Case #10: Chuck & Dr. Kastner

I'd come home, I'd sort of have that fluish feeling, and then the next morning I'd be fine. So this developed into a pattern where I was in the living room sweating out a fever with tibuprofen, and then again the next day, you'd be fine.

He started getting nodules on his body, like bumps, and he had been to so many different doctors. I just felt like they were just throwing a dart at what this could be.

You couldn't imagine that anyone could be alive and have a mutation in that gene, so something obviously was wrong.

How terrifying would it be to fight an unknown enemy, one you didn't recognize and didn't see coming. What if that enemy was coming from within a disease that even doctors couldn't identify. Nearly half of all Americans suffer from some chronic illness, and many struggle for an accurate diagnosis. These are their stories. A Lauren brit Pacheco and this

We have some big ones. They're now thirty and twenty seven, and we have a granddaughter. Her I just babysat Wednesday, which is quite an effort, but it was a lot of fun. It's interesting. My daughter's a physical therapist like my wife. My son's a chemist like I was. He just started working so in a process of cutting that final cord, which is quite enjoyable.

He's very devoted to his family and to making sure that we all.

Have good values.

That's Tracy Chuck's wife. She describes him as loving, kind and her perfect partner.

We've been so long together.

I don't know how to be me without him. I don't know how to be just Tracy without Chuck.

Busy, growing a successful career and loving family, Chuck never would have imagined that a mysterious disease would come along and threaten all of it, a journey that would have him going in and out of hospitals, even fighting to survive. He didn't realize it at the time, but in hindsight, it all started at a friendly softball game.

In the spring or summer of two thousand and nine, I decided to get on a softball team with some friends, and I found myself like instantly pulling handstrings, like when I would run to first base. I had some interesting pains in my hips right around that time as well. How old were you, I'd see two thousand and nine would put me about forty.

Five, So you probably initially just dismissed it as wear and tear and getting older, Yeah, I think so. That wasn't until other new symptoms started to pop up. Pulled hamstrings led to pain in this palvis right around the belt line. These pains would gradually fade, so they didn't concern him much. Things changed when he started to get fevers regularly.

So during the day, I'd feel like I'm just getting sick. I'd come home, I'd sort of have that fluish feeling, and then the next morning I'd be fine. So this developed into a pattern, and it really got into daily fairly high fevers where I was in the living room sweating out a fever with ibuprofen, and then again the next day you'd be fine. Something obviously was wrong.

He would fight through it, the fevers, and I could tell that it was going to be a bad day, but he would still I mean, if there was something we had to do, he would still do it. He's very methodical, and I think being a chemist help him with that.

This mysterious pattern was becoming Chuck's new normal, with fevers peaking as high as one hundred and three. His primary care physician tried many different medicines without any success, the first signs of Chuck's long journey to come until Chuck was prescribed a regimen of steroids.

I remember that that was just instant relief. Yeah, I felt good. I remember there were some big snowfalls that winter and I was out shoveling snow like it was nothing. So that worked, but a bunch of other medications did not work.

For now, Chuck has found some relief from the daily fevers and pains, but he's no closer to understanding the bizarre set of symptoms he's been living with. Little known to Chuck, there is a doctor who will change his life forever. Doctor Daniel Kastner has been working tirelessly for years in the field of genetic research, a passion that sprouted unusually from his early studies in philosophy. Doctor Castner has become somewhat of a genetic sleuth of unknown diseases.

It was a combination of being a little bit turned off by the drudge, if you will, of being in class eight hours a day, five days a week, just cramming facts into your head, versus having some exciting new things to understand and maybe even be a part of figuring out. And at that time in the early nineteen seventies was one of the most exciting times in immunology because we were just beginning to understand how immunology works.

Doctor Castner is currently the head of the Inflammatory Disease Section at the National Institutes of Health or NIH, in Bethesda, Maryland, as part of the US Department of Health and Human Services. The NIH is the nation's medical research agency. Doctor Castner's time there started with his fellowship back in the seventies.

Early in my fellowship at the NIH, there was a revolution that was happening in medicine, and that revolution was the Human Genome Project. And what the Human Genome Project allowed us to do was to comprehensively and in an unbiased fashion, survey the whole human genome to try to figure out what was the cause at least of a genetic disease.

Being on the front lines, doctor Kastner saw the potential to revolutionize how doctors diagnose, categorize, and treat diseases. He hypothesized, if you could find common genetic variants shared among people with a certain set of symptoms, you could then create a very targeted and effective way to treat them.

