Scientists discover rare genetic condition that attacks kids’ immune systems

Inheritance And Genetics Of Neurofibromatosis Type 1 (NF1)

Neurofibromatosis type 1 (NF1) is a hereditary disorder caused by an alteration – called a mutation – in the NF1 gene, which is located on chromosome 17. The NF1 gene contains a code of instructions for making a protein called neurofibromin, which is produced in many cells, including nerve cells and specialized cells surrounding nerves (Schwann cells). The neurofibromin protein acts as a tumor suppressor, preventing cells from growing and dividing too rapidly. The NF1 gene mutation leads to the production of a nonfunctional or absent neurofibromin protein that is unable to regulate cell growth and division, resulting in the growth of neurofibromas (skin tumors) along nerves throughout the body.

Inherited Mutations

All people have two copies of every gene – one copy inherited from each parent. The NF1 gene mutation is dominant, which means that only one of the two copies of the gene needs to have the mutation to produce the disorder. A parent with NF1 has a 50% chance of passing the abnormal gene copy to a child. A child who inherits the altered gene will also have the disorder.

Spontaneous Mutations

While half of the cases of NF1 are inherited from a parent, 50% of children diagnosed with NF1 appear to be the first members of their family to have the disorder. In such cases, the genetic alteration, or mutation, occurred in the sperm or egg cell that formed the child. This is called a spontaneous, or new, mutation. A person with a spontaneous mutation of the NF1 gene has a 50% chance of passing the abnormal gene copy to a child.

Determining the Source of the NF Mutation

It's important to determine whether the disorder is inherited or is the result of a spontaneous mutation, since an individual with an NF1 mutation has a 50% chance of passing on the disorder every time he or she has a child. One way to accomplish this is by means of a thorough examination of each parent whose child has been diagnosed with NF1 to determine the presence of café-au-lait spots or Lisch nodules in the iris of the eyes. If neither parent is found to have signs of NF1, the child's disorder is most likely the result of a spontaneous, or new, mutation.

Genetic testing is also currently available to confirm the presence of the NF1 gene mutation with 95% sensitivity and may be appropriate in some cases. Some people have features of NF1 that are limited to only one part or one side of their body. This is called mosaic NF1 (also called segmental NF1). Mosaic NF1 is caused by a gene mutation that has arisen after conception, during early development of the person as an embryo. Genetic testing for people with type of NF, while possible, can be more complex than for individuals who do not have this form of the disorder.

What Causes the NF1 Mutation?

In cases where a child's NF1 is determined to be the result of a spontaneous mutation, parents often wonder if they did something to cause the mutation, such as exposing their child to radiation, medications, alcohol, or other substances in the environment. It's important to understand that the specific cause of the NF1 gene mutation is currently unknown, and no environmental exposure has been implicated. It's also important to know that genetic mutations are not uncommon. Cells in the body are continuously dividing, and each time they do, a massive volume of genetic information must be copied correctly. Random errors inevitably occur in the copying process and may be the cause of mutations leading to NF1.

I Had Brain Surgery In January, Now I'm Running The NYC Marathon

Leanna Scaglione — a former ballerina who completed a half-marathon in March, just two months after getting brain surgery — is now preparing to run in the NYC Marathon Sunday.

"This is my redemption lap," the 32-year-old Upper East Sider told The Post.

Scaglione will tackle the 26.2-mile course less than a year after having a tumor removed from her brain. The procedure left her deaf in her right ear and with temporary facial paralysis. She couldn't move the right side of her face or smile, let alone walk from one side of her apartment to the other.

Scaglione had a brain tumor removed in January. Courtesy of Leanna Scaglione

"That was the toughest surgery I ever went through," said Scaglione, who works as a personal assistant. "But I just was constantly asking my doctor, 'Can I start running again yet?'"

Scaglione has been battling — and overcoming — serious health issues for years.

At 15, she got an MRI for what she thought was a ballet injury. That's when doctors saw that she had a "grapefruit-size tumor" in her lower spine. They diagnosed her with neurofibromatosis, an incurable genetic condition that causes tumors to grow throughout the body. 

Scaglione went through two surgeries to remove the tumor and was in a wheelchair for a year. "I lost sensation in my right leg, so I couldn't stand on it," she recalled. She was told she would never dance again. But that did not deter the teen. 

She eventually graduated to a walker and within two years was moving on her own. 

"I was never going to let [my illness] define how I was going to live my life," Scaglione said.  

