The nurse placed Mary Rutz’s newborn daughter in her arms. Mary gazed lovingly at this being she’d just brought into the world and thought, “She looks like a tiny doll.”
Sydney Rutz had arrived after a full nine months growing inside her mother. It had been an uneventful pregnancy. But as the birth date neared, Mary could feel that the child in her belly was not going to be as big as her two older daughters, each of whom had tipped the scales at roughly 8 pounds when they came into the world.
Still, Mary was surprised when she cradled Sydney against her chest for the first time. Four pounds, 9 ounces, the nurse said. Her head was more or less the size of Mary’s fist.
Mary stands almost 6 feet tall. She wasn’t used to a child so small, so seemingly fragile. At night, when she’d take Sydney into bed with her, she worried she might crush her young daughter. “She made me nervous,” remembers Mary. “She was just so little.”
Infant clothes didn’t fit Sydney. Even preemie outfits proved too big. So, for several months, Mary dressed her doll-sized baby in doll clothes.
At regular check-ups, Sydney’s doctor plotted her growth. At first, she charted out at the 5th percentile. But even that would prove a high-water mark; within her first year, she dropped off the chart altogether.
“She’ll catch up,” people said. When she didn’t, Sydney’s endocrinologist prescribed growth hormones for her. Mary, a physical therapy assistant, administered shots each night while her daughter slept. They seemed to have no effect.
Despite her diminutive stature, Sydney otherwise appeared to be progressing normally. She started walking and talking. She showed no cognitive delays.
But right before her third birthday, Mary noticed a “little bitty glint” in her daughter’s eye. “The next day, her pupil was completely white.” Within another day, Sydney’s left eye had clouded over as well. Mary drove Sydney from their home in Yukon to the Dean McGee Eye Institute in Oklahoma City, where doctors performed surgeries to remove the cataracts from each of her eyes.
Soon after, doctors found a weak spot in her lower abdomen with tissue bulging through. They diagnosed her with an inguinal hernia, and another surgery followed.
As Sydney’s bones and skeleton developed, they did so in a way that differed from other children. Her arms grew disproportionately long, as did her forehead and ears, while her jaw remained foreshortened. The bones in her spine twisted at an extreme angle, causing severe scoliosis. Her sternum began to protrude, causing a protrusion that Mary, affectionately, began referring to as “chicken chest.”
For several years, doctors treated Sydney’s symptoms individually. But when she was 6, Sydney’s primary physician referred her to Dr. Klaas Wierenga, who at the time held the McLaughlin Family Chair in Genetics at the University of Oklahoma College of Medicine. As a pediatric geneticist, Wierenga specializes in diagnosing and treating young patients affected by rare conditions caused by mutations—changes or abnormalities—in the DNA.
Wierenga suspected that Sydney was just such a patient. But her symptoms didn’t align with any known genetic disease.
During the course of Sydney’s treatment, a blood test revealed she not only had issues with her bones, but she also had an enzyme problem. Specifically, it showed that a class of enzymes known as lysosomes weren’t doing their jobs in her body.
Lysosomes function as cellular garbage disposals, breaking down proteins the body no longer needs. When these lysosomes fail to do their job, it causes an accumulation of cellular junk. Over time, this build-up can interfere with proper cellular function and, ultimately, prove toxic.
Fortunately, Sydney’s lysosomes seemed to be functioning just well enough to keep her healthy. Nonetheless, the test results led physicians to diagnose her with one of the almost 50 conditions known as lysosomal storage diseases, which are all characterized by an abnormal accrual of proteins in the body. Specifically, Sydney’s doctors determined she suffered from an illness known as mucolipidosis, a severe congenital disease that often proves fatal.
Wierenga, though, wasn’t so sure. In mucolipidosis, patients all show mutations in one of two specific genes. But when he tested Sydney, those genes appeared normal. So, he reached out to OMRF’s Dr. Patrick Gaffney for help.
