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Exp Clin Endocrinol Diabetes 2007; 115(3): 160-165
DOI: 10.1055/s-2007-970407
Review Article

© J. A. Barth Verlag in Georg Thieme Verlag KG · Stuttgart · New York

Genetics and Biology of Pheochromocytoma

M. Mannelli 1 , L. Simi 1 , M. S. Gaglianò 1 , G. Opocher 2 , T. Ercolino 1 , L. Becherini 1 , G. Parenti 1
  • 1Department of Clinical Pathophysiology, Endocrinology Unit, University of Florence, Florence, Italy
  • 2Department of Medical and Surgical Sciences, Endocrinology Unit, University of Padua, Padua, Italy
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Publikationsverlauf

received 15. 8. 2005 first decision 27. 11. 2006

accepted 22. 1. 2007

Publikationsdatum:
11. April 2007 (online)

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Abstract

The familial forms of pheochromocytoma have recently been demonstrated to be more frequent than believed in the past. The genes currently known to be responsible for tumor formation are RET, VHL, NF1, SDHB, SDHC and SDHD. Germline mutations of these genes increase the risk of developing pheochromocytomas and/or paragangliomas which variably associate with other neoplasms and characterize diverse clinical syndromes such as MEN 2, von Hippel-Lindau (VHL), and neurofibromatosis type 1 (NF 1), or the PGL syndromes, respectively. Although the pathogenesis of pheochromocytoma/paraganglioma formation is still largely unknown, studies of the familial forms have started to uncover some pathways that favor tumor formation, such as activation of tyrosine-kinase, induction of hypoxia-inducible factors, activation of the oncogene Ras or reduced apoptosis. These studies have also demonstrated that various gene mutations can differently affect the biological characteristics of pheochromocytoma: for example, while the tumors are mostly adrenergic (epinephrine secreting) and episodically secreting in MEN 2, they are mostly noradrenergic (norepinephrine secreting) and continuously secreting in VHL. Biological variability can also be observed in the PGL syndromes where tumors develop in the head and neck and are parasympathetic in origin and non-secreting, or in the thorax and the abdomen, where they are sympathetic in origin and catecholamine secreting. Genetic testing in patients with pheochromocytomas or paragangliomas is, at present, strongly recommended and is mandatory in young patients or in cases of multiple or recurrent tumors. The clinical picture and the biological characteristics of the tumor may suggest the priority of the genes to be tested first.

