Hereditary Paraganglioma-Pheochromocytoma Syndrome is the result of mutations in the Succinate Dehydrogenase Subunit Genes (SDHx). Patients with mutations in any of the SDH genes are at increased risk for pheochromocytoma and paraganglioma and increased risk of cancerous tumors in the kidney and GI tract. The SDHx genes include four subunits (SDHB, SDHD, SDHC, and SDHA) and an assembly co-factor (SDHAF2).
For those with a known SDHx genetic mutation, regular (often annual) screening using measurements of plasma-free metanephrines or urinary fractionated metanephrines and catecholamines, together with whole body imaging can catch tumors before they are symptomatic. The frequency and types of screening used as well as the course of treatment is influenced by the specific gene that is altered.
Mutations in SDHB are one of the most common causes of familial pheo/para. Mutations in SDHB are often associated with extra-adrenal pheochromocytomas, parasympathetic paragangliomas, and pheochromocytomas. Pheos and paras that have an SDHB mutation are more likely to be metastatic (cancerous), particularly in younger patients. Someone who carries an SDHB mutation but does not currently have a tumor has a 20-40% chance of developing one by the age of 60.
Tumors associated with mutations in the SDHD gene are passed down through families by paternal inheritance. If the mutation is inherited from the mother, the children are not at greater risk of developing the disease, but the children still carry the mutation and those children can pass it on to their children. Alternatively, if the mutation is inherited from the father, those children have a greater risk of developing the disease.
Patients with SDHD mutations typically present with head and neck paragangliomas but can have paragangliomas anywhere in the body, and these patients are more likely to have multiple tumors. These tumors are usually benign. Someone who carries a mutation in the SDHD gene passed down by their father, but who does not currently have a tumor, has an approximately 40% chance of developing one by the age of 60. The likelihood of metastasis is relatively low, approximately 5%.
SDHC is extremely rare, and much research still needs to be done. It is unlikely (but possible) that someone who carries an SDHC mutation but does not currently have a tumor will develop one by the age of 60. The risk for metastasis is relatively low.
SDHA mutations are common in the general population while the development of tumors is rare. This means, that there is only a small chance that someone who carries an SDHA mutation will have a tumor. Current data available suggests that number is as low as 0.1-5% -10%. So, you may carry the mutation, but you don’t ever remember anyone in your family having any tumors. Because of this, tumors and SDHA mutations are often found incidentally. In the unlikely event that a pheo para occurs, current research suggests that these tumors may behave aggressively. Because SDHA mutations are relatively common in the population, it is important that individuals known to have an SDHA mutation discuss this with a geneticist during reproductive planning. Babies that inherit two SDHA mutations have a different genetic condition called Leigh syndrome. You can find more information about Leigh syndrome here.
SDHAF2 is extremely rare, and much research still needs to be done. The risk of developing a tumor from a mutation in this gene (and SDHD) depends upon whether the mutated gene came from the father. This is called paternal inheritance. If the mutation is inherited from the mother, the children are not at greater risk of developing the disease, but the children still carry the mutation and can pass it on to their children. Alternatively, if the mutation is inherited from the father, those children have a greater risk of developing the disease.
The tumors associated with SDHAF2 tend to be primarily in the head and neck, and patients with this gene mutations often have multiple tumors. This gene mutation is rare and we do not know the penetrance or likelihood of developing tumors although it is likely low.
In addition, all patients with SDH gene changes are at risk of developing adrenal gland pheochromocytomas.
For more information visit the Pheo Para Alliance website.