SNP Shot: Genomic Insights

Hereditary paraganglioma-pheochromocytoma is a genetic condition where tumors grow in paraganglia, cell clusters located near nerve bundles called ganglia. A paraganglioma is a tumor of the paraganglia. Pheochromocytomas, a specific type of paraganglioma, develop in the adrenal glands (on top of the kidneys), which produce stress hormones. Other paragangliomas typically occur in the head, neck, or trunk. Individuals with this inherited condition can develop one or more paragangliomas, possibly including pheochromocytomas.

Pheochromocytomas, along with certain other paragangliomas, are linked to sympathetic nervous system ganglia. This system regulates the "fight-or-flight" response, triggering bodily changes through stress hormone release. Paragangliomas found outside the adrenal glands and connected to the sympathetic system, often in the abdomen, are known as extra-adrenal paragangliomas. Many sympathetic paragangliomas, including pheochromocytomas, release catecholamines, such as epinephrine (adrenaline) or norepinephrine. Excessive catecholamines can lead to symptoms like high blood pressure (hypertension), rapid heartbeat (palpitations), headaches, and sweating.

Most other paragangliomas are associated with parasympathetic nervous system ganglia, which control involuntary functions like digestion and saliva production. These parasympathetic paragangliomas, usually in the head and neck, typically don't produce hormones. However, large tumors can cause coughing, hearing loss in one ear, or difficulty swallowing.

Paragangliomas and pheochromocytomas are considered tumors of uncertain malignant potential. This means they can be benign (noncancerous) or malignant (cancerous), with the ability to spread to other areas of the body (metastasize). Extra-adrenal paragangliomas are more likely to become malignant than other paragangliomas or pheochromocytomas.

Researchers have identified various subtypes of hereditary paraganglioma-pheochromocytoma, each linked to a specific gene. Types 1, 2, and 3 typically involve paragangliomas in the head or neck. Type 4 usually involves extra-adrenal paragangliomas in the abdomen and carries a higher risk of malignant tumors that metastasize. Other types are rarer. The condition is typically diagnosed in a person's 30s.

Paragangliomas and pheochromocytomas can also occur in people with other inherited conditions, such as von Hippel-Lindau syndrome, Carney-Stratakis syndrome, and certain multiple endocrine neoplasia types. These other disorders involve different tumor types and distinct genetic causes. Some paragangliomas and pheochromocytomas occur in individuals with no family history of the tumors; these are considered sporadic cases, meaning they are not inherited.

Inheritance:

Hereditary paraganglioma-pheochromocytoma follows an autosomal dominant inheritance pattern. This means that inheriting just one copy of the altered gene from a parent increases the risk of developing tumors. However, a second mutation, called a somatic mutation, which deletes the normal copy of the gene is required to cause the condition. This somatic mutation happens during a person's lifetime and is only present in the tumor cells. The risk of developing hereditary paraganglioma-pheochromocytoma types 1 and 2 is only passed down if the mutated gene copy is inherited from the father. The reason for this paternal inheritance pattern is unknown. The risk of developing types 3 and 4 can be inherited from either parent.