Hereditary Paraganglioma Pheochromocytoma Syndromes

Hereditary paraganglioma-pheochromocytoma (PPGLs) syndromes refers to paragangliomas (tumors derived from neuroendocrine tissues found along the paravertebral axis extending from the skull base to the pelvis) and by pheochromocytomas (paragangliomas of the adrenal medulla).

Although paragangliomas can produce hormones, they do not produce metanephrine (a metabolite of epinephrine) due to the lack of paracrine stimulation by PNMT (requires cortisol). Conversely, pheochromocytomas can produce either metanephrine or normetanephrine (a metabolite of norepinephrine).

Paraganglioma anatomical positions

Comparison of sympathetic and parasympathetic paragangliomas

Extra-adrenal parasympathetic paragangliomas Extra-adrenal sympathetic paragangliomas 
Location:  skull base, neck, and upper mediastinumLocation : lower mediastinum, abdomen, and pelvis
Majority of them are nonsecretory (95%)Majority of them are secretory
Low malignancy riskHigh malignancy risk


Genetic Testing of paragangliomas and pheochromocytomas

All patients with PPGLs should undergo genetic testing since hereditary PPGLs are typically inherited in an autosomal dominant fashion. Although patients usually inherit a pathogenic variant from a parent, some probands may have a de novo pathogenic variant (uninherited spontaneous mutation).  

SDHA, SDHB, SDHC and SDHD (designated as the SDHx syndrome complex) represents four nuclear genes that encode the subunits of the mitochondrial enzyme succinate dehydrogenase (SDH).

Mnemonics for SDHx

SDHB = “BAD” : A high risk of malignancy and extra-adrenal sympathetic PPGLs

SDHD = “DAD” : Parent of origin effects (Deleterious effects from Dad)

What is the meaning of Parent of origin effects?

This refers to the risk of expressing a pathogenic variant based on the parent from which a mutation is inherited. A patient with an SDHD pathogenic variant inherited from their father stands a high risk of developing PPGL. Conversely, the risk is significantly low, but not negligible, if an SDHD mutation is inherited from a mother.

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