AN INTRODUCTION TO Nf

1. NEUROFIBROMATOSIS – AN INTRODUCTION
2. SO, WHAT IS NEUROFIBROMATOSIS?
3. WHAT IS NF2 - NF2 TODAY
4. THE MAJOR FEATURES
5. THE MINOR FEATURES
6. COMPLICATIONS
7. HOW THE DIAGNOSIS IS MADE

Nf – AN INTRODUCTION

While many will have never heard of neurofibromatosis, most people know something about Muscular Dystrophy or Cystic Fibrosis. Yet, with a birth incidence of Nf1 of about 1 in 2,500 and of Nf2 at 1 in 35,000 the not insignificant number of around 25,000 people in the UK are affected. In fact, Neurofibromatosis (Nf for short) is as common as Cystic Fibrosis; on a worldwide basis, it is five times more common than Muscular Dystrophy.

Why, you may wonder, is it possible that there is a disorder which affects so many people and yet still is so little known? A disorder which can occur in any family, frequently leads to specific learning difficulties and behavioural problems, affects the body's vital nervous system and can lead to serious complications and, occasionally, even premature death. Well, like everything else about neurofibromatosis, it isn't simple.

To begin with, there are two different types of neurofibromatosis, 'neurofibromatosis type 1' and 'neurofibromatosis type 2' which we refer to as Nf1 and Nf2 respectively. To simplify things here, most of the following information is about Nf1.

Secondly, the name doesn't help - NEURO-FIBROMA-TOSIS - and, with its political connotations in the UK, the fact that it is called Nf for short, can be quite a problem.

However, the main reason for its obscurity is that it is so varied in its effects, no two people necessarily being affected in the same way. Another reason may be that no famous person with Nf has yet 'come out of the closet'.

Joseph Merrick, the Elephant Man, was wrongly said to have Nf (he is now thought to have had Proteus Syndrome) but this is not an image that anyone with Nf would wish to use although, ironically, it was John Hurt's portrayal of Joseph Merrick in the film that sparked renewed interest in neurofibromatosis. Quasimodo, the Hunchback of Notre Dame, was also depicted as having neurofibromatosis. He is described as having 'wens' on his skin, lumps and bumps that we know now as neurofibromas. He also had scoliosis (curvature of the spine) and a larger head circumference, both of which are identified as being a symptom or characteristic of neurofibromatosis type 1. It is also possible, though by no means certain, that Quasimodo's creator, Victor Hugo, was also affected but, even if he was not, he did accurately describe Nf1 in his most famous character.

SO, WHAT IS NEUROFIBROMATOSIS?

It is a genetic disorder mainly of the nervous tissue. It can cause benign tumours to form on nerve tissue anywhere in or on the body at any time. The initial signs of Nf are fairly innocuous - pale coffee coloured patches or, as we know them, café au lait marks on the skin. Many people have one or two of these but if there are more than six by the time a child is five years old, it is a sign that he or she probably has Nf1.

Another sign is freckling in unusual places - for example, in the armpits, round the base of the neck or in the groin. Then, as a child gets older - and often increasingly over the years - neurofibromas (what we refer to as 'lumps and bumps') may appear, sometimes just one or two, sometimes a great many.

Some of these lumps are just soft and purplish in colour while others look - and feel - a little like peas and these can range from petit pois to quite large in size. These benign tumours are always unpleasant and disfiguring, even if they are not immediately apparent on the face or exposed areas. The effect on personal relationships and self-esteem can be imagined. Unsightly or painful neurofibromas - or those that occur in an awkward place - can often be removed surgically. There is also current evidence that shows removal by laser treatment can also be effective so anyone wanting to investigate should talk to their doctors about it.

However, if neurofibromatosis was just a skin complaint, it would have remained an obscure disorder known only to Dermatologists and Plastic Surgeons. Unfortunately, it is much, much more and the 'complications' associated with the disorder can cause serious problems and, as mentioned before, even premature death.

The most common of these 'complications' - affecting in the region of 60% of those with the condition - are specific learning difficulties and behavioural problems. Very few children with neurofibromatosis have a below normal IQ and most are outwardly bright and lively but, at school, they have particular trouble with reading, writing or sums. They may lack coordination, have poor spatial judgment, problems with short term memory and act on impulse.

The may lack normal social skills; stand too close to people, try too hard to make friends - though get on well with younger children and adults - and have problems judging facial expressions or tone of voice. Unless neurofibromatosis is diagnosed early and remedial action taken, these children may never reach their full potential and begin a downward spiral of poor attainment, frustration and isolation.

Between 30 - 35% of people with neurofibromatosis will have a 'complication' and the complications associated with Nf1 include high blood pressure, curvature of the spine (scoliosis), malformation of the long bones (below the knee and below the elbow - known as pseudarthrosis), large benign skin tumours called plexiform neurofibromas, tumours on the nerves of sight (optic glioma), internal, spinal and brain tumours (usually benign), speech problems, increased risk of epilepsy and hearing defects - all of which can lead to serious difficulties for those affected.

You may wonder what all the fuss is about since you don't have neurofibromatosis in your family. The fact that no one in the family has Nf at present does not mean that you are immune: anyone can have a child with Nf and that child could be seriously affected. The reason for this is that neurofibromatosis is caused by the mutation of a gene (alteration in the structure) on Chromosome 17. The mutation usually occurs in the egg or sperm before conception. This is no one's fault, it just happens, the DNA coding is altered making the gene imperfect and a child is born with Nf.

Nf is perpetuated in future generations by the fact that the faulty gene will be present in half the eggs or sperm of someone affected by Nf. This means that if someone with the disorder marries someone unaffected, there is a 50% chance that each child they have will be born with Nf - depending on whether fertilisation occurs with or without the defect.

