Hereditary paraganglioma-pheochromocytoma syndromes

AD; succinate dehydrogenase genes

• SDHB, SDHC, SDHD, SDHAF2, SDHA
• SDHD: Parent-of-origin effect (maternally imprinted; disease from paternal variant inheritance)

• Pheochromocytoma
• Paraganglioma (extra-adrenal)
• SDHB: Higher malignancy risk, renal cell carcinoma risk
• SDHD: More head/neck paragangliomas

• Biochemical confirmation of catecholamine excess with plasma free or 24-hour urine fractionated metanephrines, followed by anatomic imaging (CT or MRI) and functional imaging (preferentially Ga-68 DOTATATE PET) to localize tumors
• Germline panel testing of the SDHx genes (SDHB, SDHC, SDHD, SDHAF2, SDHA) and other hereditary genes is indicated; loss of SDHB staining on tumor immunohistochemistry flags an underlying SDHx defect
• Hereditary disease is suggested by multiple or extra-adrenal tumors, young age at onset, malignant behavior, or a positive family history, so germline testing is offered to essentially all affected individuals

• Lifelong surveillance with periodic plasma or urine metanephrines plus whole-body MRI given the multifocal and metachronous tumor pattern; intervals and imaging are tailored to the specific gene
• SDHB carriers warrant closer surveillance for the higher malignant potential and added screening for renal cell carcinoma
• Surgical resection is the definitive treatment for functional or growing tumors, with preoperative alpha-blockade before resection of catecholamine-secreting lesions
• Predictive germline testing and counseling for at-risk relatives; for SDHD and SDHAF2, factor in the parent-of-origin effect (disease typically manifests only with paternal transmission)