1 Introduction and classification
The neurofibromatoses (NFs) are autosomal dominant neurocutaneous disorders that can be divided into ‘peripheral’ and ‘central’ types, although there is significant overlap. The most common type of neurofibromatosis is NF1 (von Recklinghausen's disease or ‘peripheral’ neurofibromatosis). Less commonly one encounters NF2 (‘bilateral acoustic neuromas’ or ‘central’ neurofibromatosis) or a localized form of the disease (‘segmental neurofibromatosis’) (Miller and Sparks 1977).
Segmental neurofibromatosis is characterized by localized cutaneous neurofibromas and café-au-lait spots limited to one segment of the body, but which can include underlying intrathoracic or intra-abdominal neurofibromas.
Diagnostic criteria for NF1 have been developed by the Neurofibromatosis National Institutes of Health Consensus Conference (National Institutes of Health Consensus Development Conference 1988). Although not specifically mentioned in this diagnostic categorization, it is well recognized that 100 per cent of patients with NF1 will develop Lisch nodules in the iris. A grading system has also been devised for neurofibromatosis type 1 (Riccardi and Kleiner 1977).
Neurofibromatosis type 2 (NF2) is also known as ‘bilateral acoustic neurofibromatosis’ or ‘central neurofibromatosis’, because of the predisposition to develop tumours of the nervous system.
Diagnostic criteria for NF2 are:
- bilateral acoustic neuromas; or a first-degree relative with NF2
- either a unilateral acoustic neuroma, neurofibroma, glioma, meningioma, schwannoma, or early onset lens opacity.
The severity of phenotypes can be defined by age of onset of symptoms (<20 years versus >20 years), number of associated intracranial tumours (<2 tumours versus >2 tumours), and whether spinal tumours are present or absent (Evans et al. 1992a; Parry et al. 1994).
Diagnostic criteria for Neurofibromatosis type 1 (from National Institutes of Health Consensus Development Conference (1988). Neurofibromatosis conference statement. Arch. Neurol., 45, 575–8)
Two or more of:
- Six or more café-au-lait macules measuring →5 mm in greatest diameter in prepubertal individuals and →15 mm in greatest diameter in post-pubertal individuals
- Axillary or inguinal freckling
- Two or more dermal neurofibromas
- A plexiform neurofibroma
- A first-degree relative with NF1 (by the NIH consensus statement criteria)
- Optic nerve glioma
- Two or more Lisch nodules
- A distinctive osseous lesion (e.g. sphenoid dysplasia or thinning of the long bone cortex)
2 Incidence and prevalence
Neurofibromatosis affects all races and has an estimated frequency of approximately 1 in 3000 of live births and a mutation rate of 1 × 104 per gamete per generation (Crowe et al. 1956). The point prevalence of NF1 is at least 1 in 4950 (20.2/105) and NF1 accounts for 90 per cent of cases of NF (Huson et al. 1989a). The incidence and prevalence of NF2 is uncertain, but is thought to occur in approximately 1 in 40 000 live births (Evans et al. 1992b; NIH Consensus Statement 1991).
3 Genetic factors
Neurofibromatosis type 1 is an autosomal dominant condition, but about 50 per cent of all cases are new mutations. The gene for NF1 (von Recklinghausen's disease) was isolated in 1991 and is situated on chromosome 17 (17q11.2). One role of neurofibromin is as a GTPase activating protein (GAP), probably in the same pathway of signal transduction as ras proto-oncogene and involved in the regulation of cell growth. It is likely that neurofibromin is important in the formation of neurofibrosarcomas (von Deimling et al. 1995).
The NF2 tumour suppressor gene is on chromosome 22q12 and encodes for a protein (‘merlin’ or ‘schwannomin’) of the 4.1 family of cytoskeletal-associated proteins, which may link the cytoskeleton and cell membrane.
