CF discovered they had BHD after a lung CT scan following a diagnosis of a rare type of sarcoma called epithelioid PEComa (perivascular epithelioid cell tumour). Read their story and their inspiring, positive approach to life after BHD diagnosis. Since PEComas are so rare, we also interviewed Dr Andrew Wagner, a world leading expert in the field for more information on the crossover between BHD and PEComas.
Interview with CF, USA
When were you first diagnosed with BHD?
How did you get diagnosed and what was the process?
In January of 2022, with the help of the BHD Foundation and one other PEComa patient, I learned that there is a link between my PEComa and BHD diagnoses. In an effort to learn more, in February my husband and I met with Dr. Andrew Wagner (not to be confused with my oncologist mentioned earlier), the world’s leading expert in PEComas at Dana Farber in Boston. Dr. Andrew Wagner is interested in researching the link between PEComas and BHD. At this time, there are only four of us (three living) with these two diagnoses. His team will be genetically sequencing my PEComa. We are hopeful that having the FLCN mutation will help with PEComa and mTOR pathway research (See Dr Wagner’s comments below). By the way, Dr. Andrew Wagner does not think that my FLCN mutation puts me at higher risk of creating more PEComas, nor does he think that other people with BHD should worry about an occurrence of this very rare type of sarcoma.
What impact has your BHD diagnosis had on you and your family members?
Gratefully, none. My diagnosis led to my mother also getting a formal diagnosis. She had a CT scan confirming lung cysts and an abdominal MRI, which showed two small renal cysts that her doctor is monitoring. My only sibling also has fibrofolliculomas but has chosen not to be tested for BHD at this time. I am grateful that we now know about our underlying condition.
What are your symptoms of BHD and how do you manage them?
I have no symptoms aside from my lung cysts. I have been a runner most of my life, including running several half marathons, and have never felt any effects from the cysts. I practice yoga every day, and have never noticed problems breathing in any poses. I don’t avoid airline flights and have taken many flights with the lung cysts including long international flights, without any problems. I am aware of the risks of pneumothorax, so I am careful not to overdo my activity in the 24 hours after being on an airplane. I am self-conscious about my fibrofolliculomas which began showing up in my late twenties. I have them across the bridge of my nose, a sprinkling of them on my neck, upper chest and ears. I have discussed treatment options with my dermatologist but I understand that there are not any permanent solutions. My friends and family tell me that my fibrofolliculomas are not very noticeable.
What treatments/monitoring have you had/are having?
For my PEComa diagnosis, I have an annual lung CT scan and a pelvic MRI. For the BHD diagnosis and monitoring my kidneys, an abdominal MRI has been added to my scan order. Gratefully, my scans have all remained clear. I also get a thyroid ultrasound once a year due to the possibility that BHD might play a role in thyroid carcinomas (*Note from BHD Foundation: currently there is not enough evidence to conclusively say there is a link between BHD and thyroid cancers, see here for more information). In December 2021, I met with an interstitial lung specialist to learn more about my lung cysts. He informed me that although a spontaneous pneumothorax is possible, it would be unlikely to be fatal. He said that I should just live my life without worrying about the blebs, with the two exceptions of not riding in non-pressurized aircraft and avoiding scuba diving. Those restrictions pose no problems for me.
What advice would you give to someone who has been newly diagnosed with BHD?
It can be scary to find out that you have a genetic syndrome that raises your risks for cancer and spontaneous pneumothorax, but you may have been living with lung cysts unknowingly for years. Even if you get a renal cancer diagnosis, from what I understand, it is a relatively treatable cancer. It is better to know, than not know. As someone who has had a cancer diagnosis, I am very aware that the longer a cancer is allowed to grow within us, the worse the outcome will often be. Live your life, but keep up with the monitoring. It’s okay to be afraid for a while about what the future might look like, but then, just live. In some ways, I consider my diagnoses as gifts. They remind me to live each day as much in the moment as I can. It may sound trite, but I really don’t take each day for granted anymore. Living in fear of the future isn’t a great way to live. I think that the reason that BHD is rare is that most families aren’t even aware that they have it. Knowledge is power, be grateful that you have the knowledge about this condition.
What do you hope the future looks like for someone living with BHD?
I hope that families can be identified earlier, rather than after a problem arises or an unrelated scan (as in my case) identifies the syndrome. I hope that further research will lead to treatment options or, even better, prevention of the symptoms.