Key words

pheochromocytoma - paraganglioma - VHL - RET - MEN 2 - NF 1 - SDH

References

  • 1 Arias-Sella J, Valcarcel J. Chief cell hyperplasia in the human carotid body at high altitudes: physiologic and pathologic significance.  Hum Pathol. 1976;  7 361-373
    CrossrefPubMedGoogle Scholar
  • 2 Asai N, Iwashita T, Matsuyama M, Takahashi M. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations.  Mol Cell Biol. 1995;  15 ((3)) 1613-1619
    PubMedGoogle Scholar
  • 3 Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.  Am J Genet. 2001;  69 49-54
    CrossrefPubMedGoogle Scholar
  • 4 Badenhop RF, Jansen JC, Fagan PA, Lord RS, Wang ZG, Foster WJ, Schofield PR. 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
    CrossrefPubMedGoogle Scholar
  • 5 Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard 3rd CW, Cornelisse CJ, Devilee P, Devlin B. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.  Science. 2000;  287 848-851
    CrossrefPubMedGoogle Scholar
  • 6 Baysal BE. Hereditary paraganglioma targets diverse paraganglia.  J Med Genet. 2002;  39 617-622
    CrossrefPubMedGoogle Scholar
  • 7 Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery III WH, Myers EN, Ferrel RE, Rubinstein WS. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas.  J Med Genet. 2002;  39 178-183
    CrossrefPubMedGoogle Scholar
  • 8 Baysal BE, Willett-Brozick JE, Filho PA, Lawrence EC, Myers EN, Ferrell RE. An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma.  J Med Genet. 2004;  41 703-709
    CrossrefPubMedGoogle Scholar
  • 9 Borrello MG, Smith D P, Pasini B, Bongazone I, Greco A, Lorenzo MJ, Arighi E, Miranda C, Eng C, Alberti L, Bocciardi R, Mondellini P, Scopsi L, Romeo G, Ponder BAJ, Pierotti MA. RET activation by germline MEN 2A and MEN 2B mutations.  Oncogene. 1995;  11 ((11)) 2419-2427
    PubMedGoogle Scholar
  • 10 Brauch H, Kishida T, Glavac D, Chen F, Pausch F, Hofler H, Latif F, Lerman MI, Zbar B, Neumann HPH. Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect.  Hum Genet. 1995;  95 551-556
    PubMedGoogle Scholar
  • 11 Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription.  Proc Natl Acad Sci USA. 1998;  95 11715-11720
    CrossrefPubMedGoogle Scholar
  • 12 Clifford SC, Cockman ME, Smalwood AC, Mole DR, Woodward ER, Maxwell PH, Ratcliffe PJ, Maher ER. Contrasting effects on HIF-1α regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease.  Hum Mol Genet. 2001;  10 1029-1038
    CrossrefPubMedGoogle Scholar
  • 13 Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwel PH. Hypoxia-inducible factor-α binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.  J Biol Chem. 2000;  275 25733-25741
    CrossrefPubMedGoogle Scholar
  • 14 Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells Jr SA. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.  Hum Mol Genet. 1993;  2 ((7)) 851-856
    CrossrefPubMedGoogle Scholar
  • 15 Duan DR, Pause A, Burgess WH, Aso T, Chen DY, Garrett KP, Conaway RC, Conaway JW, Linehan WM, Klausner RD. Inhibition of transcription elongation by the VHL tumor suppressor protein.  Science. 1995;  269 ((5229)) 1402-1406
    CrossrefPubMedGoogle Scholar
  • 16 Eisenhofer G, Lenders JWM, Linehan WM, Walther MM, Goldstein DS, Keiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Linday disease and multiple endocrine neoplasia type 2.  N Eng J Med. 1999;  340 1872-1879
    CrossrefPubMedGoogle Scholar
  • 17 Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, Mannelli M, Goldstein DS, Linehan WM, Lenders JWM, 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
  • 18 Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Hamstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink N, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendy GN, Gharib H, Thibodeau SN, Lacroix A, Frilling A, Ponder BA, Mulligan LM. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.  JAMA. 1996;  276 ((19)) 1575-1579
    CrossrefPubMedGoogle Scholar
  • 19 Eng C, Kiuru M, Fernandez MJ, Aaltonen LA. A role for mitochondrial enzymes in inherited neoplasia and beyond.  Nat Rev Cancer. 2003;  3 193-202
    CrossrefPubMedGoogle Scholar
  • 20 Favier J, Brìere JJ, Strompf L, Amar L, Filali M, Jeunemaitre X, Rustin P. Gimenez-Roqueplo AP for the PGL.NET Network . Herdotary paraganglioma/pheochromocytoma and inherited succinate dehydrogenase deficiency.  Horm Res. 2005;  63 171-179
    PubMedGoogle Scholar
