Skip to main content
Download PDF

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 volume 23, Article number: 4 (2025) Cite this article

Abstract

Background

This study aims to identify a pathogenic SDHD mutation associated with hereditary head and neck paraganglioma (HNPGL) in a Chinese family and to explore its implications for genetic counseling.

Methods

The study involved a family with 15 members spanning three generations. A 31-year-old patient (II-4) was diagnosed with a left parotid gland tumor and a right carotid body tumor, while both the father and elder sister had right carotid body tumors, and the third sister had bilateral carotid body tumors. Whole exome sequencing and Sanger sequencing were employed to identify candidate pathogenic variants. Genetic counseling was conducted for third-generation descendants to assess the likelihood of carrying the mutation and to guide future diagnosis and treatment.

Results

A nonsense mutation in the SDHD gene (NM_001276503:exon2:c.C64T: p.R22X) was identified in the patient and three other affected family members. Genetic counseling for the third generation revealed that only one child (III-4) carried the pathogenic mutation inherited from the patient’s third sister.

Conclusion

We identified a pathogenic mutation in SDHD in a Chinese HNPGL family, which is the second reported case of its kind. Our genetic counseling analysis for the third generation provided important information for the family and guidance for future diagnosis and treatment.

Introduction

Paragangliomas and pheochromocytomas (PPCs) are rare, primarily benign vascular neuroendocrine tumors derived embryologically from neural crest cells associated with the autonomic nervous system. Among these, head and neck paragangliomas (HNPGL) arise from parasympathetic paraganglia, typically located in the carotid, tympanic, jugular, or vagal areas. These tumors present significant surgical challenges due to their proximity to critical vascular and nerve structures. The estimated overall incidence of HNPGLs ranges from 0.3 to 1 per 100,000 individuals, with a notable female predominance, as indicated by a male-to-female ratio of approximately 1:3 to 1:4 [1,2,3]. Genetic predispositions play a crucial role in the development of these tumors, with mutations in the succinate dehydrogenase complex subunit D (SDHD) gene being among the most commonly implicated [4]. Understanding the epidemiology and genetic underpinnings of HNPGL is crucial for improving early diagnosis and patient management, as timely intervention can mitigate surgical risks and improve outcomes.

Patients with HNPGL typically exhibit a range of symptoms based on the tumor’s location and growth [5]. Initial presentations often include painless, gradually enlarging neck masses, which may progress to neurological deficits due to lower cranial nerve involvement. Although most HNPGLs are slow-growing benign tumors, malignancy rates can reach up to 10% [6, 7]. Consequently, when diagnosed, these tumors are often large and intricately associated with vital structures, complicating surgical intervention and increasing the risk of postoperative complications. Therefore, genetic testing holds promise for predicting HNPGL development, enabling earlier detection and more effective management strategies.

Hereditary forms of HNPGL have been linked to mutations in various genes, including succinate dehydrogenase (SDH) subunits SDHD, SDHB, SDHC, SDHAF2, SDHA, VHL, RET, TMEM127, MAX, and NF1 [7]. The SDH complex comprised of 4 subunits, SDHA, SDHB, SDHC, and SDHD, along with the SDHAF2 assembly factor, plays a pivotal role in this context. SDH is integral to the Krebs cycle and electron transport chain in mitochondria. Dysfunction in any of the SDH subunits may lead to compensatory adenosine triphosphate (ATP) production via glycolysis, a less efficient metabolic pathway [8,9,10]. Particularly, mutations in the SDHB subunit have been linked with a heightened risk of malignancy and a worse prognosis; indeed, 50% of patients with metastatic disease possess an SDHB mutation [11, 12]. PGL4 syndrome, arising from autosomal dominant SDHB mutations on chromosome 11p35, frequently presents as sympathetic extra-adrenal PGLs, PCCs, and HNPGLs, with a malignancy rate of up to 70% [7, 13]. Typically located in the abdomen and mediastinum, SDHB mutations also significantly heighten the risk of other cancers, including renal cell carcinoma, gastrointestinal stromal tumors (GIST), breast, and papillary thyroid carcinomas [14,15,16]. In spite these risks, there are currently no establish guidelines and the patients with metastatic disease are routinely screened for the predisposing SDHB mutation.

