Hereditary Paraganglioma-Pheochromocytoma Syndrome

Hereditary paraganglioma-pheochromocytoma syndrome is a genetic condition that predisposes to the development of neuroendocrine tumors, whose location and malignancy are influenced by the specific associated gene. Mutations in genes such as SDHB are associated with an increased risk of malignant tumors, while others, such as those in SDHD, SDHAF2 and MAX must be inherited paternally to manifest, since they are maternally imprinted genes.

Hereditary paraganglioma-pheochromocytoma syndrome is caused by mutations in a set of genes, including SDHB, SDHC, SDHD, SDHAF2, MAX, and TMEM127. These genes play a crucial role in the cellular energy cycle and oxygen sensing. Mutations in the SDHx (succinate dehydrogenase) gene family lead to an accumulation of succinate, which promotes tumor formation under conditions of apparent low oxygen. The MAX and TMEM127 genes are also involved in cellular proliferation pathways, and their alteration contributes to tumor development.

The global incidence of this syndrome is low, affecting approximately 1 in every 300,000 people per year, regardless of ethnicity, although the prevalence of specific mutations can vary. The affected gene largely determines the type and location of tumors. For instance, mutations in SDHB are frequently associated with extra-adrenal paragangliomas with a high potential for malignancy. On the other hand, mutations in SDHD and SDHAF2 typically cause head and neck paragangliomas and exhibit a phenomenon of maternal imprinting, where the disease only manifests if the mutation is inherited from the father.

Symptoms depend on the tumor's location and whether it produces an excess of hormones like catecholamines. Secretory tumors can cause high blood pressure (sustained or in crises), intense headaches, excessive sweating, palpitations, and paleness. Tumors in the head and neck can cause hearing problems, hoarseness, or difficulty swallowing. The age of onset is variable, but it tends to be earlier in hereditary forms, often being diagnosed in childhood or in young adults.

The main management is surgical removal of tumors, whenever possible. Before surgery, pharmacological control with alpha-adrenergic blockers is crucial to stabilize blood pressure and prevent complications. In cases of metastatic disease or unresectable tumors, options include targeted therapies, chemotherapy, or radiotherapy with radioactive isotopes such as 131I-MIBG. Lifelong periodic follow-up with imaging tests and biochemical analyses is essential to detect recurrences or new tumors.