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Dr. Korf explains to Hannah's parents 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 the consultation is also available.
Consultation Contents: Segment 1: Dr. Korf and Hannah's parents talk about NF1 and its occurrence. Segment 2: Dr. Korf talks about Hannah's café-au-lait spots, an early sign of the disorder. Segment 3: Dr. Korf confirms and explains Hannah's diagnosis. Segment 4: Hannah's parents ask about the likelihood of Hannah developing more neurofibromas. Segment 5: Dr. Korf determines that Hannah is the first in her family to have the disorder. Segment 6: Hannah's parents ask about her life expectancy. Segment 7: Hannah's parents ask about who should be involved in her care. Segment 8: Hannah's parents ask about the likelihood of her having a learning disability. Segment 9: Hannah's parents ask about when and how they should tell her about the disorder. Segment 10: Hannah's parents ask about additional information and sources of support for families. Segment 11: Dr. Korf talks about recent progress in understanding the disorder. Segment 1: DR. KORF: As a starting point, though, it's my understanding that you were referred here by Hannah's pediatrician? ABBY AND PAUL: That's right. DR. KORF: And what was it that your pediatrician was concerned about? ABBY: He had noticed the café-au-lait spots and how many she had and he said we needed to see a specialist to figure out why she had them. DR. KORF: Did he give you any sense of what he was thinking might be going on? ABBY: He suggested that there was a possibility that she had neurofibromatosis, and we didn't have a whole lot of information on what that was or what that meant. DR. KORF: So he didn't go into much detail about what the condition is. ABBY: No, he did not. DR. KORF: Have you had a chance to read about NF in brochures or on the Internet? PAUL: We've taken a look at some of the information that is on the Internet, looked at some brochures. Right now, it's all very scary to both of us and we're not sure what it means for Hannah in the future and we're hoping to clarify some of that today. DR. KORF: The information can be quite frightening and it's important to realize that much of the written material tends to emphasize the more severe end of the spectrum. So we'll try to place all of this into perspective as we go forward now. Your pediatrician referred you because of seeing the café-au-lait spots which are, in most people, the first sign that might occur in neurofibromatosis and what, therefore, brings the condition to attention, and I think it's a good thing that this did come to attention early and that appropriate evaluation was organized. This condition, neurofibromatosis, is one that occurs in about one in 4,000 people around the world. It affects people of all racial and ethnic backgrounds, and can vary very widely from one person to another in terms of the way it can affect growth and development and, uh, the various kinds of problems that can occur as an individual grows older. There's no diagnostic test for neurofibromatosis so we can't draw, say, a blood sample or take a skin sample and send it to the laboratory and expect them to determine whether or not Hannah is affected, and in fact the way the diagnosis is made is through a set of clinical criteria. So in general, we do an examination like we did and we look to see whether the various diagnostic criteria for NF1 are met. And in some instances this can be a challenge because many of the features of NF are age-dependent, which means that they may not be seen in a young child and sometimes it can take a period of many years before the diagnosis is confirmed. Segment 2: DR. KORF: So the first thing that we look for, as we've said, is café-au-lait spots. The café-au-lait spots are by far the most common first sign of NF1 to appear. And the situation that occurred with Hannah is really a very common one. The café-au-lait spots are not noticed in the early weeks of life. They begin to appear in the first few months. They gradually get a bit darker and more distinct. Very often the first time a child will be referred is right after the summer months when the café-au-lait spots actually will tan. And as we've said, anybody can have one or two café-au-lait spots but having six or more spots measuring five millimeters in a child, or after puberty, 15 millimeters, is generally accepted as being a diagnostic sign of NF1. PAUL: Does the size of the café-au-lait spots provide any indication of the severity of NF1 with her? DR. KORF: No. ABBY: Is there any way to know if she's going to get more café-au-lait spots at this point? DR. KORF: Most children with NF1 will continue to develop café-au-lait spots for the first couple of years of life, but usually by about 2 years of age, a child will have as many café-au-lait spots as he or she will eventually have. PAUL: Now, her café-au-lait spots seem to have grown as she's grown. DR. KORF: Right. PAUL: Do they continue to grow throughout her life until she reaches puberty? DR. KORF: Café-au-lait spots will grow with a child. They do not usually spread or grow out of proportion with the way a child is growing but as she gets bigger, her café-au-lait spots will grow with her, which doesn't represent any kind of progression of the NF. It's just a natural thing as the skin gets larger. There's no correlation between the number of café-au-lait spots or the size of the café-au-lait spots and the overall severity of the NF, or between the location of a café-au-lait spot and the future location of a neurofibroma or any other NF-related feature. Café-au-lait spots do not become malignant. As I said, the sun exposure can make them darker, but that does not mean that the NF is getting more severe or progressing. We would recommend any child should be protected from sun exposure. That's, you know, no different in a child with NF1, but the sun exposure does not cause the NF to become more severe. Segment 3: DR. KORF: So usually, having seen