Despite established associations between pathogenic variants in the SDH subunit genes and specific HNPGL subtypes [17], the understanding of genotype-phenotype correlations remains limited. This gap is partly due to the rarity of the disease and the scarcity of comprehensive genotype-phenotype data. In this study, we identified a pathogenic mutation in the SDHD gene (NM_001276503:exon2:c.C64T: p.R22X) within a Chinese HNPGL family, which has parallels with findings from a previously reported French HNPGL family. By analyzing the clinical manifestations of both families, we aim to elucidate the correlation between this specific mutation and phenotypic expression, thereby contributing valuable data to the existing genotype-phenotype knowledge base. Furthermore, we are conducting genetic counseling for the offspring of the affected families to assess the likelihood of mutation transmission and offer guidance for future diagnosis and management.

Subjects and methods

Recruitment of family

Genetic counseling was provided to a Chinese family with a documented history of hereditary head and neck paraganglioma (HNPGL). The family pedigree is illustrated in Fig. 1a, encompassing 15 individuals across three generations. The proband (II-4), a 31-year-old male, presented with a left-sided glomus jugulare tumor (Fig. 2) and a right carotid body paraganglioma. His father (I-1) and eldest sister (II-1) were diagnosed with right-sided carotid body tumors, while his third sister (II-3) had bilateral carotid body tumors. Clinical evaluations of subjects I-2, II-2, and the third generation (III:1 to III:5) revealed no tumor manifestations. Prior to blood collection for DNA analysis, written informed consent was obtained from all participants. This study was approved by Ethics Committee of Beijing Tiantan Hospital (No. KY2023-131-01).

Fig. 1
figure 1

Analysis of mutations in the SDHD gene. A. Inheritance of Hereditary Non-Canonical Paraganglioma (HNPGL): Diagram illustrating the pedigree of the family under study, highlighting affected individuals (shaded) with the index patient designated as II:4. B. Validation of the c.C64T Variant: Sanger sequencing confirmation of the identified heterozygous nonsense mutation (c.C64T: p.R22X) in the SDHD gene

Full size image
Fig. 2
figure 2

Imaging findings of the tumor. CT scans of the temporal bone (a, b) and enhanced MRI of the head (c, d) depicting a mass located in the left jugular foramen area, measuring approximately 3.3 cm by 2.6 cm. The imaging shows peripheral bone resorption and destruction, with uniform enhancement on the scans. The lesion extends upward into the foramen lacerum towards the left cavernous sinus, compressing the left cerebellopontine angle posteriorly and medially, and descending along the jugular foramen to the extracranial region

Full size image

Whole-exome sequencing and sanger sequencing

Peripheral blood samples were collected, and genomic DNA was extracted using the Qiagen Blood Kit (Qiagen, Hilden, Germany) following the manufacturer’s protocols. The DNA was fragmented into 250 bp pieces using a TIANamp Blood DNA Kit (Tiangen, Beijing, China). DNA quality was assessed through gel electrophoresis before library construction. Following end repair and A-tailing, sequencing adaptors were ligated to both ends of the DNA fragments. All samples were indexed by amplifying adaptor-ligated products with index-tagged primers, and the amplified products were purified using the QIAquick PCR Purification Kit (QIAGEN).

Sonication (Thermo Fisher, FB705, Waltham, MA, USA) and hybrid capture using the xGen Exome Research Panel v1.0 (Integrated DNA Technologies, Coralville, IA, USA) were employed to enrich and sequence the genomic DNA on the Illumina HiSeq 2500 platform, achieving a coverage depth of 496x across all samples with read lengths of 250 bp. Raw image files were processed using base calling software (Illumina 1.7) with default parameters.

