Re: Digest Number 297 curious and confused?????

[Guest guest]

Hi,

I haven't written for quite a long time, but I have been staying in touch! This

question about different types of NF over and above NF1 & 2 has been discussed

before. I have been told by Dr Huson that I have a " Mosaic form " of NF. This

means that only the cells in a certain part of your body are affected and in my

case, that is the left hand side of my neck - I've had 3 spinal tumours removed

and I've still got 2 plexiform ones in my neck, lurking! There is a paper

written on this subject from the UK , which talks mostly about NF1, but does

refer to NF2 at the end.

Susie from the UK

SEGMENTAL NEUROFIBROMATOSIS: A REPORT

by Dr. o Ruggieri

· and Dr. Huson

The Churchill Hospital. Oxford, UK

The term Segmental Neurofibromatosis is used to describe patients with the

features of NFl limited to one or more areas of the body. It was originally

defined as the occurrence of one or more neurofibromas, associated cafe-au-lait

spots (CAL) -..and/or freckling on one side of the body or in a single,

unilateral segment of the body, with no crossing of the midline, family history

of NFl, or systemic involvement. Approximately 150 cases of segmental NF have

been published in the medical literature, the majority of which are isolated

cases. Not all reported patients fulfilled the clinical criteria encompassed

by the original definition, leading Roth, et al. (1987) to propose a more

complex classification as follows:

1. True segmental NFl or unilateral segmental, as described by the original

definition;

2. localized cases with deep involvement (e.g. internal neurofibromas, bony

dysplastic changes);

3. Hereditary segmental, patients with segmental NFl who have transmitted

full-blown NFl or segmental NFl to their offspring;

4. Bilateral segmental, where two areas of segmental NFl occur on both sides

of the midline. These may be symmetrical or asymmetrical.

The most likely explanation for segmental NFl is mosaicism for the NFl gene.

Mosaicism, when used in clinical genetics, describes a person with a mixture of

affected and unaffected genes. The clinical pattern of expression is

determined by the timing of and the cell type(s) affected by the mutation. For

example, a midline mutation early in embryonic development would lead to

bilateral, dermatomal involvement. Somatic mosaicism in pure segmental NFl has

not been proven at the molecular level. Some adults with mild generalized NFl,

who are the first affected person in their family and presumed to be new

mutations for the gene have been found to be mosaic at the molecular level

(Colman et a] 1996). This means the mistake (or mutation) in the gene did not

happen in the egg or sperm but very early in the developing baby.

Patients with segmental NFI who have children with generalized NFI are presumed

to represent gonosomal mosaics. In other words, they have involvement of both of

the gonads (the ovaries and testes) and somatic (other body tissues). More

difficult to explain pathogenically is the apparent occurrence of segmental NFl

in successive generations. There are few families described with vertical

transmission of segmental NFl; we have identified a further family. In this

family, the father has multiple segments of cutaneous neurofibromas and a

daughter with segmental pattern of cafe au lait spots and freckling. It might

be that these families have an NFI gene mutation which for some reason is

expressed normally and abnormally in different parts of the body.

Viskochil and Carey (1992, 1994) have suggested a new classification for

Segmental NFl based on the somatic mutation hypothesis. They divide cases into

four categories:

1. single site-single manifestation (i.e. late neural crest mutation leading

to a single disease manifestation);

2. single site-single manifestation (i.e. early neural crest mutation leading

to CAL and neurofibromas together in a distinct location);

3. multiple site-single manifestation (i.e. bilateral dermatomal

neurofibromas);

4. multiple site-multiple manifestation (i.e. full NFI phenotype).

There has been a recent increase in the number of reports of segmental NFl in

the medical literature reflecting the rising interest in the condition. Perhaps

this is an indication that the condition is more common than previously

believed. Segmental NFl is probably under-diagnosed, because it occurs with a

clinical picture that, owing to the absence of symptoms and complications, can

be ignored by the patient and pass unnoticed by physicians at examinations for

other problems.

Our experience at the Oxford NF Clinic in the past five years indicates that

the minimum prevalence for segmental NFl in our area is 1 in 400,000 and that

the clinical spectrum is more varied than the literature would suggest. It must

be stressed that most people with segmental NFl

have minimal risk of developing major NFl complications. Only 7 individuals out

of the 150 described in the medical literature have had NFl complications (such

as neurofibromas, pseudarthrosis, etc.).

With a detailed clinical study of segmental NF in the UK, we aim to determine

the clinical spectrum of involvement and the risk of someone with segmental NFl

having an affected child. We believe the risk is very low, but it would be

helpful to see if we could determine the level of risk and whether people who

have a risk of passing segmental NFl to full blown NFl to their children have

any identifying clinical features. Based on experience to date, we counsel

people with segmental NF1 that they have a very small risk of having children

with NFl, perhaps 5% at the most. For children who develop NFl it is no

different from when NFl occurs in other people. Until recently, no one had been

aware that NF2 could also occur in the mosaic form. Studies of the gene

mutations in different people with NF2, have shown that mosaicism can happen in

NF2 as well. Professor Tom Strachan's team in the UK have reported somebody

with mild generalized NF2. The person was the first in the family who was

mosaic for the change in the gene mutation. At the recent FASEB/NNFF Consortium

meeting on Neurofibromatosis, Dr. Mia MacCollin and colleagues from Boston

presented a poster describing some people with what could be called segmental

NF2, their tumors were just on one side of the brain and spinal cord. Again

these were the first people with NF2 in the family. Dr. Gareth

(Manchester, U K) has seen someone similar in the UK. At the meeting, we had a

lot of discussion as to using the term segmental to describe mosaic patients

with NFl and NF2; it was generally agreed that it was perhaps better just to say

that people had NFI and NF2 in the mosaic form.

Medical Research Is The

Cheapest Healthcare Possible