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Dr. Korf explains the diagnosis of NF1 in a young child, including how the diagnosis is made and the natural history and genetics of the disorder. The video for this interview is also available.
Dr. Korf Interview Contents:
Segment 1: The basics of the disorder.
Segment 2: Typical early signs of the disorder.
Segment 3: How the NF1 diagnosis is made.
Segment 4: The genetics of the disorder.
Segment 5: How the disorder progresses over time.
Segment 6: Learning disabilities in children with NF1.
Segment 7: Suggestions for talking about the disorder.
Segment 8: How to support a child and respond to potential complications
Segment 9: Ways to manage the disorder.
Segment 10: Current research and hope for better treatments.
NF1 is genetically determined by a change in the specific gene, the NF1 gene, and it behaves as a dominant trait. Everybody has two copies of every gene, one that they inherit from each parent. In the case of a dominant like NF1, only one of the two copies of the gene needs to be altered by mutation in order to produce the condition. About half the time, when we see an individual with NF1, it turns out that there are other members of the family -- generally one of the two parents, and perhaps other relatives -- who are already affected, and in that case the gene has apparently been passed on from parent to child. Any affected individual faces a 50/50 chance of passing NF1 to any of their children.
The other half of the time, a child will be seen who appears to be the first member of the family to be affected; even examination of both parents will reveal no signs of NF1 in either one of them. We believe that this happens due to a new mutation or a new change in the NF1 gene that occurred in the sperm or egg cell that formed that child. And such mutations are happening all the time when sperm or egg cells are made. No particular cause has ever been identified, and in fact, I don't think there is any specific cause other than random chance mistakes that are made when the genetic information is copied to make sperm or egg cells. So these mutations are actually happening in all of us all the time. Probably all men carry a few sperm cells with an NF mutation; all women, a few egg cells with a mutation, and it becomes a matter of rare chance that that particular sperm or egg formed a child that would determine that the child would have NF1.
Neurofibromatosis is a progressive disorder. It usually is first noticed in young children as showing up by the presence of café-au-lait spots. The presence of these brown spots on the skin may be the only feature of NF1 in some young children.
Over the course of time, the neurofibromas may appear, usually after early childhood or towards adolescence.
Other features of NF1 that may appear at different times would include the bone problems which are usually noticed early in life if they will occur at all, except for the scoliosis which might not be noticed until adolescence.
The plexiform neurofibromas are probably present from birth but sometimes are not made evident until a bit later on when there may be an asymmetry of the way different parts of the body grow.
So, many of the features are present from an early point in time if they will occur, and then if they haven't, they generally won't. Others, especially the neurofibromas, tend to continue and progress over the years. So, for example, individuals who have large numbers of skin neurofibromas tend to develop those very gradually, mostly during adult life.
NF1 is established as a diagnosis using a set of standardized criteria that were put together by the NIH in a conference in 1987. Any two of the features on a list would qualify an individual as fulfilling diagnosis criteria.
The features include multiple café-au-lait spots, having six or more spots bigger than five millimeters before puberty or 15 millimeters after puberty; freckles under the arms or in the groins; the occurrence of two or more neurofibromas or one plexiform neurofibroma; iris Lisch nodules which require the use of a slit lamp and an experienced ophthalmologist to visualize; the occurrence of a tumor of the optic nerve called optic glioma; a characteristic bone deformity such as bowing of the tibia or an abnormality of the formation of the bones around the eye, the orbit; and finally, the occurrence of an affected first-degree relative: a parent, sibling, or child. So an individual with any two of the features on that list can be diagnosed as having NF1, but many of these features would not be expected to be present in a very young child, and so for many such children who originally present with multiple café-au-lait spots, the diagnosis may be uncertain for sometimes even several years until a second feature should develop. Right now there's no diagnostic test for NF1, so one can't use, for example, a blood test or a skin examination or skin biopsy to make the diagnosis. Instead, the diagnosis is based on clinical criteria. Doing a laboratory test for NF1 would require the ability to identify the specific changes in the NF1 gene that have caused the disorder in a particular individual, and right now, that's very difficult to do. The gene turns out to be a very large and complicated one, and the genetic changes that might change NF, on the other hand, can be very small and very subtle. So searching for the mutations is still a bit like a needle in a haystack search, and although it's technically possible to do in a research setting, at the moment it's still very difficult to do and because of that no widely available clinical test has so far been developed. That probably will change. And the reason why it would be helpful to have a laboratory test for NF1 is first of all, it would allow us to confirm the diagnosis where it's suspected usually because of a child who just has café-au-lait spots, and for families waiting for confirmation of the diagnosis, which can take years, that can be very anxiety provoking, and many would prefer to know as soon as possible. And secondly, some families have been interested in being able to offer prenatal diagnosis for NF1 prediction as to whether the NF1 mutation has been passed on to an unborn child, and the ability to do that is critically dependent on the ability to find the specific gene mutation that has caused the disorder.
