Neurofibromatosis is now known to be one of the most common genetic disorders in humans and gained public notoriety when it was suggested that Joseph Merrick, the ‘elephant man’ was probably affected. However, subsequent review of Merrick’s photographs and skeleton led to the conclusion that he did not have neurofibromatosis but instead had a much rarer disorder known as the Proteus syndrome.

There are two main types of neurofibromatosis, NF1 and NF2. NF1 is by far the more common with an incidence at birth of approximately 1 in 35 000 and a prevalence of around 1 in 200 000, and is described here.

The most notable features of NF1 are small pigmented skin lesions, known as café-au-lait spots, and small soft fleshy growths known as neurofibromata. Café-au-lait spots first appear in early childhood and continue to increase in both size and number until puberty. A minimum of six café-au-lait spots at least 5 mm in diameter are required to support the diagnosis in childhood. Neurofibromata are benign tumours which arise most commonly in the skin. They usually appear in late childhood and adult life and show an increase in number with age.

Other clinical findings in NF1 include axillary freckling, macrocephaly (large head), mild developmental delay, and Lisch nodules. These are small harmless raised pigmented hamartomata of the iris. Most individuals with NF1 enjoy a normal healthy life and are not unduly inconvenienced by their condition. Unfortunately a small number of patients develop one or more major complications such as epilepsy, a central nervous system tumour or a scoliosis.

NF1 shows autosomal dominant inheritance with almost complete penetrance by the age of 5 years. Expression is very variable and affected members of the same family can show quite striking differences in disease severity. The features in affected identical twins are usually very similar so that variable expression in family members, who must have the same mutation, is probably due to the effects of modifying genes at other loci. Approximately 50% of cases of NF1 are due to new mutations, with the estimated mutation rate being approximately 1 per 100 000 gametes. This is around 100 times greater than the average mutation rate per generation per locus in humans.

Sequence analysis of the NF1 gene has shown that it encodes a protein, known as neurofibromin. This shows structural homology to the GTPase activating protein (GAP), which plays an important role in signal transduction by downregulating RAS activity. The NF gene plays an important role in cell growth and differentiation.

Over 100 different mutations have been identified in the NF1 gene. These include deletions, insertions, duplications and point substitutions. Most of these mutations lead to severe truncation of the protein or complete absence of gene expression. To date there is little evidence for a clear relationship between specific mutations and clinical features. This is consistent with reports of quite striking intrafamilial variation and points to the effects of modifier genes. Patients with large deletions which include the entire NF1 gene tend to be severely affected with more severe intellectual impairment than is usual in NF1 as well as a larger than average number of cutaneous neurofibromata.