A week after Deniro Bruno was born in 2007, his pediatrician noted several tan birthmarks on his skin that she called “café au lait” spots. Although the doctor seemed unconcerned, Deniro's mother, Jessica, researched that description on her computer when she got home and was frightened by what she saw. “I read about the connection of those markings to a condition called neurofibromatosis type 1 [NF1]—deformity, tumors, cancer,” she says. “It was terrifying.”

Jessica was able to suppress her fears until Deniro started exhibiting cognitive and speech delays around the time he turned 1. He was evaluated and enrolled in an early intervention program, and Jessica once again pushed away thoughts about NF1. “There were other possible explanations for Deniro's problems, so I stayed positive and did everything in my power to not think about it,” says the mother of four, who lives in Boston.

When her son was nearly 2, Jessica noticed that his left eye and face seemed puffy. Their pediatrician referred her to a neurologist, who first suggested the puffiness could be caused by Deniro sleeping on the left side of his face. That explanation didn't feel right to Jessica, especially combined with Deniro's developmental delays and tan spots, so she pressed for him to get an MRI. The scan revealed abnormalities on Deniro's brain, which the doctor said could be harmless but were also a common feature of NF1. Deniro was referred to a clinic at Children's Hospital in Boston so specialists could monitor his symptoms. A year later, one of the neurologists ordered a second MRI because the left side of Deniro's face had started to droop. Jessica and her husband also requested genetic testing.

The MRI revealed a plexiform neurofibroma, a nonmalignant tumor arising from the cells that surround nerves, in his left cheek, and the genetic blood test results confirmed what Jessica had long feared: Deniro had a change in the NF1 gene. At age 3, he was officially diagnosed with neurofibromatosis 1.

Andres Lessing, 43, was diagnosed with NF1 when he was 8 months old, and for most of his childhood his symptoms were mild. That changed when he was 27 and doctors discovered a malignant tumor on a peripheral nerve sheath, which covers and protects peripheral nerves. He underwent chemotherapy, surgery, and radiation, but the tumor came back twice, and he received more treatment to resolve it. “I'm lucky to be alive,” he says. Between 25 and 50 percent of people with this kind of tumor also have NF1, and 8 to 13 percent of people with NF1 will develop the tumor in their lifetime, according to the National Cancer Institute.

Originally called von Recklinghausen disease after the physician who first described the lesions, NF1 is a rare genetic disorder that occurs in about 1 in 3,000 births. The disease is caused by a change in the NF1 gene that results in underproduction of neurofibromin (a protein necessary for regulating cell growth) and increases the risk of multiple tumors, called neurofibromas. “When the gene is altered, cell growth is uninhibited,” says Justin T. Jordan, MD, MPH, FAAN, clinical director of the Stephen E. and Catherine Pappas Center for Neuro-Oncology and director of the Family Center for Neurofibromatosis at Massachusetts General Hospital in Boston. Most of the tumors are not malignant, although some can be cancerous, he adds. Between 30 and 50 percent of cases are from noninherited changes of the NF1 gene. NF1 is genetically distinct from (and more common than) the two types of schwannomatosis: NF2-related schwannomatosis and SMARCB1-related schwannomatosis. Recently, an international group of experts updated diagnostic criteria for all three diseases and divided them into more accurate clinical features, says Scott Plotkin, MD, PhD, executive director of the Pappas Center.

Distinguishing these conditions should result in less confusion, fewer misdiagnoses, and improved care for all patients, Dr. Plotkin adds. Different genes on different chromosomes cause these three conditions, he says. The two kinds of schwannomatosis—both characterized by schwannomas, painful tumors that grow on the sheaths of peripheral nerves—were renamed to reflect their associated gene changes.

Diverse Symptoms

Among patients with NF1, the course of the disease can vary widely, and the prognosis is difficult to predict even within families, says Dr. Jordan. Common symptoms include changes in skin coloring, freckling in the armpits or groin, and learning disabilities. Otherwise, symptoms differ from patient to patient in part because tumors can develop on any nerve in the body, says Dr. Plotkin. One person with the disease might get a tumor on a nerve leading to the right arm, while another might develop one on a nerve to the left calf.

For Deniro, who is now 15, an inoperable neurofibroma on the left side of his face affects his speech, says his mother, who sometimes finds it difficult to understand her son. “That's hard. When people don't understand him, he often says, ‘Never mind.’ I worry that he's becoming afraid to speak up.” Because his tumor is in the trigeminal nerve region, Deniro also has intense facial pain, says Jessica. “Typical kids might feel pain when they get hit or bumped in the face, but for Deniro the slightest touch hurts.”

In addition to internal neurofibromas, people with the disease often have neurofibromas on their skin—sometimes hundreds or thousands of them. They range in size and are non-cancerous but can be disfiguring, which can affect patients' social lives and quality of life. Other common health problems include scoliosis, difficulty sleeping, and learning disabilities.