The first disease where I really tried to use this Human Genome Project approach in order to solve that disease is a disease called familial Mediterranean fever, and it's a relatively rare disease. It's somewhat common in Israel and Turkey and our me, but the patients are plagued with recurrent fevers. And so I had decided that I was going to

The millial Mediterranean fever or FMF, was a potentially deadly disease before Castner was able to find the genetic variant responsible for causing it. Now it is more easily tested for and treated even in young children, saving countless lives. For doctor Casner personally, this entire journey of discovering new diseases and then effective treatments for them became a driving purpose. I've read some articles in which you referred to yourself at various points in times as a Don Quixote, the

Yeah, well, you know, I suppose that there's an element of both of those in my character. But I do like to take on something that's a bit heretical, and I love to, you know, at least sometimes show the naysayers that they're wrong, you know. And there's nothing more satisfying, at least in some cases than being able to do that. Not that there's any personal animosity or whatever, but it's just a challenge then.

A challenge that would eventually intertwine Chuck's path with doctor Castner's. By now, Chuck had repeatedly gone through his doctor steroid regimen, but couldn't keep the constant fevers away. It's been two years since the fever started, and they're continuing to get worse. When do you remember having something stick out to you where you thought something is wrong here?

Yeah, I mean probably after he started getting nodules on his body like bumps, and he had been to so many different doctors, and I just felt like they were just throwing a dart at what this could be and trying different medications, and I really thought, could this be cancer? Could this be you know, something you know more than just a flu? Chuck?

How was this impacting your daily life at this point?

Well, it was going to work saying I know I'm going to get a fever today, and then just basically sticking it out until you get home and then and then lay down and sweat it out. You know. I didn't stop working until twenty eighteen, so there was quite a bit of time in.

There that must have been one really frustrating, but two really exhausting. It was it was Chuck's rheumatologists ran every test they could think of, and nothing came back pass He was then transferred to Johns Hopkins Rheumatology in hopes they would have more tools to give him answers.

I didn't fit any particular float chart or perfect picture of symptoms that matched the disease. You know, I just got moved to Johns Hopkins. These guys are going to be able to tell me what's going on and figure things out. And then once you went there a few times, you realize they were as confused as the rhumatologist locally was well.

So during this time period, how are your symptoms progressing and what things are getting worse?

The consistent symptom has been the fevers. Other symptoms have changed. I started getting some pretty significant rashes on my body, sometimes even looking like they were going to break open and very big, and that that could have been on my face, on my ears.

Was it cystic like? What did it look like? And was it painful?

It was not painful, but they would get just very large red blotches and then they would sort of heal from the center out, so you'd see rings at the end. I'd get them on like my ear lobes, and once or twice on the bridge of my nose, and there was a fear that these things are going to break open.

I can't imagine the anxiety of the unknown continuing for that long.

Yeah, it's the balance of the anxiety of the unknown and the happiness of not being certain things. So when you're testing for certain kinds of asculitis and they're saying you don't have it, that's a good thing. So that gives you a little bit of relief and gets here with the frustration of not knowing for at least a while.

The Johns Hopkins stuff are at a loss and Chuck is stuck in a vicious cycle. He has a big flare up, goes on another round of steroids. Things get normal for a little while, and so goes the cycle on and on. Though their faith is a source of hope, Chuck and Tracy are starting to become desperate for answers. Chuck is referred to another hospital, this time to take part in a study of undiagnosed fever syndromes at the NIH, where doctor Casner and other physician researchers have already been

Well, what was distinctive about these patients was that they had recurrent fevers, they had very very severe inflammation, but they didn't have auto antibodies, or they didn't have andigen specific T cells. It's something that you see in autoimmune diseases. And then shortly thereafter, I guess the philosopher and me coming out, we wrote a paper in which we imagined all of the diseases in the medical textbook and which of them might fall into the category of auto inflammatory

Grouping the diseases in this way made it possible for Cassner and his team to start assembling the bigger picture of how all these fever syndromes were connected. This made room for an entirely new way of trying out effective treatments, in particular for one very deadly disease that targeted children, and at least one.

Of those diseases is a disease where kids that have it are born with fevers and rashes and inflammation of the lining around the brain. They go on to develop blindness, deafness, intellectual disability, and some of them die before reaching adulthood.

Finding the genetics then allowed a biotech company to develop an inhibitor for what was triggering this deadly disease.

And by giving them an inhibitor of this interluken I substance, it totally turns off the inflammation and these kids are now what we just saw one of them recently about a month ago at a meeting who's now a biochemistry graduate student.

Wow Castener's unique perspective on genetic variants and the diseases they caused continued to change people's lives with every new discovery. He kept embracing different ways of approaching problems, and that made him receptive to a new way of trying to discover genetic diseases.

First of all, I do have to give credit to the fellow in my lab who was really the proponent of taking this view. And so David Beck, who's the name of the fellow, just felt that we were too slow, and so he came up with this idea of genotype first.

