Latest / Pediatrics Now: Cases Updates and Discussions for the Busy Pediatric Practitioner / A Devastating Syndrome Leads to Incredible Advancements in Medicine: What is VHL?

Transcript

A Devastating Syndrome Leads to Incredible Advancements in Medicine: What is VHL? · Pediatrics Now: Cases Updates and Discussions for the Busy Pediatric Practitioner

• 0:00
  I'm Holly Wehmint, and this is Pediatrics Now, cases, updates,
• 0:05
  and discussions for the busy pediatric practitioner.
• 0:08
  Click on the link in this podcast for free credit that may include CME,
• 0:12
  MOC, or ethics credit, depending on our topic or podcast.
• 0:17
  I'm thrilled today because joining me here are two experts.
• 0:21
  So today we're talking about something called Bonhippel-Lindau syndrome,
• 0:27
  and joining me here is Dr. Gail Tomlinson.
• 0:30
  She's our Head Doctor Division Chief for Pediatric Oncology,
• 0:34
  and she holds the Greehe Chair in Cancer and Genetics at the University of Texas
• 0:40
  Health Science Center and University Hospital, and Dr.
• 0:45
  Patricia Daya. Dr. Daya is the Robert Tucker Hayes Distinguished Chair in Oncology,
• 0:51
  Professor in the Department of Medicine, Division of Hematology and Medical
• 0:55
  Oncology at the University of Texas Health Science Center, and she's the co-leader
• 1:00
  of the Cancer Development and Progression Program at the Mays Cancer Center.
• 1:05
  Dr. Tomlinson, Dr. Daya, thank you for being here on Pediatrics Now.
• 1:10
  Thank you for having us. Yes, it's a pleasure to be here today.
• 1:15
  So von Hippel-Lindau syndrome, the name came from two doctors?
• 1:20
  That's right. Dr.
• 1:24
  Von Hippel Lindau. And Dr. von Hippel Lindau was an ophthalmologist,
• 1:28
  and he described an unusual finding in the eyes of blood vessels.
• 1:35
  He recorded this back then in the literature, and then about a generation later, Dr.
• 1:41
  Arvid Lindau came along, and he was a pathologist, initially from Sweden, educated in Denmark,
• 1:50
  and he described lesions in the kidneys, pancreas, and other organs that were
• 1:56
  similar to these lesions in the eyes as well and made the connection.
• 2:02
  This happened across the 1900s, and it was in 1960 after Dr.
• 2:09
  Von Hippel had passed away and when Dr.
• 2:12
  Lindau was an older gentleman professor.
• 2:15
  And the disease was named Bonn-Hippel-Lindau syndrome in their honor.
• 2:21
  In a lot of diseases now, we try not to name them or refer to them after the
• 2:25
  doctors discovered them, but rather according to what symptoms or manifestations
• 2:31
  of disease. But this one has stuck.
• 2:34
  And for short, it's just called BHL. And Bonn-Hippel-Lindau disease may not
• 2:39
  roll off the tongue as easily, me, but BHL certainly does.
• 2:42
  So that name has stuck for now several generations.
• 2:47
  And it is a rare condition caused by a change or a mutation in a gene?
• 2:54
  Yes, that's right. The gene is called BHL, and maybe Dr.
• 2:59
  Daya could expand on that just a little bit. Sure.
• 3:02
  So the BHL gene is one of the genes of a class called tumor suppressors,
• 3:08
  which means that its main function in cells, and it's present in every cell
• 3:13
  of the body, its main function is to control cell growth.
• 3:18
  So it's almost like it works like a break, right?
• 3:22
  So cells are prone to growth and in the presence of genes such as the VHL and
• 3:29
  others, this growth is controlled so that cells don't overgrow or become tumorous.
• 3:35
  And patients that have VHL disease have a mutation in the VHL gene such that
• 3:42
  the gene doesn't work as intended.
• 3:44
  So the break is gone and certain cell types or tissue types that are more vulnerable
• 3:51
  to its absence become tumorous, either with benign tumors or with cancerous or malignant tumors.
• 3:59
  Patricia, does this condition develop in the early 20s?
• 4:03
  So yeah, it's a very broad age range for patients that have BHL disease.
• 4:08
  And because they have different types of tumors, the ages, preferential ages
• 4:13
  for certain types of tumors vary.
• 4:15
  So it can start very early on in children at the age of five or so.
• 4:22
  So there are recommendations for patients who can get into that later on,
• 4:26
  but it can affect individuals from early ages all the way to adulthood and then
• 4:33
  even beyond, right, 60 years of age and so.
• 4:36
  And we'll talk about the warning signs, symptoms to look for.
• 4:40
  Dr. William Kalin, professor of medicine at the Dana-Farber Cancer Institute
• 4:44
  and Brigham and Women's Hospital Harvard Medical School. Dr.
