In Cincinnati Children's laboratories, researchers have uncovered a surprising culprit behind the chronic pain that haunts people with neurofibromatosis type 1: not tumors, but the very cells designed to protect nerves. Using mouse models, scientists led by Michael P. Jankowski found that Schwann cells—the supportive nerve cells that normally insulate and nourish nerve fibers—can trigger debilitating pain long before any tumors appear.
NF1 affects about one in 3,000 people worldwide, causing a constellation of symptoms from café-au-lait skin spots to learning disabilities and skeletal problems. But perhaps most puzzling to patients and doctors alike is the chronic pain that strikes even in areas where no tumors have developed. Until now, this non-tumor pain remained largely a mystery, leaving people with NF1 searching for answers.
The Cincinnati team, with first author Namrata G. R. Raut, discovered the mechanism behind this mysterious pain. When the NF1 gene was deleted in Schwann cells, those cells began releasing excessive amounts of glial cell line–derived neurotrophic factor—a protein known as GDNF. This excess GDNF acts on a receptor called GFRα1 found on pain-sensing nerve fibers, essentially turning up the volume on pain signals. The finding was published in Science Signaling and helps explain why many people with NF1 experience significant pain even in tumor-free areas.
What makes this discovery particularly promising is what came next. The researchers found that blocking MAPK signaling with a MEK inhibitor—specifically mirdametinib, a drug already approved for treating some NF1-related tumors—lowered GDNF levels in Schwann cells and reduced pain-like responses in the mice. In other words, a medication that doctors were already using for NF1 tumors may also hold the key to alleviating the mysterious, widespread pain that has long plagued patients.
"The work helps explain why many people with NF1 report significant pain even in areas where no tumors are present," Jankowski noted. "Importantly, we also found that blocking MAPK signaling with a MEK inhibitor lowered GDNF levels in Schwann cells and reduced pain-like responses in the mice." This insight opens a door that has been closed for decades, suggesting that intervention could begin before tumors even form, potentially giving people with NF1 earlier relief and a better quality of life.
The path from mouse models to human patients requires caution and further study. Researchers must confirm that the same mechanism operates in people and that treatments can safely ease pain in real-world settings. But the direction is clear: by understanding that Schwann cells, not just tumors, drive NF1 pain, doctors may soon offer patients something they have long lacked—a scientific explanation and a potential solution for the pain that has defined their condition.