We have begun to understand why neurofibromas form in terms of what is actually going on inside the cell. The NF1 gene appears to act as what is now referred to as a tumor-suppressor gene. It is a gene which needs to be present in order to prevent the uncontrolled growth of particular types of cells. In this case, the major cell that seems to be the target for the NF mutation is called the Schwann cell, which is a cell that contributes to the sheath that surrounds a nerve.
We believe that what's happening is that all individuals with NF1 are born with one functioning copy of their NF gene, and one non-functioning copy, which is the copy with the mutation. Probably that in and of itself does not cause major problems in the function of the nerve. But there is a chance for anybody at some point in life that a mutation might arise in the NF gene.
Ordinarily, if you've got two functioning copies, if one of those copies were to be damaged by mutation during the life of the individual, no harm would occur because there's a sort of backup copy that still functions. But if you have NF1, that backup copy is already knocked out, and therefore losing function of the one remaining unaffected copy leaves you with no functioning copy at all, and that seems to lead to the uncontrolled growth of these cells that causes a neurofibroma.
One way to think about this is to think about the brakes on a car. A car has front brakes and rear brakes, and you know when you're driving the car that there is a possibility that the brakes might fail, but you figure that if they do, probably it will be only the front brakes or only the rear brakes and not both, and therefore the car will stop. But if somebody were to loan you their car and they were to say to you, "Well, the front brakes are out on this car but don't worry, the rear brakes still work," you probably wouldn't feel comfortable driving the car because you would know that there's some possibility that the rear brakes, too, could fail, and if they did, the car would crash.
Well, having NF1 is like being born with one set of brakes already knocked out, and it turns out that the chances that the other set will fail somewhere in the course of an individual's lifetime are relatively high, which is why neurofibromas appear to form.
Some of the features of NF1 might be present from birth -- for example, the larger plexiform neurofibromas or the problems in the way bones grow -- and some children with NF1 will experience slow development from a very early age. If these things do not occur at an early age, they probably won't occur.
During the early childhood years is when the café-au-lait spots emerge, when skin-fold freckles are first likely to be seen, and some neurofibromas may begin to appear around that time.
During the school-age years, early school-age years, optic glioma, if it's going to occur, might surface, and that's the time when optic gliomas may progress. If plexiform neurofibromas are already present they may grow at that point in life. Iris Lisch nodules may first come to attention after about age 6. And during the years up to adolescence is when learning disabilities are likely to surface if they haven't already, when neurofibromas on the skin might form or ones already present might grow, and when curvature of the spine might become a problem.
From that point on, from adolescence through adult life, the major issues are the appearance of new neurofibromas which can occur at any time in life, and then the eventual accumulation of neurofibromas that may cause cosmetic problems. Malignancy can occur at any point but seems to be most common in childhood, adolescence, and young adulthood, and at least NF-related malignancies seem to be less common in older adults.
Learning disabilities are one of the most common problems that people with NF1 experience. They can encompass the full range of learning disabilities seen in the general population -- for example, both verbal and nonverbal learning disabilities, problems with reading or problems with math, or following complex directions. All of these things are seen in individuals with NF1, and they don't seem to be clearly different from similar learning problems that occur in the general population; they're simply more common.
It's very important to be alert to the presence of learning disabilities if there's any suspicion that they might be present to provide an evaluation to assess the areas of strength and weakness that a particular individual has, and then to try to provide a program of educational support both in school and at home to help that individual use their abilities as well as they possibly can, and to learn strategies that help deal with some of the limitations that they might experience.