• 4:49
  Was intrigued by von Hippel-Lindau disease and how it's characterized by a perfusion
• 4:55
  of extra blood vessels and overproduction of erythropoietin, or EPO,
• 5:00
  a hormone that stimulates production of the red blood cells that carry oxygen,
• 5:05
  according to the New York Times.
• 5:06
  And he ended up winning the Nobel Prize.
• 5:10
  And he sounded like he did not think he had any sort of close chance of getting
• 5:17
  it and was stunned when he won. And that's pretty incredible.
• 5:21
  And he said that he likes, like any scientist, he likes solving puzzles.
• 5:26
  Dr. Kalin's example is really a symbol of what happens in so many researchers
• 5:32
  and researcher scientists.
• 5:34
  You start with a question from sometimes a rare disease and you end up with
• 5:40
  answers that you did not anticipate.
• 5:42
  And the fact that some of the mechanisms of understanding how cells are regulated
• 5:49
  can be so broad. We learn from rare models.
• 5:54
  So from the VHL disease and the observations that vessels were overgrown in
• 6:00
  the tumors of patients that had this disease,
• 6:03
  he came to the conclusion that what VHL does as a protein, so every gene will
• 6:09
  be translated into a protein.
• 6:11
  In the case of VHL, VHL blocks the activity of a very important protein that
• 6:19
  controls and it's induced or is increased whenever the cells feel the lack of oxygen.
• 6:26
  So in the presence of VHL, this protein does not, it's degraded or it's terminated.
• 6:33
  And so that gave...
• 6:37
  The field and other scientists a clue as to how the cells in our body regulate
• 6:44
  or understand or sense the levels of oxygen that our cells need to survive.
• 6:50
  So from the VHL, the rare VHL disease came this gene and its very critical function
• 6:58
  in controlling oxygen levels in the cells.
• 7:00
  So that deserved the Nobel Prize of Dr. Kalin and other colleagues that worked in the same field.
• 7:07
  Dr. Kalin, he said that this cancer was really fascinating.
• 7:11
  He's voted also in the New York Times as saying, talking about the unusual features
• 7:15
  like causing the body to make a substance, VEG-F, that stimulates the formation of blood vessels.
• 7:22
  And like we're talking about, and the cancer can cause the body to make too
• 7:26
  many red blood cells by increasing the production of EPO.
• 7:29
  And he had such a hunch about what was going awry. And he thought it had something
• 7:34
  to do with oxygen sensing.
• 7:37
  And it turned out he was right. And he says he thought his chances of winning
• 7:42
  the Nobel Prize were so astronomically small. He didn't think much about it.
• 7:46
  And then when you win the Nobel Prize, you get a call at 5 a.m. from Sweden.
• 7:51
  And he dreamt that it was 5 a.m. and he didn't get the call.
• 7:55
  And then he woke up and it was really 1.30 and he went back to sleep.
• 7:59
  And then he was woken up at 5 a.m.
• 8:02
  By a call from Sweden yesterday.
• 8:05
  Telling him he won the Nobel Prize. It's pretty interesting.
• 8:08
  Yeah, that's an incredible story. Really incredible story.
• 8:12
  It also, that brings up the similarity of the tumors, because one of the types
• 8:17
  of tumors and manifestations, and we talked about von Hippel,
• 8:21
  who described tumors in the eye, and then Dr.
• 8:24
  Lindau, who described tumors elsewhere, including the brain.
• 8:27
  But the tumors under the microscope, you see a lot of blood vessels.
• 8:31
  You see a lot of blood vessels growing.
• 8:34
  And even in some of the kidney tumors, and the kidney tumors have a little different histology.
• 8:39
  They look more like traditional kidney cancers, but they're very bloody.
• 8:43
  They have a lot of blood vessels in them. So I think that clinical insight that
• 8:48
  probably came decades before, you know, set a precedent for looking into this.
• 8:54
  And then, of course, Dr. Kalin and his group did, you know, a huge amount of molecular biology.
• 8:59
  It had the hunch about the oxygen and the growth of the growth factors.
• 9:04
  It stimulated the EPO and growth of the vascular system, feeding what then became tumors.
• 9:12
  So that fits together too. And I think it's just an incredible story that really evolved over,
• 9:19
  actually it's about a century almost, from the time that von Hibbel made his
• 9:24
  initial observations until the Nobel Prize.
• 9:28
  Yes, and how a lot of this is about oxygen, where we need oxygen for life.
• 9:35
  And too much oxygen is not good, and too little is not good.
• 9:40
  That's right. So I just wanted to make a point here, since we're talking about,
• 9:45
  you know, the mechanisms or how VHL functions and how it's related to oxygen.
• 9:51
  It's this association between the two that has led to more research that eventually
• 9:58
  discovered a way to block these effects of VHL deficiency.
