Familial Phaeochromocytoma-Paraganglioma Syndrome

Familial phaeochromocytoma paraganglioma syndromes are inherited predispositions to catecholamine secreting adrenal tumours (phaeochromocytoma) and extra-adrenal paragangliomas, including head and neck paragangliomas that do not secrete.

About 35 to 40% of patients with these tumours carry a germline variant. Genes include SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, NF1, TMEM127, MAX, FH and EPAS1.

SDHB variants are associated with extra-adrenal tumours and a high malignancy risk (about 30 to 70%). SDHD variants (paternal inheritance) cause multiple head and neck tumours. VHL type 2 and MAX variants cause bilateral adrenal disease.

Pathophysiology.

Succinate dehydrogenase loss causes succinate accumulation and pseudohypoxic signalling, driving tumour growth. VHL loss stabilises hypoxia inducible factors.

Tumours release noradrenaline, adrenaline or (in SDHx tumours) dopamine, causing hypertension and arrhythmia.

• Episodic headache, sweating and palpitations with hypertension, sometimes sustained hypertension, pallor, anxiety and tremor.
• Head and neck paraganglioma: pulsatile tinnitus, hearing loss, neck mass, cranial nerve palsies.
• Syndromic features: retinal angiomas and cysts (VHL), neurofibromas (NF1), medullary thyroid carcinoma (RET).

Red flags.

• Hypertensive crisis, arrhythmia, stroke or heart failure.
• Metastases (bone, lung, liver), particularly with SDHB variants.

• Plasma free metanephrines (supine, after 20 to 30 minutes) or 24-hour urinary fractionated metanephrines, and plasma 3-methoxytyramine for dopamine secreting tumours. Results over 3 times the upper limit are highly specific.
• CT or MRI of the neck, chest, abdomen and pelvis. Functional imaging: somatostatin receptor PET-CT for SDHx tumours, fluorodeoxyglucose PET-CT for SDHB and metastases, or meta iodobenzylguanidine scanning for treatment planning.
• Genetic testing for every patient with a phaeochromocytoma or paraganglioma (gene panel), followed by cascade testing of relatives.

Differential diagnosis.

• Primary aldosteronism, essential hypertension with anxiety and panic disorder.
• Drug and food effects on metanephrines (tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, paracetamol in some assays).
• Carcinoid syndrome and other neuroendocrine tumours.

• Surgery is curative for localised disease. Start alpha blockade 7 to 14 days before: doxazosin 2 to 16 mg daily or phenoxybenzamine 10 mg twice daily increasing as tolerated, with a high sodium diet and fluid intake. Add a beta blocker (propranolol 10 to 40 mg three to four times daily) only after alpha blockade is established.
• Adrenal disease: laparoscopic adrenalectomy, cortical sparing in bilateral or hereditary disease when feasible. Replace cortisol after bilateral total adrenalectomy.
• Head and neck paraganglioma: observation, surgery or radiotherapy by site and symptoms. Assess for catecholamine secretion.
• Metastatic disease: surgery of accessible lesions, radiotherapy, high dose iodine-131 metaiodobenzylguanidine, peptide receptor radionuclide therapy, chemotherapy (cyclophosphamide, vincristine and dacarbazine) or sunitinib.
• VHL disease: belzutifan 120 mg daily may be used for associated tumours.

Special groups. Pregnancy: alpha blockade with surgery in the second trimester, or caesarean delivery with tumour removal; avoid beta blockade before alpha blockade. Genetic counselling: 50% risk for children, with SDHD and SDHAF2 variants causing disease only when inherited from the father.

Monitoring. Plasma metanephrines 2 to 6 weeks after surgery, then yearly for life; imaging every 1 to 2 years for carriers and after surgery, and more frequently for SDHB variants.

Referral and escalation. Specialist endocrine surgery and oncology team; clinical genetics; urgent admission for hypertensive crisis.