SDHD – Carney-Stratakis Syndrome

Carney-Stratakis syndrome (CSS) is a rare, autosomal-dominant disorder with incomplete penetrance characterized by the dyad of paragangliomas and gastrointestinal stromal tumors (GISTs). Germline heterozygous mutations in SDHD have been repeatedly identified in CSS patients, establishing SDHD as a key tumor suppressor gene in this syndrome.

Clinical Validity

The SDHD–CSS association meets ClinGen Strong evidence: germline SDHD variants have been reported in ≥3 unrelated kindreds presenting paraganglioma and GIST (PMID:29339836; PMID:28739378; PMID:32944103), autosomal-dominant segregation with incomplete penetrance, and concordant functional data showing SDH complex II loss.

Genetic Evidence

Inheritance is autosomal dominant with incomplete penetrance. SDHD pathogenic variants (missense and splice-site) have been identified in multiple CSS probands, with segregation in affected relatives across at least 4 family members in one kindred (PMID:29339836). The variant spectrum includes missense changes, e.g., c.149A>G (p.His50Arg), leading to SDH inactivation. No recurrent founder variants have been described. Carrier frequency is extremely low in population databases.

Functional Evidence

SDHD mutations cause loss of mitochondrial complex II activity, succinate accumulation, and a pseudohypoxic state. Biochemical assays and immunohistochemistry demonstrate absent SDH activity in tumors, and yeast and cellular models confirm pathogenicity of SDHD missense alleles through impaired ubiquinone reduction and increased reactive oxygen species (PMID:17636259; PMID:14500403).

Conflicting Evidence

Epigenetic SDH inactivation via SDHC promoter hypermethylation causes Carney triad, a phenocopy without germline SDHD mutations; this distinction underscores the specificity of germline SDHD defects for CSS (PMID:28739378).

Conclusion

Germline SDHD variants underlie Carney-Stratakis syndrome by a classical tumor-suppressor mechanism, with robust segregation and functional data supporting a Strong gene–disease relationship. Genetic testing for SDHD should be incorporated into the diagnostic workup for patients presenting paraganglioma and GIST.

Key Take-home: SDHD mutation screening enables early identification of CSS patients and family members for targeted surveillance.

References

• Laboratory investigation; a journal of technical methods and pathology | 2018 | The role of metabolic enzymes in mesenchymal tumors and tumor syndromes: genetics, pathology, and molecular mechanisms. PMID:29339836
• Molecular and cellular endocrinology | 2018 | Succinate dehydrogenase (SDH) deficiency, Carney triad and the epigenome. PMID:28739378
• Radiology case reports | 2020 | Carney-Stratakis syndrome: A dyad of familial paraganglioma and gastrointestinal stromal tumor. PMID:32944103
• Cancer research | 2003 | Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. PMID:14500403
• 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

Evidence Based Scoring (AI generated)