• 10:04
  So the new drug that was approved by the FDA in 2022 was approved in patients
• 10:12
  with VHL disease, and it was a tremendous breakthrough because what it does,
• 10:18
  it blocks the effect of these oxygen activating proteins that lead to all these blood growth,
• 10:28
  VEGF, and all the other molecules that are in effect of the lack of VHL.
• 10:34
  VHL function in the cells.
• 10:35
  So now this drug is available for patients with VHL disease and it has been transformational.
• 10:41
  It's still early days, so we don't know the impact of the drug in the long term,
• 10:47
  but it has become a game changer in the treatment of many patients that can
• 10:53
  no longer undergo surgery for various reasons.
• 10:55
  We can get to that, but I wanted to take this opportunity to talk about how
• 11:00
  basic research ended up finding a potential way to reverse the effects of VHL, the VHL mutation.
• 11:10
  So maybe Dr. Tom Linson and I will kind of go back and forth on this,
• 11:15
  but I wanted to highlight the fact that patients with VHL disease start having
• 11:20
  tumors very early on in life sometimes, and they go on through life with multiple recurrences.
• 11:26
  So these tumors are usually operated on, so they are surgically removed,
• 11:32
  but they can come back multiple times.
• 11:35
  And it gets to a point where surgery becomes not feasible for various technical reasons.
• 11:42
  And the location of the tumors is also an impediment to surgery.
• 11:46
  So in the past, patients had very, very few opportunities to be treated if they
• 11:53
  could no longer be operated.
• 11:54
  And if they had multiple tumors at a time, the surgical procedure became incredibly
• 12:03
  complex and potentially life-threatening.
• 12:07
  So the possibility of having a drug that reverses the impact of the tumor systemically,
• 12:13
  so you take it by mouth and it affects every cell in the body that needs to be controlled,
• 12:21
  then it's a systemic treatment.
• 12:24
  It's pretty dramatic.
• 12:27
  So patients with the blood vessel type tumors that happen in the central nervous
• 12:33
  system, in the retina or in the cerebellum,
• 12:37
  in the spinal cord, those patients had sometimes limited opportunities to even surgery.
• 12:43
  And now they can take this drug. And in many cases, in the majority of cases,
• 12:48
  it reverses the tumors, make them so small that they can no longer give any symptoms.
• 12:53
  So it's a pretty dramatic change for the life of patients with VHL.
• 12:59
  That sounds incredible. And I know here at the University of Texas Health Science
• 13:04
  Center or UT Health San Antonio, we have a special center.
• 13:09
  Can you tell me about that? And do you have to be dialed into a center like
• 13:13
  this, the patient has to, in order to get this drug? Well, we do have a center, and I think Dr.
• 13:20
  Daya was one of the people who helped get this center started.
• 13:25
  The DHL Alliance is a national group that provides education and general directions
• 13:32
  for patients on where to get care.
• 13:34
  And we're one of the centers that has the designation where patients are directed
• 13:40
  to our center, which is multidisciplinary, has surgeons, oncologists, ophthalmologists,
• 13:48
  pediatricians, pediatric oncologists.
• 13:51
  It's a group that maybe doesn't meet all at the same time in one room,
• 13:55
  but sees patients with this disease and then can conference about it and come
• 14:01
  up with a multidisciplinary plan.
• 14:04
  And Belsutophan is a rather new drug. It's only been around for about three years now.
• 14:11
  And so we're starting to use it and we're using it in different settings.
• 14:16
  And one of the things that, because there's a central mechanism that a developing
• 14:22
  brain tumor, angioblastoma, may have the same molecular defect than a tumor
• 14:28
  in the eye or a tumor in the kidney.
• 14:30
  If you start out, say, aiming to shrink a kidney lesion because you want to
• 14:36
  eventually get it to the fact where it can be easily surgical removed.
• 14:41
  If there are tiny tumors developing elsewhere, a nice side effect of this drug
• 14:47
  is the other tumors and the other lesions that maybe aren't large enough to
• 14:51
  cause problems, but they shrink too.
• 14:54
  So you gain multiple benefits in multiple parts of the body.
• 14:59
  So it's a very interesting drug because it treats the syndrome,
• 15:02
  not just one specific cancer, but it treats the multiple manifestations of this BHL syndrome. them.
• 15:11
  Wow. Is it covered by insurance usually? Yes.
• 15:14
  It's FDA approved and there are very specific indications for it,
• 15:19
  but insurance will cover it.
• 15:21
  Like a lot of new drugs, it was developed specifically for this disease.
• 15:27
  It's not particularly inexpensive, but we work with the families and we get
• 15:32
  the drug for them. We can get the drug for them.
• 15:35
  And it just sounds, I mean, incredible, everything we're talking about,
• 15:39
  but such an incredibly devastating disease when someone gets the news that they
• 15:44
  have this, that it's not just a cancer tumor or a few,
• 15:48
  that it's going to be many, and it often causes blindness.
