Clinical characteristics and prognosis of <i>SDHD</i> pathogenic variant carriers: a systematic review and meta-analysis.

Abstract

Germline pathogenic variants (PVs) of succinate dehydrogenase subunit D (<i>SDHD</i>) are major genetic causes of pheochromocytomas and paragangliomas. Existing studies have reported inconsistent findings and lack a comprehensive synthesis regarding penetrance, multifocality and metastatic risk in carriers of <i>SDHD</i> PVs. To systematically assess age-specific penetrance (in all carriers) and the proportions of multifocality, metastatic disease and mortality among affected carriers, and explore potential genotype-phenotype associations through a systematic review and meta-analysis. Eligible observational studies were selected from PubMed, MEDLINE and EMBASE that reported age-specific penetrance (in all carriers) and the proportions of multifocality, metastatic disease and mortality among affected carriers (those with tumours). Additionally, data on specific <i>SDHD</i> variants associated with tumour multifocality or metastatic behaviour were collected. Following independent data extraction and quality assessment by two reviewers, these proportions were meta-analysed using random-effects models or fixed-effect model to generate pooled estimates with 95% CIs and prediction intervals. Age-specific penetrance increased from 20% at 20 years of age (95% CI 16% to 25%) to 58% at 40 years (95% CI 48% to 67%) and 82% at 60 years (95% CI 75% to 90%). Among the affected <i>SDHD</i> PV carriers, the pooled proportions were 75% (95% CI 72% to 79%) for multifocal tumours, 3% (95% CI 2% to 4%) for metastatic disease and 1% (95% CI 1% to 2%) for mortality. <i>SDHD</i> PV carriers exhibit increasing age-specific penetrance, with a high proportion of patients having multifocal tumours but low proportions of metastatic disease and mortality, providing partial evidence for the need for lifelong monitoring of <i>SDHD</i> PV carriers. However, evidence linking specific variants to these phenotypes is limited and requires further investigation. CRD420251060752.