The decision of when and how to tell a child about NF needs to be individualized to the child. It depends in part on what are the kinds of problems that child has experienced. Sometimes those problems will be very subtle and the child may not be that curious about them. And other times the child may have required very significant medical intervention and naturally would have other questions about that. I find that the most important thing is to be truthful, to answer a child's questions in an honest way, laying a foundation of trust so that they know that they can go to their parent or their physician and get an honest answer.
Now, this doesn't mean that when they ask a question you need to go into every single detail which, for very young children especially, would be impossible to understand. So you tell them what you feel they are capable of understanding and reacting to, and as they get older, likely they will ask more and more questions and you'll need to provide more and more information. So I find that this really needs to be individualized, but remaining truthful I think is probably the most important principle in order to earn the trust of the child. The decision about what to tell a teacher and for that matter, whether to tell teachers I think is a personal one and needs to be individualized to the needs of a particular child. On the one hand, if a child has obvious features of NF1 or if the child has recognized learning problems, then it's very important for the teachers to be aware of what it is this child is dealing with and how they can help and participate as part of the care team for that child. There may be medical issues that they need to be alert to, and they certainly should be alert to the learning problems the child has, and be prepared to help provide support.
Many families find that if the child does not have obvious features or does not have known learning disabilities, that they've been reluctant to tell teachers because they're afraid of setting up a self-fulfilling prophesy; the teachers will come to expect the child to have learning problems even if he or she doesn't. And probably as many as 50% of children with NF1 do not have learning disabilities and so that kind of self-fulfilling prophecy might be a risk.
The most important thing for the parent of a child with NF1 to recognize is that they need to treat their child like a basically healthy child and not limit their activities unless they have a particular medical problem that requires that they limit their activities. So most children with NF1 remain healthy and active and should be encouraged to stay active.
The kinds of things that might occur in children with NF1 that parents might be alert to are, first of all, the growth of neurofibromas, either the enlargement of ones already present or the presence of new ones. In general, we don't need to do anything special in terms of treatment of those, so a small skin bump here or there for the most part does not require any particular treatment. If there's already known to be a plexiform neurofibroma, it may be important to watch it to make sure that it doesn't grow to a point where it causes significant either deformity or impairment of function, for example, weakness of an arm or a leg.
Right now there's no cure. There's no medication that has been discovered which either prevents the various features of NF from occurring or reverses them, although there's a great deal of research being done aimed at finding effective treatments. So for the present, the management of individuals with NF1 includes providing guidance so that they can anticipate some of the kinds of problems and, we hope, diagnose them early, and then to deal one by one with particular problems that might occur. For example, neurofibromas can be removed using surgery, which can achieve a good outcome in terms of removal of any particular skin neurofibroma; the excess tissue bulk associated with some of the larger plexiform neurofibromas can also be removed surgically; various bone problems can be treated using orthopedic procedures; and the learning problems, if not treated, can at least be managed by providing an appropriate assessment and appropriate help both at home and at school. So there are ways of managing particular parts of NF1 even though we don't yet have any treatment that makes the condition completely go away. The management, to a degree, needs to be individualized to a particular person. There are some individuals, for example, who are already known to be dealing with particular complications so the management very much depends on what that complication is and how it can be appropriately treated.
For an individual, though, who has signs of NF1 but at the moment no major complications, my recommendation is that person should be seen by a physician who is familiar with NF about once a year to do a regular physical exam and then to be available to answer questions both at that visit and anytime in between visits, for that matter, when questions come up.
We recommend that children also have annual eye exams done by an ophthalmologist who's familiar with NF1, mainly following them for the possibility of optic glioma, the tumor of the optic nerve.
There's been major research progress in understanding NF1. The most important advance in recent times was the discovery of the NF1 gene which occurred in 1990, and that opened the door to first understanding how that gene functions in cells in individuals who do not have NF1, and then the kinds of changes in the gene that lead to the various features of NF1.
At this point, we have at least the beginnings of an understanding of what makes a neurofibroma grow, and we hope, over the course of time, that this will translate into our ability to develop better tests to help establish the diagnosis, and eventually better means of treatment. We also now have animal models for NF1, especially a mouse model, which is of importance because it provides us, first of all, a way to better study how and why the features of NF form, and second, provides us a situation where we can test potential treatments in a safe way before they might be used in clinical trials on people.