• 15:54
  It can. And may I tell you an anecdote that I think is relevant to what you
• 16:00
  just said about hearing the news about VHL that actually had an interesting twist, please?
• 16:06
  So early in my career, before we had commercial genetic testing, we knew about genes.
• 16:13
  We knew there was a gene for VHL, but you couldn't just draw a blood sample,
• 16:17
  send it to the lab, and three weeks later find out what the read on the genetics was.
• 16:23
  But we were creating a familial cancer registry and interviewing people who
• 16:29
  we thought might have familial cancer.
• 16:31
  And I was summoned to a patient's room, a young man around 30-ish years of age
• 16:38
  who had bilateral kidney cancer.
• 16:41
  And the cancer was progressing and the prognosis was very poor.
• 16:46
  And when I walked into the room, there was another man standing at the bedside who was his brother.
• 16:53
  And then a doctor was talking about end-of-life care, so it was a very sad moment
• 16:59
  because they didn't have treatment for this young man's bilateral kidney cancer.
• 17:06
  And it was a very awkward and sad moment, so I just...
• 17:10
  Introduced myself, let them know what I was doing, that we were just trying
• 17:15
  to understand these types of cancers and got a little bit of information from them and then left.
• 17:24
  And we didn't have further information with the family.
• 17:28
  There wasn't a lot to offer them, but just that we were trying to learn more
• 17:32
  about their family's tumors.
• 17:35
  And then a couple of years later, there was a patient on the pediatric ward.
• 17:40
  It was a 15-year-old who had, I think they had a seizure and was found to have a mass.
• 17:46
  And it was a young girl, like teenage, about 15, who they found a mass in her
• 17:53
  brain, which looked like one of these hemangioblastomas, typical of EHL.
• 17:59
  The tumor was removed and she did fine. And then, again,
• 18:04
  a year or so later, I was in my pediatric cancer,
• 18:07
  and I was about to walk into a patient room, and there was a patient who was
• 18:12
  referred to me from the ophthalmologist for possible treatment for what was a retinal hemangioma.
• 18:20
  And we put together that this was the younger brother of this girl with the brain tumor.
• 18:26
  We knew that. And then I looked across the waiting room. I saw this man that
• 18:32
  I didn't initially recognize, but it was the brother of the patient with the
• 18:37
  bilateral kidney cancer.
• 18:38
  So I had a conversation with him, and he mentioned the genetic counselor we
• 18:44
  worked with and said, I just want to thank Linda.
• 18:48
  That was the genetic counselor. She is a gift from God, a gift from the angels
• 18:53
  or something like that. And I looked at them and wasn't exactly sure.
• 18:59
  What he meant by that but he said you don't remember
• 19:02
  me but you came to see my brother when he was dying
• 19:05
  and then my daughter got a brain
• 19:08
  tumor and my and and then my
• 19:11
  my son is going blind now so i thought that this was the wrath of god punishing
• 19:17
  our family and now i understand that they have von hippo lindau and it's because
• 19:24
  of a genetic mutation and there's a reason for it and is not God punishing our family.
• 19:29
  And I took a step back and I went, oh, well, that's right.
• 19:34
  But it really impressed on me the devastation that families feel when they have
• 19:40
  these different things happening to different members of their family and they don't know what it is.
• 19:45
  Yet, after with all the now the genetic knowledge and the scientific investigation
• 19:51
  and the ability to read genes at individuals, we can put it all together for the family.
• 19:56
  And that was a real milestone for the family to understand finally why all these
• 20:02
  things were happening to them. And they seemed so unrelated.
• 20:05
  The young man dying of bilateral kidney cancer, and then the girl who was fine,
• 20:11
  but then had a brain tumor, had it taken out and then survived and was fine.
• 20:16
  And then his son going blind, which we were able to intervene with some therapy and stop the blindness.
• 20:24
  You can't reverse the blindness, but you can stop the progression.
• 20:29
  So that was really sort of a changing moment in my perception of how families
• 20:36
  can view this particular disease.
• 20:39
  Gail, thank you for sharing that story, and I'm so glad that you're now a regular
• 20:43
  contributor here on Pediatrics Now, and that story is just amazing and so touching.
• 20:51
  To stop the blindness, are the tumors removed from the eyes?
• 20:54
  So this was before we had the day, before the days of when we had this new drug called Belsudophan.
• 20:59
  But yes, an ophthalmologist can go in and with cryotherapy or laser therapy
• 21:04
  can sometimes zap or treat the individual part of the retina that's affected.
• 21:09
  It's a very delicate procedure and there are limitations on how much,
• 21:14
  you know, you can do, but for very small tumors, you can eliminate them or stop
• 21:19
  the growth through what we call local therapy.