This approach started by finding a common genetic variant and then seeing what symptoms that caused, going from cause to effect. A subtle but life altering shift and perspective. But it didn't come without its challenges.

It is like looking for a needle within a needle, and certainly it was a huge undertaking, no question about that. For a while we kind of wondered whether it was going to be successful. Theoretically it should work, so you know, we just have to do it until you know, finally, Is that.

What kept you going, this kind of stubborn optimism.

Yeah, you know, that's see the Don Quixote coming out.

Doctor cassner By now had a decades long track record of methodically searching and testing for the specific gene variants causing fever syndrome. Similar to Chucks, he recategorized how doctors view auto inflammatory diseases, trusting his instincts to approach the diagnosis journey in new ways. He set up clinical research at the NIH with his learnings at the forefront. This

So? I was pretty excited about that. It was that you're going to the place that knows about these fever syndromes. Doctor Casner, of course was probably the first person, or one of the first few people I met there. Although I was in the part of the tested group that did not show positive for any of those syndromes. I think it was about half that could be diagnosed and half could not, and I was in it could not.

And at that time he was one of a number of patients are referred to us with unexplained fevers, and so at the time that we saw him, he was in his mid forties and had developed just seemingly out of the blue, unexplained fevers and elevations of various blood studies that indicated that there was inflammation going on in his body. But actually at that time, there weren't very many clues in terms of what was actually the basis of that inflammation.

So each time you get that like hope, Oh, this doctor's going to be it, this doctor's going to be the one that's going to figure it out, and they see you a couple times and then you just know it's They didn't really have anything else to offer, you know, just try different medications, and you sort of feel like they're spinning a wheel.

After six years of symptoms and countless tests, there's little left for Chuck to hold on to besides hope. And though the nia now offers him a sliver of optimism for finding answers, a terrifying flare up will test Chuck's resilience in this search and possibly cost him his life.

It was a life or death concern because this thing had gone full force at the heart.

We'll be right back with Symptomatic a Medical Mystery podcast. Now back to Symptomatic a Medical Mystery podcast. It's been almost a decade since Chuck first started showing symptoms of a mysterious illness that was slowly chipping away at his quality of life. It started with fevers and muscle pain and progressed to include nodules and rashes, all of for

We were in the mountains at his parents' house.

We were there alone, and there was a snowstorm.

He was having this pain in his abdomen.

So another thing that Chuck would have as the disease progressed was bloating in his stomach, and he.

Said, I think I need to go to the hospital. So we had to call.

Nine one one Hello. The reception was terrible. I remember having a difficulty getting even through to nine to one one Hello, and thank god I was able to get them there.

So went to the emergency room and my heart function was quite low, but not knowing what it was. You know, is this something that's going to you know, is this some kind of cancer that's going to take your life.

Chuck was increasingly dependent on his steroid use, doubling his dosage just to get his fever, gut pain, and energy back to equilibrium. But Chuck knew this was not sustainable, and he soon returned to the NIH, hoping they could save him from the treatment loop. He was hopelessly stuck in.

So went through the holidays just feeling bad, and then I had an appointment at NIH for a heart MRI. My heart function had just taken another nosedive, so they weren't gonna let me leave. I was admitted at that point, and that's when, you know, we knew about the my carditis and the cardio myopathy, and they really had to hit me with a couple of days of high steroids just to try to get the heart to recover.

What were your fears at that time.

Well, at that time, it was more I'm gonna drop over dead from a part attack.

Ugh, I would just sit with cold rags on his head, just trying to say, I just want the fever to break.

I just want the fever to break.

I didn't want to leave a side because I didn't really I didn't want anything to happen and may not be there.

This would go on for almost three weeks before the team at the NIH could finally get him stabilized and bring his heart function closer to normal levels. So on top of just the fear that you're gonna drop dead, have there been other lingering impacts of that episode.

That's really when I started losing physical abilities. It just took a lot out of me. I lost a lot of muscle mass. I felt a lot weaker as far as what I could do.

Just as Chuck was getting worse, Kassner and his team at the NIH finally found a clue. It seemed the pieces were starting to come together.

What happened was a gradual realization. It was like peeling an onion.

You know.

When we first found something, this gene that had a mutation in at uba one was known to be so important. You couldn't imagine that anyone could be alive and have a mutation in that gene.

The gene mutation on the X chromosome was found in three minute aged men who were part of the fever study. As the NIH team looked closer, they noticed all three men also had little bubble like structures called vacuoles in their bone marrow.

We went back and looked up patients, my patients from eight years ago that had these vacuoles, and sure enough, when we did sequencing on them, they also had the same mutations in this gene. And so emerging out of the mist, you have this idea of what is this disease?