To identify pathogenic variants, whole-exome sequencing (WES) was conducted along with pedigree co-segregation analysis for the nuclear family members (I-1, I-2, II-1, II-2, II-3, and II-4). Additionally, WES was performed for the third generation (III-1 to III-5) to evaluate the presence of pathogenic mutations. Following sequencing, the quality of the raw reads was assessed using FastQC, and low-quality reads were filtered with Fastp (https://github.com/OpenGene/fastp) to obtain clean reads. Subsequently, clean reads were aligned to the human GRCh37/hg19 reference genome using the Burrows-Wheeler Aligner (http://bio-bw.sourceforge.net/, accessed on 04/01/2022). Variant calling, including single nucleotide variants (SNVs) and small insertions/deletions (InDels), was performed, and variants were annotated using ANNOVAR (http://annovar.openbioinformatics.org). Variants classified as missense, nonsense, or splice-site mutations were also characterized alongside other genomic features. Variants with a minor allele frequency < 0.001 in the Exome Aggregation Consortium (ExAC), 1000 Genomes Project, and Exome Sequencing Project (ESP6500) were excluded. Retained variants were focused on exonic regions and splice sites.

For coding or splice-site mutations, conservation of the variant sites and their predicted impacts on protein function were evaluated using in silico tools, including SIFT, PolyPhen-2, MutationTaster, and CADD (Combined Annotation-Dependent Depletion) [18,19,20,21]. The pedigree co-segregation analysis classified I-1, II-1, II-3, and II-4 as the disease group, while I-2 and II-2 served as the control group.

To validate the potential pathogenic variant, Sanger sequencing was performed. PCR primers were designed using Primer-BLAST (National Center for Biotechnology Information) with the following sequences: F-CCCTGGTCTTAACTTCACAG and R-ATAAATGGCATCATTCAACC. Sanger sequencing data were analyzed using 4Peaks DNA sequence trace viewer software (version 1.8).

Bioinformatics analysis

Three-dimensional protein structure predictions for the SDHD variant were conducted using AlphaFold (https://www.alphafold.ebi.ac.uk/, accessed on 28/05/2022) and visualized with PyMOL (version 2.5.2).

Results

Clinical characterization

The proband, a 31-year-old male, was referred from the Department of Otolaryngology at Beijing Tiantan Hospital, Capital Medical University, presenting with hoarseness and pulsatile tinnitus. Fiberoptic laryngoscopy revealed fixed left vocal cords. Imaging studies, including CT of the temporal bone and enhanced MRI of the head, identified a mass in the left jugular foramen measuring approximately 3.3 × 2.6 cm. This mass exhibited peripheral bone resorption and destruction, with significant enhancement on imaging. The lesion extended upward into the foramen lacerum towards the left cavernous sinus, compressing the left cerebellopontine angle, and descended along the jugular foramen into the extracranial space (Fig. 2).

Following diagnosis, the patient underwent resection of the left tumor via an infratemporal fossa type A approach. Post-operative follow-up over 2.5 years indicated no recurrence of the tumor. The proband also had a right carotid-body paraganglioma, which was managed conservatively with ongoing observation, showing no signs of enlargement. Furthermore, familial history revealed that his father (I-1) and eldest sister (II-1) were diagnosed with right carotid body tumors, while his third sister (II-3) exhibited bilateral carotid-body tumors. Clinical evaluations of I-1, II-2, and all individuals in the third generation (III:1, III:2, III:3, III:4, III:5) revealed no evidence of tumors. Given that most hereditary head and neck paraganglioma (HNPGL) patients present symptoms between the fourth and seventh decades of life, it was critical to investigate potential pathogenic mutations in the third generation despite the absence of tumors at this stage. Notably, the third generation was not utilized as normal controls for family segregation analysis.

Identification of candidate gene

Through whole-exome sequencing, we identified a total of 165,911 unique variants. Following family segregation analysis, 2,213 variants remained. After filtering for non-exonic and synonymous mutations, we retained 555 variants in the exome and splice regions, ultimately narrowing this down to 270 variants. Further analysis excluded variants with a frequency greater than 0.001 in the Exome Aggregation Consortium (ExAC), 1000 Genomes Project, and Exome Sequencing Project (ESP6500), resulting in 22 candidate genes: DMRTA2, LEXM, IL17RE, EFHB, CYP3A43, MUC12, TMEM123, SDHD, PLA2G4E, NRN1L, CLUH, RAP1GAP2, ZBTB4, TRIM16, NCOR1, KLHL10, EFCAB13, KIF2B, FOXJ1, ASCC2, IFT27, and SREBF2.

Through functional prediction and literature review, we identified a pathogenic nonsense mutation in the SDHD gene (NM_001276503: exon2: c.C64T: p.R22X) as the likely cause of the HNPGL in this family. This heterozygous stop-gain mutation results in premature termination of protein translation, leading to haploinsufficiency of the SDHD gene. The pathogenic nature of this variant was confirmed through Sanger sequencing (Fig. 1b).