• 21:23
  And, you know, we had tried some other therapy as well for these eye tumors.
• 21:27
  There's anti-VEGF therapy. It didn't work as well. Other therapies we would
• 21:33
  try in those days as well.
• 21:35
  And now we don't have a lot of experience
• 21:39
  in treating the eye tumors with balsudafan, but it's certainly a...
• 21:43
  Gail, it's still about 10,000 people in the United States have this. The warning signs.
• 21:51
  A lot of the symptoms are what, of course, pediatric practitioners see on a
• 21:56
  daily basis. So how do you know when to worry?
• 21:59
  Well, it's rare. I believe it's about one in 35,000 individuals. So that's quite rare.
• 22:06
  The best way to diagnose this is to pay attention to the family history, obviously.
• 22:13
  Family history is very important. So if you see these different types of tumors,
• 22:17
  the constellation of tumors associated with von Hippel-Lindau syndrome,
• 22:23
  hemangiomas of the brain, maybe a kidney cancer in a young adult, eye problems.
• 22:30
  And then there's a tumor that Dr. Daya studies called pheochromocytoma,
• 22:37
  which is a neuroendocrine tumor.
• 22:39
  It's a little bit different than the other VHL tumors, but it's seen in families with VHL.
• 22:44
  So when you see that constellation in the family, which even for physicians
• 22:50
  isn't going to obviously, you have to know about von Hippel-Lindau.
• 22:56
  It may not be obvious to every practitioner, but it is a pattern that will lead
• 23:02
  you down to the diagnosis of the HL.
• 23:05
  And then there are surveillance methods that are recommended.
• 23:10
  They're started young children, typically around age five, looking for these
• 23:16
  different types of tumors with imaging, MRI scans.
• 23:20
  Some of the tumors secrete chemicals, which you can pick up in the urine or plasma.
• 23:26
  So we screened biochemically, we screened with.
• 23:30
  With MRIs of the body, the abdomen, pelvis, brain, and then also just having good eye exams.
• 23:39
  Now, that's after you know the family has von Hippel-Lindau.
• 23:42
  Putting together and diagnosing the first, what we call the Provan,
• 23:46
  in any one family that's the first member that comes to medical attention,
• 23:51
  that can be hard because it's rare and you don't, even an oncologist might not
• 23:56
  immediately think about it.
• 23:58
  On the other hand, it is a known entity, so I think most cancer specialists
• 24:02
  would consider it in the setting of, say.
• 24:06
  A kidney cancer that occurs early, like in the 20s or early 30s,
• 24:11
  or it occurs in both kidneys.
• 24:13
  They would consider the fact that maybe we should look at the genetics of this
• 24:18
  because there's more than one thing going on at the same time.
• 24:21
  Dizziness is one symptom? That can be a symptom of the brain lesions.
• 24:26
  It can be dizziness, it can be headache, it can be nausea, vomiting,
• 24:32
  other symptoms of a brain tumor because it is a mass-occupying lesion in the
• 24:37
  brain, so it gives you the symptoms of a brain tumor.
• 24:41
  Is it always in the brain and then it develops and it always develops elsewhere
• 24:45
  in the body? It develops independently in different parts of the body,
• 24:50
  and the brain is one place.
• 24:51
  But it's not like a cancer that metastasizes, like breaks off at little parts,
• 24:57
  get into the bloodstream, and ends up in the lungs.
• 24:59
  That's not a pattern of growth. These are, but it can occur in independent places
• 25:05
  in the body because the whole body is sort of affected by this change in its response to oxygen.
• 25:13
  So the multiple tumors can occur
• 25:15
  at the same time or at different times in different parts of the body.
• 25:19
  So this is a disease that has high penetrance, meaning that everybody who carries the mutation.
• 25:26
  Will at some point in their life have a very high chance of developing a tumor.
• 25:32
  But it doesn't mean that everyone in the same family will have the same symptoms
• 25:37
  or the same tumor types, which makes it all the more challenging to define families,
• 25:43
  right, and bring all the diagnosis together.
• 25:46
  So being attentive to the various different types of tumors and how they can
• 25:51
  appear and manifest is really important.
• 25:56
  And the fact that you see, so the tumors that I study the most,
• 26:02
  pheochromocytomas and paragangliomas, they are the tumors on the adrenal gland.
• 26:06
  And they produce adrenaline and noradrenaline, which are the fight or flight response hormones.
• 26:11
  Those are the hormones that, as Dr. Tomlinson was saying, they can be detected
• 26:16
  in the blood or in the urine. So they can be used as tests.
• 26:19
  And these tumors can arise as early as five children with five years old and beyond.
• 26:26
  So the part of the surveillance is detecting or collecting or testing these
• 26:33
  hormones early on and early after the family is diagnosed or somebody is found to have a mutation.
• 26:40
  So I think it's important to keep that in mind as well.