These patients from the fever studies included Chuck Stoner.

It almost was a shock at that point because you're not waiting every morning to get up and hear this, and then one morning it finally does happened.

I'll never forget about it, you know, finding that gene and the moment that we found that gene. And so it was David Beck who did that. I know that he was exhilarated when that happened, and I know that Chuck was too.

Castner and his colleague could finally give Chuck an explanation for what was causing these symptoms going back over a decade. At this point, all of the pain, the suffering, the time spent hoping the fever would break, the nodules, the rashes, the declining mobility, the trips to the er clinging to life, all of that now had a name, a name created by doctor Kasner and his team, Vexus.

So Vexus is a disorder that's caused by somatic mutations in this gene UBA one, in just the myloid subset of cells in the blood. So just to unpack that a little bit, V is for vacuoles. E is for E one ligase, which is the UBA one gene. X is for X link because the genes on the X chromosome a auto inflammatory and S for somatics. So somatic mutations means mutations that arise during the course of your life,

In the year.

Some of the patients had been labeled as having Sweet syndrome, where you have pustules all over your body. Some of them had been labeled as having a certain kind of inflammation of the blood vessels called polyardoritis nodosa. But they didn't have these diseases.

They have vexus It was a relief just to be able to put a name to the disease that I had had for I guess eleven years. At this point, I'm very grateful for the EDIH. Their dedication to finding a cure is there, but also the personal commitment that they've shown me.

It was an email I think that he got and it was like, Wow, there's really a name for this. And at the beginning he was like one of five. It's like, wow, we didn't hit the lottery, but got something really rare going on here.

Now knowing the root genetic cause of the disease, Chuck has been able to get a lot of relief through a hyper focused steroid regimen. Before the discovery of vexis, his treatments were like throwing spaghetti against a wall and hoping something would stick. Now, Chuck at least has two options that are shown to both be effective against vexus steroids or a bone marrow transplant.

The fact that there was promise, either for me or for the future, that this thing could be attacked a little more directly, I mean, that was just the greatest And since then, you know, it's good to be able to tell somebody what you have.

Even after decades discovering new diseases and helping countless people, doctor Kassner still has that same urgent drive as when he first started. He enjoys seeing all the patience he's treated, but is constantly intrigued by the mysterious cases they still

Well, you know, certainly it is a rebellious streak, there's no question about that. As for what gave me that confidence and conviction, well, I suppose that, you know, some of it is just youthful naivete. You know that one doesn't fully understand the hurdles that are there but it's just that youthful persistence and optimism, and I must say that I'm young at heart still at this time, I'm willing to go after the next windmill that may be out there in front of me.

And one of the most poetic things about Chuck and Tracy's story, the place that gave Chuck his life back is the same place that gave Tracy life in the first place.

Years ago, my mom was involved in a fertility study at NIH, and she was the last one in her group to get pregnant, and I was the person of that. So when that doctor referred Chuck to this program at NIH, to me, those are all little like just pearls from heaven and saying I'm going to get you through this. I'm going to get you through this and just keep following my path. That's like where my life started.

I have I have goosebas me too. Me. It's amazing after all these years, constant, selfless, constantly thinking of others, trying not to be a burden, even when he is in more pain than anyone could imagine. That is Chuck. Vexus has taken so much from him, yet there still remains a genuine and unrelenting sense of optimism. What do you hope people take away from your story?

Well, I hope that they see that there is hope. We all may not get an answer to an undiagnosed disease, and if we get an answer, we might not reap the ultimate benefit of a cure, but being part of that process can be something rewarding. Or even just dealing with it in a proper way. To stay active, know your life is still meaningful and there are still things to do, even though you may not be doing which you were prior to your disease.

To find out more about Vexus or the National Institutes of Health, visit NIH dot gov.

My name is Chuck Stoner, and for eleven years I struggled with a previously undiagnosed disease called Vexus.

On the next symptomatic DROD goes from being a busy young father, PhD student and community activist to barely being able to get out of bed. As what began with shortness of breath, a sore throat, and an inability to keep food down spirals into a life threatening crisis.

I started thinking can I fight this? Can I beat this?

As this something that's going to just change my life completely?

Are these my last days?

Will Drowd find the diagnosis and relief he so desperately needs before things get even worse? That's it for this week's episode of Symptomatic. Thanks for listening. What did you think of this week's episode? We would love to hear from you. Send us your thoughts or share a medical mystery of your own at Symptomatic at iHeartMedia dot com. Symptomatic Medical Mystery Podcast is a production of Ruby Studio from iHeartMedia. Our show is hosted by me Lauren breg Pacheco.