cooper DN, et al. Monozygotic twins discordant for neurofibromatosis type 1 due to a postzygotic NF1 gene mutation. Hum Mutat. 2011;32(6):E2134–47.PubMedCrossRefGoogle Scholar
  20. 20.
    Nielsen SM, Rhodes L, Blanco I, Chung WK, Eng C, Maher ER, et al. Von Hippel-Lindau disease: genetics and role of genetic Counseling in a multiple Neoplasia syndrome. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(18):2172–81.CrossRefGoogle Scholar
  21. 21.
    Maher ER, Neumann HP, von Richard S. Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet EJHG. 2011;19(6):617–23.PubMedCrossRefGoogle Scholar
  22. 22.
    Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, et al. Von Hippel- Lindau disease: a genetic study. J Med Genet. 1991;28(7):443–7.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Delman KA, Shapiro SE, Jonasch EW, Lee JE, Curley SA, Evans DB, et al. Abdominal visceral lesions in von Hippel-Lindau disease: incidence and clinical behavior of pancreatic and adrenal lesions at a single center. World J Surg. 2006;30(5):665–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Boedeker CC, Erlic Z, Richard S, Kontny U, Gimenez-Roqueplo AP, Cascon A, et al. Head and neck paragangliomas in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2009;94(6):1938–44.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Gaal J, van Nederveen FH, Erlic Z, Korpershoek E, Oldenburg R, Boedeker CC, et al. Parasympathetic paragangliomas are part of the Von Hippel-Lindau syndrome. J Clin Endocrinol Metab. 2009;94(11):4367–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer. 2015;15(1):55–64.PubMedCrossRefGoogle Scholar
  27. 27.
    Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002;2(9):673–82.PubMedCrossRefGoogle Scholar
  28. 28.
    Min JH, Yang H, Ivan M, Gertler F, Kaelin WG Jr, Pavletich NP. Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling. Science. 2002;296(5574):1886–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Czyzyk-Krzeska MF, Meller J. von Hippel-Lindau tumor suppressor: not only HIF's executioner. Trends Mol Med. 2004;10(4):146–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Nordstrom-O’Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010;31(5):521–37.PubMedGoogle Scholar
  31. 31.
    Chen F, Slife L, Kishida T, Mulvihill J, Tisherman SE, Zbar B. Genotype-phenotype correlation in von Hippel-Lindau disease: identification of a mutation associated with VHL type 2A. J Med Genet. 1996;33(8):716–7.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Rechsteiner MP, von Teichman A, Nowicka A, Sulser T, Schraml P, Moch H. VHL gene mutations and their effects on hypoxia inducible factor HIFalpha: identification of potential driver and passenger mutations. Cancer Res. 2011;71(16):5500–11.PubMedCrossRefGoogle Scholar
  33. 33.
    Forman JR, Worth CL, Bickerton GR, Eisen TG, Blundell TL. Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel-Lindau disease and suggests molecular mechanisms of tumorigenesis. Proteins. 2009;77(1):84–96.PubMedCrossRefGoogle Scholar
  34. 34.
    Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44(2):81–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Primers. 2017;3:17004.PubMedCrossRefGoogle Scholar
  36. 36.
    Johannessen CM, Johnson BW, Williams SM, Chan AW, Reczek EE, Lynch RC, et al. TORC1 is essential for NF1-associated malignancies. Curr Biol. 2008;18(1):56–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis type 1 revisited. Pediatrics. 2009;123(1):124–33.PubMedCrossRefGoogle Scholar
  38. 38.
    Bausch B, Borozdin W, Neumann HP. European-American Pheochromocytoma study G. Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. N Engl J Med. 2006;354(25):2729–31.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Hyde SM, Cote GJ, Grubbs EG. Genetics of multiple endocrine Neoplasia type 1/multiple endocrine Neoplasia type 2 syndromes. Endocrinol Metab Clin N Am. 2017;46(2):491–502.CrossRefGoogle Scholar
  40. 40.
    Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid Off J Am Thyroid Assoc. 2015;25(6):567–610.CrossRefGoogle Scholar
  41. 41.
    Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86(12):5658–71.PubMedCrossRefGoogle Scholar
  42. 42.
    Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med. 2005;257(1):60–8.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Wohllk N, Schweizer H, Erlic Z, Schmid KW, Walz MK, Raue F, et al. Multiple endocrine neoplasia type 2. Best Pract Res Clin Endocrinol Metab. 2010;24(3):371–87.PubMedCrossRefGoogle Scholar
  44. 44.