• 26:44
  And these are patients that can have high blood pressure as very young children.
• 26:49
  So this should be an alert for any patient with high blood pressure when they are children.
• 26:55
  You should consider the possibility of a tumor that produces hormones that affect the blood pressure.
• 27:01
  Should first-degree relatives be tested? What is your advice on genetic testing
• 27:06
  if someone in the family has this?
• 27:08
  We recommend that for a number of different cancer genes for different syndromes.
• 27:13
  But once you identify the genetic marker of one person and the family,
• 27:21
  then it's very straightforward.
• 27:23
  It's a very simple, readily available genetic test to use that as a marker for
• 27:28
  different members of the families.
• 27:30
  And a lot of the genetic companies will actually do family members for free
• 27:34
  after you identify the marker in the family. It should be done in conjunction
• 27:38
  with a genetic counselor, so everyone who's being tested understands the significance
• 27:44
  of what they're going through.
• 27:45
  And we could test children at a young age because the younger you know about
• 27:51
  this disease, the more you can do preventative medicine.
• 27:55
  Children who have this disease and have lesions in the eye, they don't really
• 27:59
  recognize that they're going blind because it's a very gradual process.
• 28:04
  And so they may not realize that they're not seeing until it progresses to a
• 28:11
  very, very advanced state.
• 28:12
  If you know what the EHL is in the family, you can test people and get the ones
• 28:19
  who need screening in sooner.
• 28:21
  And then the ones that don't have the gene, you don't need to screen and you
• 28:25
  don't need to worry or do anything outside of general pediatric care.
• 28:30
  So we have two types of centers here, Centers of Excellence for Study of Hereditary Cancers and Tumors.
• 28:39
  So the VHL Center of Excellence is one designation by the VHL Alliance.
• 28:47
  And because of its multidisciplinary nature, it has doctors in the pediatric
• 28:54
  oncology department, ophthalmology, genetic counselors are part of it, endocrinology.
• 29:00
  And these are not necessarily under the same roof, but they are covered by our
• 29:07
  clinics at the Cancer Center,
• 29:12
  Mays Cancer Center, the University Hospital, and the UT Health San Antonio.
• 29:18
  Right, Gail? That's correct. That's correct. We do the pediatrics at University
• 29:22
  Hospital, but a lot of the adult care is done in the Mays Cancer Center.
• 29:27
  For the patients that come through, sometimes the patients come through depending
• 29:31
  on their symptoms, right?
• 29:32
  And they can come with pheochromocytoma as their first symptom.
• 29:37
  So those are the tumors of the adrenal gland that produce adrenaline and noradrenaline.
• 29:42
  So they can come to endocrinology first.
• 29:45
  And at endo, there is the Pheopara Alliance Center of Excellence,
• 29:50
  which is the only one in Texas.
• 29:52
  And it also really draws patients from many other states coming to us because
• 29:59
  of the multidisciplinary care in this rare case.
• 30:03
  People come from all around the state, you're saying. So there's no center of
• 30:06
  its kind in Texas like this. Or Pheopera, no.
• 30:11
  I'm sorry. Gail, go ahead. I was going to say, and the doctors and the genetic
• 30:16
  counselors, we may be in different parts of the university system. But Dr.
• 30:21
  Dahiya and her colleagues also have a hereditary endocrine tumor board,
• 30:26
  which is virtual, where they meet and discuss all these entities that we're
• 30:32
  discussing, the multidisciplinary approach.
• 30:36
  For VHL, where every cell in the body has two copies of every gene,
• 30:41
  bar those found in the sex chromosomes X and Y.
• 30:44
  In VHL disease, one copy of the VHL gene has a mutation and produces a faulty VHL protein.
• 30:51
  However, the second copy still produces a functional protein.
• 30:56
  And this is what I found on the internet. The condition is inherited in an autosomal
• 31:02
  dominant manner. or one copy of the faulty gene is sufficient to increase someone's
• 31:06
  risk of developing tumors?
• 31:10
  That's correct. And sometimes in the actual tumor cells, the normal copy is lost.
• 31:18
  So there's no backup anymore. And that's when the tumors become more clinically
• 31:24
  detectable oftentimes.
• 31:27
  And so The patients carry one defective copy through life, and then the second
• 31:34
  copy may or may not be lost at specific cell types, and that facilitates the tumor to grow.
• 31:40
  I just wanted to bring attention also to other less common.
• 31:45
  So we talked about the most common tumor types in VHL, the renal tumors that
• 31:51
  can be both cysts and renal cancer.
• 31:54
  The hemangioblastomas, which can be in the retina, in the cerebellum,
• 31:59
  and the spinal cord, right?
• 32:01
  So the brain tumors, the adrenal gland tumors, phyochromocytomas,
• 32:05
  but there are also less common tumors in the pancreas.