In silico analysis of SDHD variant

Prediction of the three-dimensional structure of the SDHD protein was conducted using AlphaFold, and visualized with PyMOL. The analysis indicated substantial loss of the amino acid sequence in the mutant protein compared to the wild-type structure (Fig. 3).

Fig. 3
figure 3

Three-Dimensional Structural Prediction of the SDHD Protein. Three-dimensional structural models of the SDHD protein generated using AlphaFold and visualized with PyMOL. Panel (a) illustrates the wild-type SDHD protein structure, while panel (b) shows the structural impact of the p.R22X mutation, indicating the significant loss of a portion of the amino acid sequence due to this pathogenic variant

Full size image

The impact of the pathogenic mutation on the third generation

As part of our investigation, we performed whole-exome sequencing on the third-generation family members. Notably, only one child (III-4) was found to carry the SDHD gene mutation, which was inherited from the proband’s sister (II-3), who suffers from bilateral carotid body tumors. Importantly, SDHD mutations display distinct genetic imprinting, wherein mutations inherited from the mother do not lead to HNPGL, whereas paternal inheritance does confer risk. Consequently, all third-generation family members are not expected to develop HNPGL, thereby highlighting the significance of parental origin in the manifestation of this hereditary condition.

Discussion

The prevalence of hereditary non-epithelial paragangliomas (HNPGLs) with a positive family history varies significantly across studies, ranging from 9.5–50% [22, 23]. Among families affected by HNPGL, mutations in the SDHB, SDHC, and SDHD genes have been identified, with SDHD mutations being the most prevalent. Reports indicate that SDHB mutations are present in approximately 20% of cases, SDHC in 10%, and SDHD in 50% within families studied in the USA [24, 25]. In the Netherlands, these rates were reported as 6%, 0%, and 94%, respectively, across 32 families consistent with the recent trend [26, 27]. Similarly, an Australian cohort demonstrated rates of 9%, 0%, and 82% for SDHB, SDHC, and SDHD [28, 29]. In contrast, germline mutations in non-familial HNPGLs show greater variability, with only 11–29% of cases exhibiting SDH mutations [22, 29,30,31]. In our study, we identified a pathogenic mutation in the SDHD gene within a family affected by HNPGL, underscoring the importance of genetic screening in familial cases.

Recent investigations have sought to elucidate the relationship between SDHx gene mutations and clinical phenotypes. However, due to the rarity of HNPGLs and the limited sample sizes in existing studies, findings remain inconclusive. For instance, while SDHB mutations are correlated with a higher risk of malignancy, including renal cell carcinoma [32,33,34], SDHD and SDHC variants are predominantly associated with HNPGL [35,36,37]. Notably, mutations in SDHAF2 have been linked to younger patients presenting with multiple HNPGLs [38, 39]. HNPGL encompasses various tumor types, including glomus jugulotympanicum (GJT) and carotid body tumors (CBTs), indicating that identical mutations can manifest as different tumor phenotypes, ranging from unilateral to bilateral, benign to malignant, and solitary to multifocal. In our family study, along with findings from a previously reported French family [40], we observed that the SDHD mutation (NM_001276503: exon2: c.C64T: p.R22X) led to diverse clinical presentations, with CBTs accounting for 75% of cases, GJTs for 16.7%, and an ectopic mediastinal pheochromocytoma for 8.3%. This highlights the mutation’s predominant association with CBTs.

The penetrance of SDH gene mutations varies considerably, with SDHA, SDHB, and SDHC exhibiting low penetrance (< 25%), while SDHD mutations show high penetrance (> 80%). The average age of onset for HNPGL patients with SDHD mutations is approximately 36 years [41]. Longitudinal studies have revealed that penetrance rates for SDHD mutations increase with age, reaching 50% by age 31 and 86% by age 50 [42]. More recent reports indicate that by age 40, 54% of individuals with SDHD mutations exhibit HNPGL, rising to 68% by age 60 and 87% by age 70 [43]. In our study, the third-generation family members were significantly younger than 36, prompting their exclusion from direct analysis, although we provided genetic counseling to them.

