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

He started getting nodules on his body like bumps. 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. I'm Lauren Bright-Pacheco, and this is Symptomatic. A chemist by profession, Chuck Stoner has always been a meticulous and strong figure for everyone in his life. With a straightforward sense of pride in what his faith and hard work has given him, Chuck is a through and through family man, extremely proud of his two kids and their growing lives.

We have some big ones. They're now 30 and 27. We have a granddaughter daughter. I just babysat Wednesday, which is quite an effort, but it was a lot of fun. It's interesting. My daughter is a physical therapist like my wife. My son is a chemist like I was. He just started working in the 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 spent 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 and 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 2009, I decided to get on a softball team with some friends. I found myself instantly pulling hamstrings when I would run the first base. I had some interesting pains in my hips right around that time as well.

How old were you?

Let's see, 2009 would put me about 45.

You probably initially just dismissed it as wear and tear and getting older.

Yeah, I think so.

That was until other new symptoms started to pop up. Pulled hamstrings led to pain in this pelvis right around the beltline. These pains would gradually fade, so they didn't concern him much. But things changed when he started to get fevers regularly.

During the day, I'd feel like I'm just getting sick. I'd come home, I'd have that fluish feeling, and then the next morning, I'd be fine. 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 Thybuprofen. 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 helped him with that.

This mysterious pattern was becoming Chuck's new normal. With fevers peaking as high as 103, 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 remembered that that was just instant relief. Yeah, it felt good. I remember there were some big snowfalls that winter, and I was out shoveling snow and snow like it was nothing. 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 and philosophy, Dr. Kastner has become somewhat of a genetic sleuth of unknown diseases.

It was a combination of being a little bit turned off by the drudgery, 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 1970s was one of the most exciting times in immunology because we were just beginning to understand how immunology works.

Dr. Kastner 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. Dr. Kastner's time there started with his fellowship back in the '70s.

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, Dr. Kastner saw the potential to revolutionize how doctors diagnose, categorize, and treat diseases. He hypothesized, if you 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 Armenia, but the patients are plagued with recurrent fevers. And so I had decided that I was going to use that as a test case. And there were a lot of people who would say, Oh, Dan, why are you wasting your time with this rare disease that's only found in certain corners of the world?

Femoral Mediterranean fever, or FMF, was a potentially deadly disease before Kastner 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 Dr. Kastner 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 classic literary character prone to nobles and impractical ideals. Yeah.

I.

Would think that Sherlock Holmes would be more applicable.

Yeah, well, 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 at least sometimes show the naysayers that they're wrong. There's nothing more satisfying, at least in some cases, than being able to do that. Not that there's personal animosity or whatever, but it's just a challenge then.

A challenge that would eventually intertwine Chuck's path with Dr. Kastner's. By now, Chuck had repeatedly gone through his doctor's 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. 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. I really thought, could this be cancer? Could this be something 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 lay down and sweat it out. I didn't stop working until 2018, 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 positive. 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 flow chart or perfect picture of symptoms that matched the disease. 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. Then once you went there a few times, you realize they were as confused as the rheubatologist locally was.

Wow. 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. 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 heal from the center out. You'd see rings at the end. I'd get them on my earlobes and once or twice on the bridge of my nose. 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. When you're testing for certain kinds of vasculitis, and they're saying you don't have it, that's a good thing. That gives you a little bit of relief and gets you rid of the frustration of not knowing for at least a while.

The Johns Hopkins 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 Dr. Kastner and other physician researchers have already been revolutionizing medicine using genomics. After he discovered the genetic variants that cause FMF, Kasner continued to use genomics to pinpoint the source of other genetic diseases. The thrill of scientific discovery and seeing how that work changes people's lives kept up his determined energy. After solving several other recurrent fever syndrome mysteries, Kasner has another revolutionary idea. He proposed an entirely new way of categorizing these types of diseases. You then would later propose the idea of grouping a subset of autoimmune diseases into their own distinct group called autoinflammatory disease.

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 antigen-specific T cells. That'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 autoinflammatory disease and even categorize them. And then, and this was just a real lucky time, it turned out that a year later, a couple of the diseases that we had proposed that many people scoffed at as they're just having fun or whatever with things, it turned out that those two diseases, the genetic cause of them was found, and it turned out to share a common domain in the gene with the familial Mediterranean fever gene.

Grouping the diseases in this way made it possible for Kastner 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 genetic source then allowed a biotech company to develop an inhibitor for what was triggering this deadly disease.

And by giving them an inhibitor of this interleukin-1 substance, it totally turns off the inflammation. And these kids are now, well, we just saw one of them recently, about a month ago at a meeting, who's now a biochemistry graduate student.

Wow. Kessner'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 in perspective. But it didn't come without its challenges.