• 32:09
  So neuroendocrine tumors of the pancreas and some tumors close to the gonads.
• 32:17
  So closer testes and close to the ovaries and also some tumors of the inner
• 32:22
  ear called endolymphatic sac tumors.
• 32:25
  So this is a very broad spectrum disease and not all patients will have all
• 32:31
  tumors, but some patients have multiple of them.
• 32:34
  So it's important to be aware of these rare tumors and any combination of rare
• 32:39
  tumors should alert a physician to something being potentially hereditary.
• 32:45
  And putting that puzzle together.
• 32:48
  Exactly. Yeah, precisely. Patricia and Gail, do you have any advice for our listeners worldwide?
• 32:56
  No, no specific advice other than to stay alert.
• 33:00
  I mean, this is a rare syndrome, so we don't expect it to come to mind in every practitioner.
• 33:06
  But just to file this away in the back of your brain, that VHL is an important
• 33:11
  entity and can show up at different parts of the body with a variety of different kinds of cancers.
• 33:18
  And for VHL, there are different places in Texas. for the Pheochromocytoma Alliance, I think we're it. Dr.
• 33:28
  Tahia and her colleagues are it in the state of Texas.
• 33:33
  BHL, there are several places in comprehensive cancer centers and usually large medical centers.
• 33:39
  You want to go to a place where you get all the multidisciplinary care, the care you need.
• 33:45
  And it is an incredibly rare syndrome. So even in a busy clinic, we don't see this.
• 33:52
  We don't see a new patient every month or maybe every year we do, but it is quite rare.
• 33:57
  But they do tend to present in the pediatric setting.
• 34:02
  And sometimes pediatricians are the first line of defense in a child who has
• 34:07
  unusually high blood pressure or unusual headaches.
• 34:11
  And these symptoms can be due to a lot of other things, too.
• 34:16
  But if you keep looking, this is definitely on the list of syndromes and entities that you may find.
• 34:24
  And is VHL research, is it helping in stroke research and other areas of medicine
• 34:32
  that involves oxygen, too little oxygen, too much oxygen?
• 34:38
  Absolutely. So the same way that studying VHL, a rare disease,
• 34:43
  led to understanding how our cells sense oxygen and respond to oxygen,
• 34:48
  and that in turn led to the development of a drug to block that excess of the
• 34:54
  proteins that control oxygen and make the cells grow more and grow more vessels.
• 35:00
  This has been used as a way to consider other circumstances where blood vessels
• 35:08
  are abnormal, like in various cancers, and also considering for stroke.
• 35:13
  So in stroke, sometimes what you have is a lack of oxygen, right?
• 35:19
  So restoring the oxygen flow to some cells is important.
• 35:23
  So, but because we understand how oxygen is regulated, then new drugs can be
• 35:30
  developed that will do just the reverse in some areas. And in fact, Dr.
• 35:35
  Kalin was, again, involved in developing drugs that make oxygen flow better
• 35:41
  to some cells where it's missing.
• 35:44
  So I think it's really important how, you know, when the thought of studying
• 35:50
  a rare disease may be just self-contained.
• 35:53
  No, in fact, it has so much broader impact in so many areas.
• 35:57
  And just going back to the question about what to look for and what to be aware, I echo Dr.
• 36:05
  Tomlinson's comments and would just kind of remind the pediatricians and other
• 36:10
  clinicians that might be listening to this.
• 36:13
  So having patients with unusual symptoms at unusual ages and if you end up diagnosing a tumor,
• 36:23
  having multiple tumors in any patient or bilateral tumors in organs that are
• 36:29
  twins like kidneys or adrenal glands should be an alert for patients.
• 36:35
  Physician. So this is not common. This should raise an alert for potential for hereditary disease.
• 36:42
  Patricia and Gail, this is so interesting. Thank you so much for sharing your vast knowledge.
• 36:48
  It's such an honor to talk to both of you. Is there anything else you want to mention about VHL?
• 36:53
  Can I just plug in the VHL Alliance and their very resourceful website with
• 37:00
  guidelines for patient surveillance.
• 37:03
  So if you come across a patient who has VHL, they have really excellent tables
• 37:08
  telling how often to test and what kind of tests to do for these patients,
• 37:13
  for carriers of the mutation.
• 37:16
  So I would invite everybody to look at the VHL Alliance website, vhl.org.
• 37:23
  VHL.org. That's great. Thank you. And Patricia, I know you have your PhD and MD.
• 37:32
  Was there a defining moment in your career that led you to where you are today?
• 37:40
  Several. From graduate school, I did my MD before I did my PhD,
• 37:45
  and I did them separately.
• 37:47
  But I loved genetics, and I think I came across families with combinations of
• 37:54
  tumors, and in this case, pheochromocytomas and paragangliomas.