Among the third-generation family members, we identified one child (III-4) carrying the disease-causing mutation, inherited from their mother, who has bilateral carotid body tumors. Importantly, the SDHD gene displays maternal imprinting, meaning that the allele inherited from the mother is transcriptionally silent, while the allele from the father is active [44]. As a result, despite carrying the mutation, III-4 is unlikely to develop HNPGL. This critical information alleviated the family’s concerns regarding the potential for disease manifestation in future generations. Our findings emphasize that when a pathogenic mutation in SDHD is identified within an HNPGL family, genetic testing for offspring should focus on the male lineage, as maternal inheritance does not confer risk.

Limitations

Despite the significant findings of our study, several limitations should be acknowledged. First, the sample size of the family under investigation is small, which may limit the generalizability of our results to broader populations. The rarity of hereditary non-epithelial paragangliomas (HNPGLs) presents challenges in recruiting larger cohorts for comprehensive analysis. Additionally, while we identified a pathogenic mutation in the SDHD gene, the exact penetrance and expressivity of this mutation within the family remain uncertain due to the limited follow-up of younger family members.

Conclusion

In conclusion, our study identified a pathogenic mutation in the SDHD gene within a Chinese family affected by hereditary non-epithelial paragangliomas, marking it as the second documented family with such a mutation. This research contributes to the understanding of SDHD-related pathogenesis and highlights the importance of genetic counseling for affected families. Our findings are invaluable for guiding targeted genetic counseling and informed management strategies to better support individuals at risk of inheriting SDHD mutations.

Data availability

Data is provided within the manuscript files.

References

  1. Sandow L, Thawani R, Kim MS, Heinrich MC. Paraganglioma of the Head and Neck: a review. Endocr Practice: Official J Am Coll Endocrinol Am Association Clin Endocrinologists. 2023;29(2):141–7.

    Article  Google Scholar 

  2. Papaspyrou K, Mewes T, Rossmann H, Fottner C, Schneider-Raetzke B, Bartsch O, Schreckenberger M, Lackner KJ, Amedee RG, Mann WJ. Head and neck paragangliomas: report of 175 patients (1989–2010). Head Neck. 2012;34(5):632–7.

    Article  PubMed  Google Scholar 

  3. Boedeker CC. [Paragangliomas and paraganglioma syndromes]. Laryngo- rhino- otologie. 2011;90(Suppl 1):S56–82.

    Article  PubMed  Google Scholar 

  4. Katabathina VS, Rajebi H, Chen M, Restrepo CS, Salman U, Vikram R, Menias CO, Prasad SR. Genetics and imaging of pheochromocytomas and paragangliomas: current update. Abdom Radiol (NY). 2020;45(4):928–44.

    Article  PubMed  Google Scholar 

  5. Darrat M, Lau L, Leonard C, Cooke S, Shahzad MA, McHenry C, McCance DR, Hunter SJ, Mullan K. Clinical management and outcome of head and neck paragangliomas (HNPGLs): a single centre retrospective study. Clin Endocrinol. 2024;101(3):243–8.

    Article  CAS  Google Scholar 

  6. Valero C, Ganly I. Paragangliomas of the head and neck. J oral Pathol Medicine: Official Publication Int Association Oral Pathologists Am Acad Oral Pathol. 2022;51(10):897–903.

    Article  Google Scholar 

  7. Guha A, Musil Z, Vicha A, Zelinka T, Pacak K, Astl J, Chovanec M. A systematic review on the genetic analysis of paragangliomas: primarily focused on head and neck paragangliomas. Neoplasma. 2019;66(5):671–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Boedeker CC, Hensen EF, Neumann HP, Maier W, van Nederveen FH, Suárez C, Kunst HP, Rodrigo JP, Takes RP, Pellitteri PK, et al. Genetics of hereditary head and neck paragangliomas. Head Neck. 2014;36(6):907–16.

    Article  PubMed  Google Scholar 

  9. Pacak K, Wimalawansa SJ. Pheochromocytoma and paraganglioma. Endocr Practice: Official J Am Coll Endocrinol Am Association Clin Endocrinologists. 2015;21(4):406–12.

