Pheochromocytoma paraganglioma syndrome

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome predisposes to tumours arising from neural crest-derived paraganglia distributed from the skull base to the pelvis, as well as the adrenal medulla. Head and neck paragangliomas, which are primarily parasympathetic, are usually non-secretory (approximately 5% secrete catecholamines) and most commonly present through local mass effects.

Pheochromocytomas are catecholamine-secreting tumours confined to the adrenal medulla. Extra-adrenal sympathetic paragangliomas carry a higher risk of metastasis, where up to 45% of individuals with metastatic extra-adrenal paraganglioma harbour a germline SDHB pathogenic variant. Catecholamine excess may manifest with episodic or sustained hypertension, headaches, palpitations, arrhythmias, sweating, pallor, and anxiety.

Clear cell renal cell carcinoma and gastrointestinal stromal tumours are also observed at increased frequency, particularly in individuals with SDHB or SDHD pathogenic variants. Clinical presentation is highly variable, with tumours arising from childhood into adulthood and most diagnoses occurring between the second and fifth decades.

The estimated incidence is approximately 0.6 in 100,000 per year. Approximately 35-40% of all paragangliomas and pheochromocytomas are associated with a hereditary predisposition.

Hereditary PGL/PCC syndrome is genetically heterogeneous, and pathogenic variants in seven genes account for the majority of hereditary cases. The most frequently implicated genes are SDHB (~52%), SDHD (~22%), SDHC (~8%), TMEM127 (~5%), and MAX (~4%), with SDHA (~4%) and SDHAF2 (~1%) accounting for the remainder. SDHA, SDHB, SDHC, SDHD, and SDHAF2 encode subunits or an assembly factor of mitochondrial succinate dehydrogenase (complex II of the electron transport chain) and act as tumour-suppressor genes; somatic biallelic inactivation leads to succinate accumulation, pseudohypoxic HIF1α stabilisation, and aberrant DNA hypermethylation. TMEM127 regulates mTOR signalling, and MAX heterodimerises with MYC to control transcription of tumorigenesis-related genes.

Hereditary PGL/PCC syndrome is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the familial pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Hereditary PGL/PCC syndrome is diagnosed primarily by the identification of a germline pathogenic variant in one of the associated genes. Biochemical testing, including plasma-free or 24-hour urinary fractionated metanephrines and catecholamines, supports the diagnosis of a catecholamine-secreting paraganglioma or pheochromocytoma; however, many head and neck paragangliomas are non-secretory. CT or MRI is used to localise tumours and assess disease extent, while functional imaging with 68Ga-DOTATATE PET-CT, 123I-MIBG scintigraphy, or FDG-PET can be used to further characterise tumour biology and detect metastases.