SDHB – Carney-Stratakis syndrome

Carney-Stratakis syndrome (CSS) is a rare, autosomal-dominant dyad of paraganglioma and gastrointestinal stromal tumor, with incomplete penetrance and variable expressivity. Germline heterozygous mutations in the succinate dehydrogenase subunit B gene (Gene Symbol) underlie CSS (Disease Name).

Multiple independent CSS probands have been reported with SDHB missense and splice‐site variants. A novel germline SDHB c.282T>A (p.Ile44Asn) was identified in a 26-year-old GIST patient without paraganglioma, with loss of the wild-type allele and absent SDHB expression in the tumor, and the same mutation in an unaffected mother, suggesting incomplete penetrance (PMID:22160509). Bronchial paraganglioma arising in a 22-year-old with prior KIT/PDGFRA-wild-type GIST also harbored SDHB deficiency (PMID:26895210). Additional unrelated adults with multifocal paragangliomas and SDHB-deficient GISTs carry c.137G>A (p.Arg46Gln) and other missense alleles (PMID:32944103; PMID:36387130). Two pediatric CSS cases with splice-site SDHB variants (c.287-2A>G and c.287-1G>C) further broaden the spectrum (PMID:31883676).

Inheritance is autosomal dominant with incomplete penetrance; no multigenerational segregation has been documented beyond single‐generation carriers. Approximately six unrelated probands carry distinct SDHB variants in CSS, with zero additional affected relatives reported.

The variant spectrum in CSS is dominated by missense changes (Ile44Asn, Arg46Gln), splice‐site alterations (c.287-2A>G), and rare recurrent alleles. Recurrent p.Arg46Gln has been observed in multiple adult CSS presentations, indicating a potential hotspot.

Functional studies demonstrate biallelic inactivation of SDHB in tumors, with loss of heterozygosity at 1p36 and complete loss of SDHB immunostaining in GIST and paraganglioma specimens. SDH complex II activity is markedly reduced in SDH‐deficient GISTs, confirming the two-hit tumor suppressor mechanism (PMID:22160509; PMID:21173220).

Mechanistically, SDHB loss leads to succinate accumulation, pseudohypoxia via HIF stabilization, and global hypermethylation, driving oncogenesis in CSS. Rescue of complex II assembly in model systems restores enzymatic function, highlighting haploinsufficiency and two-hit inactivation.

No studies have refuted the SDHB-CSS link, although incomplete penetrance underscores the need for surveillance of asymptomatic carriers.

Strong genetic and concordant functional evidence support a definitive association between SDHB and Carney-Stratakis syndrome. SDHB mutation screening is recommended for patients with wild-type GIST or early-onset paraganglioma, enabling tailored surveillance. Key take-home: Germline SDHB variants are a core molecular driver of CSS with clear diagnostic and management implications.

References

• Familial Cancer • 2012 • A novel germline SDHB mutation in a gastrointestinal stromal tumor patient without bona fide features of the Carney-Stratakis dyad. PMID:22160509
• Endocrine Pathology • 2016 • Bronchial Paraganglioma with SDHB Deficiency. PMID:26895210
• Radiology Case Reports • 2020 • Carney-Stratakis syndrome: A dyad of familial paraganglioma and gastrointestinal stromal tumor. PMID:32944103
• Frontiers in Oncology • 2022 • Bladder paraganglioma, gastrointestinal stromal tumor, and SDHB germline mutation in a patient with Carney-Stratakis syndrome: A case report and literature review. PMID:36387130
• Cancer Genetics • 2020 • Pediatric gastrointestinal stromal tumor: Report of two novel patients harboring germline variants in SDHB and SDHC genes. PMID:31883676
• Proceedings of the National Academy of Sciences of the United States of America • 2011 • Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. PMID:21173220

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