  • 21 Frank-Raue K, Hoppner W, Frilling A, Kotzerke J, Dralle H, Haase R, Mann K, Seif F, Kirchner R, Rendl J, Deckart HF, Ritter MM, Hampel R, Klempa J, Scholz GH, Raue F. Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group.  J Clin Endocrinol Metab. 1996;  81 ((5)) 1780-1783
    CrossrefPubMedGoogle Scholar
  • 22 Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A, Jeunemaitre X. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzyme activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway.  Am J Hum Genet. 2001;  69 1186-1197
    CrossrefPubMedGoogle Scholar
  • 23 Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, Jeunemaitre X. COMETE Network. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas.  Cancer Res. 2003;  63 5615-5621
    PubMedGoogle Scholar
  • 24 Gimm O, Koch CA, Januszewicz A, Opocher G, Neumann HP. The genetic basis of pheochromocytoma.  Front Horm Res.. 2004;  31 45-60
    PubMedGoogle Scholar
  • 25 Gagel RF, Tashjian Jr AH, Cummings T, Papathanasopoulos N, Kaplan MM, DeLellis RA, Wolfe HJ, Reichlin S. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience.  N Engl J Med. 1988;  318 ((8)) 478-484
    PubMedGoogle Scholar
  • 26 Hagerhall C. Succinate: quinone oxidoreductases. Variations on a conserved theme.  Biochim Biophys Acta. 1997;  1320 107-141
    PubMedGoogle Scholar
  • 27 Heutink P, van der Mey AGL, Sandkuijl LA, van Gils AP, Bardoel A, Breedveld GJ, van Vliet M, van Ommen GJ, Cornelisse CJ, Oostra BA. A gene subject to genomic imprinting and responsible for hereditary paraganglioma maps to 11q23-qter.  Hum Mol Genet. 1992;  1 7-10
    CrossrefPubMedGoogle Scholar
  • 28 Kibel A, Iliopoulos O, DeCaprio JA, Kaelin Jr WG. Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C.  Science. 1995;  269 ((5229)) 1444-1446
    CrossrefPubMedGoogle Scholar
  • 29 Kwock JB, Gardner E, Warner JP, Ponder BA, Mulligan LM. Structural analysis of the human ret proto-oncogene using exon trapping.  Oncogene. 1993;  8 ((9)) 2575-2582
    PubMedGoogle Scholar
  • 30 Lancaster CRD. editor . Special issue on bioenergetics.  Biochim Biophys Acta. 2002;  1553 1-176
    PubMedGoogle Scholar
  • 31 Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou F, Li H, Wei MH, Chen F, Glenn G, Choyke P, Walther MM, Weng Y, Duan DSR, Dean M, Glavac D, Richards FM, Crossey PA, Ferguson-Smith MA, Le Paslier D, Chumacov I, Cohen D, Chinault C, Maher ER, Linehan WM, Zbar B, Lerman M. Identification of the von Hippel-Lindau disease tumor suppressor gene.  Science. 1993;  260 ((5112)) 1317-1320
    CrossrefPubMedGoogle Scholar
  • 32 Lee S, Nakamura E, Yang H, Wai W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin Jr WG, Schlisio S. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes:developmental culling and cancer.  Cancer Cell. 2005;  (2) 155-167
    PubMedGoogle Scholar
  • 33 Lonergan KM, Iliopoulos O, Ohh M, Kamura T, Conaway RC, Conaway JW, Kaelin Jr WG. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2.  Mol Cell Biol. 1998;  18 ((2)) 732-741
    PubMedGoogle Scholar
  • 34 Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. Von Hippel-Lindau disease.  Lancet. 2003;  361 2059-2067
    CrossrefPubMedGoogle Scholar
  • 35 Maddock IR, Moran A, Maher ER, Teare MD, Norman A, Payne SJ, Whitehouse R, Dodd C, Lavin M, Hartley N, Super M, Evans DG. A genetic register for von Hippel-Lindau disease.  J Med Genet. 1996;  33 ((2)) 120-127
    CrossrefPubMedGoogle Scholar
  • 36 Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA. Clinical features and natural history of von Hippel-Lindau disease.  Q J Med.. 1990;  77 1151-1163
    PubMedGoogle Scholar
  • 37 Maher ER, Eng C. The pressure rises: update on the genetics of phaeochromocytoma.  Hum Mol Genet. 2002;  11 ((20)) 2347-2354
    CrossrefPubMedGoogle Scholar
  • 38 Manger WM, Gifford Jr RW. Clinical and experimental pheochromocytoma. Cambridge, MA: Blackwell Science 1996
  • 39 Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJ. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.  Nature. 1993;  363 ((6528)) 458-460
    CrossrefPubMedGoogle Scholar
  • 40 Neumann HP, Wiestler OD. Clustering of features and genetics of von Hippe-Lindau syndrome.  Lancet. 1991;  338 258
    PubMedGoogle Scholar
  • 41 Neumann HPH, Eng C, Mulligan LM, Glavac D, Zauner I, Ponder BA, Crossey PA, Maher ER, Brausch H, 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, Eng C. Freiburg-Warsaw-Columbus Pheochromocytoma Study Group . Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II.  JAMA. 1995;  274 ((14)) 1149-1151
