Abstract
Although it is well established that paternally transmitted germline variants in SDHD are associated with multifocal paragangliomas and lifelong follow-up is generally advised, the risk of metachronous lesions is presently unknown. In a large Dutch cohort of SDHD variant carriers, we studied the development of new paragangliomas, and the evolution of symptoms and cranial nerve impairment. Recurrent event analysis and the Kaplan–Meier product limit estimator were used to study the risk of new lesions. The relation between several predictors and development of new symptoms was assessed using logistic regression. Of the 222 SDHD variant carriers included, 65% presented with symptoms and 11% with cranial nerve dysfunction. Over a median period of 8 years, 42% reported new symptoms, and new cranial nerve impairment was observed in 11% of subjects. The estimated fraction of subjects that developed new HNPGL increased to 73% (95% CI: 52–85%) after 22 years of follow-up. Males were more likely to develop new HNPGL compared to females (HR: 1.63, 95% CI: 1.10–2.40), as were subjects that presented with symptoms, compared to subjects that were asymptomatic at baseline (HR: 1.61, 95% CI: 1.01–2.55). In addition, the risk of new lesions decreased with number of HNPGL present at first diagnosis (HR: 0.68 and 95% CI: 0.56–0.82). Carriers of a paternally inherited SDHD variant face a considerable risk for new HNPGL. In addition, nearly 50% of subjects reported new symptoms. However, new cranial nerve deficits were observed in only 11%, which is less than reported in surgical series. These risks should be taken into account when considering treatment strategies and counseling.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Hensen EF, van Duinen N, Jansen JC, et al. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin Genet. 2012;81:284–8.
Taschner PEM, Jansen JC, Baysal BE, et al. Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene. Genes Chromosom Cancer. 2001;31:274–81.
Taïeb D, Kaliski A, Boedeker CC, et al. Current approaches and recent developments in the management of head and neck paragangliomas. Endocr Rev. 2014;35:er20141026.
Hensen EF, Jordanova ES, van Minderhout IJHM, et al. Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families. Oncogene. 2004;23:4076–83.
Bayley J-P, Oldenburg RA, Nuk J, et al. Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations. BMC Med Genet. 2014;15:111.
Hoekstra AS, Devilee P, Bayley J-P. Models of parent-of-origin tumorigenesis in hereditary paraganglioma. Semin Cell Dev Biol. 2015;43:1–8.
Hoekstra AS, Addie RD, Ras C, et al. Parent-of-origin tumorigenesis is mediated by an essential imprinted modifier in SDHD -linked paragangliomas: SLC22A18 and CDKN1C are candidate tumor modifiers. Hum Mol Genet. 2016;25:ddw218.
Neumann HPH, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004;292:943–51.
HJLM Timmers, Gimenez-Roqueplo AP, Mannelli M, Pacak K. Clinical aspects of SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer. 2009;16:391–400.
Piccini V, Rapizzi E, Bacca A, et al. Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. Endocr Relat Cancer. 2012;19:149–55.
Ricketts CJ, Forman JR, Rattenberry E, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010;31:41–51.
Evenepoel L, Papathomas TG, Krol N, et al. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 2015;17:610–20.
Heesterman BL, Bayley JP, Tops CM, et al. High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations. Eur J Hum Genet. 2013;21:469–70.
Lepoutre-Lussey C, Caramella C, Bidault F, et al. Screening in asymptomatic SDHx mutation carriers: added value of (18)F-FDG PET/CT at initial diagnosis and 1-year follow-up. Eur J Nucl Med Mol Imaging. 2015;42:868–76.
Mediouni A, Ammari S, Wassef M, et al. Malignant head/neck paragangliomas. Comparative Study. Eur Ann Otorhinolaryngol Head Neck Dis. 2014;131:159–66.
Fruhmann J, Geigl JB, Konstantiniuk P, Cohnert TU. Paraganglioma of the carotid body: treatment strategy and SDH-gene mutations. Eur J Vasc Endovasc Surg. 2013;45:431–6.
Neumann HPH, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–66.
Havekes B, van Der Klaauw AA, Weiss MM, et al. Pheochromocytomas and extra-adrenal paragangliomas detected by screening in patients with SDHD-associated head-and-neck paragangliomas. Endocr Relat Cancer. 2009;16:527–36.
van Hulsteijn LT, Heesterman B, Jansen JC, et al. No evidence for increased mortality in SDHD variant carriers compared with the general population. Eur J Hum Genet. 2015;23:1713–6.
van Hulsteijn LT, den Dulk AC, Hes FJ, Bayley JP, Jansen JC, Corssmit EPM. No difference in phenotype of the main Dutch SDHD founder mutations. Clin Endocrinol. 2013;79:824–31.