    Benn DE, Robinson BG, Clifton-Bligh RJ. 15 YEARS OF PARAGANGLIOMA: clinical manifestations of paraganglioma syndromes types 1-5. Endocr Relat Cancer. 2015;22(4):T91–103.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Boedeker CC, Hensen EF, Neumann HP, Maier W, van Nederveen FH, Suarez C, et al. Genetics of hereditary head and neck paragangliomas. Head Neck. 2014;36(6):907–16.PubMedCrossRefGoogle Scholar
  46. 46.
    Bezawork-Geleta A, Rohlena J, Dong L, Pacak K, Neuzil J. Mitochondrial complex II: at the crossroads. Trends Biochem Sci. 2017;42(4):312–25.PubMedCrossRefGoogle Scholar
  47. 47.
    Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287(5454):848–51.PubMedCrossRefGoogle Scholar
  48. 48.
    Gimm O, Armanios M, Dziema H, Neumann HP, Somatic EC. Occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer Res. 2000;60(24):6822–5.PubMedGoogle Scholar
  49. 49.
    Astuti D, Douglas F, Lennard TW, Aligianis IA, Woodward ER, Evans DG, et al. Germline SDHD mutation in familial phaeochromocytoma. Lancet. 2001;357(9263):1181–2.PubMedCrossRefGoogle Scholar
  50. 50.
    Hirawake H, Taniwaki M, Tamura A, Amino H, Tomitsuka E, Kita K. Characterization of the human SDHD gene encoding the small subunit of cytochrome b (cybS) in mitochondrial succinate-ubiquinone oxidoreductase. Biochim Biophys Acta. 1999;1412(3):295–300.PubMedCrossRefGoogle Scholar
  51. 51.
    Ricketts CJ, Forman JR, Rattenberry E, Bradshaw N, Lalloo F, Izatt L, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010;31(1):41–51.PubMedCrossRefGoogle Scholar
  52. 52.
    Badenhop RF, Cherian S, Lord RS, Baysal BE, Taschner PE, Schofield PR. Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. Genes Chromosomes Cancer. 2001;31(3):255–63.PubMedCrossRefGoogle Scholar
  53. 53.
    Cascon A, Ruiz-Llorente S, Fraga MF, Leton R, Telleria D, Sastre J, et al. Genetic and epigenetic profile of sporadic pheochromocytomas. J Med Genet. 2004;41:3):e30.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Yamashita R, Usui T, Hashimoto S, Suzuki H, Takahashi M, Honkura K, et al. Predominant expression of mutated allele of the succunate dehydrogenase D (SDHD) gene in the SDHD-related paragangliomas. Endocr J. 2009;56(9):1129–35.PubMedCrossRefGoogle Scholar
  55. 55.
    Pigny P, Vincent A, Cardot Bauters C, Bertrand M, de Montpreville VT, Crepin M, et al. Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab. 2008;93(5):1609–15.PubMedCrossRefGoogle Scholar
  56. 56.
    Yeap PM, Tobias ES, Mavraki E, Fletcher A, Bradshaw N, Freel EM, et al. Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect. J Clin Endocrinol Metab. 2011;96(12):E2009–13.PubMedCrossRefGoogle Scholar
  57. 57.
    Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004;292(8):943–51.PubMedCrossRefGoogle Scholar
  58. 58.
    Dannenberg H, van Nederveen FH, Abbou M, Verhofstad AA, Komminoth P, de Krijger RR, et al. Clinical characteristics of pheochromocytoma patients with germline mutations in SDHD. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(9):1894–901.CrossRefGoogle Scholar
  59. 59.
    Bayley JP, Kunst HP, Cascon A, Sampietro ML, Gaal J, Korpershoek E, et al. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol. 2010;11(4):366–72.PubMedCrossRefGoogle Scholar
  60. 60.
    Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009;325(5944):1139–42.PubMedCrossRefGoogle Scholar
  61. 61.
    Kunst HP, Rutten MH, de Monnink JP, Hoefsloot LH, Timmers HJ, Marres HA, et al. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17(2):247–54.CrossRefGoogle Scholar
  62. 62.
    Badenhop RF, Jansen JC, Fagan PA, Lord RS, Wang ZG, Foster WJ, et al. The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. J Med Genet. 2004;41(7):e99.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet. 2002;39(3):178–83.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Schiavi F, Boedeker CC, Bausch B, Peczkowska M, Gomez CF, Strassburg T, et al. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA. 2005;294(16):2057–63.PubMedCrossRefGoogle Scholar
  65. 65.