A geneticist who holds the J.G. Puterbaugh Chair in Medical Research at OMRF, Gaffney had established a “next-generation” DNA sequencing facility in his laboratory. With an array of sophisticated equipment, he and his research team could perform analyses of people’s genes that were far more sophisticated than those available through standard laboratory or commercial testing facilities. Specifically, using a technique known as exome sequencing, Gaffney could isolate and analyze that small part of the genome—less than 2 percent of the three 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 Gaffney. Even when results pointed to a genetic culprit, physicians often could not be sure. “But with the advent of exome sequencing, you could conclusively identify mutations.”
When Gaffney performed an exome sequence on DNA from Sydney’s blood, he confirmed Wierenga’s findings. She didn’t have the mutation for mucolipidosis.
However, she did have a mutation in another gene. In fact, she had two mutations in that same gene.
Known as MBTPS1, the gene was known to be involved with lysosome function. But, here, Sydney’s bones were clearly affected, too.
When Gaffney and Wierenga searched the medical literature, they could find no cases of a patient with a disruption in this gene. Sydney, it seemed, was unique.
Wherever the Rutz family went, people would gravitate toward Sydney. In stores, other shoppers—and even workers—would follow her up and down the aisles, stealing surreptitious glances at this toddler-sized elementary schooler.
Children were often less subtle. They’d unabashedly stare at her. Or they’d approach her and blurt out a question: “You know you’re small?”
Sydney typically resorted to humor to deal with the situation. “I had no idea,” she’d say with a grin. If they asked about her protruding chest, she’d respond, “Oh, that? That’s my heart.” When their eyes widened, she’d let them in on the joke. “I was just messing with you,” she’d say.
Testing had shown that Sydney’s bones lacked density, making them prone to breakage. Her hips are compressed, and she wears a back brace to counter the curvature of her spine. “She can’t run or jump,” says Mary. Instead of a full jaw bone, “she has just a sliver.”
Still, Mary balanced Sydney’s special needs with the desire for her daughter to have a normal childhood. Sydney attended Yukon Public Schools, which assigned her an individual classroom aide. Sydney walked and carried a backpack when she could—“She doesn’t like to use a rolling one,” says Mary—but sometimes pain forced her to use a wheelchair.
One day, Sydney’s teacher took Mary aside. “I love watching her come into my class every morning,” the teacher said. “Lots of kids show up grouchy, complaining. But here’s Sydney, a child who has a real reason to mope, and she’s always smiling.”
Even though Sydney’s orthopedist urged her not to play sports, Mary eventually succumbed to her daughter’s pleas and allowed her to try gymnastics. “But I had to quit because of my back,” says Sydney. “It hurt too much.”
In spite of her physical challenges, though, Sydney was a kid surrounded by other kids. And sometimes, she’d forget about her limitations, with unfortunate results.
During a parents’ night out, Mary received a frantic call. She arrived to find Sydney unable to walk: Her knee had buckled when she tried to jump. Another time, an attempted back roll off of playground equipment resulted in a fractured wrist.
The ensuing visits to the orthopedist frightened Sydney. “She’d worry he was going to say she needed surgery,” says Mary. But he didn’t. And, so, they soldiered on.
For Mary, it was nothing new. Two siblings had suffered from Friedreich’s ataxia, a rare genetic disorder unrelated to Sydney’s condition. The disease slowly robbed her brother and sister of the ability to control their limbs, to walk and, finally, even to speak. Both died in their 40s.
Still, says Mary, “In our family, you didn’t say you couldn’t do something.” There was always a way—you just needed to find it.
That’s how the Rutzes came to view Sydney’s condition, too. “We don’t look at her as handicapped,” Mary says. “We just see her as different.”