Amorim LDAF, Cai J. Modelling recurrent events: a tutorial for analysis in epidemiology. Int J Epidemiol. 2015;44:324–33.
Therneau TM. A package for survival analysis in S. version 2.38. 2015. https://CRAN.R-project.org/package=survival
Hensen EF, Jansen JC, Siemers MD, et al. The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family. Eur J Hum Genet. 2010;18:62–66.
Benn DE, Gimenez-Roqueplo AP, Reilly JR, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006;91:827–36.
Benn DE, Robinson BG, Clifton-Bligh RJ. 15 Years of paraganglioma: clinical manifestations of paraganglioma syndromes types 1-5. Endocr Relat Cancer. 2015;22:T91–103.
Schiavi F, Demattè S, Cecchini ME, et al. The endemic paraganglioma syndrome type 1: origin, spread, and clinical expression. J Clin Endocrinol Metab. 2012;97:637–41.
Heesterman BL, de Pont LMH, Verbist BM, et al. Age and tumor volume predict growth of carotid and vagal body paragangliomas. J Neurol Surg B Skull Base. 2017;78:497–505. in press
Lonser RR, Butman Ja, Huntoon K, et al. Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2014;120:1055–62.
Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell. 2005;7:77–85.
Hussain I, Husain Q, Baredes S, Eloy JA, Jyung RW, Liu JK. Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management. J Neurosurg. 2014;120:321–30.
Chen Y, Fu L, Han Y, et al. Testosterone replacement therapy promotes angiogenesis after acute myocardial infarction by enhancing expression of cytokines HIF-1a, SDF-1a and VEGF. Eur J Pharmacol. 2012;684:116–24.
Gimenez-Roqueplo AP, Caumont-Prim A, Houzard C, et al. Imaging work-up for screening of paraganglioma and pheochromocytoma in SDHx mutation carriers: a multicenter prospective study from the PGL.EVA investigators. J Clin Endocrinol Metab. 2013;98:4578–87.
Woolen S, Gemmete JJ. Paragangliomas of the head and neck. Neuroimaging Clin N Am. 2016;26:259–78.
Barsky AJ, Peekna HM, Borus JF. Somatic symptom reporting in women and men. J Gen Intern Med. 2001;16:266–75.
Gijsbers Van Wijk CMT, Kolk AM. Sex differences in physical symptoms: the contribution of symptom perception theory. Soc Sci Med. 1997;45:231–46.
Suárez C, Rodrigo JP, Bödeker CC, et al. Jugular and vagal paragangliomas: systematic study of management with surgery and radiotherapy. Head Neck. 2013;35:1195–204.
Suárez C, Rodrigo JP, Mendenhall WM, et al. Carotid body paragangliomas: a systematic study on management with surgery and radiotherapy. Eur Arch Otorhinolaryngol. 2014;271:23–34.
van Duinen N, Steenvoorden D, Kema IP, et al. Increased urinary excretion of 3-methoxytyramine in patients with head and neck paragangliomas. J Clin Endocrinol Metab. 2010;95:209–14.
Burnichon N, Rohmer V, Amar L, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009;94:2817–27.
Martucci VL, Pacak K. Pheochromocytoma and paraganglioma: diagnosis, genetics, management, and treatment. Curr Probl Cancer. 2014;38:7–41. https://doi.org/10.1016/j.currproblcancer.2014.01.001.
Archier A, Varoquaux A, Garrigue P, et al. Prospective comparison of 68Ga-DOTATATE and 18F-FDOPA PET/CT in patients with various pheochromocytomas and paragangliomas with emphasis on sporadic cases. Eur J Nucl Med Mol Imaging. 2016;43:1248–57.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Heesterman, B.L., de Pont, L.M.H., van der Mey, A.G. et al. Clinical progression and metachronous paragangliomas in a large cohort of SDHD germline variant carriers. Eur J Hum Genet 26, 1339–1347 (2018). https://doi.org/10.1038/s41431-018-0116-4
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41431-018-0116-4
This article is cited by
-
Identification of a pathogenic SDHD mutation in a Chinese family with hereditary head and neck paraganglioma: implications for genetic counseling and management
World Journal of Surgical Oncology (2025)
-
International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers
Nature Reviews Endocrinology (2021)
-
Genetik von Phäochromozytomen und ihre Bedeutung in der Chirurgie
Der Chirurg (2019)
-
European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma
European Journal of Nuclear Medicine and Molecular Imaging (2019)
