Approximately 10-20% of all phaeochromocytomas (PCs) and paragangliomas (PGLs) occur in childhood. Paediatric PC/PGLs are likely to be associated with carriage of variants in predisposition genes: ~70% are associated with germline variants in VHL or SDHB, and less frequently in SDHD, RET, NF1 and MAX. Von Hippel Lindau syndrome in childhood is associated with PC that may be bilateral, and the pathogenic VHL variant may be de novo with this presentation. Conversely, thoraco-abdominal PGLs in children are highly likely to be associated with a pathogenic SDHB variant; these tumours are often multifocal and/or metastatic. A striking pedigree may be observed wherein a pathogenic SDHB variant is diagnosed in the index child, with subsequent identification of clinically unaffected parental and grandparental carriers. Occasional reports of PGLs that exhibit loss of SDHB immunostaining without germline pathogenic SDHx variants suggest that epigenetic factors (such as SDHC promoter hypermethylation) may account for at least some of the non-hereditary component of paediatric PC/PGLs. It is however crucially important that analysis for large-scale SDHx deletions is performed in every paediatric PC/PGL case. Somatic mosaicism for pathogenic EPAS1 variants defines a particular syndrome that can present in childhood: multifocal PGLs often but not always associated with congenital erythrocytosis and/or duodenal somatostatinomas.
In summary, all paediatric PC/PGL cases should be referred for comprehensive genetic testing for germline predisposition variants, and in selected cases also somatic testing for EPAS1. Genetic testing of families with childhood onset PC/PGL requires expert counseling and the advent of educational resources is welcome. Paediatric PC/PGL cases that are not yet diagnosed with causative genetic variants represent a unique discovery cohort for new predisposition genes.