European Journal of Pediatrics

, Volume 175, Issue 1, pp 137–141 | Cite as

Sporadic paraganglioma caused by de novo SDHB mutations in a 6-year-old girl

  • Hideaki ImamuraEmail author
  • Koji Muroya
  • Etsuko Tanaka
  • Takao Konomoto
  • Hiroshi Moritake
  • Takeshi Sato
  • Noriko Kimura
  • Kazuhiro Takekoshi
  • Hiroyuki Nunoi
Short Communication


Germline mutations in the succinate dehydrogenase complex subunit B (SDHB) gene (SDHB) cause susceptibility to paragangliomas and pheochromocytomas; however, it is exceedingly rare in childhood and especially in sporadic cases. We report the first Japanese pediatric case of paraganglioma with a de novo mutation in the SDHB gene. A 6-year-old girl with convulsions and hypertension was found to have a paravertebral abdominal tumor. Urinary and blood examinations revealed markedly elevated levels of norepinephrine. Following treatment for hypertension, the tumor was removed completely and histological findings were consistent with paraganglioma. Immunohistochemistry studies demonstrated the absence of SDHB protein expression, indicating an underlying SDH mutation with high probability. Germline mutation analysis of the SDHB gene revealed a heterozygous splice site mutation in intron 4 (C.423 + 1G > A). Subsequently, a second somatic genetic change was confirmed by multiplex ligation-dependent probe amplification (MLPA) analysis, showing that deletion of the wild-type allele resulted in loss of function of SDHB. No germline mutations in SDHB were detected in her parents.

Conclusion: Genetic testing should be considered for pediatric patients with paragangliomas, even in the absence of familial history, as closer lifelong screening to detect the development of malignancy will be required for patients with SDHB mutations.

What is Known

Most sporadic cases of paraganglioma with SDHB mutations occur between adolescence and adulthood.

Screening methods for carriers of SDHB mutations assessing recurrence and detecting developing metastases are yet to be standardized.

What is New

The current case of an extra-adrenal paraganglioma with a de novo SDHB mutation had an onset at 6 years.

We suggest much closer periodical observation for these high-risk children.


Paraganglioma Childhood Succinate dehydrogenase complex subunit B Screening Multiplex ligation-dependent probe amplification Loss of heterozygosity 



Loss of heterozygosity


Multiplex ligation-dependent probe amplification






Succinate dehydrogenase


Succinate dehydrogenase complex subunit B



We are grateful to Hirohito Shima and Keiko Matsubara, Department of Molecular Endocrinology, National Research Institute for Child Health and Development, for performing microsatellite analysis to confirm the paternity.


None declared.

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 ethics committee of the Medical Faculty of Miyazaki University, Miyazaki, Japan, and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Authors’ contribution

HI, ET, and TK clinically managed the patient. HI wrote the manuscript under HN’s supervision. KM and TS were responsible for the genetic analysis. NK was responsible for the immunohistochemistry study of SDHB and wrote the manuscript. KT and HM contributed to genetic analysis and interpretation. KM, TS, NK, KT, HM, and HN critically reviewed the manuscript. All the authors approved the final copy of the manuscript.


