SUFU – a newly described gene linked to Gorlin Syndrome.

• Most people with Gorlin Syndrome have mutations (genetic spelling mistakes) in PTCH1
• Some people with Gorlin Syndrome have a mutation in the SUFU  gene
• People with the SUFU mutation frequently get a brain tumour called medulloblastoma
• People with the SUFU  mutation rarely get dental cysts
• We do not know if these mutations affect the response to treatments.
• It is important that people with Gorlin Syndrome know which of these genes is affected

What is SUFU ?

For several years it’s been known that most cases of Gorlin Syndrome are caused by mutations in a gene called PTCH1. Knowing this helped many families confirm individuals had inherited Gorlin Syndrome.

It has also been known for several years that PTCH1 is involved in a process taking place inside the cell called the hedgehog pathway. The names of the pathways and genes are often made up by PhD students doing research – that’s why they are so strange! The role of hedgehog pathway is to control how cells grow. If cells grow excessively they can produce the problems we’re all very familiar with from having Gorlin Syndrome.

In 2009 it became clear that mutations in another gene in the sonic hedgehog pathway can also cause Gorlin Syndrome. This gene is called SUFU .

Do faults in SUFU  and PTCH1 cause the same problems?

People with a mutation in SUFU  have a 1:3 chance of developing a brain tumour called a medulloblastoma. People with Gorlin Syndrome and a PTCH1 mutation only rarely develop medulloblastoma, although more often than the general population.

Medulloblastomas usually affect children. The usual treatment involves radiotherapy. People with Gorlin Syndrome are very sensitive to radiotherapy. Quite a few people who have received radiotherapy for medulloblastoma have then developed many basal cell cancers on their heads and around the spine. Some of these people have also developed a third type of tumour called a meningioma, which can cause epilepsy. For these reasons, it’s important that children with medulloblastoma and Gorlin Syndrome only receive radiotherapy  when absolutely necessary: Fortunately, other treatment options are available. 

Do faults  in SUFU  and PTCH1 differ in other ways?

Yes – People with the SUFU  mutations differ from people with the PTCH1 mutation in a few ways. For example, people with the a SUFU  mutation do not get keratocysts (dental cysts), although over 60% of people with the PTCH1 mutation do.

It would be very unlikely for a person to have mutations in both the SUFU  and PTCH1 genes.

How common are faults in SUFU in people with Gorlin Syndrome?

We don’t know for sure. Because not every family with Gorlin Syndrome has had a SUFU gene testing, we cannot yet be certain. It could be very rare or account for a significant minority of people with Gorlin Syndrome.

Should I have a genetic test?

First check to see if anyone in your family has previously had genetic tests confirming which of SUFU or PTCH1 is at fault. If no one has been tested, then please arrange to get tested. This is most important if you plan to have children or grand children, to know the risk of them getting medulloblastoma.

The tests for faults in SUFU or PTCH1 are  done by clinical geneticists in hospitals. You should receive genetic counseling before and after the test. These are not done by the types of commercial test available on line

Is the treatment the same?

Another important difference is that drugs such as vismodegib or itraconazole may not work as well in people the different mutations causing Gorlin Syndrome. Now that we know about the two different genes, we can expect researchers to find out if people with the different mutations respond differently to treatments. However, at present it is thought that vismodegib does not work when a person has a SUFU mutation

Glossary

Hedgehog pathway – a process inside cells, which stop them growing too rapidly

PTCH1 – a gene which controls one part of the sonic hedgehog pathway.

SUFU  – a gene which controls another  part of the sonic hedgehog pathway.

Medulloblastoma – a type of brain tumour, usually affecting children.

Meningioma – a type of tumour affecting the membranes around the brain.

For more detailed information please see Ogden, The relevance of a suppressor of fused (SUFU ) mutation in the diagnosis and treatment of Gorlin syndrome, Journal of The American Academy of Dermatology, 2018.