Pseudohypoxia and family history are key predictors of severe outcomes in hereditary pheochromocytoma and paraganglioma syndromes
Authors' conclusion
Machine learning identified combined clinical and genetic characteristics for predicting hereditary PPGL syndromes, and multifocal/metastatic PPGL. This enables personalized risk stratification to guide genetic testing and surveillance in patients with PPGL and their relatives.
Study context
- Population
- Patients with pheochromocytoma and paraganglioma (PPGL), family history of PPGL, or suspected PPGL-related hereditary syndrome; age 33.5 ± 19.9 years, 45.2% males
- Participants
- 221 patients
- Outcome
- Germline pathogenic variants (PPGLgPV) and PPGL development
Methodological detailsmulticenter, machine-learning analyses
- Multicenter
- Machine-learning analyses
Main finding
As reported in the abstract
- Harbored PPGLgPV
- 143 (64.7%)
- Developed PPGL
- 91 (41.2%)
- Pheochromocytoma
- 46
- Paraganglioma/both
- 45
- Multifocal/metastatic PPGL
- 29
- PPV for carrying PPGLgPV: age at diagnosis <41 years with positive family history
- 100%
- NPV for carrying PPGLgPV: diagnosed at age >40 years with solitary PPGL
- 86%
Observational data: associations, not effects.
Further findings
Pseudohypoxia (PH)-related PPGLgPV carriers
- PH-related PPGLgPV carriers were younger at PPGL diagnosis and had an increased risk of multifocal/metastatic disease
Prediction of metastatic/multifocal disease
- PPV: elevated catecholamine metabolites and PH-related PPGLgPV
- 80%
- NPV: non-elevated catecholamine metabolites with negative family history
- 100%
- NPV: non-elevated catecholamine metabolites with non-PH gene alterations
- 91%
PPGL risk: PV found incidentally vs carriers screened due to a family member with PPGL
- Lower PPGL risk in patients with PV found incidentally vs carriers screened due to family member with PPGL (P = .026)
Original publication
Pseudohypoxia and family history are key predictors of severe outcomes in hereditary pheochromocytoma and paraganglioma syndromes. Eur J Endocrinol. Published 5 March 2026. doi:10.
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