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Genetik der Phäochromozytome

Genetics of pheochromocytoma

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Zusammenfassung

Etwa ein Drittel aller Patienten mit Phäochromozytomen sind einem hereditären Tumorsyndrom zuzuordnen. Hierzu gehören die multiple endokrine Neoplasie Typ 2 (MEN2), verursacht durch Mutationen des RET-Gens, das von-Hippel-Lindau-Syndrom (VHL, VHL-Gen), die Neurofibromatose Typ 1 (NF1, NF1-Gen), die Paragangliomsyndrome Typ 1 bis 4 (PGL1–4, SDHD-, SDHAF2-, SDHC-, SDHB-Gene) und die familiären Phäochromozytomsyndrome (SDHA-, TMEM127-, MAX-Gene). Patienten mit hereditären Phäochromozytomen haben ein lebenslanges Rezidivrisiko. Daneben kommen extraparaganglionäre Tumoren häufig bei der MEN2 als medulläres Schilddrüsenkarzinom, beim VHL-Syndrom als Nierenzellkarzinom oder neuroendokrines Pankreaskarzinom sowie als Hämangioblastome von Retina und Zentralnervensystem und vereinzelt als Nierenzellkarzinom beim PGL4-Syndrom und beim PGL3-Syndrom vor. Das genetische Screening ist somit unverzichtbarer Bestandteil der Klassifikation von Phäochromozytomen geworden und stellt den Eckpfeiler für eine erfolgreiche präventivmedizinische Versorgung der Patienten und ihrer Angehörigen dar.

Abstract

About one third of all patients with a pheochromocytoma are carriers of germ line mutations of 1 of the 10 susceptibility genes. Thus, these patients can be diagnosed and classified with specific tumor syndromes. This group is composed of the entities of multiple endocrine neoplasia type 2 (MEN2) due to mutations in the RET gene, von Hippel-Lindau disease (VHL, VHL gene), the paraganglioma syndromes types 1–4 (PGL1–4) due to mutations of the genes SDHD, SDHAF2, SDHC, SDHB, neurofibromatosis type 1 (NF1) due to mutations of the NF1 gene and familial pheochromocytoma syndromes due to mutations of the SDHA, TMEM127 and MAX genes. Patients with hereditary pheochromocytomas run a lifelong risk of relapse of pheochromocytoma. In addition extraparaganglial tumors are frequent and include medullary thyroid carcinoma in MEN2 or renal cancer or neuroendocrine pancreatic cancer as well as hemangioblastomas of the retina and the central nervous system in VHL. Furthermore, renal cancer may be associated with PGL4 and PGL3. In conclusion, molecular genetic screening is essential for the diagnosis of pheochromocytoma-associated cancer syndromes and is thus the cornerstone for successful lifelong preventive medicine of such patients and their relatives.

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Literatur

  1. Anonymous (1988) Neurofibromatosis. Conference statement. National institutes of health consensus development conference. Arch Neurol 45:575–578

    Article  Google Scholar 

  2. Astuti D, Ricketts CJ, Chowdhury R et al (2010) Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility. Endocr Relat Cancer 18:73–83

    Article  PubMed  Google Scholar 

  3. Bausch B, Borozdin W, Mautner VF et al (2007) Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1. J Clin Endocrinol Metab 92:2784–2792

    Article  PubMed  CAS  Google Scholar 

  4. Bausch B, Borozdin W, Neumann HP (2006) Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. N Engl J Med 354:2729–2731

    Article  PubMed  CAS  Google Scholar 

  5. Bayley JP, Kunst HP, Cascon A et al (2010) SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 11:366–372

    Article  PubMed  CAS  Google Scholar 

  6. Burnichon N, Briere JJ, Libe R et al (2010) SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19:3011–3020

    Article  PubMed  CAS  Google Scholar 

  7. Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F et al (2011) Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 43:663–667

    Article  PubMed  CAS  Google Scholar 

  8. DeLellis RA, Heitz PU, Lloyd RV, Eng C (Hrsg) (2003) Pathology and molecular genetics of endocrine tumours (WHO classification of tumours of endocrine organs). IARC Press, Lyon

  9. Frank-Raue K, Rybicki LA, Erlic Z et al (2011) Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat 32:51–58

    Article  PubMed  CAS  Google Scholar 

  10. Gutmann DH, Aylsworth A, Carey JC et al (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278:51–57

    Article  PubMed  CAS  Google Scholar 

  11. Hao HX, Khalimonchuk O, Schraders M et al (2009) SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325:1139–1142

    Article  PubMed  CAS  Google Scholar 

  12. Hensen EF, Jordanova ES, Minderhout IJ van et al (2004) Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families. Oncogene 23:4076–4083