    Article  Google Scholar 

  10. Bouillaud F. Inhibition of succinate dehydrogenase by pesticides (SDHIs) and energy metabolism. Int J Mol Sci. 2023;24(4):4045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Asban A, Kluijfhout WP, Drake FT, Beninato T, Wang E, Chomsky-Higgins K, Shen WT, Gosnell JE, Suh I, Duh QY. Trends of genetic screening in patients with pheochromocytoma and paraganglioma: 15-year experience in a high-volume tertiary referral center. J Surg Oncol. 2018;117(6):1217–22.

    Article  PubMed  Google Scholar 

  12. Fishbein L, Khare S, Wubbenhorst B, DeSloover D, D’Andrea K, Merrill S, Cho NW, Greenberg RA, Else T, Montone K, et al. Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun. 2015;6:6140.

    Article  CAS  PubMed  Google Scholar 

  13. Muth A, Crona J, Gimm O, Elmgren A, Filipsson K, Stenmark Askmalm M, Sandstedt J, Tengvar M, Tham E. Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma. J Intern Med. 2019;285(2):187–204.

    Article  CAS  PubMed  Google Scholar 

  14. Kavinga Gunawardane PT, Grossman A. The clinical genetics of phaeochromocytoma and paraganglioma. Arch Endocrinol Metab. 2017;61(5):490–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Opocher G, Schiavi F. Genetics of pheochromocytomas and paragangliomas. Best Pract Res Clin Endocrinol Metab. 2010;24(6):943–56.

    Article  CAS  PubMed  Google Scholar 

  16. Williams MD. Paragangliomas of the head and neck: an overview from diagnosis to genetics. Head Neck Pathol. 2017;11:278–87.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Richter S, Gieldon L, Pang Y, Peitzsch M, Huynh T, Leton R, Viana B, Ercolino T, Mangelis A, Rapizzi E, et al. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Medicine: Official J Am Coll Med Genet. 2019;21(3):705–17.

    Article  CAS  Google Scholar 

  18. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Current protocols in human genetics 2013, Chap. 7:Unit7.20.

  19. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(7):1073–81.

    Article  CAS  PubMed  Google Scholar 

  21. Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11(4):361–2.

    Article  CAS  PubMed  Google Scholar 

  22. Baysal BE. Hereditary paraganglioma targets diverse paraganglia. J Med Genet. 2002;39(9):617–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mete O, Wenig BM. Update from the 5th edition of the world health organization classification of head and neck tumors: overview of the 2022 WHO classification of head and neck neuroendocrine neoplasms. Head Neck Pathol. 2022;16(1):123–42.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 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(9):703–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Andrews KA, Ascher DB, Pires DEV, Barnes DR, Vialard L, Casey RT, Bradshaw N, Adlard J, Aylwin S, Brennan P. Tumour risks and genotype–phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018;55(6):384–94.

    Article  CAS  PubMed  Google Scholar 

  26. Bayley JP, van Minderhout I, Weiss MM, Jansen JC, Oomen PH, Menko FH, Pasini B, Ferrando B, Wong N, Alpert LC, et al. Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma. BMC Med Genet. 2006;7:1.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Rijken JA, Van Hulsteijn LT, Dekkers OM, Niemeijer ND, Leemans CR, Eijkelenkamp K, Van Der Horst-Schrivers AN, Kerstens MN, Van Berkel A, Timmers HJ. Increased mortality in SDHB but not in SDHD pathogenic variant carriers. Cancers. 2019;11(1):103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Baysal BE. Clinical and molecular progress in hereditary paraganglioma. J Med Genet. 2008;45(11):689–94.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Guha A. New methods of classification and prognosis in paragangliomas and pheochromocytomas. 2023.

  31. Bruce-Brand C, van Wyk AC. Prevalence of succinate dehydrogenase deficiency in paragangliomas and phaeochromocytomas at a tertiary hospital in Cape Town: a retrospective review. J Endocrinol Metabolism Diabetes South Afr. 2021;26(1):9–15.

    Article  Google Scholar 

  32. van Hulsteijn LT, Dekkers OM, Hes FJ, Smit JW, Corssmit EP. Risk of malignant paraganglioma in SDHB-mutation and SDHD-mutation carriers: a systematic review and meta-analysis. J Med Genet. 2012;49(12):768–76.