the café-au-lait spots, the next feature to become apparent, and in most children what confirms the diagnosis would be freckling, especially freckling under the arms or in the groin in areas where skin folds meet. So people with NF of course can have freckles like anybody else in sun-exposed areas like on the face or on the shoulders, but what distinguishes individuals with NF1 is that they also get freckles in areas of the body which are not exposed to the sun like under the arms or in the groin. Most of the time this begins at about 3 years of age, usually in the groin before under the arms, and then will increase over the years, and in fact, some people with NF, as they get older, will have freckles that are pretty widely distributed along their body. They'll have them on the trunk, sometimes around the chin -- rather, on the lower chin, even around the area under the nose. And the skin-fold freckles are completely harmless. They have no impact on health; they do not predict the course of NF. It's just something we don't understand very well but seems to be something about the way skin pigmentation behaves in NF and other than being useful as a way of making the diagnosis, it has no other significance. So skin-fold freckling and café-au-lait spots both were seen when we did the exam of Hannah, and as a result, we can say she fulfills two diagnostic criteria for NF1 and be confident, therefore, that she is indeed affected. ABBY: What exactly is a neurofibroma and what does it look like? DR. KORF: To understand what a neurofibroma is, we need to think first about how a nerve is put together. A nerve can be thought of like a wire, and just like a wire, you have the wire in the center surrounded by a protective covering and insulation. In the case of a nerve, this insulation is made up of cells, the most important of which are cells called Schwann cells. And what happens in a neurofibroma is that there's something that goes awry in the control of the way these Schwann cells grow. So they will grow in particular regions of the nerve to an excessive degree and they form a kind of growth or a mass around the nerve. The nerve itself, which you might think of like the wire that runs through the insulation, is generally unaffected as best we know, and in fact, unless there's pressure put on the nerve, will function normally in spite of the presence of the neurofibroma. They can occur in two different kinds of ways. Some neurofibromas occur along a restricted region of a nerve -- for example, a nerve ending in the skin -- where they form a localized swelling of the nerve which appears on the skin as either a small bump on the surface of the skin or sometimes nothing that you can see but you might feel almost like a depression in the skin in that region, and often the skin there will have a pinkish or purplish discoloration. Or they can occur deeper in the inside of the body and show up, once again, as just an isolated bump. The other major kind of neurofibroma is called a plexiform neurofibroma, and in this case, the neurofibroma growth extends along a length of nerve and also may involve multiple branches of a large nerve. So in plexiform neurofibromas, there can be a whole region of the body that is affected, causing sometimes overgrowth of part of the body -- the face, an arm or a leg, for example -- and sometimes invasion of surrounding tissues by the neurofibroma growth, causing soft tissues to become overgrown and swollen. The skin may become thickened in that region. There can be increases in pigmentation in the skin overlying a plexiform neurofibroma. So in some instances, they can be quite extensive. You may have seen pictures of people with NF who have a growth around the eyes where their faces can be distorted in some way by the growth. PAUL: Yes. DR. KORF: And that is due to plexiform neurofibroma occurring in a nerve that actually begins behind the eye and then may also extend onto the face. ABBY: Is that something that can still happen to Hannah? DR. KORF: That is not something that can still happen at this point. The plexiform neurofibromas are believed to be present from birth and by this age, if that particular kind of plexiform neurofibroma were going to occur, you would already have seen it. ABBY: So does that mean she doesn't have any plexiform tumors at all? DR. KORF: No, we can't be sure of that. We can say that she doesn't have plexiform neurofibromas that are visible from the surface, but there's no way that we can know whether other plexiform neurofibromas might exist deeper inside the body where they would not be visible on the surface. Now, I must say we don't go looking for plexiform neurofibromas if they are not obvious, and the reason is that just knowing that one is there deeper inside the body, for the most part, really doesn't help us much in terms of how to take care of them. Unlike the skin neurofibroma, the plexiforms are pretty difficult to remove in their entirety. Removing a plexiform neurofibroma is like trying to take up the roots of a tree; no matter how much you remove, you're almost certainly going to leave some behind and the neurofibroma can grow back from what's left behind. So in general, we leave them alone unless they cause some kind of a symptom, like pressing a nerve against a bone which can cause weakness or numbness, for example, or if they cause pain, which occasionally might be the case. ABBY: So these really are two different kinds of growths, these dermal neurofibromas and plexiform neurofibromas? DR. KORF: That's right. Very different in terms of the way they behave. The plexiform neurofibromas often grow sometimes pretty rapidly during the early childhood years and then for unknown reasons, they frequently stop growing and may or may not grow again as a person gets older. We have not identified any particular risk factor that causes neurofibromas to grow. They don't seem to be related to diet or to exposure to medications of any sort. We do have evidence that neurofibroma growth may be related