The neurofibromatoses are among the most common and clinically important disorders affecting the human nervous system and are associated with the most common tumours, such as neurofibroma, acoustic neuroma, meningioma, and astrocytoma.

Two well-defined forms of neurofibromatosis are recognized: type 1 and type 2. Although other types may exist they are not yet well characterized. The condition is diagnosed using a combination of physical examination and radiological imaging. Both type 1 and type 2 neurofibromatosis are transmitted in an autosomal dominant manner, and show high penetrance. The loci of the genes coding for type 1 and type 2 have recently been assigned to chromosome 17 and chromosome 22 respectively. The genes have been cloned and the protein sequences identified.

Neurofibromatosis type 1 occurs approximately once in every 4000 births, and half of these patients inherit the disorder from an affected parent. The others represent new mutations of this gene, which has a high rate of spontaneous mutation. Although the condition is common and is highly penetrant, expression is variable. Its most common manifestations are multiple cutaneous neurofibromas, café-au-lait marks, freckling in the axillae or groin creases, and Lisch nodules of the iris. Other diagnostic features include developmental abnormalities of the skeletal system such as sphenoid wing dysplasia, scoliosis, congenital pseudoarthrosis, and thinning of the tibia or other long bones. Learning disorders, and macrocephaly may also be present.

Plexiform neurofibromas are peripheral nerve tumours composed of Schwann cells, fibroblasts, and connective tissue. Complete surgical removal may entail resection of the nerve as well as the tumour. Most neurofibrosarcomas in patients with neurofibromatosis type 1 probably arise from plexiform neurofibromas. An enlarging lesion or one associated with pain should have biopsy specimens taken to allow the possibility of malignant degeneration to be assessed.

Most spinal nerve root neurofibromas remain asymptomatic and do not need to be removed. Non-invasive screening of patients with neurofibromatosis type 1 can be performed using MRI; this allows early treatment of expanding lesions.

Low grade astrocytomas of the optic pathways affect about 10 per cent of patients with neurofibromatosis type 1; most of them cause no symptoms. The radiological picture of an optic glioma is so typical that biopsy examination is rarely required for confirmation of the diagnosis. Although less common than optic gliomas, astrocytomas of the brain occur in patients with neurofibromatosis type 1 at a higher incidence than in the general population.

Neurofibromatosis type 2 is less common (less than 1 in 100000 births) than neurofibromatosis type 2, but the growth of multiple intracranial and spinal tumours can cause progressive neurological dysfunction. The hallmark of type 2 disease is bilateral acoustic neuromas, Schwann cell tumours of the eighth cranial nerve. A diagnosis of neurofibromatosis type 2 should be considered in any individual with a first-degree relative (parent, child, sibling) with documented neurofibromatosis type 2, in children with a meningioma or schwannoma, in patients developing an acoustic neuroma before the age of 30 or with multiple neurological tumours of uncertain cause, and in patients for whom a possible diagnosis of neurofibromatosis type 1 is raised, but who do not fit the standard criteria for this condition.

Lisch nodules are absent in patients with neurofibromatosis type 2, but presenile lens opacities occur in half of these patients and may serve as a marker for the presence of the gene in some families. However, because skin stigmata may be minimal, the diagnosis of neurofibromatosis 2 rarely rests upon physical examination alone. Anyone in high-risk categories should undergo high resolution gadolinium-enhanced MRI scanning. This is the most sensitive screening test for neurofibromatosis type 2. If MRI is not available, an audiogram, with determination of word discrimination, and testing of brain-stem auditory evoked responses will detect all but the smallest intracanalicular tumours. Patients with definite neurofibromatosis type 2 should undergo MRI of the entire neuraxis to establish the tumour burden and to plan future care.

Bilateral acoustic neuromas are typical of neurofibromatosis type 2. These schwannomas generally arise from one of the two vestibular branches, allowing complete removal of small tumours or partial removal of large tumours with preservation of hearing in some cases. Spinal nerve root Schwann cell tumours occur in both type 1 and type 2 neurofibromatosis. They are often multiple and their diagnosis and indications for treatment are similar in both disorders; however, in type 1 disease they are usually neurofibromas, while in type 2 the histology is typically that of a schwannoma. Meningiomas in patients with neurofibromatosis type 2 are often multiple. Some may remain stable for years without requiring treatment, while others may grow and need removing, and others may progress to malignancy. Spinal ependymomas are also common and are treated by surgery, and sometimes with radiation therapy if symptomatic.

In the general population sporadic meningiomas are commonly associated with loss of one copy of chromosome 22. Acoustic neuromas in patients with neurofibromatosis type 2 have also been shown to be associated with a loss of genetic material on chromosome 22. Similar results were found in a study of DNA from meningiomas. It was later shown that loss of genetic material on chromosome 22 is associated with all of the tumour types in patients with neurofibromatosis type 2. These studies provide a unifying model for the development of schwannomas and meningiomas. The long arm of chromosome 22 contains a gene (or genes) in the general class of tumour suppressors or anti-oncogenes; loss or inactivation of both copies of this gene leads to tumour formation. This mechanism is similar to that proposed for retinoblastoma. The neurofibromatosis type 2 gene has been cloned. Its protein is called Merlin.

Genetic linkage studies of multiple families have allocated the gene for neurofibromatosis type 1 to chromosome 17, and a large portion of this gene has been cloned. The neurofibromatosis type 1 protein is called neurofibromin. However, the means by which this gene causes the tumours associated with neurofibromatosis type 1 (neurofibroma, astrocytoma) is not yet clear. Loss of part or all of one copy of chromosome 17 has not yet been demonstrated in such tumours. The genes coding for types 1 and 2 neurofibromatosis may induce tumour formation by different mechanisms.