    Article  PubMed  Google Scholar 

  33. Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007;92(10):3822–8.

    Article  CAS  PubMed  Google Scholar 

  34. Aghamir SMK, Heshmat R, Ebrahimi M, Ketabchi SE, Parichehreh Dizaji S, Khatami F. The impact of succinate dehydrogenase gene (SDH) mutations in renal cell carcinoma (RCC): a systematic review. OncoTargets Therapy 2019:7929–40.

  35. Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, Niccoli P, Gaillard D, Chabrier G, Chabolle F, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009;94(8):2817–27.

    Article  CAS  PubMed  Google Scholar 

  36. Bayley JP, Bausch B, Rijken JA, Van Hulsteijn LT, Jansen JC, Ascher D, Pires DEV, Hes FJ, Hensen EF, Corssmit EP. Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma–paraganglioma. J Med Genet. 2020;57(2):96–103.

    Article  CAS  PubMed  Google Scholar 

  37. Williams ST, Chatzikyriakou P, Carroll PV, McGowan BM, Velusamy A, White G, Obholzer R, Akker S, Tufton N, Casey RT. SDHC phaeochromocytoma and paraganglioma: a UK-wide case series. Clin Endocrinol. 2022;96(4):499–512.

    Article  CAS  Google Scholar 

  38. Bayley JP, Kunst HP, Cascon A, Sampietro ML, Gaal J, Korpershoek E, Hinojar-Gutierrez A, Timmers HJ, Hoefsloot LH, Hermsen MA, et al. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol. 2010;11(4):366–72.

    Article  CAS  PubMed  Google Scholar 

  39. Kunst HP, Rutten MH, de Mönnink JP, Hoefsloot LH, Timmers HJ, Marres HA, Jansen JC, Kremer H, Bayley JP, Cremers CW. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin cancer Research: Official J Am Association Cancer Res. 2011;17(2):247–54.

    Article  CAS  Google Scholar 

  40. Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rötig A, Jeunemaitre X. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet. 2001;69(6):1186–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Heesterman BL, de Pont LM, van der Mey AG, Bayley J-P, Corssmit EP, Hes FJ, Verbist BM, van Benthem PPG, Jansen JC. Clinical progression and metachronous paragangliomas in a large cohort of SDHD germline variant carriers. Eur J Hum Genet. 2018;26(9):1339–47.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004;292(8):943–51.

    Article  CAS  PubMed  Google Scholar 

  43. Hensen EF, Jansen JC, Siemers MD, Oosterwijk JC, Vriends AH, Corssmit EP, Bayley JP, van der Mey AG, Cornelisse CJ, Devilee P. The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family. Eur J Hum Genetics: EJHG. 2010;18(1):62–6.

    Article  PubMed  Google Scholar 

  44. Pigny P, Vincent A, Cardot Bauters C, Bertrand M, de Montpreville VT, Crepin M, Porchet N, Caron P. Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab. 2008;93(5):1609–15.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

None.

Funding

This study was funded by Beijing Natural Science Foundation-Youth Project (No. 7234361).

Author information

Authors and Affiliations

  1. Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tiantan Hospital, Capital Medical University, No. 119, South Fourth Ring Road West, Fengtai District, Beijing, 100070, China

    Pu Wang, Liming Gao, Wenyang Zhang, Rui Guo & Yin Xia

Authors
  1. Pu Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Liming Gao
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Wenyang Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Rui Guo
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Yin Xia
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

PW and LG contributed to the conception and design of the study. WZ and RG contributed to the acquisition of data. YX contributed to the analysis of data. PW and LG wrote the manuscript. YX revised the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Yin Xia.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Beijing Tiantan Hospital (NO.KY2023-131-01). Prior to blood collection for DNA analysis, all Patients and their families participated voluntarily and signed informed consent forms, and the study was performed in accordance with the Helsinki II declaration. Informed consent was obtained from all the study subjects before enrollment.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, P., Gao, L., Zhang, W. et al. Identification of a pathogenic SDHD mutation in a Chinese family with hereditary head and neck paraganglioma: implications for genetic counseling and management. World J Surg Onc 23, 4 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12957-024-03641-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12957-024-03641-w

Keywords

World Journal of Surgical Oncology

ISSN: 1477-7819

Contact us