At OMRF, Sydney and her family underwent further testing, as Gaffney worked to understand what was going on within her body. He found her genetic condition resulted from a mutation in the MBTPS1 gene encoded in the DNA of her father, Jon, and another, different variation in that same gene carried by Mary. In Sydney’s parents, those single variations didn’t seem to affect how their bodies functioned. But, when combined in Sydney, they had profound effects.
Or so it appeared. But without a deeper analysis, all Gaffney had found was an association between the genetic variation and Sydney’s symptoms. While it was intriguing, this correlation fell far short of explaining what was happening on a molecular level. And without such an explanation, there could be little real hope of helping Sydney.
To get to the root of this medical mystery, Gaffney sought the help of Dr. Lijun Xia. A hematologist by training, Xia treated patients suffering from blood disorders in his native China before coming to OMRF in 1995 to focus on medical research. At OMRF, he initially studied the blood. But over time, his interests expanded. In particular, he developed expertise in the workings of a group of sugars known as glycans. These sugars seemed to play a key role in the function of lysosomes, the enzymes at the heart of Sydney’s condition.
Still, Xia was going to have difficulty taking on the project. He serves as chair of 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, all of which he and his research team needed to work on, and 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 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 to use as one of the building blocks for bones and connective tissues.
Sydney’s cells were producing sufficient amounts of collagen, but without a properly functioning MBTPS1 gene, the protein was getting stuck where it shouldn’t. As so often happens in the body, that breakdown gave birth to others.
“Lack of collagen supply is an issue for bone growth, but the bigger problem is collagen accumulation,” says Xia. Specifically, the build-up of proteins triggered the body’s cellular garbage disposal system to kick into gear. And when it did, it not only swept away the collagen, says Xia, “but it also sends out a signal that causes the death of chondrocytes.” These cells, says Xia, “are essential to bone growth.”
For Sydney, “at the age of 6 or so, the bones accelerated their growth,” Xia says. “This made things worse.” The body kicked into overdrive, producing more collagen. When excess collagen piled up, unable to reach its final destination, cellular trash collectors scooped it up—and, in the process, killed off most of her chondrocytes. “As a result, she essentially stopped growing.”
Xia, Wierenga and Gaffney invited Mary and Sydney to OMRF to explain what they’d discovered about Sydney’s condition. The science was, not surprisingly, difficult for mother and daughter to digest.
Xia attempted to make the findings more understandable by showing a snippet from a movie about a girl with a—different—rare genetic disease. While well-intentioned, the approach did not achieve the desired result; Sydney began to sob.
“I thought I was going to die,” remembers Sydney, then 10.
Mary and the researchers, though, were quickly able to calm her down. They explained that while her condition made her different, nothing the scientists had found should make her worry.
In fact, they said, 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 says.
The scientists explained that Sydney was so special they were going to write a paper about her. When it was published in the scientific journal JCI Insight in 2018, the paper created a new disease classification: spondyloepiphyseal dysplasia, Kondo- Fu type. (According to naming conventions for diseases, they bear the name of the first listed author on the research paper that first identified the condition. Here, because Kondo and Fu decided to share that distinction as first authors, the condition they discovered does, too.)
Sydney can’t quite pronounce the name of “her” disease. “It’s a mouthful,” says Mary. But she’s nevertheless embraced it as part of her identity.
Nowhere is that more evident than when she’s playing her favorite online video game. In that world, all the other players know her simply by her username: Oneinfivebillion.
“I chose that name because I thought there were five billion people in the world, and I’m the only one with this condition,” she says. “You have to own who you are.”
These days, that person is 13 years old, an eighth grader at Yukon Middle School. She loves drama class and singing in the choir. Last year, she even had the chance to be in a production of Hercules, where she played the gatekeeper to the underworld.
Standing at a height of 3 feet, 10 inches, she made one-half of a memorable stage pairing. “The guy who played Hades is, like, tall,” she says, giggling. “The two of us were really funny together.”
She’s also a long-time Girl Scout. When she attended Scout camp, her physical limitations threatened to derail her from participating in the rigorous schedule of activities until Mary came up with a solution: “I’d just pull her in a wagon when her back was giving her problems.”
