Clinical characteristics and prognosis of SDHD pathogenic variant carriers: a systematic review and meta-analysis
Clinical Snapshot
PICO Framework
| P — Population | Germline SDHD pathogenic variant (PV) carriers, including both affected carriers (those with tumours — pheochromocytoma or paraganglioma) and all carriers (for penetrance estimation) |
| I — Intervention | Carrier status for SDHD germline pathogenic variants (genetic predisposition) |
| C — Comparator | No formal comparator group; proportional meta-analysis of single-arm observational cohorts; age-specific penetrance compared across age strata |
| O — Outcomes | Primary: age-specific penetrance at 20, 40, and 60 years. Secondary: proportion of multifocal tumours, proportion of metastatic disease, proportion of mortality among affected carriers; genotype-phenotype associations for specific SDHD variants |
Bottom Line
This systematic review and meta-analysis provides the most comprehensive quantitative synthesis to date of penetrance and tumour behaviour in SDHD germline pathogenic variant carriers. The key finding — that penetrance reaches 58% by age 40 and 82% by age 60 — strongly supports initiating surveillance in early adulthood and continuing lifelong. The strikingly high multifocality rate of 75% among affected carriers underscores the need for whole-body imaging at diagnosis and follow-up, not targeted single-site evaluation. Reassuringly, metastatic disease (3%) and disease-related mortality (1%) are uncommon, which is important for patient counselling and risk stratification. However, clinicians must interpret these estimates cautiously: ascertainment bias likely inflates penetrance, and the critical maternal imprinting effect of SDHD — whereby maternally inherited variants rarely cause disease — is not explicitly addressed in the abstract, potentially confounding penetrance calculations. Genotype-phenotype associations remain insufficiently characterised. In Australian practice, these data support early referral to clinical genetics, initiation of surveillance from late adolescence in paternally inherited variant carriers, and use of whole-body functional imaging. The evidence base is observational and moderate quality; GRADE assessment is absent. Further prospective registry studies stratified by parent-of-origin and specific variant are needed.
Key Findings
P Value: Not reported in abstract
Effect Size: Pooled proportions: multifocal tumours 75%; metastatic disease 3%; mortality 1% among affected carriers
Primary Outcome: Age-specific penetrance in all SDHD PV carriers: 20% at age 20 years, 58% at age 40 years, 82% at age 60 years
Nnt Or Sensitivity: Not applicable (proportional meta-analysis of prognosis/penetrance data). Clinically relevant threshold: by age 60, approximately 4 in 5 SDHD PV carriers will have developed at least one tumour, and 3 in 4 affected carriers will have multifocal disease
Confidence Interval: Penetrance at 20y: 95% CI 16–25%; at 40y: 95% CI 48–67%; at 60y: 95% CI 75–90%. Multifocality: 95% CI 72–79%; Metastatic disease: 95% CI 2–4%; Mortality: 95% CI 1–2%
Clinical Application
Findings support lifelong biochemical and imaging surveillance for SDHD PV carriers, beginning in early adulthood (penetrance reaches 20% by age 20). The high multifocality rate (75%) reinforces the need for whole-body imaging protocols rather than site-specific surveillance. The low metastatic rate (3%) and mortality (1%) provide reassurance for risk stratification discussions but do not eliminate the need for monitoring. Genetic counselling implications are significant given the imprinting effect. In Australia, SDHD genetic testing is available through state-based clinical genetics services and increasingly through hereditary cancer panels. Medicare Benefits Schedule (MBS) item numbers cover genetic testing for hereditary PPGL syndromes in appropriate clinical contexts. Surveillance imaging (MRI, functional imaging with 68Ga-DOTATATE PET/CT) is available at major centres and partially subsidised. The Endocrine Society of Australia and RACGP guidelines recommend referral to clinical genetics for all PPGL patients under 45 years or with multifocal/bilateral disease. These penetrance data could inform Australian consensus statements on surveillance intervals and age of initiation for SDHD carriers. TGA-approved 68Ga-DOTATATE (Lutathera-related diagnostics) is available for functional imaging. The founder variant issue is less relevant in the Australian context given population diversity, but European-derived estimates remain the best available evidence. Individuals identified as germline SDHD pathogenic variant carriers through clinical genetic testing, including probands with pheochromocytoma/paraganglioma (PPGL) and their at-risk relatives identified through cascade genetic testing. Most applicable to carriers of paternally inherited SDHD variants given the maternal imprinting effect.
Abstract
BACKGROUND: Germline pathogenic variants (PVs) of succinate dehydrogenase subunit D (SDHD) 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 SDHD PVs. OBJECTIVE: 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. METHODS: 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 SDHD 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. RESULTS: 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 SDHD 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. CONCLUSION: SDHD 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 SDHD PV carriers. However, evidence linking specific variants to these phenotypes is limited and requires further investigation. PROSPERO REGISTRATION NUMBER: CRD420251060752.
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