Most of the tumours associated with NF2 are benign (e.g. schwannomas, meningiomas, ependymomas). These tumours also occur sporadically in the general population. In sporadic cases of acoustic neuroma and some cases of meningioma NF2, there are also aberrations at the NF2 locus, strongly suggesting that there is a tumour suppressor gene at this site.
DNA-based diagnostic testing is now available for neurofibromatosis. Presymptomatic diagnosis is possible in multigeneration NF2 families using tightly linked DNA markers and mutational analysis (Bijlsma et al. 1995). In at-risk individuals who do not carry the NF2 mutation, DNA testing can exclude the condition and prevent needless clinical investigations (Baser et al. 1996).
4 Clinical features and imaging diagnosis
Neurofibromatosis type 1
The characteristic features of NF1 are café-au-lait spots, neurofibromas, Lisch nodules, osseous lesions, macrocephaly, short stature and mental retardation, axillary freckling, and can be associated with several different types of tumours. Café-au-lait spots tend to increase in number and size in the first and second decades.
Cutaneous neurofibromas are soft, violet-coloured lesions, varying from 0.1 cm to several centimetres in diameter. Subcutaneous neurofibromas commonly appear after the age of six and are present in all affected cases by age 17. They are firm nodules in the distribution of the trunks of peripheral nerves.
They increase in number and size, especially during pregnancy or with use of the oral contraceptive pill. Lisch nodules are melanocytic hamartomas of the iris (brown nodules), which develop in early childhood and are seen by slit-lamp examination in 93–100 per cent of patients with NF1 by the age of 20 years (Huson et al. 1989a; Lubs et al. 1991).
Plexiform schwannomas are benign peripheral nerve sheath tumours that generally arise in the dermis or subcutaneous tissues. They may be single or multiple, focal or diffuse. Plexiform neurofibromas of the eyelid are frequently associated with glaucoma.
Malignant schwannomas occur in almost 30 per cent of patients, and sarcomatous degeneration in neurofibromas occurs in 1–5 per cent of patients (Brasfield and Das Gupta 1972; Huson et al. 1988).
Sudden enlargement of plexiform neurofibromas or the occurrence of pain should lead to urgent investigation for evidence of malignant peripheral nerve sheath tumour.
It has been suggested that there is a fourfold increase in relative risk of cerebral tumours (Sorensen et al. 1986). Intracerebral tumours occur in 1.5–8 per cent of cases of NF1 (Brasfield and Das Gupta 1972; Huson et al. 1989b). These are commonly optic nerve or brainstem gliomas or gliosarcomas.
Optic nerve glioma associated with neurofibromatosis accounts for almost 10 per cent of all patients with optic nerve gliomas, and approximately 1.5% of patients with NF1 will develop an optic nerve glioma. These tumours are commonly bilateral or involve the optic chiasm (Font and Ferry 1972; Listernick et al. 1989). Occasionally, optic nerve gliomas extend into the hypothalamus and cause precocious puberty. Optic nerve gliomas are commonly low grade and may not progress for many years (Listernick et al. 1994). There appears to be an association between plexiform eyelid neurofibromas and optic nerve glioma. There is also a high frequency of second malignancies (40% of patients).
The frequency of aqueduct stenosis is increased in NF1 (Senveli et al. 1989). Ventriculo-peritoneal shunting or ventriculo-atrial shunting should only be contemplated in symptomatic patients (Spadero 1986). Up to 40 per cent of patients with NF1 have mild learning difficulties and 6–10 per cent have epilepsy, which may be associated with minor abnormalities such as gliosis, neuronal heterotopia, and ependymal overgrowth (Carey et al. 1979; Riccardi 1981).
Bony anomalies, such as scoliosis, bone cysts, bone hypertrophy, or skull and facial deformities, occur in 40–60 per cent of patients with NF1. Orthopaedic complications such as scoliosis and pseudoarthrosis of the tibia or fibula occur in about 9 per cent of patients (Akbarnia et al. 1992).