    CrossrefPubMedGoogle Scholar
  • 42 Neumann HPH, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C. Germ-line mutations in nonsyndromic pheochromocytoma.  N Eng J Med. 2002;  346 ((19)) 1459-1466
    CrossrefPubMedGoogle Scholar
  • 43 Neumann HPH, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A. Eng C for the European-American Paraganglioma Study Group . Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations.  JAMA. 2004;  292 943-951
    CrossrefPubMedGoogle Scholar
  • 44 Niemann S, Mueller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3.  Nat Genet. 2000;  26 ((3)) 268-270
    CrossrefPubMedGoogle Scholar
  • 45 Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AC, Louis DN, Gavin BJ, Kley N, Kaelin WG, Iliopoulos O. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix.  Mol Cell. 1998;  1 959-968
    CrossrefPubMedGoogle Scholar
  • 46 Pause A, Lee S, Worrell RA, Chen DY, Burgess WH, Linehan WM, Klausner RD. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins.  Proc Natl Acad Sci USA. 1997;  94 ((6)) 2156-2161
    CrossrefPubMedGoogle Scholar
  • 47 Pause A, Lee S, Lonergan KM, Klausner RD. The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal.  Proc Natl Acad Sci USA. 1998;  95 993-998
    CrossrefPubMedGoogle Scholar
  • 48 Pomares FJ, Canas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ. Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma.  Clin Endocrinol. 1998;  48 195-200
    CrossrefPubMedGoogle Scholar
  • 49 Ritter MM, Frilling A, Crossey PA, Hoppner W, Maher ER, Mulligan L, Ponder BA, Engelhardt D. Isolated familial pheochromocytoma as a variant of von Hippel-Lindau disease.  J Clin Endocrinol Metab. 1996;  81 1035-1037
    CrossrefPubMedGoogle Scholar
  • 50 Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH, Di Fiore PP. Activation of RET as a dominant transforming gene by germline mutations of MEN 2A and MEN 2B.  Science. 1995;  267 ((5196)) 318-383
    PubMedGoogle Scholar
  • 51 Sato T, Kobayashi K, Miura Y, Sakuma H, Yoshinaga K. High epinephrine content in the adrenal tumors from Sipple's syndrome.  Tohoku J Exp Med. 1975;  115 15-19
    PubMedGoogle Scholar
  • 52 Schiavi F, Boedeker CCB, Peczkowska M, Gomez CF, Strassburg T, Pavlu C, Buchta M, Salzmann M, Hofmann MM, Berlis A, Brink I, Cybulla M, Muresan M, Walter MA, Forre F, Valimaki M, Kawecki A, Szutkowski Z, Schipper J, Walz MK, Pigny P, Bauters C, Willewt-Brozick JE, aysal BE, Januszewicz A, Eng C, Opocher G, Neumann HPH. European-American Paraganglioma Study Group . and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene.  JAMA.. 2005;  294 ((16)) 2057-2063
    CrossrefPubMedGoogle Scholar
  • 53 Simi L, Sestini R, Ferruzzi P, Gaglianò MS, Gensini F, Mascalchi M, Guerrini L, Pratesi C, Pinzani P, Nesi G, Ercolino T, Genuardi M, Mannelli M. Phenotype variability of neural crest-derived tumours in six italian families segregating the same founder SDHD mutation Q109X.  J Med Genet. 2005;  42 ((8)) e52
    CrossrefPubMedGoogle Scholar
  • 54 Takahashi M, Cooper GM. Ret transforming gene encodes a fusion protein homologous to tyrosine kinases.  Mol Cell Biol. 1987;  7 ((4)) 1378-1385
    PubMedGoogle Scholar
  • 55 van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, Schmidt PH, van de Kamp JJ. Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory.  Lancet. 1989;  2 ((8675)) 1291-1294
    PubMedGoogle Scholar
  • 56 von Deimling A, Krone W, Menon AG. Neurofibromatosis type 1: pathology, clinical features and molecular genetics.  Brain Pathol. 1995;  5 ((2)) 153-162
    CrossrefPubMedGoogle Scholar
  • 57 White R, O’Connel P. Identification and characterization of the gene for neurofibromatosis type 1.  Curr Opin Genet Dev. 1991;  1 ((1)) 15-19
    CrossrefPubMedGoogle Scholar
  • 58 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 HP, 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
  • 59 Zoller ME, Rembeck B, Oden A, Samuelsson M, Angervall L. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population.  Cancer. 1997;  79 ((11)) 2125-2131
    CrossrefPubMedGoogle Scholar

Correspondence

M. Mannelli

Department of Clinical Pathophysiology

Endocrine Unit

University of Florence

Viale Pieraccini 6

50139 Florence

Italy

Telefon: +39/055/427 14 28

Fax: +39/055/427 14 13

eMail: m.mannelli@dfc.unifi.it

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