Paraganglioma-pheochromocytoma hereditary (Hereditary paraganglioma-pheochromocytoma) - Genes SDHA, SDHB, SDHC, SDHD and SDHAF2  

Paraganglioma-pheochromocytoma hereditary is a process characterized by the growth of benign tumors in paraganglia. One type of paraganglioma known as pheochromocytoma develops in the adrenal glands, which are located on top of each kidney and produce hormones in response to stress. Other paraganglioma are usually found in the head, neck or trunk. People with hereditary paraganglioma-pheochromocytoma develop one or more paragangliomas, which may include pheochromocytomas.

Pheochromocytomas and paragangliomas some other nodes associated with the sympathetic nervous system. The sympathetic nervous system controls the "fight or flight", a series of changes in the body because the hormones released in response to stress. Sympathetic paragangliomas that are outside the adrenal glands, usually in the abdomen, called Nonadrenal paragangliomas. Most sympathetic paragangliomas, pheochromocytomas including produce catecholamines, such as epinephrine or norepinephrine. These excess catecholamines can lead to signs and symptoms such as hypertension, palpitations, headaches or sweating. Most paragangliomas are associated with the nodes of the parasympathetic nervous system that controls involuntary bodily functions, such as digestion and saliva formation. Parasympathetic paragangliomas, often found in the head and neck, usually do not produce hormones. However, larger tumors may cause signs and symptoms such as cough, loss of hearing in one ear or difficulty swallowing. Although most paragangliomas and pheochromocytomas are not cancerous, some may become malignant and lead to metastasis. The extra-adrenal paraganglioma become malignant more often than other types of paraganglioma or pheochromocytoma.

They have identified several types of hereditary paraganglioma-pheochromocytoma depending on their genetic cause. People with type 1, 2 and 3 paragangliomas develop normally in the region of the head or neck. People with type 4 usually develop extra-adrenal paraganglioma in the abdomen and have a higher risk of developing malignant tumors that metastasize. The other types are very rare. Hereditary paraganglioma-pheochromocytoma's is usually diagnosed in the early 30.

Paragangliomas and pheochromocytomas can develop in individuals with hereditary other processes, such as Von Hippel syndrome Lindau syndrome, Carney-Stratakis and certain types of multiple endocrine neoplasia. These other processes exhibit other tumor types and have different genetic causes. Some paragangliomas and pheochromocytomas are sporadic and develop in people with no history of tumors in their families, so they do not appear to be inherited.

Mutations have been identified in at least four genes that increase the risk of developing different types of hereditary paraganglioma-pheochromocytoma. Mutations in the gene SDHD (succinate dehydrogenase complex subunit D), located on the long arm of chromosome 11 (11q23.1) predispose an individual to develop paraganglioma-feocromocitomatipo hereditary 1; Mutations in the gene SDHAF2 (succinate dehydrogenase complex assembly factor 2), located on the long arm of chromosome 11 (11q12.2), give rise to development of type 2; Mutations in the gene SDHC (succinate dehydrogenase complex subunit C), located on the long arm of chromosome 1 (1q23.3), predispose to type 3; and mutations in the gene SDHB (succinate dehydrogenase complex of iron sulfur subunit B), located on the short arm of chromosome 1 (1p36.13) predispose to type 4.

SDHB, SDHC and SDHD genes encoding the synthesis of three of the four subunits of succinate dehydrogenase (SDH). In addition, the protein encoded by the gene SDHAF2 is necessary for the SDH enzyme can act. SDH enzyme plays a critical role in mitochondria. Inside the mitochondria, the enzyme SDH joining two important routes in energy conversion: the citric acid cycle (Krebs cycle or) and oxidative phosphorylation. During this reaction, electrons are released. In oxidative phosphorylation, electrons help create an electrical charge that provides the energy to produce adenosine triphosphate (ATP), the major source of cellular energy. Succinate, the compound in which the enzyme acts SDH, is an oxygen sensor in the cell and can help provide specific pathways that stimulate cells to grow into a low oxygen environment. In particular, succinate stabilizes a protein called hypoxia - inducible factor (HIF) by preventing a reaction would allow HIF decompose. HIF controls several important genes involved in cell division and the formation of new blood vessels in a hypoxic environment. The SDHA, SDHB, SDHC, SDHD and SDHAF2 genes are tumor suppressor genes.

Mutations in SDHB, SDHC, SDHD and SDHAF2 genes give rise to the loss or reduction of the activity of the enzyme SDH. Since the enzyme can not convert SDH mutated succinate fumarate, succinate accumulates in the cell. Excess succinate stabilizes HIF abnormally, which also accumulates in the cells. Excess HIF stimulates cells to divide and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the formation of new blood vessels, may lead to the development of tumors in people with hereditary paraganglioma-pheochromocytoma.

This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to increase the risk of developing tumors. An additional mutation that eliminates the normal copy of the gene is necessary for the disease to develop. This second mutation, called somatic mutation, is acquired during the life of a person and is only present in tumor cells. The risk of developing hereditary paraganglioma-pheochromocytoma types 1 and 2 are transmitted only if the mutated copy of the gene is inherited from the father. The mechanism of this pattern of inheritance is unknown. The risk of developing type 3 and 4 can be inherited from the mother or father.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with hereditary paraganglioma-pheochromocytoma, by complete PCR amplification of the exons of SDHA, SDHB, SDHC, SDHD and SDHAF2 genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).