Some kids collect baseball cards. Others fill their shelves with stuffed animals. Madison Cain? She loves her beads.
A 7-year-old whose bubble-gum-hued glasses frame a cherubic face, she’s decorated her bedroom walls with yards of beads in a riot of colors and shapes. She enjoys showing them off and, on occasion, donning them as necklaces or bracelets.
Some are green or blue. Others red, orange or purple. A few are larger than others.
She smiles and holds up a strand longer than she is tall. “I get different ones from different doctors,” she says.
Every pea-sized memento represents a page of her medical history. The hospital that cares for Madison awards her these minuscule trophies as part of its “beads of courage” program. In an era where privacy laws lock down every imaginable tidbit of information about a person’s well-being, the elementary schooler from Broken Arrow can literally wear hers on her sleeve.
Hundreds upon hundreds of tiny pieces of plastic and glass. Each standing in for an MRI or a blood draw. A stick with an IV needle. A visit to one of her many physicians. An X-ray. An infusion with a new medication. A surgery.
Already, in her young life, Madison had endured so much: broken bones, impaired mobility, cataracts, stunted growth, crippling digestive issues. Yet her doctors could find no answers.
Her case seemed like the beads, strewn across the floor of a child’s room. Madison suffered from a mishmash of symptoms, with no ascertainable link or organizing principle. But, surely, there had to be something that made sense of it all.
Then, one day, one of her physicians found a study in a medical journal from a scientist at OMRF. The language was extremely technical, but Madison’s mother—a nurse practitioner—did her best to decode it. And when she did, she had a powerful realization.
This, she thought, could be the string that pulls everything together.
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Melissa Cain’s pregnancy was uneventful. Although Madison was small at birth, no one voiced concerns. When, at 15 months, she seemed to stop growing, Melissa and her husband, Clifton, took their daughter to an endocrinologist. “They checked her heart and kidneys and did labs,” says Melissa. “They finally said she was just small for her age.”
But Melissa suspected something more was going on.
Madison lagged behind her peers in learning to crawl and walk. When she eventually started toddling around the house, her mother noticed a slight limp and an uneven gait. An orthopedic specialist diagnosed Madison with hip dysplasia, a condition where the joint doesn’t function properly, leading to a cartilage breakdown and chronic pain.
Madison underwent surgery just after she turned 2, and doctors placed her in a cast that ran from her chest to her knees and immobilized both hip joints. Melissa did her best to keep the toddler occupied with wagon rides and lots of coloring and play time.
One day, as they played, Melissa noticed that one of Madison’s eyes looked cloudy. In each eye, an ophthalmologist found cataracts, one so severe it rendered the eye sightless. Two operations removed the cataracts—and restored Madison’s vision.
Despite extensive testing, her pediatrician could offer no insight as to why a 2-year-old might have issues with her bones and growth, along with an eye malady that typically strikes senior citizens. “Maybe science hasn’t come far enough to know what’s going on,” the doctor told Melissa. “We’ll just keep watching her.”
Madison suffered from chronic constipation and didn’t absorb nutrients from the food she ate, and she failed to potty-train. More lab work yielded little more than a bruised arm and beads for her collection. Despite a diet packed with calorie-dense foods like cream cheese and coconut oil, she couldn’t seem to put on weight.
Melissa noticed a marked decrease in Madison’s strength. Even after physical therapy sessions, she couldn’t run or jump. She was falling behind on her motor skills, unsteady on her feet and failing to grow. At age 5, she tripped and suffered a complete break of both the large bones in her forearm.
Melissa grew desperate for answers. She scheduled session after session with specialists. To each visit, she’d bring a green, three-ring binder of Madison’s medical records. The notebook swelled as Melissa added new X-rays, MRIs and the results of every test and examination her daughter underwent.
“I got more and more assertive with doctors,” she says. “My medical friends and I spent hours and hours looking up what was happening and scouring the internet.” Still, “Everything we came up with, every result, said there was nothing we could do.”
Madison couldn’t stay awake in kindergarten. She was sleeping 14 or 15 hours a day. “She had zero energy,” her mother says.
A pediatric GI specialist installed a port called a MIC-KEY in Madison’s abdomen to enable extra feedings. “I’m a girl, so mine’s a Minnie, not a Mickey,” she says. Although regular doses of liquid packed with fats and sugars helped her gain a little weight, doctors still couldn’t understand why her body continued to flush out the lion’s share of those calories.