  1. 1.
    Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Sköldberg F, Husebye ES, Eng C, Maher ER (2001) Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69:49–54PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Bayley JP, van Minderhout I, Weiss MM, Jansen JC, Oomen PH, Menko FH, Pasini B, Ferrando B, Wong N, Alpert LC, Williams R, Blair E, Devilee P, Taschner PE (2006) Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma. BMC Med Genet 7:1PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, Niccoli P, Gaillard D, Chabrier G, Chabolle F, Coupier I, Thieblot P, Lecomte P, Bertherat J, Wion-Barbot N, Murat A, Venisse A, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP, PGL.NET network (2009) The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab 94:2817–2827PubMedCrossRefGoogle Scholar
  4. 4.
    DeLellis R, Lloyd R, Heitz P, Eng C (2004) Pathology and genetics of tumours of endocrine organsGoogle Scholar
  5. 5.
    Fishbein L, Nathanson KL (2012) Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet 205:1–11PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Fliedner SM, Lehnert H, Pacak K (2010) Metastatic paraganglioma. Semin Oncol 37:627–637PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, Jeunemaitre X, Network C (2003) Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 63:5615–5621PubMedGoogle Scholar
  8. 8.
    Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rötig A, Jeunemaitre X (2002) Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab 87:4771–4774PubMedCrossRefGoogle Scholar
  9. 9.
    Hensen EF, van Duinen N, Jansen JC, Corssmit EP, Tops CM, Romijn JA, Vriends AH, van der Mey AG, Cornelisse CJ, Devilee P, Bayley JP (2012) High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin Genet 81:284–288PubMedCrossRefGoogle Scholar
  10. 10.
    Jafri M, Maher ER (2012) The genetics of phaeochromocytoma: using clinical features to guide genetic testing. Eur J Endocrinol 166:151–158PubMedCrossRefGoogle Scholar
  11. 11.
    King KS, Prodanov T, Kantorovich V, Fojo T, Hewitt JK, Zacharin M, Wesley R, Lodish M, Raygada M, Gimenez-Roqueplo AP, McCormack S, Eisenhofer G, Milosevic D, Kebebew E, Stratakis CA, Pacak K (2011) Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol 29:4137–4142PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Lefebvre M, Foulkes WD (2014) Pheochromocytoma and paraganglioma syndromes: genetics and management update. Curr Oncol 21:e8–e17PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF, Society E (2014) Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99:1915–1942PubMedCrossRefGoogle Scholar
  14. 14.
    Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J et al (2002) Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466PubMedCrossRefGoogle Scholar
  15. 15.
    Pasini B, Stratakis CA (2009) SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. J Intern Med 266:19–42PubMedCrossRefGoogle Scholar
  16. 16.
    Pollard PJ, Brière JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14:2231–2239PubMedCrossRefGoogle Scholar
  17. 17.
    Prodanov T, Havekes B, Nathanson KL, Adams KT, Pacak K (2009) Malignant paraganglioma associated with succinate dehydrogenase subunit B in an 8-year-old child: the age of first screening? Pediatr Nephrol 24:1239–1242PubMedCrossRefGoogle Scholar
  18. 18.
    van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, Sleddens HF et al (2009) An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol 10:764–771PubMedCrossRefGoogle Scholar
  19. 19.
    Waguespack SG, Rich T, Grubbs E, Ying AK, Perrier ND, Ayala-Ramirez M, Jimenez C (2010) A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 95:2023–2037PubMedCrossRefGoogle Scholar
  20. 20.
    Wyszyńska T, Cichocka E, Wieteska-Klimczak A, Jobs K, Januszewicz P (1992) A single pediatric center experience with 1025 children with hypertension. Acta Paediatr 81:244–246PubMedCrossRefGoogle Scholar
  21. 21.
    Young WF, Abboud AL (2006) Editorial: paraganglioma—all in the family. J Clin Endocrinol Metab 91:790–792PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Hideaki Imamura
    • 1
    Email author
  • Koji Muroya
    • 2
  • Etsuko Tanaka
    • 1
  • Takao Konomoto
    • 1
  • Hiroshi Moritake
    • 1
  • Takeshi Sato
    • 3
  • Noriko Kimura
    • 4
  • Kazuhiro Takekoshi
    • 5
  • Hiroyuki Nunoi
    • 1
  1. 1.Division of Pediatrics, Department of Reproductive and Developmental Medicine, Faculty of MedicineUniversity of MiyazakiMiyazakiJapan
  2. 2.Department of Endocrinology and MetabolismKanagawa Children’s Medical CenterYokohamaJapan
  3. 3.Department of PediatricsKeio University School of MedicineShinjuku-kuJapan
  4. 4.Department of Clinical Research, Pathology Division, National Hospital OrganizationHakodate HospitalHakodateJapan
  5. 5.Division of Sports Science, Faculty of MedicineUniversity of TsukubaTsukubaJapan

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