Reflections on Neurofibromatosis
Elizabeth (Betty) Schorry, MD, Cincinnati Children’s Hospital Medical Center
Professor, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center
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I first became involved in the neurofibromatosis field in 1985, when I was a fellow in medical genetics at Cincinnati Children’s Hospital. I was assigned the project of helping to develop a neurofibromatosis clinic, along with Dr. Peter Dignan (Genetics), Dr. Alvin Crawford (Orthopaedics) and Dr. Daniel Stowens (Neurology). The impetus for starting a multidisciplinary NF clinic in Cincinnati was provided by Delores Goldfinger, the mother of a child with NF1 and the president of the Ohio Chapter of the Neurofibromatosis Foundation, who lobbied vigorously for the clinic.
Our first multidisciplinary NF clinic was held in 1986. Initially the clinic was held once per month, and 6-8 patients were seen by physicians from the 3 specialties at each visit. We quickly added additional providers (social work, developmental pediatrics, neuro-oncology, and family medicine). The clinic grew rapidly from that point on. Currently, more than 15 NF clinics per month are held at our center, and we have seen over 1600 patients with NF1, NF2, and schwannomatosis.
All in the field were excited when, in 1987, the NF1 gene was localized to chromosome 17 by research groups from the University of Utah and University of Michigan. Cloning of the gene in 1990 allowed for improved diagnostic tools and better understanding of the action of the gene on the Ras pathway. Shortly thereafter, the NF2 gene was localized to chromosome 22 and cloned. In 2006, Cincinnati Children’s Hospital recruited Dr. Nancy Ratner, PhD, a cell biologist whose research was focused on neurofibromatosis, and who added valuable basic science and translational research strength to our clinical neurofibromatosis program.
When we initially began seeing patients with neurofibromatosis in our clinic, we were limited by lack of treatments. Most of the visits were spent monitoring for clinical complications of NF such as learning disabilities, ADHD, tumors, scoliosis, etc. The only management option available for plexiform neurofibromas was surgery or clinical monitoring. Bracing and surgery were standard treatments for NF1-related scoliosis and tibial dysplasia. Dr. Alvin Crawford was a well known orthopaedist with a long interest in NF1 osseous complications, particularly scoliosis and tibial dysplasia. Working closely with him encouraged my interest in how bone is affected by NF1 mutations, and designing clinical trials to document best outcomes. We began working with a group of other orthopaedists, geneticists, and bone scientists from multiple institutions with an interest in NF, to better understand NF1 bone disease. This subsequently led to proposals of clinical trials for biologics (BMP2) to be used at surgery in repair of NF1 tibial pseudarthrosis.
As knowledge about the neurofibromatoses increased over time, based on basic science and translational research, the NF Clinical Trials Consortium (NFCTC) was established in 2007, funded by the Department of Defense and headed by the University of Alabama as the Operations Center. The goal was to perform clinical trials for therapies for NF1, NF2, and schwannomatosis. Cincinnati Children’s was privileged to be one of the participating centers in the NFCTC since its inception. Clinical trials performed by the Consortium so far have investigated therapies for plexiform neurofibromas, vestibular schwannomas, optic nerve gliomas, learning disabilities, and even a bone trial (for tibial dysplasia, which sadly could not be completed due to poor enrollment for this very rare complication). The most exciting trial for us, of course, was the MEK inhibitor trial (Selumetinib/ Koselugo) which showed significant shrinking of plexiform neurofibromas in children with NF1. Fast forward to today, and we have FDA-approved drugs for NF1 and NF2 based on these multi-center clinical trials, and many other potentials in the pipeline.
The most important lesson I have learned from my time in the NF field is the value of working as a team. From the beginning of our four-physician NF Clinic team, we all learned a great deal by working with others from different disciplines. It was clear that the sum of what the group of four could accomplish working together was much greater than what each could accomplish individually. The same is of course true for larger groups such as the Consortium. It has been a privilege to work with and share ideas with so many other physicians and scientists in the NF field. I am excited to see what the future will hold for our patients!
I retired (or thought I did!) from my clinical duties at Children’s Hospital in December 2020. However, my colleagues and my patients were always in my thoughts. I have recently returned to very part-time work seeing NF patients after two of our geneticists moved to other centers. I continue to be grateful for the opportunity to be involved in their care.