However, even if a parent is mildly affected, there is no way of predicting how seriously affected any of their children will be. Their child may have some serious complications, or may be relatively unaffected; there is no recognised pattern of the disorder and no predictions can be made as to what the future holds for each individual in the light of how severely the parent is affected.

So far, this article has told you only the bad news but it is not all bad. In 1991, the gene causing Nf1 was found and cloned (copied). This is a huge step forward and an effective treatment is now a realistic hope - though there is much more work to be done before a treatment can be found.

In March 1993, the gene causing Nf2 was found on Chromosome 22 and, although Nf2 is rarer, the gene has important implications for all those in the wider public who develop certain types of brain or spinal tumours - for example, Schwannomas, meningiomas and acoustic neuromas.

Although not themselves cancers, both types of Nf also have great importance for research into a number of common cancers - colon cancer, breast cancer, leukaemia and melanomas included. A cure for Nf is unlikely but there is a distinct hope that it will be possible - in the not too distant future - to arrest the progression of both forms of Nf and it is the next generation who are likely to reap most reward.

These successes may begin to bring Nf into the limelight which now shines on better known disorders (which often affect fewer people): motor neurone disease, muscular dystrophy etc. Now that Nf has been shown to be a 'model' of great importance for cancer research - because the proteins the genes control are involved with the control mechanism of cell formation or division - this has led scientists to take a much closer interest in Nf and this can only be good for those affected.

WHAT IS NF2?

NF2 TODAY
Nf2 is rarer than the von Recklinghausen form of neurofibromatosis. However, this is little consolation to the individuals and families with Nf2 since it sometimes imposes a very heavy burden. There may be many years in which a young person is aware of close relatives becoming progressively deaf and having intracranial operations. Delays in diagnosis add to the predicament, as the later surgery is carried out the poorer the outcome, so increased awareness of the condition by the lay and medical personnel is of paramount importance.

It is therefore very exciting that the gene for Nf2 has been cloned. This research success will make it possible, on simple blood tests, to tell whether an individual has inherited the Nf2 gene long before there is any chance of their developing tumours. This will be a great relief to those who have not inherited the gene. It promises also to explain why tumours develop and perhaps how they might be stopped without operations.

Although the gene fault is present from conception, these tumours usually do not grow to a size where they cause symptoms until the teens or early twenties and sometimes later. The tumour on one acoustic nerve may grow at a different rate from the other, so that problems may arise on one side before the other. The first symptom may be loss of hearing which is often noticed when using the telephone. Intermittent ringing or roaring in one or both ears may occur and some people notice unsteadiness, especially when walking on uneven ground or when they get up at night. Less commonly a change in the sensation to the face, weakness of the face muscles, headache or a change in vision may be noticed. Earache is not usually a sign of a vestibular Schwannoma (acoustic neuroma).

The growth of tumours in Nf2 is unpredictable. Most are slow growing and can cause minimal problems for years, others may lead to increasing problems over a few weeks. Small tumours can often be completely removed before leading to serious difficulty so regular health surveillance is recommended for all people with Nf2.

Cataracts - these are cloudy patches in the lens of the eyes. In Nf2, they are different from those that occur with age and can be present when quite young. They can be detected by a thorough eye examination. They rarely cause a significant loss of vision but can help tell that a person has the Nf2 gene. Sometimes glasses need to be worn or the cataracts need to be removed by an operation.

Spinal tumours - a tumour on the spinal cord or on a nerve as it leaves the spine can cause a change in sensation, such as tingling or numbness, pain or weakness down an arm or leg. When the spinal cord is affected high in the neck, the symptoms may affect the face and cause problems with closing an eye, chewing food, smiling or talking. Usually only one side of the face or one limb is affected.

Skin tumours - these are lumps that can occur anywhere on the skin. The lumps (Schwannomas) are made of the tissue that surrounds the nerves and are similar to the lumps called neurofibromas that occur in Nf1. They are not cancers but if they become painful, grow rapidly or change in any way, they should be checked by a specialist. They can be removed if they cause problems or for cosmetic reasons. Sometimes a deep lump may cause a swelling that is harder to feel; this may indicate a tumour on a deeper nerve.

• Nf2 type cataract.
• Nf2 type skin tumour.
• brain or spinal tumour.

It is now being recognised that not everyone with Nf2 will develop a tumour on both ears and that in some families the tumours are largely confined to the skin and spinal nerves.

The vestibular Schwannoma is usually diagnosed by performing a brain scan. There are two types of scan that can be used: the CAT scan involves putting the head in a big dome and passing X-rays through at different angles; the second scan is a magnetic scanner (MRI) which builds a picture using magnetic vibrations. This makes a lot of noise but is a more sensitive test than the CAT scan. The MRI scanners are now widely available but the patient still often has a CAT scan first. It is usually necessary to have a small injection into a vein to help brighten the picture on the scanner. Both these scans are very safe and do not cause pain or need an anaesthetic except, occasionally, on young children.

These scans are also used to diagnose the brain and spinal tumours that occur in Nf2.

It is usually necessary to have detailed hearing tests before going to have a scan. These tests measure the signals or messages leaving the ear (BSER), the reflexes of the bones in the ear and the ability to hear soft sounds at different pitches (high and low). They will often take an entire morning or afternoon and involve putting little wires onto the scalp. Again, these tests are not painful but require experts and are only available at certain centres. They are very sensitive and can detect acoustic neuromas long before they produce any symptoms.

As said earlier, Nf2 is rare but the incidence of a single vestibular Schwannoma is quite common. For anyone reading this who believes they have similar symptoms, please consult a physician to get a diagnosis; in spite of the complications, progress on treatment is being made all the time.