The GI specialist recommended that Madison undergo a specialized form of genetic testing. Known as exome sequencing, the technique isolates and analyzes that small part of the genome—less than 2 percent of the 3 billion nucleotides or “letters” that make up DNA—that tells cells how to build all the proteins in the body. It’s in this precious real estate that errors leading to genetic diseases typically occur.
“Up until exome sequencing, you’d have to do other, less specific tests,” says Dr. Patrick Gaffney, who heads the Genes and Human Disease Research Program at OMRF. Even when those results pointed to a genetic culprit, physicians often could not be sure. “But with the advent of exome sequencing, you could conclusively identify mutations.”
The test was a Hail Mary. It also wouldn’t be covered by insurance. But the Cains saw no other path forward.
Madison’s test results revealed that her genetic code differed from others’ in one fundamental way. She had a mutation—an alteration—in a gene known as MBTPS1.
Melissa puzzled over this information. What, exactly, did it mean?
She asked a geneticist to review Madison’s results. But even with her years of specialized training, the physician struggled to deduce their relevance. She’d never encountered this mutation in her years of practice. She scoured the medical literature to educate herself; all she found was a study involving a single patient who shared this same genetic mutation.
“There’s one published paper on this,” the geneticist told Melissa, “but it’s not what Madison has.”
When Melissa got home, she jumped on the internet and found the paper. Like most articles in scientific journals, its language rendered it borderline inscrutable. But having spent her career in healthcare, Melissa was more equipped than most to unravel it.
As she deciphered the jargon, her excitement grew. “I’d been waiting and looking for years,” says Melissa. “It wasn’t a perfect match, but I knew there was something to it, some connection.”
She decided to email the scientist who’d written the article. When she found the author’s contact information, she experienced another jolt. His lab was just down the Turner Turnpike, less than 100 miles away.
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Dr. Lijun Xia treated patients suffering from blood disorders before joining OMRF to focus on medical research. In the lab, his interests expanded. In particular, he developed an expertise in the workings of a group of sugars known as glycans. These sugars seemed to play a key role in the function of certain enzymes at the heart of a mysterious condition afflicting Sydney Rutz, a Yukon girl.
Two of Xia’s colleagues—Gaffney and Dr. Klaas Wierenga, a pediatric geneticist then at the University of Oklahoma Health Sciences Center—had sought Xia’s help to get to the heart of Sydney’s case. Like Madison, she suffered from bone deformities, cataracts and growth deficits. And she also had a mutation in the MBTPS1 gene.
Why would this genetic mutation cause Sydney’s problems?
Xia wanted to help, but was going to have difficulty taking on the project. He leads OMRF’s Cardiovascular Biology Research Program, where he oversees the work of more than 50 scientists and their staffs. As the Merrick Foundation Chair in Biomedical Research, he also has several National Institutes of Health grants of his own, none of which had anything to do with Sydney’s condition.
However, as luck would have it, a new post-doctoral fellow had recently joined Xia’s lab. With a freshly minted Ph.D. from Nagoya University in Japan, Dr. Yuji Kondo needed an assignment that would allow him to get his feet wet and familiarize himself with lab operations.
“We thought this would be a simple project,” says Xia. “I estimated it would require a maximum of three months to finish.” Instead, it took three years.
The project became more and more complex as it unfolded. Xia, Kondo and Dr. Jianxin Fu, another scientist in Xia’s lab, discovered that Sydney’s genetic mutation had caused a failure in the cellular machinery responsible for bone growth. The malfunction centered on collagen, a protein the body creates as one of the building blocks for bones and connective tissues.
For Sydney, “at the age of 6 or so, the bones accelerated their growth,” Xia says. The body kicked into overdrive, producing more collagen. But because of the genetic mutation, her body couldn’t utilize the collagen, which triggered a series of damaging cellular events. “As a result, she essentially stopped growing.”
The scientists invited the Rutz family to OMRF to explain what they’d discovered about Sydney’s condition. They told Sydney that, as far as they knew, she occupied a unique position in the world. She was the only person whose genes were this way.
“I’m special,” she said.
The researchers explained that Sydney was so special they were going to write a paper about her. When they published it in the scientific journal JCI Insight in 2018, the paper created a new disease classification: spondyloepiphyseal dysplasia, Kondo-Fu type (or SEDKF).
