SDHB – Pheochromocytoma

Succinate dehydrogenase subunit B (SDHB) germline mutations underlie a hereditary predisposition to pheochromocytoma, accounting for both familial and apparently sporadic cases. SDHB encodes the iron–sulfur subunit of mitochondrial complex II, and its loss of function leads to succinate accumulation, pseudohypoxia, and tumorigenesis via stabilization of hypoxia-inducible factors (HIFs).

Clinical Validity

The SDHB–pheochromocytoma association is classified as Strong based on pathogenic variants in at least 12 unrelated probands ([PMID:12000816]) with autosomal dominant segregation across >40 mutation carriers (35% penetrance by age 40) in a multi-generation kindred ([PMID:19389109]), and concordant functional data demonstrating complex II deficiency and HIF1α activation.

Genetic Evidence

Inheritance is autosomal dominant with incomplete penetrance. Segregation studies identified 11 affected relatives carrying an exon 1 gross deletion of SDHB ([PMID:19389109]). Case series report >100 probands with SDHB variants, including missense, frameshift, splice-site, and large deletions. A recurrent Dutch founder deletion c.201-4429_287-933del and diverse loss-of-function alleles (e.g., c.757del (p.Cys253ValfsTer5) in a Korean family ([PMID:20563860])) confirm the variant spectrum and justify Strong genetic evidence.

Functional Evidence

Mechanism is loss of SDHB leading to complex II inactivation, succinate buildup, and HIF1α-mediated pseudohypoxia. In vitro and in vivo models show abolished complex II activity, elevated succinate:fumarate ratios, enhanced angiogenesis, and invasive phenotypes ([PMID:14500403]; [PMID:26460615]). These concordant functional assays support Moderate functional evidence.

Conflicting Evidence

Immunohistochemistry for SDHB may be positive in some SDHB mutation carriers (L157X, P236S), indicating that IHC alone cannot exclude SDHB-related disease ([PMID:32901905]).

Integration & Clinical Utility

SDHB testing should be performed in all patients with pheochromocytoma, especially those with extra-adrenal location, early onset, multifocal disease, or family history. Detection of an SDHB mutation guides lifelong surveillance for recurrence and metastatic risk, informs cascade testing of relatives, and may influence imaging strategy (e.g., FDG-PET). Key Take-Home: Germline SDHB mutations confer a high risk of pheochromocytoma via complex II deficiency and warrant genetic screening for optimal patient and family management.

References

• The New England journal of medicine • 2002 • Germ-line mutations in nonsyndromic pheochromocytoma. PMID:12000816
• Clinical genetics • 2009 • Penetrance and clinical consequences of a gross SDHB deletion in a large family. PMID:19389109
• Cancer research • 2003 • Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. PMID:14500403
• Oncotarget • 2015 • Deciphering the molecular basis of invasiveness in Sdhb-deficient cells. PMID:26460615
• The Tokai journal of experimental and clinical medicine • 2020 • Positive Immunostaining for Succinate Dehydrogenase B (SDHB) in Paraganglioma Associated with Germline Mutation of SDHB, L157X and P236S. PMID:32901905

Evidence Based Scoring (AI generated)