• 37:58
  So that became a passion of mine. I wanted to find the gene that caused tumors
• 38:03
  in those families. It ended up being a different gene than VHL,
• 38:06
  but that got me really interested in studying hereditary cancer syndromes. So here I am.
• 38:13
  And how about you, Gail? My pre-trajectory was somewhat parallel to Patricia's.
• 38:20
  I got my PhD first, and then I got my MD a couple years later,
• 38:25
  so that was a little bit different.
• 38:27
  But in the time that I was training, there was a whole.
• 38:35
  Bursting of new knowledge about genetics. And I just loved genetics as well.
• 38:40
  I just fell in love with the idea of looking at families, looking at different generations,
• 38:45
  looking at how genes are passed on from one generation to the other,
• 38:48
  and also the idea of informing families and helping them navigate their genetic
• 38:54
  predisposition when found.
• 38:56
  And across the first 10 years of my career, there were so many new genes found.
• 39:01
  There was so much to work with and so much to be done. And it's just evolved
• 39:06
  into a wonderful field where we can intervene and sort of combat these not-so-common diseases,
• 39:14
  including the very rare syndromes like VHL.
• 39:17
  I love that. It's so impressive. Just to end here, Holly, I just wanted to mention
• 39:23
  something interesting.
• 39:25
  VHL has now become one of really good examples of precision medicine.
• 39:29
  I think the term precision medicine has become kind of household name, right?
• 39:35
  So this is how you treat the defect that any individual patient might have in their genes.
• 39:41
  So the story that we told you about how VHL started,
• 39:46
  how it was connected to oxygen, how it was connected to excess blood vessel
• 39:50
  growth, and how a drug was created to reverse that is a perfect example of precision
• 39:56
  medicine. So we are the future.
• 40:00
  That's incredible. And if someone with this medication, Patricia,
• 40:03
  do some tumors still need to be removed?
• 40:08
  Yeah, that just doesn't take away the surgical component necessarily.
• 40:12
  And not all patients are eligible to take this drug.
• 40:16
  So we are still at early days, as Dr. Tomlinson highlighted.
• 40:20
  It's really important to keep in mind that it's not for everyone and it's not
• 40:25
  for every circumstance, but it's really a game changer for many patients.
• 40:30
  It's wonderful to hear about hope and more hope on the horizon.
• 40:34
  And here on Pediatrics Now, I like to talk about in this high stress,
• 40:39
  high burnout field, what do you like to do in your spare time?
• 40:44
  What recharges your batteries and helps you to unplug?
• 40:48
  We talk about it's really hard to maybe impossible to have any sort of balance in medicine.
• 40:53
  But how do you unplug or recharge? Patricia, do you want to start?
• 40:58
  Sure. Well, I like so many other things outside work. But I love movies.
• 41:02
  I love reading. And I like to travel a lot.
• 41:05
  So between the three of these, that helps me change the scenario and keep me calm.
• 41:12
  Do you have a favorite movie or something recently you saw and or travel experience?
• 41:19
  Yeah, well, yeah, I've been to Europe very recently and it was great.
• 41:25
  Great to be there and just relax. Where in Europe did you go? Terry's in London.
• 41:32
  A couple weeks ago oh a couple weeks ago wow that was very good Patricia in
• 41:41
  Paris it sounds like a show,
• 41:45
  Who knows? Thank you.
• 41:49
  Awesome. So what about you, Gail? I struggle with finding a lot of personal
• 41:56
  time outside of work because work keeps me pretty busy.
• 41:58
  But I really make it an effort to, in the evening, to take a little break from
• 42:03
  work and do something, call my family, talk on the phone, maybe go for a walk.
• 42:09
  I really find that that's important to just kind of refresh my brain and clear my I fear my mind.
• 42:16
  And then sometimes I'll settle down later in the evening and,
• 42:19
  you know, review some things I've done over the day. I do like to travel.
• 42:23
  I used to travel a whole lot, both professionally and personally.
• 42:27
  I like to go to Europe. I haven't traveled as much since the pandemic.
• 42:31
  Just the pandemic changed a lot of things about our lifestyle.
• 42:34
  And I haven't gotten back to much traveling.
• 42:37
  But I hope to take some interesting trips in the future. Dr.
• 42:41
  Patricia Daya and Dr. Gail Tomlinson with the University of Texas Health Science
• 42:46
  Center and University Hospital, the VHL Alliance Care Center.
• 42:51
  Thank you both for being here today on Pediatrics Now.
• 42:57
  Thank you very much for having us. Thank you.
• 43:00
  Don't forget to click on the link in this podcast for free credit that may include
• 43:04
  CME, MOC, or ethics credit, depending on our topic or podcast.
• 43:09
  Pediatrics Now is brought to you by the Department of Pediatrics at the University
• 43:13
  of Texas Health Science Center and University Health's new women's and children's
• 43:17
  hospital. I'm Holly Wayment.