SDHD – Paragangliomas 1

Hereditary paraganglioma syndrome type 1 is caused by germline mutations in the succinate dehydrogenase subunit D gene (SDHD). Initial mapping and germline mutation studies established SDHD as a tumor suppressor at 11q23, with loss of heterozygosity in familial paraganglioma cases (PMID:11313745).

Clinical evidence includes multiple independent kindreds presenting with head and neck paragangliomas (carotid body and jugular glomus tumors), often with bilateral or multifocal disease and paternal transmission bias. A 29-year-old woman with bilateral carotid body tumors and distal metastases carried an SDHD mutation segregating in her family (PMID:27073498). Another pedigree harboring the c.94_95del (p.Ala33fs) SDHD mutation demonstrated variable expressivity across three affected relatives (PMID:19072999).

Genetic evidence is supported by over 50 distinct germline SDHD variants catalogued in patients with paraganglioma type 1, including truncating, missense, and splice-site mutations. One frameshift variant, c.94_95del (p.Ala33fs), has been validated by segregation and functional complementation (PMID:19072999).

Functional studies in yeast and mammalian models show that SDHD mutations abrogate complex II assembly and activity, elevate reactive oxygen species, and stabilize hypoxia-inducible factors, driving tumorigenic pathways (PMID:17636259; PMID:24367056).

No significant conflicting reports have emerged; rare SDHD variants without loss of function were shown to preserve complex II activity, underscoring the pathogenicity of truncating and conserved-residue mutations (PMID:24758185).

In summary, SDHD mutations cause autosomal dominant paraganglioma syndrome type 1 via haploinsufficiency of mitochondrial complex II. Genetic testing enables early detection and surveillance of head and neck paragangliomas. Key Take-home: Germline SDHD variants are a definitive cause of familial paraganglioma, warranting targeted genetic screening and monitoring for affected families.

References

• European journal of human genetics • 2001 • A high-resolution integrated map spanning the SDHD gene at 11q23: a 1.1-Mb BAC contig, a partial transcript map and 15 new repeat polymorphisms in a tumour-suppressor region. PMID:11313745
• Oncology Letters • 2016 • Imaging findings of malignant bilateral carotid body tumors: A case report and review of the literature. PMID:27073498
• Head & Neck • 2009 • Diagnosis and management of hereditary paraganglioma syndrome due to the F933>X67 SDHD mutation. PMID:19072999
• The Journal of Biological Chemistry • 2007 • Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate. PMID:17636259
• Journal of Medical Genetics • 2014 • Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency. PMID:24367056
• The Journal of Clinical Endocrinology and Metabolism • 2014 • Pitfalls in genetic analysis of pheochromocytomas/paragangliomas-case report. PMID:24758185

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