Conditions & Treatments

Hereditary Paraganglioma-Phaeochromocytoma Syndrome - Causes and Risk Factors

What causes PGL/PCC?

There are two causes of PGL/PCC:

Hereditary
Mainly 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 the 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).
Sporadic
Caused by age, chance events and/or environmental factors

Most 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.

How is hereditary PGL/PCC syndrome inherited?

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:

1 copy comes from our father
1 copy comes from our mother

Hereditary Paraganglioma-Phaeochromocytoma Syndrome - Dominant Inheritance Pattern

A parent with a faulty gene(s) has a 50% chance of passing down their faulty gene(s) to their children.
A child, sibling or parent of a family member with a faulty gene(s) has a 50% chance of also inheriting the same faulty gene(s).
Extended relatives may also inherit the faulty gene(s).

A maternally or paternally inherited faulty SDHx gene can determine the risk of tumour/cancer development in an individual.

Genes associated with hereditary PGL/PCC syndrome	Inheritance
*SDHA, SDHB* and *SDHC*	Inheriting the faulty gene *from your mother or father* will result in hereditary PGL/PCC syndrome and its associated tumour/cancer risks.
*SDHD* and *SDHAF2*	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).

Genes associated with hereditary PGL/PCC syndrome

Inheritance

SDHA, SDHB and SDHC

Inheriting the faulty gene from your mother or father will result in hereditary PGL/PCC syndrome and its associated tumour/cancer risks.

SDHD and SDHAF2

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.