Hereditary Paraganglioma-Pheochromocytoma syndrome
Hereditary Paraganglioma-Pheochromocytoma syndrome is a genetic condition in which individuals have a higher chance to have certain noncancerous tumors. It is caused by mutations in the genes SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX and TMEM127, each of which are involved in making the protein called succinate dehydrogenase.
Characteristics of Hereditary Paraganglioma-Pheochromocytoma syndrome
Hereditary Paraganglioma-Pheochromocytoma syndrome (PGL/PCC) is a rare genetic condition characterized by an inherited predisposition to develop paragangliomas (tumors that usually occur along the spine) and pheochromocytomas (tumors on the adrenal glands the organ that sits on top of the kidneys). These tumors (most often the pheochromocytomas) overproduce hormones called catecholamines. This overproduction often results in symptoms such as elevated blood pressure, headaches, episodes of sweating, heart flutters, paleness, and anxiety. Individuals with PGL/PCC are more likely to have bilateral disease (in both adrenal glands) and more likely to develop more than one tumor during their lifetime. Individuals with PGL/PCC may also have an increased risk of developing kidney cancer, thyroid cancer and tumors of wall of the gastrointestinal tract (e.g., gastrointestinal stromal tumors or GIST). Approximately 30-60% of individuals with PGL/PCC develop a pheochromocytoma or paraganglioma by age 35, and almost 80% will have developed a one by age 60, although there are some differences in risk depending on the known gene.
Most patients with PGL/PCC have a change or mutation in one of seven genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX and TMEM127. These genes are involved in making a protein or enzyme called succinate dehydrogenase (SDH). This enzyme works in the mitochondria (i.e., the energy factories of the cells) to turn sugars into energy. Mutations in these genes are thought to decrease the amount of SDH enzyme that is made. Because of this, a chain of events occurs which ultimately leads to the increased chance of tumor development.
Management of PGL/PCC involves screening for early detection of these tumors. This may include: 24 hour urine collection to test for catecholamines and another hormone, metanepharine, with follow up imaging (e.g., MRI, CT or PET scan) if needed, skull, neck, abdomen and pelvis imaging tests every 2 years, and further investigation of anyone with gastrointestinal symptoms for GISTs, and clinical exams to examine the thyroid. For individuals with SDHB mutations, screenings should begin at age 10. There are no clear recommendations for when to begin screening for the other associated genes so this should be determined by ages of onset in the family history.
Individuals with PGL/PCC are sensitive to low oxygen environments and it is recommended that they do not smoke or live at high altitudes.
Mode of inheritance
PGL/PCC is inherited in an autosomal dominant manner. This means inheriting one mutation is enough for an individual to be affected with PGL/PCC. The mutation can be inherited from an affected parent or it can occur brand new (de novo) in an affected child. It is important to note that the SDHD (and possibly SDHAF2 and MAX) mutations have a parent of origin effect meaning that when a SDHD mutation is inherited from a mother, while the child may be a carrier, he/she typically does not develop tumors associated with PGL/PCC. However, if a child inherits a SDHD mutation from the father, the child is at risk of developing the tumors associated with PGL/PCC.
Risk to family members
The risk to family members depends on whether or not the individual with PGL/PCC has a parent affected with PGL/PCC. If a parent also has PGL/PCC, the risk of having a child with PGL/PCC is 50% with each pregnancy. If a parent does not have PGL/PCC, the risk of future pregnancies being affected is very low.
Genetics Home Reference: Hereditary Paraganglioma and Pheochromocytoma
Created by:Jilliane Sotelo, MS, LCGC
Edited by:Seema Jamal, MSc, LCGC