    Article  PubMed  CAS  Google Scholar 

  13. Kloos RT, Eng C, Evans DB et al (2009) Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19:565–612

    Article  PubMed  Google Scholar 

  14. Malinoc A, Sullivan M, Wiech T et al (2012) Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3. Endocr Relat Cancer [Epub ahead of print]

  15. Mannelli M, Castellano M, Schiavi F et al (2009) Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab 94:1541–1547

    Article  PubMed  CAS  Google Scholar 

  16. Mannelli M, Ercolino T, Giache V et al (2007) Genetic screening for pheochromocytoma: should SDHC gene analysis be included? J Med Genet 44:586–587

    Article  PubMed  CAS  Google Scholar 

  17. Milos IN, Frank-Raue K, Wohllk N et al (2008) Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC > TGG) mutation. Endocr Relat Cancer 15:1035–1041

    Article  PubMed  CAS  Google Scholar 

  18. Munirajan AK, Ando K, Mukai A et al (2008) KIF1Bbeta functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptotic cell death. J Biol Chem 283:24426–24434

    Article  PubMed  CAS  Google Scholar 

  19. Neumann H (2008) Pheochromocytoma. In: Fauci A, Longo DL, Braunwald E (Hrsg) Harrison’s principles of internal medicine, 17. Aufl. McGraw-Hill Professional

  20. Neumann HP, Bausch B, McWhinney SR et al (2002) Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466

    Article  PubMed  CAS  Google Scholar 

  21. Neumann HP, Pawlu C, Peczkowska M et al (2004) Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292:943–951

    Article  PubMed  CAS  Google Scholar 

  22. Peczkowska M, Cascon A, Prejbisz A et al (2008) Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab 4:111–115

    Article  PubMed  CAS  Google Scholar 

  23. Qin Y, Yao L, King EE et al (2010) Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 42:229–233

    Article  PubMed  CAS  Google Scholar 

  24. Schussheim DH, Skarulis MC, Agarwal SK et al (2001) Multiple endocrine neoplasia type 1: new clinical and basic findings. Trends Endocrinol Metab 12:173–178

    Article  PubMed  CAS  Google Scholar 

  25. Tischler AS (2008) Pheochromocytoma and extra-adrenal paraganglioma: updates. Arch Pathol Lab Med 132:1272–1284

    PubMed  Google Scholar 

  26. Vanharanta S, Buchta M, McWhinney SR et al (2004) Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet 74:153–159

    Article  PubMed  CAS  Google Scholar 

  27. Walther MM, Herring J, Enquist E et al (1999) von Recklinghausen’s disease and pheochromocytomas. J Urol 162:1582–1586

    Article  PubMed  CAS  Google Scholar 

  28. Wohllk N, Schweizer H, Erlic Z et al (2010) Multiple endocrine neoplasia type 2. Best Pract Res Clin Endocrinol Metab 24:371–387

    Article  PubMed  CAS  Google Scholar 

  29. Yao L, Schiavi F, Cascon A et al (2010) Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA 304:2611–2619

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Abteilung Innere Medizin II, Gastroenterologie, Hepatologie, Endokrinologie und Infektiologie, Universitätsklinikum Freiburg, Freiburg, Deutschland

    B. Bausch

  2. Abteilung Innere Medizin IV, Nephrologie und Allgemeinmedizin, Sektion für präventive Medizin, Universitätsklinikum Freiburg, Freiburg im Breisgau, Deutschland

    A. Malinoc &  H.P.H. Neumann

  3. Abteilung Allgemeine Radiologie, Radiologische Klinik, Universitätsklinikum Freiburg, Freiburg, Deutschland

    L. Maruschke

  4. Hals-Nasen-Ohren Klinik, Universitätsklinikum Freiburg, Freiburg, Deutschland

    C. Offergeld & C.C. Boedeker

  5. Neurochirurgische Klinik, Universitätsklinikum Freiburg, Freiburg, Deutschland

    S. Gläsker

  6. Abteilung Nuklearmedizin, Radiologische Klinik, Universitätsklinikum Freiburg, Freiburg, Deutschland

    H.C. Rischke

  7. Department of Surgery, Haukeland University Hospital Bergen, Bergen, Norway

    M. Brauckhoff

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  1. B. Bausch
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  2. A. Malinoc
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  9. H.P.H. Neumann
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Correspondence to H.P.H. Neumann.

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Bausch, B., Malinoc, A., Maruschke, L. et al. Genetik der Phäochromozytome. Chirurg 83, 511–518 (2012). https://doi.org/10.1007/s00104-011-2191-8

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  • DOI: https://doi.org/10.1007/s00104-011-2191-8

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