Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, catecholamine-producing tumors that are usually sporadic. However, about 30% of these tumors have been identified as being of inherited origin. To date, nine genes have been confirmed as participating in PHEO or PGL tumorigenesis. Germline mutations were found in 100% of syndromic cases and in about 90% of patients with positive familial history. In nonsyndromic patients with apparently sporadic tumors, genetic mutations have been found in up to 27%, and genetic testing is now recommended for all patients with PHEOs and PGLs. Patients with syndromic lesions, a positive family history, or both should be tested for the appertaining gene. Recent discoveries have shown that the order of tested genes in nonsyndromic, nonfamilial cases can be based on histologic evaluation, location, and the biochemical phenotype of PHEOs and PGLs--the "rule of three." Identification of a gene mutation may lead to early diagnosis and treatment, regular surveillance, and a better prognosis for patients and their relatives.

3rd Department of Internal Medicine University Hospital Olomouc 1 P Pavlova 6 Olomouc 77520 Czech Republic

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Koch CA, Vortmeyer AO, Huang SC, et al. Genetic aspects of pheochromocytoma. Endocr Regul. 2001;35:43–52. Erratum in: Endocr Regul 2001, 35:94. PubMed

Bryant J, Farmer J, Kessler LJ, et al. Pheochromocytoma: the expanding genetic differential diagnosis. J Natl Cancer Inst. 2003;95:1196–1204. PubMed

Benn DE, Robinson BG. Genetic basis of phaeochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2006;20:435–450. PubMed

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

Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. 2005;23:8812–8818. PubMed

Raue F, Frank-Raue K. Multiple endocrine neoplasia type 2: 2007 update. Horm Res. 2007;68(Suppl 5):101–104. PubMed

Pacak K, Eisenhofer G, Ilias I. Diagnosis of pheochromocytoma with special emphasis on MEN2 syndrome. Hormones (Athens) 2009;8:111–116. PubMed PMC

Mulligan LM, Marsh DJ, Robinson BG, et al. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med. 1995;238:343–346. PubMed

Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366:665–675. PubMed

Eisenhofer G, Walther MM, Huynh TT, 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;86:1999–2008. PubMed

Maher ER, Yates JR, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990;77:1151–1163. PubMed

Elder EE, Elder G, Larsson C. Pheochromocytoma and functional paraganglioma syndrome: no longer the 10% tumor. J Surg Oncol. 2005;89:193–201. PubMed

Petri BJ, van Eijck CH, de Herder WW, et al. Phaeochromocytomas and sympathetic paragangliomas. Br J Surg. 2009;96:1381–1392. PubMed

Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–215. PubMed

Hes FJ, Höppener JW, Lips CJ. Clinical review 155: Pheochromocytoma in Von Hippel-Lindau disease. J Clin Endocrinol Metab. 2003;88:969–974. PubMed

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

Zöller ME, Rembeck B, Odén A, et al. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer. 1997;79:2125–2131. PubMed

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

Bausch B, Borozdin W, Neumann HP. European-American Pheochromocytoma Study Group: Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. N Engl J Med. 2006;354:2729–2731. PubMed

Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69:49–54. Erratum in: Am J Hum Genet 2002, 70:565. PubMed PMC

Niemann S, Müller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet. 2000;26:268–270. PubMed

Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287:848–851. PubMed

Timmers HJ, Gimenez-Roqueplo AP, Mannelli M, Pacak K. Clinical aspects of SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer. 2009;2:391–400. PubMed PMC

Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–1033. PubMed PMC

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

Jiménez C, Cote G, Arnold A, Gagel RF. Review: Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J Clin Endocrinol Metab. 2006;91:2851–2858. PubMed

Lee J, Wang J, Torbenson M, et al. Loss of SDHB and NF1 genes in a malignant phyllodes tumor of the breast as detected by oligo-array comparative genomic hybridization. Cancer Genet Cytogenet. 2010;196:179–183. PubMed

Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004;292:943–951. Erratum in: JAMA 2004 292:1686. PubMed

Brouwers FM, Eisenhofer G, Tao JJ, et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006;91:4505–4509. PubMed

Benn DE, Gimenez-Roqueplo AP, Reilly JR, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006;91:827–836. PubMed

Pacak K, Eisenhofer G, Ahlman H, et al. International Symposium on Pheochromocytoma: Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. 2007;3:92–102. PubMed

Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma

An update on the genetics of pheochromocytoma