This past winter, she joined a school color guard team. The group performed flag ceremonies and competed with other squads. With a specially modified flag that she spun and tossed alongside her fellow team members, Sydney found the experience exhilarating. “She loved being a part of that,” says Mary, “because she’s never been on a team before.”
Sydney understands her growth is likely at an end. But that realization in no way stunts her dreams.
“I really want to be a lawyer. Oh, and I also want to be an actress,” she says. “So, maybe actressing can be a part-time job.”
Sydney keeps talking, explaining that being a lawyer would let her “yell at people.” Mary, sitting nearby, cracks up. That’s just Sydney being Sydney. Sassy and rambunctious. A typical teen.
It is, Mary says, what she most wants for Sydney.
“I don’t want anyone to treat her any differently. I don’t want her to be always scared.”
Sydney is sitting beneath a sign that reads, “It’s never too late to live happily ever after.”
Mary looks over at her daughter and smiles. “I want her to have a full life.”
For OMRF’s Xia, Sydney’s story is not over. “Our goal was to help. That was our motivation.”
And they have helped. When Sydney’s case was referred to them, she’d been given a diagnosis of mucolipidosis. That condition carried with it a dire prognosis: vision problems, diminished mental capacity and, often, death. “I looked it up,” says Mary. “It was very scary.”
Through their work, the researchers were able to give Sydney a correct diagnosis, one that came with far brighter prospects. Could the scientists say for certain what the coming years hold for Sydney? No. But they could honestly tell Mary that her daughter’s fate, like so many of our tomorrows, would reveal itself only with time.
That wasn’t all, says Xia. “Unlike many diseases, we now know its exact molecular mechanism.” With that information comes the possibility of a treatment.
At OMRF, Xia has identified a compound that can reduce collagen accumulation. That compound has already been approved by the U.S. Food and Drug Administration for the treatment of another condition and is commercially available.
In laboratory experiments, they’ve found it decelerates collagen production and accumulation. “It may not resume the rate of normal growth,” says Xia, “but it slows it down so the cells can handle it and maintain a low rate of growth.”
Xia is now working with OMRF’s Technology Ventures Department to devise a path to bring this therapeutic to patients. In addition to treating Sydney’s mutation, he hopes this treatment approach will be effective on a wide range of rare skeletal disorders that stem from similar genetic variations.
Because Sydney is now a teenager, she’s likely passed the point where such a therapy could stimulate bone growth. But, Xia says, it might still help her to avoid other, as-of-yet unforeseen problems down the road. “It’s hard to know,” Xia says, “what her future looks like.”
Without a crystal ball, he says, the best hope is to continue to investigate every lead he can find. “Right now, all we know about the disease is from this one girl. This is not enough.”
Using a database for rare diseases, he’s identified another eight patients from around the country who might share this mutation. He is planning to contact their physicians in hopes he can gather more information from each of their cases. “Our goal is to track patients and analyze them in a systematic way. We want to learn how to diagnose them and how to manage their care.”
Recently, a nurse practitioner from Broken Arrow contacted him. Her 6-year-old daughter had just been diagnosed with an MBTPS1 mutation and showed some—but not all—of the same symptoms as Sydney.
That got Xia thinking. “Even within Oklahoma, we have two patients already. And those are just the ones who’ve had genetic testing.” How many more, he wonders, might still be out there?
For Sydney, the news that she was not the only one was, at first, a bit deflating. “But I told her to chill out,” says Mary. “You’ll always be the first.”
Sydney’s now excited to meet her genetic “twin.” And, knowing there’s someone out there just like her who could benefit, she now has a reason to keep donating her blood for studies. Even though she hates, hates, hates the needles.
“I’ll help,” she says. Then she rubs her forearm and widens her eyes for comic effect. “I just might be fashionably late for my appointment.”