to hormone changes, because neurofibromas commonly grow during puberty, obviously when hormones are changing, and in women during pregnancy. But the particular hormones that are responsible have not yet been identified. Segment 4: ABBY: Is there any way to predict how many she's going to have as she gets older? DR. KORF: At this point, no way for us to predict the number of neurofibromas that she might eventually have. There are some people who get very few, some who get very large numbers and are completely covered with them, and there's, at a young age especially, no way to predict how many neurofibromas any child with NF1 might get. But being completely covered with neurofibromas, which does occur in some people, is really more the exception than the rule. PAUL: That's actually some of the pictures that we saw in some of the literature that we did read ahead of time were patients who were fairly well covered with these neurofibromas and very noticeable on the skin covering themselves. DR. KORF: That's right. ABBY: It's scary. PAUL: It's pretty frightening. ABBY: It's scary. DR. KORF: The thing to realize is that a lot of the written information has tended to emphasize the more severe end of the spectrum, partly because these are the more dramatic things that might happen and it causes people to be more motivated to write about them or to tell their stories. Sometimes it just brings attention to the condition to point out some of the sort of worst-case scenarios. The truth is that we would estimate that in general, about two-thirds of children are mildly affected by this and do not have major medical problems due to the neurofibromatosis. And then as you'll see later, among the remaining one-third would be included certain things that would already have occurred if they were going to happen. So the severity is quite variable from one person to another, and often the written literature tends to emphasize the more severe kinds of problems. Segment 5: PAUL: Is this something that we could have prevented from happening to Hannah? DR. KORF: Definitely not. There is nothing that has been discovered that so far causes these mutations. There's nothing that you did or, for that matter, failed to do, that made NF occur here. This is not due to drinking alcohol during pregnancy or smoking or being exposed to paint fumes or anything else. ABBY: Does it have anything to do with our age when she was conceived? DR. KORF: Probably not. There actually are genetic conditions where there has been a relationship of the age of the parents, especially, as it turns out, the age of the father in causing mutations, but that really hasn't been confirmed to be the case in NF1 and it really appears as though there's no clearly defined cause for these mutations. The thing to realize is that mutations are a natural thing. They're happening in all of us all the time. Every time a sperm cell is made or an egg cell is made, a tremendous amount of genetic information needs to be copied, and a mutation is a little bit like having a typographical error on one letter on a page in a very large book. And occasionally this typographical error copying the genetic information will be made in the NF gene, and neurofibromatosis will result. Actually, in any population of sperm cells or eggs cells in anybody, there are probably a few that have the NF mutation, and it becomes a matter of rare chance that that particular sperm or egg formed a child that results in NF occurring. So from the genetic point of view, it looks like Hannah is the first affected member of the family, what we call a new mutation. Probably there is minimal risk, if you were to have other children. For Hannah herself when she grows up, it would be a 50/50 chance. In your family, as I understand it, you have one other child, a son, right? ABBY AND PAUL: That's right. DR. KORF: And he's a bit older than Hannah? PAUL: He's four years older, yes. DR. KORF: And he does not have any of the café-au-lait spots or any other signs. ABBY: No. PAUL: Right. DR. KORF: And also, as I understand it, neither one of you has more than one or two café-au-lait spots. PAUL: That's right. ABBY: Just the one each, yeah. DR. KORF: So actually we could arrange for each of you to be examined to confirm that you don't have signs of NF both on your skin and also looking for Lisch nodules in the iris if that would be of interest. But based on what you say, it really does not appear that anybody else in your family, including in previous generations, has ever had multiple café-au-lait spots or has ever had a diagnosis of NF1, is that right? PAUL: That's right, yeah. DR. KORF: So it appears as though Hannah, then, is the first member of the family to be affected with NF. And that kind of situation actually happens about half the time. In other words, among all people who we might see in clinic, about half the time it will turn out that a child is the first member of the family to be affected. And we believe that that occurs because the genetic change or mutation actually arose in the sperm or egg cell that formed that child. DR. KORF: One of the other important questions that often comes up and also actually represents another diagnostic criterion concerns the genetics of NF, and as you're probably aware, NF1 is a hereditary disorder. It is due to a change in a gene. The inheritance pattern of NF1 is what we call dominant inheritance, which means that everybody has two copies of every gene, one that they inherit from their mother and one from their father, and in a condition like NF which is dominant, only one of the two copies of the gene needs to be altered in some way -- what's called a gene mutation -- in order to produce the condition. So you don't need to have both copies mutated; just one of the two copies needs to be mutated. Now, the implication of that is that if a person has NF, they have two copies of the NF gene, one of which has been changed by mutation, one of which has not, and there's a 50-50 chance that they'll pass either the mutated