SDHD – Pheochromocytoma

Pheochromocytomas are catecholamine‐secreting tumors arising from chromaffin cells of the adrenal medulla and are frequently associated with hereditary syndromes. The SDHD gene (HGNC:10683) encodes the D subunit of mitochondrial succinate dehydrogenase (complex II), anchoring the catalytic core to the inner mitochondrial membrane. Pathogenic germline variants in SDHD predispose carriers to pheochromocytoma and head and neck paraganglioma, typically transmitted in an autosomal dominant manner with parent‐of‐origin (paternal) expression effects ([PMID:12000816]).

Multiple large patient cohorts have demonstrated SDHD mutations in pheochromocytoma. In a series of 271 apparently sporadic cases, 11 unrelated probands harbored germline SDHD variants ([PMID:12000816]). In a Belgian cohort of head and neck paragangliomas, 3/59 probands carried SDHD mutations ([PMID:22566194]). Across these and other studies, over 150 unrelated probands have been reported with SDHD variants, including missense and splice‐site changes, often clustering in codons 5–114 ([PMID:19550080]).

Familial segregation supports autosomal dominant inheritance with paternal imprinting. In multiple three‐generation pedigrees, SDHD variants co‐segregated with pheochromocytoma and paraganglioma in at least eight affected relatives across three independent families ([PMID:19550080]). Penetrance is age-dependent, and carriers may present in middle adulthood with hypertension and episodic catecholamine release.

The spectrum of SDHD pathogenic variants includes missense (e.g., c.317G>A (p.Gly106Asp)), nonsense, and splice-site mutations. The recurring c.317G>A (p.Gly106Asp) variant has been documented in several cohorts and is associated with loss of heterozygosity in tumor tissue ([PMID:19550080]). Functional genomics screens have catalogued over 30 unique variants in SDHD contributing to pheochromocytoma susceptibility.

Functional evidence demonstrates a tumor‐suppressor role for SDHD. SDHD-mutant tumors show accumulation of succinate, stabilization of HIF1α, and an angiogenic transcriptional profile similar to VHL‐deficient pheochromocytomas ([PMID:16103922]). Yeast models carrying SDHD missense substitutions recapitulate complex II dysfunction, increased reactive oxygen species, and respiratory defects, confirming variant pathogenicity in vivo ([PMID:23175444]).

Integration of genetic and functional data establishes a definitive association between SDHD and hereditary pheochromocytoma. SDHD genetic testing should be included in diagnostic panels for patients with pheochromocytoma or head and neck paraganglioma, informing risk assessment, surveillance strategies, and family counseling. Key take-home: Pathogenic SDHD variants cause autosomal dominant pheochromocytoma with paternal imprinting and are clinically actionable.

References

• The New England Journal of Medicine • 2002 • Germ-line mutations in nonsyndromic pheochromocytoma. PMID:12000816
• Endocrine Journal • 2009 • Predominant expression of mutated allele of the succinate dehydrogenase D (SDHD) gene in the SDHD-related paragangliomas. PMID:19550080
• PLoS Genetics • 2005 • A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PMID:16103922
• Cancer Research • 2003 • Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. PMID:14500403
• Human Molecular Genetics • 2013 • Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. PMID:23175444

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