Fiercely independent, Anya Magnuson has always been driven. Even now, after surviving multiple near-fatal medical events, her sights are set on returning to work, to her life, to resume her place in the world after suffering through so much to remain in it.

The medical journey Anya has endured unfolds like a suspense novel, with each new chapter bringing the heroine closer to a frightening ending. It started late fall 2017, when Anya was 19 and a sophomore studying photojournalism at Arizona State University. First came excruciating and debilitating migraine headaches. Next, Anya’s vision went funny. Then her hands began to tingle and go numb. A cascade of symptoms followed, extending months and then years into Anya’s life.

Affecting her brain, spine, blood, limbs, and eyes, the illness was identified by her Mayo Clinic care team as a rare blood cancer known as Erdheim-Chester disease (ECD). But treatments that usually worked for ECD patients — most of whom are middle-aged men — failed for Anya.

More than a year passed before a multidisciplinary team of Mayo Clinic physicians, pathologists, and laboratory scientists, armed with information gained through advanced genetic sequencing of the tumor, found the clue that broke open Anya’s case: a genetic variant of unknown significance (VUS) that had never before been reported.

The discovery not only opened the door for Anya to receive lifesaving treatment but uncovered a new genetic etiology for a rare and often misdiagnosed condition — one that has since been used to identify and treat another patient.

“The science is advancing so quickly, and next generation sequencing is becoming more common, and so we’re finding more and more of these VUSs,” says Mayo Clinic hematopathologist Karen Rech, M.D. “It takes a clinical suspicion and advocacy to try to determine if they’re pathogenic. A lot of common mutations are already established, so we are at the edge of what we know. But we are never going to get to the end of learning, which is exciting about medicine and medical discovery.”

Anya’s recovery and return to health was celebrated by her family and Mayo Clinic team and provided the satisfying ending everyone had hoped for. But Anya’s story has an epilogue, one that picked up just as the 23-year-old was moving forward from the events of the preceding four years. In October 2021, Anya was a pedestrian casualty in horrific car crash. Anya suffered near-fatal injuries, including a devastating traumatic brain injury, that left Anya once again on the path to recovery.

A long, painful road

When Anya first arrived at Mayo Clinic in late December 2017 experiencing an array of neurological symptoms, a team of physicians quickly coalesced around her. Anya was diagnosed with intercranial hypertension and in early January underwent shunt placement surgery. As part of the operation, a small bit of brain tissue was biopsied, but the test came back inconclusive. Presumed to have fungal meningitis, Anya was placed on an antifungal medication. The ensuing months, however, brought with them more problems: infection, emergency surgery, a second shunt, another brain surgery.

Anya persevered. She returned to her studies in Arizona, received a photojournalism internship in Oklahoma, and traveled to Peru for a reporting trip. By February 2019, Anya had developed a new symptom: numbness in her feet and toes, which interfered with her ability to walk.

A member of her Mayo Clinic team suspected neurosarcoidosis, an inflammatory disease affecting the nervous system, and an MRI scan was ordered. That scan revealed a series of masses along her lower spine.

“It was horrifying,” said Anya’s mom, Colleen. “You do not need to be a doctor to see it and think, Oh my God, that’s awful. Whatever that is, it is not good.”

A tumor biopsy was sent to Mayo Clinic Laboratories for pathology consultation. Rather than confirming neurosarcoidosis, however, the biopsy showed the tumor was full of a type of white blood cells called histiocytes, which may indicate a histiocytic neoplasm such as ECD.

To Anya’s medical team, which included hematologist-oncologist Ronald Go, M.D., and hematology-oncology fellow Jithma Abeykoon, M.D., the findings were unexpected. Not only is ECD rarely diagnosed in women and children, but the histiocytic neoplasm is extremely rare, with less than 2,000 cases having ever been reported. Anya was prescribed a targeted therapy called cobimetinib, which had been used successfully to treat other ECD patients.

For Anya, however, the medication backfired.

“The cobimetinib had multiple debilitating side effects,” says Colleen, who was intermittently flying to Arizona to help. “She was bedridden, vomiting, had uncontrolled diarrhea. I wondered, What was the point of shrinking the tumors if you’re literally lying in bed immobilized?”

In late October, the introduction of another treatment, interferon, sent Anya into a tailspin. Colleen returned to Arizona to help Anya, who over the next three weeks went to the emergency room three times. In early November, Anya flew home to Minnesota. At that point, she was using a wheelchair because she was too weak to walk.

Anya next received chemotherapy, undergoing six rounds of methotrexate. While the side effects were manageable, the treatment did not slow the cancer’s progression.

Anya’s tight focus on survival and breaking down the barriers preventing her from fully experiencing life was the engine that powered her throughout the ordeal, her parents say.

“Anya was so driven to get through the experience,” says Jeff Magnuson, Anya’s dad. “She was taking pictures of people she met and putting together her portfolio of her experiences and thinking that she would like to use her journalism and photography skills in a medical setting because it meant so much to her what was being done for her. It seems to me the drive and insistence on developing herself helped carry her through a lot of very difficult times where people did not know what she had.”

A glimmer of light illuminating the path forward

By the winter of 2020, Anya’s medical team, hoping to confirm that Anya did in fact have ECD despite being treatment-resistant, drew Dr. Rech onto Anya’s team. Dr. Rech is a member of Mayo Clinic’s Histiocytosis Working Group and regularly consults on the pathology cases when the possibility of a histiocytic neoplasm has been raised by a patient’s clinical and radiologic findings.

