Increased Mortality in SDHB but Not in SDHD Pathogenic Variant Carriers

Area of Science:

• Endocrinology
• Genetics
• Oncology

Background:

• Germline mutations in succinate dehydrogenase subunit B (SDHB) and D (SDHD) genes are linked to hereditary paraganglioma (PGL) and pheochromocytoma (PHEO).
• The clinical presentation and outcomes associated with pathogenic variants differ based on the specific gene involved.
• Understanding the mortality risks associated with these genetic mutations is crucial for patient management.

Purpose of the Study:

• To estimate and compare the mortality rates of Dutch individuals carrying SDHB or SDHD germline mutations.
• To compare the mortality of these cohorts against a matched general Dutch population.
• To identify potential differences in mortality risk based on the specific succinate dehydrogenase subunit gene involved and the presence of PGL.

Main Methods:

• Retrospective cohort study design.
• Inclusion of 192 SDHB variant carriers and 232 SDHD variant carriers.
• Comparison of mortality data using Standard Mortality Ratios (SMR) against a matched general population cohort.

Main Results:

• SDHB variant carriers exhibited an SMR of 1.89, which increased to 2.88 for those with PGL.
• SDHD variant carriers had an SMR of 0.93, with a slight increase to 1.06 for affected carriers.
• Mortality risk appears elevated in SDHB carriers, especially with PGL, while SDHD carriers show general population-level mortality.

Conclusions:

• Mortality risk is significantly increased in SDHB mutation carriers, particularly those diagnosed with PGL.
• SDHD mutation carriers demonstrate mortality rates comparable to the general population, irrespective of PGL diagnosis.
• These findings highlight the importance of gene-specific risk assessment and tailored management strategies following DNA testing in PGL and PHEO patients.