copy of NF1 or the non-mutated copy on to any of their children, and therefore they face a 50-50 chance of any of their children inheriting NF1. And this would apply to any person who's known to be affected, so it will be important for Hannah to understand this when she's grown up. Segment 6: ABBY: I was curious at to how the NF is going to affect Hannah's life expectancy. DR. KORF: There is some research that addresses the overall life expectancy in NF1 and it would suggest that if you look across the entire population, that there are certain life-threatening complications that do sometimes occur, the most important of which probably is malignancy or cancer. The neurofibromas themselves are not malignant growths, but there is some risk over the course of a person's lifetime that a neurofibroma might become malignant. Most typically it would be either a plexiform neurofibroma or one of the deeper and larger neurofibromas. And the signs of that occurring would be either unexplained pain, especially a plexiform neurofibroma might be painful if it's bumped, but usually the pain doesn't last too long. But pain that occurs and doesn't go away, that you should call to medical attention, or if a neurofibroma seems to be suddenly growing a lot faster than it ever grew before, or if a neurofibroma that was previously soft suddenly develops a region that might be firm or hard. Any of those things would be important to bring to medical attention. So there is a risk of malignancy. The exact amount of risk is not totally clear. It's best estimated between about 5 and 10% over a person's lifetime with NF. And if that sounds like a lot, remember that 25% of people in the general population -- this is without NF -- will develop a malignancy sometime during their life. ABBY: So I guess I'm wondering, aside from these plexiform tumors that can become malignant, is she at a greater risk of developing any other kind of cancer? DR. KORF: There are other cancers that have been found to be more common in children with NF than in the general population. For example, there is a kind of leukemia that has been reported in children with NF more frequently than other children, but actually, although the risk is higher, the absolute chance of it happening is still very slim. So it is one of those things that is increased in risk, but the actual chance it will happen to any particular child is still very low. So, most of the kinds of cancers that occur in NF are either the, what are called malignant peripheral nerve sheath tumors that are derived from nerves; the optic gliomas which can behave in a malignant fashion in some children; there can be other kinds of brain tumors that can occur in individuals with NF; or there are rare instances where there can be either pressure on a blood vessel or growth even inside a blood vessel that can cause either high blood pressure or interference with blood circulation or sometimes even damage to the blood vessel wall and episodes of bleeding. Although these are rare complications, they, too, can be life threatening. So if you look across the board, there is a somewhat reduced life expectancy that has been found among the larger population, but much of that has been accounted for by the risk of malignancy in some of these other rarer complications, and many individuals with NF1 lead long and basically healthy lives. Segment 7: ABBY: Can you tell us how many different specialists Hannah's going to need to see, especially in the short term, and should she still be seeing her regular pediatrician who doesn't have a whole lot of experience with NF? DR. KORF: The first and more important thing is that she should continue to see her pediatrician or as she gets older, have a primary care doctor, because people with NF can get any of the same various illnesses that anybody can get, and you want to have contact with a primary care doctor who can become the kind of main person that you would go to with any particular medical question. Then there should be a physician who is expert in NF who works together with you and with your pediatrician or primary care doctor to deal with NF-related issues as they come up. As far as other specialists are concerned, there is a long list of things that could occur in people with NF, and many of these are covered by different kinds of medical specialists -- neurologists or neurosurgeons or dermatologists or plastic surgeons, for example. We generally work closely with a very large number of specialists but we haven't found that it's helpful for any particular child to automatically see all of these specialists. We generally work together with the family and the primary care doctor to assess a particular child's needs and then may ask for help from other specialists on a case-by-case basis as we think that help is needed. Segment 8: ABBY: So one of the things we had read before we came to see you that was something else that was scary was that many, many kids with NF have learning disabilities. Is there any way to predict that, or what kind of learning disabilities do these kids have? DR. KORF: Right. It's a very important part of NF1. It appears that about roughly half of people with NF1 have some kind of learning disability. It can vary from being fairly severe and associated with major developmental problems, or it can be very subtle and might not become evident until they're really pushed to do some of the more difficult work at school. There's no way to predict whether a person with NF will or won't have learning disabilities; if they do have them, exactly what those learning disabilities will consist of. Some will have problems with reading or with math or the ability to follow complex directions; some will have problems maintaining attention. Sometimes there'll be associated hyperactivity. And there's no easy way to predict at any point in time what the future holds except to say that in general, the learning problems don't get worse as a child gets older. If a child is carefully evaluated for learning