Scaglione was a promising young ballerina until it was discovered that she had neurofibromatosis, an incurable genetic condition that causes tumors to grow throughout the body.  Courtesy of Leanna Scaglione

She's since had 13 tumors removed — along her spine, along her wrists and most recently in her brain. 

She took up running during the pandemic as a means to escape being stuck inside.

"Like everyone else, I needed air," she said. "At first I was afraid with the nerve damage in my right leg … [but] next thing I knew, I ran a mile. I was so proud of myself and so in shock and hyped-up that I was like, 'I gotta try this again!'" 

She's since had 13 tumors removed — along her spine, along her wrists and most recently in her brain.  Courtesy of Leanna Scaglione

She now regularly races to raise money for the Children's Tumor Foundation. 

Scaglione competed in the NYC Marathon last year, but she had to walk much of it after a brain tumor growing on a main nerve leading to her right ear grew so large it disrupted her hearing and balance.

This past January, doctors removed the brain tumor and added an auditory brainstem implant to help her with sound recognition.

Scaglione is aiming to finish the marathon in under 4 hours. Olga Ginzburg for NY Post

Now, she's aiming to run a speedy race on Sunday and finish in under four hours. She's already signed up for three marathons — London, Berlin and New York City — in 2025 as a national ambassador for the Children's Tumor Foundation.

"By doing these races, it's a physical way for me to say, 'I can do this. I get it. I tackled this. I can keep going,'" Scaglione said. "The thing that I learned the most is that this diagnosis doesn't have to control and define our lives. It doesn't mean our lives stop. We just pivot."

Reduction Of Cutaneous Neurofibroma Number On Face May Improve QoL In Individuals With Neurofibromatosis Type1: JAMA

Researchers have found that the presence and severity of cutaneous neurofibromas, especially those on the face, significantly lower the quality of life in individuals with neurofibromatosis type 1(NF 1). This result came from a broad study that aimed at estimating the correlation between some certain features of cNFs with quality of life (QoL). NF1 is a rare genetic disorder leading to significant morbidity. The study was recently published in JAMA Dermatology by Lin M.J. And colleagues.

cNFs are benign tumors that grow on the skin surface of NF1 patients and often may be the source of physical discomfort and emotional distress. The aims of the study were the development of a large, decentralized platform for NF1 patients and the study of how certain characteristics-number, size, location-of cNFs are associated with QoL, pain, and itch. By establishing a registry that included clinical survey data, photography, and genetic sequencing, the authors hoped to overcome some of the challenges in subject recruitment intrinsic to studying this rare condition and glean some insights into how therapeutic interventions may improve patient outcomes.

From May 2021 to December 2023, a decentralized and globally utilized platform was used for participant recruitment, individuals aged 40 years or above with NF1 and at least one cNF. They had survey data with photographs and genetic sequencing from 49 U.S. States and 12 countries of the world. The photographs of 583 participants were scored for 12 key features of cNF, including features about their general severity, number, size, facial severity, color, and subtypes. These features were then analyzed in relation to QoL outcomes assessed using the Skindex scale, with subdomains for symptoms, emotions, function, pain, and itch.

Results

The 583 participants included 384 (65.9%) females, of mean age 51.7 years, ranging from 40.0 to 83.0 years.

Impaired QoL, represented as higher overall Skindex scores, was related to female sex, overall severity, number of cNFs, and facial severity.

The number of cNFs and the presence of cNFs on the face had the greatest negative impact on QoL.

Even patients with less than 10 cNFs showed deterioration in QoL, demonstrating their important burden.

Besides QoL, increased number and severity were associated with higher levels of pain and itch, further increasing the impact on livelihood in these patients.

The conclusion derived from this study was that the number and severity of cutaneous neurofibromas, especially in the facial region, directly influence QoL in NF1 patients. Consequently, early intervention to reduce the number of cNFs would have maximum benefit among the patients. This offers not only an opportunity for a deeper understanding of the relationship between cNF features and QoL, but also of the effectiveness of a decentralized, photograph-validated approach to studying ultra-rare genetic diseases.

Reference:

Lin, M. J., Yao, H., Vera, K., Patel, E., Johnson, M., Caroline, P., Ramos, J., Mehta, J., Hu, X., Blakeley, J. O., Romo, C. G., & Sarin, K. Y. (2024). Cutaneous neurofibromas and quality of life in adults with neurofibromatosis type 1. JAMA Dermatology (Chicago, Ill.). Https://doi.Org/10.1001/jamadermatol.2024.2912

---