Some NF1 symptoms develop early in childhood; others may develop later in life. Deniro's uncertain future is both a challenge and a blessing, says Jessica. While many people with NF1 live a normal life span, the likelihood of developing other cancers can reduce life expectancy by 10 to 15 years, compared to the general population. “The phrase we hear most often is ‘wait and see,’ because Deniro's doctors can't predict how he will be affected,” Jessica says. “I can manage what we have now, but I don't know whether things will stay the same or if it will be harder down the road when and if Deniro develops more tumors.”

Treating Symptoms

No cure exists for NF1, but physicians can treat symptoms in several ways, including through surgery, medication, and occupational and physical therapies. “Even if you can make patients feel only 2 percent better, you can substantially improve their quality of life,” says Dr. Jordan.

Over the years, Deniro has had speech and occupational therapy and adopted strategies to compensate for his limitations, says Jessica. For example, she says, “it's hard for him to turn a doorknob, so he's learned not to be the first person to the door.”

Jessica and her husband are also helping their son to become a better advocate for himself.

When Deniro was 9, a tumor on his eyelid grew so heavy it started affecting his peripheral vision. He underwent surgery to correct the problem. When he was 12, surgeons removed part of his jawbone because the neurofibroma had grown into the bone and affected his bite. “The tumor is like a ball of elastics that wraps itself around the nerves,” says Jessica, “and we can't have it removed or dissected neatly because it's entangled.”

Without a cure, physicians have historically focused on optimizing surgical therapies for tumors, improving screening to identify problems early, and providing supportive care, says Dr. Plotkin. “We were pretty good at that, and if we followed people closely and caught things early, we could improve lives.”

In 1996, advocacy efforts led to congressional appropriation of $300 million for NF1 research—an investment that led to the approval of selumetinib (Koselugo), a targeted forms of chemotherapy that inhibits the MEK enzyme, slowing cell growth, says Dr. Jordan.

In an attempt to shrink Deniro's neurofibroma, Jessica enrolled her son in a two-year clinical trial for binimetinib (Mektovi), another MEK inhibitor that is not yet approved by the US Food and Drug Administration. Deniro was considered a “responder” because the tumor shrank 32 percent. “You could actually see the difference,” says Jessica. The medication, however, caused uncomfortable side effects like hair loss and nausea, and about six months after the trial ended and Deniro stopped treatment, the tumor grew back to its original size.

Deniro was later readmitted to the trial and started taking binimetinib at a lower dose. His side effects are more manageable, but the tumor has shrunk just 12 percent. “Still, the tumor isn't growing, and that's a major goal,” says his mother.

“There is great breadth of research right now,” says Dr. Jordan. “We finally have a foothold, approved drugs, and promising trials.” Advances in treatment and new approaches to gene therapy are generating much hope in the NF1 community, Dr. Plotkin says. “There is so much exciting research in progress that we hope will become a reality” and result in new treatment options, he says. Drugs under development include a topical medication for the disfiguring neurofibromas that appear on the skin.

Jessica and her family actively lobby Congress to keep funding for NF1 a priority. “I am still hopeful for a cure,” she says. “I am grateful for the things Deniro can do, because I know many kids are worse off.”

Neurofibromatosis Clinical Trials

The federal government's Neurofibromatosis Research Program (NFRP) lists at least 15 trials on its website. To find other studies, visit clinicaltrials.gov and type “neurofibromatosis” in the search field. In addition to contacting members of Congress to encourage continued funding, here are two ways to get involved in research.

NF1 Biospecimen Repository

• What: Researchers at Johns Hopkins University and Stanford University are recruiting people 40 years and older who have neurofibromatosis to establish a biobank that can be used to identify genetic variants, understand the pathogenesis of the disease better, and provide more personalized treatment and management.
• For more information: Email Carlos Romo, MD, at cromo1@jhmi.edu or Ekshika Patel at ekshika@stanford.edu.

Antioxidant Therapy

• What: Cincinnati Children's Hospital Medical Center is enrolling children between the ages of 8 and 16 in an on-site trial to assess the safety and clinical benefit of N-acetylcysteine (NAC) for patients with cognitive, behavioral, and motor impairments.
• For more information: Email Lindsey Aschbacher-Smith at Lindsey.Aschbacher-Smith@cchmc.org or Laurie Bailey at Laurie.Bailey@cchmc.org.

Resources for Neurofibromatosis Type 1

• American Academy of Neurology: BrainandLife.org
• Children's Tumor Foundation: ctf.org; 800-323-7938
• National Institute of Neurological Disorders and Stroke: ninds.nih.gov; 800-352-9424
• National Organization for Rare Disorders: rarediseases.org; 617-249-7300
• Neurofibromatosis Consortium: uab.edu; 205-934-5140
• Neurofibromatosis Network: nfnetwork.org; 800-942-6825
• Neurofibromatosis Research Program: cdmrp.health.mil; 301-619-7071
• NF Registry: ctf.org/nf-registry