When Melissa Cain discovered this paper in 2019, she emailed Xia. She explained that, like Sydney, Madison had a mutated MBTPS1 gene and suffered from skeletal dysplasia. “If you are able to converse or share any information, I would be so grateful,” she wrote. “We are willing to help in any way needed.”
Xia responded immediately, inviting the Cains to OMRF. If Madison really was SEDKF patient number two, he needed to learn all he could about her. And he wanted to figure out if there was any way to help her.
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Melissa clutched her green binder as she entered the conference room in OMRF’s research tower, joined by Clifton, Madison and Madison’s younger brother, along with both of the children’s grandmothers. “This was a big deal, and I wanted to share the moment with our family, since it might have the potential to change Madison’s care,” she says.
She helped Madison climb onto the grownup-sized chair beside her. As they sat across from Xia, Gaffney and other scientists who’d worked on Sydney’s genetic mutation, Melissa told her daughter’s story. Xia and Gaffney asked lots of questions and scoured the medical records Melissa had brought.
When the kids grew restless, the grandmothers took them to OMRF’s cafeteria so they could play and wait for the grownups to finish talking. Before long, Xia and Gaffney accompanied Melissa and Clifton to the cafeteria to take a closer look at Madison. The pair sat with Melissa and her, asking questions about her legs, her eyes, her abilities. They analyzed her gait, her balance, her strength.
“Talking to patients, with that physical exam and conversation, is one of the most important things you can do,” says Gaffney, who holds the J.G. Puterbaugh Chair in Medical Research at OMRF. “That’s where you really learn a lot more than lab test values show.”
But, as scientists, they need lab tests, too. In OMRF’s clinic, a nurse drew blood from Madison, her mother and father. Gaffney, Kondo and Xia would then analyze those samples, doing a deeper dive to understand precisely how Madison’s genetic makeup differed from her parents, and why that might matter.
That bloodwork would represent a key component to Xia’s understanding of a condition that, until he’d met Madison, he’d believed was unique to Sydney. That personal encounter—putting a face and a beating heart to a set of symptoms—can make all the difference to a scientist.
“You work in a lab with mice and test tubes, and sometimes you forget the real need. You sort of become desensitized to the real problem,” says Xia. “But once you see the patient, you see the need, and it makes you think how your research can help solve a real problem. It gives you more motivation.”
With genetic diseases, he says, the need for therapies is especially profound. “These patients will live with their conditions for life.” And because they can pass from parent to child, these illnesses can haunt families for generations.
Xia knew that he had his work cut out for him.
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Since that day at OMRF, Xia’s research paper has helped identify more SEDKF patients, with physicians, families and researchers reaching out to him. “Last year, we only knew of two: Sydney and Madison,” he says. “Now we have confirmed eight cases—from Germany to Brazil to San Francisco and beyond—and we’re working to confirm even more.”
Xia has launched a website for physicians and families to use as a resource. He’s also assembled a working group of scientists and physicians to review case information as it arrives. Misdiagnosis of rare diseases is common, he says, and often triggers the wrong treatment. It can also lead to severe complications, so the more information he and his colleagues can gather and share, the better.
“We’ve come together to try to see if we can identify more patients with this same genetic problem in the gene,” says Gaffney. “Our work has expanded to more than one gene. We’re now looking at a molecular pathway, and that’s blossomed out of some detective work and publicly available papers.”
At first, Sydney seemed unique. “But Madison was one of the first to make us think this might not be that rare,” Gaffney says. “Now we might be able to create a database, and that could be the first step toward a clinical trial.”
Xia would like to test an existing medication he believes—based on work he’s done in his lab at OMRF—might help SEDKF children like Madison. But, he says, “Trials aren’t cheap. We’re probably talking about $1 million at minimum to start.”
To generate statistically reliable results, the trial would need at least 20 patients to participate. That means finding more cases. The fact that the handful of identified cases are spread around the globe presents further logistical challenges to organizing a clinical trial.
Although Xia thinks the therapy currently on the market could improve bone development in young SEDKF patients, he doesn’t believe physicians should prescribe the drug until scientists can assess its efficacy and safety in those children in a rigorous, controlled way. “We’d like to treat them right now, but we can’t,” he says.