problems and determined to have them, then he or she can be offered help both at home and in school to compensate for these, to learn where their strengths and weaknesses are, to play to their strengths and to try to learn to bypass some of the areas of weakness and when that's done, a child can do very well. Their intelligence may be quite good, and once they're given strategies to help to deal with the learning problems, they can enjoy success both at school and later on in careers even. On the other hand, if a child has learning problems that go unrecognized, frequently there's a kind of downward spiral that occurs. They develop poor self-esteem, teachers expect less of them, sometimes their parents come to expect less of them and they expect less of themselves, too. And they will kind of move to the bottom of the class and tune out and really lose out on major opportunities that will follow them through their whole lives. So it's important to recognize the learning problems when they occur and to make sure that they're properly attended to. Segment 9: PAUL: What and when should I tell Hannah about her NF1? DR. KORF: It's a very important question to think about when and how to explain NF to a child, and there's no single answer that works for all families or all children. I think the decision has to be made based on your knowledge of Hannah and what she can understand and the kinds of questions that come up in her mind as she gets older. If there's any rule of thumb here, it's that a child's questions should be answered when they ask them, and they should be answered honestly, which is not to say that you have to tell her every single detail, a lot of which she probably won't understand until she's older, but I think of this as kind of laying a foundation of trust, to answer her questions in terms that she'll understand which are honest if not maybe complete, and then as she gets older and better able to understand things, to let more and more of the picture be filled in so that she knows that she can come to you for answers to questions or she can come to her doctors for answers to questions and that she can trust that what you tell her is what's really happening. Segment 10: ABBY: This is a little bit overwhelming, as I'm sure you can understand. Is there any way we can be put in contact with parents that also have a child with NF who've obviously been through this already? It might be very helpful to us. DR. KORF: This question comes up often and we have been able to connect families with others who have been through many of the same things that you're experiencing now. There are also family support organizations that are dedicated to NF, and through those, it's also possible to arrange to meet with other families who are at various stages of dealing with NF and some of its manifestations. And in fact, in some cases, there are actually family support meetings and fund-raising events and the like that you can become part of if you're interested and we can provide you with contact information to become involved if you would like. ABBY: That would be helpful. I feel like we're only beginning to think of the questions now and as we go through this we're going to think of so many more things we need the answers to. DR. KORF: Absolutely. Partly the first time hearing this, there's so much to take in, it's difficult to absorb it all. Frequently, people don't think of the questions that are really on their minds until they walk out of the office. PAUL: What are some of the best sources of information not only for ourselves but anyone else that we choose to acknowledge Hannah's NF1 to, that they can go to to learn the right information about this particular disorder? DR. KORF: There are many forms now of written information or information on the Internet that are provided by a number of different organizations that are either dedicated to providing information about NF, or more broadly, information about various genetic conditions. So there are patient support and advocacy groups that are focused on NF, either NF1 or NF2; there are government organizations that have issued public information about NF, and we can direct you to sources of both written and computer-based information that we think are reliable and good sources to both learn about the condition further yourself and also may help you to explain it to others. Segment 11: PAUL: Dr. Korf, what sort of research is being done right now in the area of NF1, NF2, particularly with NF1? DR. KORF: There's been a major thrust towards doing research on NF1 and NF2, for that matter, over this past ten years or so, especially since the genes for these two conditions were discovered. We have a pretty good idea, we think, about some of the events that are going on inside the cell that cause neurofibromas to grow. To some extent, this information gradually is likely to improve our ability to achieve a diagnosis. For example, eventually I think we will have genetic testing available. But even more importantly, we hope that we'll be able to translate this information into better methods of treatment. Right now, the treatment of neurofibromas especially, is basically surgery, removing neurofibromas when and if they cause symptoms. What we wish we had were medications that would either shrink neurofibromas that are already there, or even better, prevent neurofibromas from forming in the first place. And there actually now are beginning to be some clinical trials of medications that maybe will help move us in that direction. I think one way to think about this is that for a child like Hannah, who's 3, we would not want to predict her future based on the way current adults are affected, because the chances are good, I believe, that as she grows older, new approaches to management will emerge that will probably make the long-term sort of outcome when she's an adult very different from what it is for present-day adults who were diagnosed 30, 40, or 50 years ago.
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