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Hereditary paraganglioma-phaeochromocytoma syndrome is a hereditary tumour/cancer syndrome.
Hereditary paraganglioma-phaeochromocytoma (PGL/PCC) syndrome is an inherited condition associated with an increased risk of noncancerous tumours (called paragangliomas and phaeochromocytomas) developing in certain parts of the body.
While these tumours are generally noncancerous, some can become cancerous (malignant) and spread (metastasise) to other parts of the body.
Other noncancerous tumours can also cause medical problems. There may also be a small increased risk of kidney cancer, gastric tumours and pituitary gland tumours in individuals who have this condition.
Paragangliomas (PGL) are rare tumours, usually noncancerous, and found near nerve cells. These tumours can develop in various parts of the body, such as the base of the skull, neck, chest, abdomen and pelvis. PGL tumours can also develop in other areas of the body.
Phaeochromocytomas (PCC) are tumours that develop in the adrenal glands, which are located on top of our kidneys.
Hereditary tumours and cancers develop because of the presence of a faulty gene. Some genes function to protect us from cancer/tumour growth. When they are not working well, it causes an increased risk of tumours/cancer developing. We refer to genes that are not working well as faulty genes.
Individuals who carry a faulty tumour/cancer gene(s) have a higher chance of developing certain tumours/cancers over their lifetime compared to the general population. The types of tumours/cancers that they may be at increased risk for will depend on the gene(s) involved.
If you have a faulty tumour/cancer gene, you may be at increased risk of developing certain tumours/cancers. As genes are shared among family, other family members may have inherited the faulty gene and may be at increased risk of tumours/cancer too.
Hereditary tumours account for up to 40% of all paraganglioma and phaeochromocytoma cases.
Genetic testing is offered to individuals where a hereditary cause of their personal and/or family history of tumours/cancer is suspected.
Genes contain the instructions that our body reads to carry out different functions. Genetic testing involves analysing your genes to understand if there are faults (i.e., mutations) that may increase the risk of tumours/
There are 3 types of results you may receive:
Depending on where these tumours develop in the body, they may cause different symptoms (see figure below). The symptoms vary among individuals while some may even be asymptomatic.
Head and neck PGL Most head and neck PGL tend not to overproduce hormones, and thus individuals do not show the signs associated with abnormal hormonal regulation.
PCC PCC, which are tumours in the adrenal gland, can release excess hormones that can lead to symptoms such as high blood pressure, a fast heartbeat and excessive sweating.
If these tumours are unundetected or untreated, more serious risks such as heart attacks, stroke or sudden death may occur.
Other symptoms associated with PGLs/PCCs include:
There may be an increased risk of kidney or thyroid cancer, and stomach or pituitary tumours developing in individuals with PGL/PCC syndrome. However, these risks are small.
1. Kidney cancerIndividuals with PGL/PCC syndrome may have an increased risk of developing a certain type of kidney cancer.
2. Thyroid cancerSome individuals with PGL/PCC syndrome may have an increased risk of developing thyroid cancer.
3. Gastric tumours Individuals with PGL/PCC syndrome may also be at increased risk of developing a type of stomach tumour called gastrointestinal stromal tumours (GISTs). GISTs develop within the walls of the stomach or small intestine.Small GISTs may not cause any symptoms and are usually detected through bleeding in the gastrointestinal tract.
Some symptoms that an individual with GISTs might experience include:
4. Pituitary tumoursThe pituitary gland is a pea-sized gland found at the base of the brain and produces hormones which regulate growth and sexual function, and controls other glands such as the thyroid and adrenal glands.Pituitary tumours are almost always benign but can cause problems, as a tumour can result in the pituitary gland making too little or too much hormones. Occasionally, pituitary tumours can cause headaches, or press on the eye nerves causing loss of vision.
The risk of tumours/cancers depends on which SDHx gene is faulty.
Note: The conditions associated with different faulty SDHx genes and their risk estimates may change as more information is available. Insufficient information is known about the risk of SDHAF2 carriers, thus it is not included in the table.
While individuals carrying a faulty
SDHx gene face an increased risk of the tumours/cancers listed above, it does not mean that they will definitely develop them.
There are two causes of PGL/PCC:
HereditaryMainly caused by a faulty
SDHx gene (hereditary PGL/PCC syndrome)Approximately 35-40% of individuals who are diagnosed with PGL/PCC may have a hereditary cause. This means that they may have inherited the condition from a parent and can pass it on to their children. Other family members may also be at risk.Hereditary PGL/PCC syndrome is caused by the presence of a faulty (i.e., disease-causing) gene in any of the following genes:
SDHA, SDHB, SDHC, SDHD and
SDHAF2 – collectively termed
SDH family of genes(SDHx).However, the development of PGL and PCC can also occur in other genetic syndromes like von Hippel-Lindau (VHL), Neurofibromatosis type 1 (NF1) and multiple endocrine neoplasia type 2 (MEN2).
SporadicCaused by age, chance events and/or environmental factorsMost PGL/PCC happen sporadically (by chance) and are driven by factors such as age or lifestyle/environmental exposures (i.e. not hereditary/inherited).Genetic testing can help to clarify if a personal or family history of PGL/PCC is due to a hereditary or sporadic cause.
Hereditary PGL/PCC syndrome follows a dominant inheritance pattern. This means that having one faulty copy of any SDHx gene (i.e., SDHA, SDHB, SDHC, SDHD and/or SDHAF2) gene can cause the condition. It affects both males and females.
Everyone has 2 copies of each gene in their body’s cells:
A maternally or paternally inherited faulty
SDHx gene can determine the risk of tumour/cancer development in an individual.
Inheriting the faulty gene from your father will result in hereditary PGL/PCC syndrome and its associated tumour/cancer risks.
Individuals who inherit the faulty SDHD/SDHAF2 gene from their mother almost never develop tumours/cancer (few cases have been reported to present with tumours/cancer).
Individuals who inherit a faulty
SDHx gene, regardless of whether they have symptoms or not, still have a 50% chance of passing the faulty gene onto their children.
You should consider genetic testing if you or your family members meet one or more of the following criteria:
Confirming a diagnosis of hereditary PGL/PCC syndrome would be beneficial for early diagnosis and timely surveillance. This helps to detect tumours/cancers at their earliest and most treatable stage, avoiding irreversible or serious medical complications. For individuals planning a family, reproductive options may also be available.It is also important to identify which faulty
SDHx gene you may have inherited, as the different genes are associated with different tumour/cancer risks which would influence how doctors plan for your medical management.
Your genetic test result can also help you understand if other family members are at risk of hereditary PGL/PCC syndrome. They can subsequently consider their own testing (predictive testing) to clarify their carrier status to determine tumour and cancer risks.Family members who
have inherited the same faulty
SDHx gene may be at increased risk of tumours and cancer and can benefit from management options such as screening (to detect tumours and cancer at an early and manageable stage) or surgery (to reduce their risk of cancer).Family members who
did not inherit the faulty
SDHx gene can avoid unnecessary screening and worry. Their children will also not be at risk.
Screening helps to detect (and in some cases treat) tumours and/or cancer at an early and manageable stage.
Your managing doctor(s) will discuss these options with you in greater detail. The age, onset and frequency for screening may change according to the faulty SDHx gene that you have, and your personal and/or family history of tumours/cancer. Screening guidelines may change as more information is known.