How can the BHD Foundation better support the BHD community?
I am very thankful for the quick and informative responses from the BHD Foundation (particularly Katie Nightingale). I believe that the foundation is interested in researching every avenue with BHD for the betterment of the BHD community. I’ve read several BHD Foundation blog posts and find them enlightening. They are written in an easy-to-read, educational manner. The illustrations are the most helpful and I have sent a few to my extended family. The only suggestion that I have would be to create a database of BHD expert providers. Are there any? (*Note from the BHD Foundation: Our website has a map featuring BHD specialists from around the world. We are also happy to help you locate a BHD specialist in your area via email.) I have not found a provider who is familiar with BHD. It would be nice to have my BHD-related health monitored by an BHD expert who is familiar with the symptoms. For example, someone who is familiar enough with BHD that could look over my lung CTs, abdominal MRIs, thyroid ultrasounds and skin and help direct me to experts when or if any of these scans looked unusual. At this time, that role is being filled by my sarcoma and genetic oncologists, not BHD experts.
Interview with Dr Andrew Wagner
What is PEComa?
Perivascular epithelioid cell tumors (PEComa) are rare soft tissue neoplasms that can be benign (no risk of spreading) or malignant (or cancerous, with a risk of spreading). Malignant PEComa are a type of soft tissue sarcoma and can arise anywhere in the body. The cell of origin is unknown, and the name is purely descriptive, reflecting their predilection to be in proximity to small blood vessels (“perivascular”) and shape (cuboidal, or “epithelioid”). About 80% of patients with PEComa are women, for reasons that are not well understood. PEComas express muscle proteins like another type of sarcoma called leiomyosarcoma, and pigment producing proteins that are present in normal melanocytes and melanomas. Because of these features, PEComas are frequently misdiagnosed as leiomyosarcoma or melanoma. Many PEComa have mutations in the genes TSC1 or TSC2 which make proteins that suppress the activity of another protein called mTOR. mTOR normally is tightly regulated and controls the growth and proliferation of cells. When TSC1 or TSC2 are mutated, mTOR is hyperactivated and this can lead to dysregulated growth of cells and formation of tumors. Some other PEComas do not have mutations in TSC1 or TSC2 and instead have a gene rearrangement involving TFE3. A gene rearrangement is when two genes usually on different chromosomes are inappropriately stuck together, leading to changes in when they are expressed or changes in their activity. In the case of PEComa, a gene rearrangement involving TFE3 leads to it being present when it should not be, and TFE3 in turn activates other genes to make proteins that drive the growth of cells. For other PEComas, we do not know what mutations lead to their formation.
Could you explain the possible association of BHD with PEComa?
There is very little research in this area, but there are some very intriguing possible connections between BHD and PEComa. Some of the published literature is conflicting so it is still pretty confusing. One possible connection is that folliculin, the protein encoded by FLCN (the gene that is mutated in BHD) can cause some modifications on the TFE3 protein that lead to changes of where it is located within a cell. In doing so, it may be able to reduce the activity of TFE3. When FLCN is mutated, though, TFE3 activity may increase and this can lead to tumor formation. The interaction of FLCN and TFE3 may be through mTOR but this remains uncertain.
How common is the association between BHD and PEComa?
PEComa are ultra-rare tumors, and a very small proportion of patients with PEComa have underlying BHD. Of approximately 120 patients I have seen with PEComa, 3 that are known to have BHD as well.
What research would you like to see done on the association of BHD with PEComa?
We need to understand more between the interplay of FLCN, mTOR, and TFE3, how they regulate each other, and the key pathways that they influence within a cell. Studying the relationship of BHD and PEComa may lead to some fundamental discoveries of each of these diseases and provide key insights into signaling pathways and gene regulation.
What advice would you give to the BHD community?
There is so much to learn from networks of patients and families with rare diseases, and in bringing together groups of scientists and clinicians to focus on the biology and mechanisms by which tumors arise. Sharing experiences, participating in studies, providing clinical materials such as tumor samples and blood for research are critical to advancing our understanding of disease. Communities of patients can also help educate each other (and doctors!) about credible resources to learn about the disease and identify centers of excellence in clinical care and research.
The BHD Foundation would like to thank both CF and Dr Wagner for their time.
If you would like to share your BHD story please let us know by email.