It is like looking for a needle within a needle. Certainly, it was a huge undertaking. No question about that. For a while, we wondered whether it was going to be successful. Theoretically, medically, it should work. We just have to do it until finally.

Is that what kept you going? This stubborn optimism?

Yeah. You know, that's… See, the Don Quayote coming out.

Dr. Kastner, 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 autoinflammatory 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 is where he and Chuck would soon cross paths. In 2012, you are linked with the National Institutes of Health and Dr. Kassner. Right. Tell me the first time you went there and were you hopeful or were you just now what?

So I was pretty excited about that. It was that you're going to the place that knows about these fever syndromes. Dr. Kassner, of course, was probably the first person or one of the first few people I met there, although I was in 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 the could not.

And at that time, he was one of a number of patients who are referred to us with unexplained fevers. And so at the time that we saw him, he was in his mid-40s 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.

Each time you get that like, hope, this doctor is going to be it. This doctor is going to be the one that's going to figure it out. They see you a couple of times and then you just know, they don't really have anything else to offer. Just try different medications and you 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. Though the NIH 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 over his body. Nine years of bouncing between doctors with little to no answers as to what was causing this. But Chuck was now being treated by a team at the National Institutes of Health, including Dr. Kastner, a self-described Don Quixote figure who gave Chuck hope he could finally get some answers as to what had been plaguing him. But even as research at the NIH forged ahead, Chuck had a flare-up that would take him to the brink of death.

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 911. Nine, 911.

Hello?

The reception was terrible. I remember having a difficulty getting even through to 911. Hello?

911.

Thank God I was able to get them there.

I went to the emergency room and my heart function was quite low, but not knowing what it was. Is this something that's going to... Is this some 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.

I went through the holidays just feeling bad. Then I had an appointment at NIH for a heart MRI. My heart function had just taken another nosedive. They weren't going to let me leave. I was admitted at that point. That's when we knew about the myocarditis and the cardiomyopathy, 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 going to drop where we're dead from a heart attack.

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 his side because I didn't want anything to happen and me 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. On top of just the fear that you're going to 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, Kastner 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. When we first found something, this gene that had a mutation in it, UBA1, 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 middle-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 vacules in their bone marrow.

We went back and looked up patients, my patients, from eight years ago that had these vacules. 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 happen.

I'll never forget about it, 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.

Kassner 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 Dr. Kassner and team, Vexus.

So, Vexus is a disorder that's caused by somatic mutations in this gene, UBA1, in just the myeloid subset of cells in the blood. So just to unpack that a little bit, V is for vacuols, E is for E1 ligase, which is the UBA1 gene, X is for X-linked because the gene is on the X-chromosome, A autoinflammatory, and S for somatic. Somatic mutations means mutations that arise during the course of your life that you were not born with those mutations. The gene UBA1 happens to be a gene that's involved in various markings of proteins in the cell. Some of the patients that we now know have vexus syndrome, in fact, were labeled as having relapsing polychondritis, this inflammation of the cartilage in the nose and the ear. 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 inflammation of the blood vessels called polyarteritis nodosa. But they didn't have these diseases. They have vexed us.

It was a relief just to be able to put a name to the disease that I had had for, I guess, 11 years at this point. I'm very grateful for the NIH. 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.

At.

The beginning, he was like, one of five. I was 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 hyperfocused steroid regimen. Before the discovery of Vexxus, 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 Vexxus: 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. Since then, it's good to be able to tell somebody what you have.

Even after decades discovering new diseases and helping countless people, Dr. Kessner still has that same urge and drive as when he first started. He enjoys seeing all the patients he has treated, but is constantly intrigued by the mysterious cases they still have yet to solve at the NIH. Going all the way back to your early career and that rebelliousness that you had in terms of stubborn optimism, do you see that as maybe a rebellious streak, renegade? What gave you that confidence and conviction?

Well, 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 some of it is just youthful naivety. That one doesn't fully understand the hurdles that are there, but it's just that youthful persistence and optimism. 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.

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. When that doctor referred Chuck to this program at NIH, to me, those are all little just pearls from heaven 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 where my life started.

I have goosebumps. Yeah, me too. I have goosebumps. That's amazing. After all these years, constantly 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. Lexus 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 what you were prior to your disease.

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

My name is Chuck Stoner, and for 11 years I struggled with a previously undiagnosed disease called Vexxus.

On the next symptomatic, Gerard 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?

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

Are these my last days?

Will Gerard 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@iheartmedia. Com. Symptomatic, a medical mystery podcast is a production of Ruby Studio from iHeartMedia. Our show is hosted by me, Lauren Bragg Pacheco. Executive producers are Matt Romano and myself. Our ERP of post-production is James Foster. Our producers are Cierra Kaiser and John Irwin. This episode was researched by Diana Davis.