Clinical and genetic studies of von Recklinghausen neurofibromatosis.
A population-based study in South East Wales (population 668,100)
identified 69 families with 135 affected members with von Recklinghausen
neurofibromatosis (NF-1), giving a disease prevalence of 20/105 of
population. In these families penetrance of the NF-1 gene was 100% by the
age of five years. 41/135 cases were judged to represent new disease
mutations and the mutation rate was estimated to lie between 3.1x10-5 and
10.4x10-5. A parental age effect for new mutations was not demonstrated,
nor was a maternal effect on disease severity.
The clinical features and natural history of NF-1 in this cohort were
used to derive data for genetic counselling and recommendations for the
management of affected individuals. For counselling purposes the
complications of NF-1 can be usefully divided into 4 categories (the
frequency of each, based on this study, are shown in parentheses):
intellectual handicap (33% overall, moderate/severe retardation 3.2%,
minimal retardation/ learning difficulties 29.8%); complications developing
in childhood and causing lifelong morbidity, e. g. facial plexiform
neurofibromas, scoliosis, pseudoarthrosis (8.5%); 'treatable' complications
which can develop at any age, e. g. benign disorders of the nervous system,
visceral and endocrine tumours, renal artery stenosis (15.7%) and malignant
or CNS tumours (4.4-5.2%).
The study population indicates that sufferers are not being diagnosed
sufficiently early, nor receiving appropriate follow-up and counselling.
It is recommended that patients with NF-1 have regular clinical assessments
to monitor for the development of complications, although none occur often
enough to warrant biochemical or radiological screening. As many of the
complications develop early in life, children should have biannual review;
in adults, unless a particular complication indicates more frequent review,annual clinical examination is sufficient.
Alongside the population survey, genetic linkage studies were
undertaken in selected large families to determine the chromosomal
localisation of the NF-1 gene. At the outset of this work, two families
had been reported in which NF-1 and Myotonic Dystrophy (DM) appeared to
co-segregate, suggesting that the two genes were closely linked and on
chromosome 19. However, linkage studies of 3 chromosome 19 markers linked
to DM showed significantly negative lod scores, therefore excluding this
possibility. Other chromosomes were then studied using random unique
sequence DNA probes and samples from the largest families were made
available to collaborators in the USA for linkage studies using possible
candidate genes (ß nerve growth factor and oncogenes). No marker studied
showed evidence of linkage.
The negative data were used to produce an exclusion map for NF-1, using
the computer program 'EXCLUDE'. The presentation of this work was one of
the factors which precipitated the formation of an international consortium
for NF-1 linkage in February 1987; the first task of the consortium was to
produce an expanded exclusion map. A small positive lod score for a marker
on chromosome 17, taken with the exclusion data, showed that NF-1 was seven
times more likely to be on chromosome 17 than any other chromosome; this
was rapidly confirmed by two North American groups, one of which was using
samples from the 5 largest families presented in the thesis. Subsequent
linkage analysis of pericentromeric chromosome 17 markers in the Welsh
family panel showed no evidence of non-allelic heterogeneity and identified
closely linked flanking markers for the NF-1 gene suitable for
prenatal/presymptomatic diagnosis. The chromosomal localisation of NF-1
represents a major step towards the eventual understanding of the disease
pathogenesis and the development of possible treatments.