He knows that means Madison and her family must wait. But, he says, it’s too dangerous simply to give her a drug that hasn’t been tested in her condition and see what happens. “We have to do clinical trials first.”
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In the meantime, Madison has been receiving infusions every three months with a drug to help improve her bone density. These IV treatments had initially proven quite challenging.
“At first, she kind of lost it,” says Melissa. “So then, she’d sit in my lap, and I’d help hold her down.” But at her most recent visit, Madison volunteered to sit in the infusion chair all by herself. Each time Melissa asked her daughter if she should come over and help, Madison shrugged her off. “She sat there for the whole time, no problem,” says Melissa. “That was a big accomplishment.”
This past fall and winter, though, Madison grew chronically listless and fatigued. She suffered from prolonged bouts of vomiting, forcing her to miss dozens of days of school. Finally, following a battery of tests and several months of struggles, her physicians uncovered a bacterial condition, which they successfully treated with antibiotics and probiotics.
As she recovered, Madison began to seem her old self, regaining energy and weight. By the end of the school year, she weighed 44 pounds—a half-dozen more than when she’d begun. She’d also grown to 3 feet, 6 inches tall, adding an inch over the course of the year. “So, she’s still growing!” says Melissa. “We got really excited about that.”
Madison spent a lot of the summer at her grandmother’s pool, swimming with her younger brother, Maddux. (While nearly three years younger, he is now taller than his sister.) The two of them like to play Monopoly Jr. and eat ice cream and popsicles.
Madison is excited to get back to school. She’s about to turn 8 and will be a second grader at Anderson Elementary in the Tulsa Union district. However, with the pandemic and possibility of virtual attendance, there’s no telling how long before she’ll get to enjoy her favorite part of school: joining her best friend on the playground at recess.
In the past year, Madison has realized she’s different from other children. “She knows that not all kids have tube feeds, go to infusion therapy, and can’t run,” says Melissa. “But it doesn’t seem to bother her.” So, the Cains are doing their best to enjoy the moment.
“Right now, she’s not isolated from her peers. They don’t seem to notice,” Melissa says. “When she hits her teenage years, that’s going to change.”
As they imagine their daughter’s future, Clifton and Melissa worry about disease progression, too. “At some point is Madison not going to be able to walk without assistance?” Melissa wonders. Will she eventually need hip replacement? Knee replacement? “We don’t know exactly what this looks like.”
However, they have accepted a hard truth: “She’s never going to be completely independent. She may always need some help from us.”
Still, receiving a diagnosis has made a big difference. “It’s given us a certain element of peace,” Melissa says. “Now I don’t feel like there’s this huge thing we’re missing.” No longer must she play medical detective. “It’s a relief not trying to piece things together any more. It really helps emotionally.”
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What diagnosis has also brought another, unexpected benefit—a new friend for Madison.
With Xia’s help, the Cains connected with the one family in Oklahoma who could understand what they were going through: the Rutzes. Since then, the two families have gotten together on several occasions, and Sydney—now 14 and an incoming freshman at Yukon High—has taken Madison under her wing.
“Sydney is so sweet to Madison,” says Melissa. And, she says, that friendship has helped Madison recognize something about herself. “I think she understood much more about her condition once she met Sydney. She was able to identify a person who was like her,” Melissa says. “Even at her young age, she knows she is the smallest person in her grade and does not physically keep up with people. Sydney shares that with her.”
Knowing she is not alone, says Melissa, will help Madison. And watching as Sydney navigates the obstacles of teenage life, like driving and high school, will provide a preview of what lies ahead for Madison.
“Mary”—Sydney’s mother—“wants Sydney to be an independent person,” says Melissa. “We want the same thing for Madison.”
To that end, the Cains have done their best not to shelter their daughter. “We basically let Madison do what she wants to do,” says Melissa. “Now, we may not let her climb to the top of something. But we try to keep her daily function as normal as possible.”
That normal still involves many trips to see different doctors. But, with each trip, there’s an upside: more beads for Madison’s collection.
Not long after her visit to OMRF confirmed Madison’s SEDKF diagnosis, she received some new ones. “They’re my favorite,” she says.
Unlike her others, these beads are designed to be strung in a specific order. And when they are, they reveal a key piece of information about the little girl who treasures them.
They spell M-A-D-I-S-O-N.