    Peczkowska M, Cascon A, Prejbisz A, Kubaszek A, Cwikla BJ, Furmanek M, et al. Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab. 2008;4(2):111–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69(1):49–54.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, et al. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab. 2002;87(10):4771–4.PubMedCrossRefGoogle Scholar
  68. 68.
    Pollard PJ, El-Bahrawy M, Poulsom R, Elia G, Killick P, Kelly G, et al. Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. J Clin Endocrinol Metab. 2006;91(11):4593–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006;91(3):827–36.PubMedCrossRefGoogle Scholar
  70. 70.
    Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006;91(11):4505–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst. 2008;100(17):1260–2.PubMedCrossRefGoogle Scholar
  72. 72.
    Gill AJ, Chou A, Vilain R, Clarkson A, Lui M, Jin R, et al. Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol. 2010;34(5):636–44.PubMedGoogle Scholar
  73. 73.
    Heller M, Elaraj D, Aleppo G, Sturgeon C. Novel Germline SDHB mutation in a 35-year-old male with malignant bladder Paraganglioma. World J Endocr Surg. 2010;2(3):135–8.CrossRefGoogle Scholar
  74. 74.
    Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet. 1995;11(2):144–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Burnichon N, Briere JJ, Libe R, Vescovo L, Riviere J, Tissier F, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010;19(15):3011–20.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011;96(9):E1472–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Dwight T, Benn DE, Clarkson A, Vilain R, Lipton L, Robinson BG, et al. Loss of SDHA expression identifies SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors. Am J Surg Pathol. 2013;37(2):226–33.PubMedCrossRefGoogle Scholar
  78. 78.
    Dwight T, Mann K, Benn DE, Robinson BG, McKelvie P, Gill AJ, et al. Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. J Clin Endocrinol Metab. 2013;98(6):E1103–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Dénes J, Swords F, Rattenberry E, Stals K, Owens M, Cranston T, et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metab. 2015;100(3):E531–41.PubMedCrossRefGoogle Scholar
  80. 80.
    Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 2010;42(3):229–33.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Yao L, Schiavi F, Cascon A, Qin Y, Inglada-Perez L, King EE, et al. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA. 2010;304(23):2611–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Burnichon N, Lepoutre-Lussey C, Laffaire J, Gadessaud N, Molinie V, Hernigou A, et al. A novel TMEM127 mutation in a patient with familial bilateral pheochromocytoma. Eur J Endocrinol. 2011;164(1):141–5.PubMedCrossRefGoogle Scholar
  83. 83.
    Neumann HP, Sullivan M, Winter A, Malinoc A, Hoffmann MM, Boedeker CC, et al. Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. J Clin Endocrinol Metab. 2011;96(8):E1279–82.PubMedCrossRefGoogle Scholar
  84. 84.
    Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43(7):663–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N, et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res. 2012;18(10):2828–37.PubMedCrossRefGoogle Scholar
  86. 86.
    Korpershoek E, Koffy D, Eussen BH, Oudijk L, Papathomas TG, van Nederveen FH, et al. Complex MAX rearrangement in a family with malignant pheochromocytoma, renal oncocytoma, and erythrocytosis. J Clin Endocrinol Metab. 2016;101(2):453–60.PubMedCrossRefGoogle Scholar
  87. 87.
    Castro-Vega LJ, Buffet A, De Cubas AA, Cascon A, Menara M, Khalifa E, et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet. 2014;23(9):2440–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Cascon A, Comino-Mendez I, Curras-Freixes M, de Cubas AA, Contreras L, Richter S, et al. Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene. J Natl Cancer Inst. 2015;107(5)Google Scholar
  89. 89.
    Pacak K, Jochmanova I, Prodanov T, Yang C, Merino MJ, Fojo T, et al. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(13):1690–8.CrossRefGoogle Scholar
  90. 90.
    Buffet A, Smati S, Mansuy L, Menara M, Lebras M, Heymann MF, et al. Mosaicism in HIF2A-related polycythemia-paraganglioma syndrome. J Clin Endocrinol Metab. 2014;99(2):E369–73.PubMedCrossRefGoogle Scholar
  91. 91.
    Lorenzo FR, Yang C, Ng Tang Fui M, Vankayalapati H, Zhuang Z, Huynh T, et al. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med. 2013;91(4):507–12.PubMedCrossRefGoogle Scholar
  92. 92.
    Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med. 2012;367(10):922–30.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. 2007;3(2):92–102.PubMedCrossRefGoogle Scholar
  94. 94.
    Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002;287(11):1427–34.PubMedCrossRefGoogle Scholar
  95. 95.
    Lenders JW, Pacak K, Eisenhofer G. New advances in the biochemical diagnosis of 895 pheochromocytoma: moving beyond catecholamines. Ann N Y Acad Sci. 2002;970:29–40.PubMedCrossRefGoogle Scholar
  96. 96.
    Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D, et al. Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer. 2012;48(11):1739–49.PubMedCrossRefGoogle Scholar
  97. 97.
    van Duinen N, Corssmit EP, de Jong WH, Brookman D, Kema IP, Romijn JA. Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of biochemically active HNPGL than 24-h urinary excretion rates of catecholamines and metabolites. Eur J Endocrinol. 2013;169(3):377–82.PubMedCrossRefGoogle Scholar
  98. 98.
    Van Der Horst-Schrivers AN, Osinga TE, Kema IP, Van Der Laan BF, Dullaart RP. Dopamine excess in patients with head and neck paragangliomas. Anticancer Res. 2010;30(12):5153–8.PubMedGoogle Scholar
  99. 99.
    Eisenhofer G, Lenders JW, Goldstein DS, Mannelli M, Csako G, Walther MM, et al. Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin Chem. 2005;51(4):735–44.PubMedCrossRefGoogle Scholar
  100. 100.
    Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, et al. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab. 2001;86(5):1999–2008.PubMedCrossRefGoogle Scholar
  101. 101.
    Castro-Vega LJ, Letouze E, Burnichon N, Buffet A, Disderot PH, Khalifa E, et al. Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas. Nat Commun. 2015;6:6044.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    van der Harst E, de Herder WW, de Krijger RR, Bruining HA, Bonjer HJ, Lamberts SW, et al. The value of plasma markers for the clinical behaviour of phaeochromocytomas. Eur J Endocrinol. 2002;147(1):85–94.PubMedCrossRefGoogle Scholar
  103. 103.
    Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, et al. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011;57(3):411–20.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Timmers HJ, Pacak K, Huynh TT, Abu-Asab M, Tsokos M, Merino MJ, et al. Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene. J Clin Endocrinol Metab. 2008;93(12):4826–32.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Hume DM. Pheochromocytoma in the adult and in the child. Am J Surg. 1960;99:458–96.PubMedCrossRefGoogle Scholar
  106. 106.
    Cascon A, Inglada-Perez L, Comino-Mendez I, de Cubas AA, Leton R, Mora J, et al. Genetics of pheochromocytoma and paraganglioma in Spanish pediatric patients. Endocr Relat Cancer. 2013;20(3):L1–6.PubMedCrossRefGoogle Scholar
  107. 107.
    Bausch B, Wellner U, Bausch D, Schiavi F, Barontini M, Sanso G, et al. Long-term prognosis of patients with pediatric pheochromocytoma. Endocr Relat Cancer. 2014;21(1):17–25.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Caty MG, Coran AG, Geagen M, Thompson NW. Current diagnosis and treatment of pheochromocytoma in children. Experience with 22 consecutive tumors in 14 patients. Arch Surg. 1990;125(8):978–81.PubMedCrossRefGoogle Scholar
  109. 109.
    Dahia PL. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer. 2014;14(2):108–19.PubMedCrossRefGoogle Scholar
  110. 110.
    Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(34):8812–8.CrossRefGoogle Scholar
  111. 111.
    Curras-Freixes M, Pineiro-Yanez E, Montero-Conde C, Apellaniz-Ruiz M, Calsina B, Mancikova V, et al. PheoSeq: a targeted next-generation sequencing assay for pheochromocytoma and paraganglioma diagnostics. J Mol Diagn JMD. 2017;19(4):575–88.PubMedCrossRefGoogle Scholar
  112. 112.
    Fishbein L, Khare S, Wubbenhorst B, DeSloover D, D'Andrea K, Merrill S, et al. Whole- exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun. 2015;6:6140.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Flynn A, Benn D, Clifton-Bligh R, Robinson B, Trainer AH, James P, et al. The genomic landscape of phaeochromocytoma. J Pathol. 2015;236(1):78–89.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Endocrinology, Metabolism and Molecular Medicine and Center for Genetic MedicineFeinberg School of Medicine, Northwestern UniversityChicagoUSA

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