NFRP 2018 Investigator Vignette

Title: Confronting the Challenge of Neurofibromatosis

Investigator: Douglas C. Miller, MD, PhD; University of Missouri School of Medicine

Neurofibromatosis as a name encompasses at least three diseases in fact. They are called neurofibromatosis type one, neurofibromatosis type two, and Schwannomatosis. So each of these are genetic disorders that involve, in most cases, a cell in the body called a Schwann cell, which results mostly in syndromes where there are tumors of particular types that are different for each of the three diseases.

While these are none of them very common, neurofibromatosis 1 is the most common. They create significant health problems for the patients who have them, and these are chronic diseases, although some of them do end up in malignancies and can be fatal diseases.

For NF1, the manifestations will begin in childhood. And some of these are neurocognitive manifestations. Many of these children have some autistic features; some of them have attention deficit hyperactivity disorder.

The tumors tend to grow later in life, so beginning in, say, adolescence and on up on into adulthood. And most of these tumors are benign tumors that are called neurofibromas.

They can appear on the skin or in the deep tissues underneath the skin. And if they’re near a vital structure, they can be life-threatening. Some of them are on sensory nerves and they’re painful. In older people, the majority of patients who have NF1 will get many of these cutaneous neurofibromas on the skin, and these are visible, and they’re disfiguring, and they have a psychological impact, even though they’re benign.

Rarely, there are malignant tumors that develop in NF1 in the brain that are malignant gliomas, just as patients can have without NF1. And then the neurofibromas can progress into malignant tumors as well. This is the most devastating of the many consequences of NF1 because it’s fatal. So what we call malignant peripheral nerve sheath tumor, or MPNST, is an often fatal malignancy.

NF2 has, as its most important manifestation, the development of benign tumors on the eighth cranial nerves, the vestibular nerves next to the brain stem.

These are benign tumors, but they make people deaf if they’re not operated on, and sometimes even when they are operated on, depending on what size they are when they’re discovered. That’s sort of the hallmark of the disease, but patients can get Schwannomas in other sites, attached to spinal nerve roots, compressing the spinal cord, or out in the periphery underneath the skin or in soft tissue.

In Schwannomatosis the patients get multiple Schwannomas, similar to what we see with patients with NF2, but they don’t get them on the eighth nerve. Those patients have a lot of pain problems. So the Schwannomas uniquely cause pain that may not be alleviated by anything except surgical removal. And even that doesn’t always do it, so—so those patients live I think fairly normal lives in terms of duration, but they can have these serious health problems because of the pain and associated psychological disturbances because they are in a lot of pain a lot of the time.

So we have these three different diseases, and they’re all different. They have a different genetic basis.

In general, most physicians don’t know a lot about this, and most scientists aren’t interested in most of the problems here because funding, to be frank, if you’re going to be a scientist competing for grant money, there’s more funding for more common diseases. And so, it’s hard to interest people, except if there’s an intellectual problem that they would like to solve.

So recruiting more people into the field is a goal for the CDMRP and—and in general for the field of neurofibromatosis research. One of the things that the research program for the Department of Defense does is there’s a new investigator award mechanism to attract young people just coming out of, say graduate school or post-doc fellowship, who would look at this and say here’s an area of interest that I could get involved in, have a career in.

The other kind of person we’d like to attract in is somebody who is already an established investigator in another field, say in cancer biology of some kind, who could then take that knowledge and those techniques and apply them into neurofibromatosis research. And so that adds a new kind of perspective into the work that’s being done.

In addition, the CDMRP includes a clinical trials consortium. So this is a multi-center project that’s spread all across the country at Mass General in Boston, at NYU in New York, at UCLA, and lots of places in between, plus a couple places in other countries, especially there’s a program in Australia that’s hooked up with it.

So its headquarters is at the University of Alabama at Birmingham, which is a major center for neurofibromatosis research and treatment.

Their mandate is to have clinical trials that look at patients with NF1, patients with NF2, and patients with Schwannomatosis. They look at innovative drugs. They look at neuropsychological interventions that are not drugs. And they’ve worked to establish guidelines for all future research in these areas that fit the manifestations of the individual diseases.

Our goals, as set from the start, are to eventually help the patients to, not necessarily cure anybody because these are genetic diseases and we’re probably not going to cure them, but to alleviate pain and suffering and make life better for patients. And that’s our ultimate goal. The impact is always part of the grant process.