Gastrointestinal neurofibromas are usually asymptomatic but can cause abdominal pain. Renal hypertension occurs in 1.5 percent of affected individuals, sometimes as a result of renal artery stenosis. Phaeochromocytoma affects less than 1 per cent of all cases (Huson 1994). Screening non-hypertensive patients for phaeochromocytoma is not cost effective (Riccardi and Eichner 1986).
In NF1, optic nerve gliomas, astrocytomas, plexiform neurofibromas, and ‘unidentified bright objects’ may only be identified by MR. Prenatal risk assessment is only possible in NF1 families if two or more suitable family members are available for blood donation, for study of intragenic polymorphic markers. There is usually no increased risk during pregnancy, but if there is significant kyphoscoliosis labour can be difficult and, rarely, there may be pelvic neurofibromas that can obstruct labour.
Neurofibromatosis type 2
In NF2 typical tumours are benign schwannomas of the vestibular portion of the acoustic nerves, although meningiomas frequently coexist. 95% of patients with an acoustic neuroma do not have NF2. Most commonly, patients with NF2 have few or no cutaneous manifestations of neurofibromatosis; however, café-au-lait spots, axillary freckling, and subcutaneous neurofibromas do rarely occur.
Multiple cutaneous plexiform schwannomas can also occur occasionally in NF2. There may be a family history of acoustic neuroma. More than 95 per cent of people with the NF2 gene develop bilateral vestibular nerve tumours. Presentation is generally with deafness or tinnitus, although headache, vertigo, or unsteadiness related to cerebellar involvement can occur. The characteristic hearing-loss pattern is sensorineural hearing loss with impairment of speech discrimination more so than pure tone loss. There is delayed conduction on brainstem auditory evoked potentials.
Bilateral acoustic neuromas of NF2 are likely to be identified earlier by MRI than by CT. Most tumours are hypointense (66 per cent) or isointense (33 per cent) with brain on T1-weighted images. All enhance with gadolinium, either homogeneously (66 per cent) or patchily (33 per cent). The coexistence of NF and tuberous sclerosis or von Hippel–Lindau disease is well recognized.
Neurofibromatosis type 1
Although CNS tumours, aqueduct stenosis, and high-signal lesions on T2-weighted MRI scans are more commonly found in patients with NF1, MRI brain scans are not justified in the absence of symptoms or signs. MRI is the most useful diagnostic investigation in patients with cognitive or focal symptoms. High-signal areas on T2-weighted MRI scans are common in neurofibromatosis type 1 (approximately 50%) but are of no direct relevance in the absence of cognitive or focal symptoms or signs (Duffner et al. 1989; Sevick et al. 1992).
MRI of the brain should include orbits and optic nerves if there is any visual field defect, new visual acuity problem, cognitive problem, or focal neurological signs suggestive of an intracranial cause.
Optic nerve gliomas virtually never develop after age 30.
Neurofibromatosis type 2
The defining feature of NF2 is bilateral vestibular schwannomas (acoustic neuromas). Increasingly, small asymptomatic acoustic neuromas are being identified. It is uncertain what the best form of management is, and some centres favour a wait-and-see approach, while others advise early stereotactic radiosurgery or even neurosurgery.
6 Prognosis and complications of treatment
Malignant neoplasms or benign central nervous system tumours occur in 45 per cent of probands. The prognosis in patients with tumours affecting the nervous system depends on the age of the patient, the type of tumour, the site of the tumour, and the level of disability at the time of presentation. The complication rate from treatment of these tumours appears to be no higher than in patients with these tumours but without neurofibromatosis. Epilepsy is well controlled with medication in approximately 50–70% of patients.
Hypertension will increase the risk of cerebrovascular disease and there is possibly a higher incidence of cerebral aneurysm and stenosis of intracranial major arteries. Scoliosis and thoracic neurofibromas may lead to thoracic pain, chest infections, and reduced lung volumes. Hydronephrosis due to neurofibromas can lead to renal failure and abdominal pain.