“The biopsies were inconclusive (for ECD) because we didn’t identify one of the more commonly recognized driver mutations, such as BRAF V600E, so it couldn’t be confirmed that it was the diagnosis,” Dr. Rech says.

Although genetic confirmation of ECD was lacking, Dr. Rech recognized that the pathology features under the microscope looked strikingly similar to other cases of ECD that she has seen.

“So I was able to say this is really suspicious for histiocytic neoplasm, we just have to find the mutation that is driving this process,” Dr. Rech says.

To do that, another biopsy — and more tissue — was needed. So in March 2020, Anya’s team, racing to beat the clock against both Anya’s worsening condition and the first wave of COVID-related operating room closures, performed a second spine biopsy. Like before, the biopsy failed to return obvious answers to explain Anya’s treatment-resistant disease. But this time the larger biopsy specimen allowed identification of the VUS, which gave Anya’s team a clue about the underlying genetic cause.

The VUS was in the CSF1R gene. This gene, says myeloid biologist Terra Lasho, Ph.D., who was brought onto Anya’s medical team to help determine the functional significance of the finding, is one of a family of genes that code for proteins known as receptor tyrosine kinases (RTKs). This gene family is highly conserved and critically important for regulating signals in the blood associated with cell growth and differentiation.

The variant sequence was located in a critical area of the gene known as the hinge region, named so because this part of the CSF1R protein overlaps the functional core, keeping it in an inactive state. Anya’s variant resulted in six amino acids being deleted and replaced by one different one, so a large piece of this hinge region was missing.

Because this protein’s crystal structure had been characterized, Dr. Lasho was able to model the variant using a computational 3-D protein algorithm to visualize the predicted disruption of the structure and chemical bonds in the region.

“This variant changed the protein structure in a significant way,” Dr. Lasho says. “It released the hinge region – the receptor wasn’t being held shut anymore. The functional end was now exposed and had autonomous ability to function independent of normal stimulation, that is what I initially thought when I looked at this mutation.”

DISCOVERING THE ACTIVATION OF THE GENE WAS LIKE “PURE ADRENALINE,” DR. LASHO SAYS. “IT WAS VERY EXCITING — WE JUST EAT AND SLEEP FOR THIS KIND OF TARGETABLE DISCOVERY.”

Rebound, then knocked back down

Dr. Lasho quickly reached out to Dr. Abeykoon to alert him of the discovery. Although the genetic variation was new, CSF1R is associated with a rare joint condition that has an approved treatment. Pexidartinib, a CSF1R inhibitor, blocks the receptor’s activity by engaging with protein bonds just downstream of where Anya’s mutation was impacting protein activity. However, since the drug had never been used to treat blood cancer, the family’s insurance company did not want to pay for the medication. It was only after several personal appeals by Dr. Abeykoon to the carrier that the medication was approved.

“The thing we were most excited about wasn’t finding the mutation, but the finding of the drug,” Colleen says. “It had been lifesaving for her. Finding a mutation that used a drug that had never been used before, but worked so well, that is what excited us.”

Anya started taking the medication right away. Within weeks, she had regained her vision and her ability to walk. Three months later, an MRI scan indicated that the dark masses running up and down her spine had significantly diminished. A PET scan also showed no signs of new growth.

“AT SOME POINT I REMEMBER FEELING LIKE I WAS FINALLY LIVING THE LIFE THAT I SHOULD’VE BEEN LIVING THE LAST COUPLE OF YEARS,” ANYA SAYS.

By the summer of 2021, Anya’s life had returned to the frenetic pace she’d previously enjoyed: working multiple jobs, going out with friends, dating. “It was like nirvana for her,” Colleen says.

In late October, however, that bliss was shattered when Anya’s body was broken by an SUV driven by an unlicensed driver. Anya has recovered her physical abilities for the second time, but her brain is still healing. Her short-term memory, self-awareness, and executive functioning ability remain affected. Yet Anya is determined to reclaim her place in the world. 

“Recently I’ve been thinking, I wonder whether I’ll ever be happy again,” says Anya. “I don’t feel good right now.”

Anya’s primary goal, and one that would be a step toward reclaiming her happiness, is going back to work. “It’s all I want to do.”

Recently Anya was able to begin job shadowing at the restaurant she worked at when she was struck by the SUV. The experience, says Anya, was “Amazing,” and she and her family are hopeful she will be able to return to work in the very near future.

That motivation to get back to work, to feel normal, is the force that moves Anya through her days. It’s the same drive that helped her persevere through years of unknowns, unrelenting painful and debilitating symptoms, a ground-breaking diagnostic odyssey, and novel therapy.

“When Anya decides to do something she perseveres and pushes through no matter what obstacle is there,” Jeff says “And that’s helping her also in grappling with the brain injury. Most of her tools have been taken away from her, and yet she still has that, what’s helped is the drive. She is moving across her life, picking up the experiences she picks up, learning from it what way she can learn, and learning who she is.”

Though far from over, Anya’s journey has enabled medical advances that cannot be understated, Dr. Lasho says.

“The patient needs to be highlighted more than the team,” Dr. Lasho says. “They are providing their life’s material for us to be able to have the ability to discover, characterize, and expose therapeutic opportunities, and this ultimately underscores the importance of personalized medicine.”

Read the journal article that was based on Anya’s case.

This story first appeared on the Mayo Clinic Laboratories blog

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