Section 1: Epidemiology and aetiology
The German pathologist Friedrich von Recklinghausen identified neurofibromas as tumours arising from a peripheral nerve sheath.
Neurofibromatosis (NF) is a neurocutaneous disorder resulting in the development of multiple tumours from the sheaths of peripheral and cranial nerves.
It is classified as type-1 (NF1, von Recklinghausen's disease) and type-2 (NF2). Both types are inherited in an autosomal dominant manner and NF1 is more prevalent than NF2.
It is estimated that half of NF cases are due to de novo mutations in the absence of a positive family history. Most of these are due to germ cell mutations that are paternal in origin.1 The severity of disease varies substantially within affected families making it difficult to predict morbidity from genetic testing alone.
NF1 occurs when there is a mutation of one copy of the NF1 gene on the arm of chromosome 17.2 Normally the NF1 gene encodes expression of a protein called neurofibromin, which acts as a tumour suppressor in the nervous system.
Mutation of the gene leads to aberrant protein expression.
In affected individuals, both benign and malignant tumours may proliferate in peripheral and cranial nerve sheaths.
Worldwide, the birth incidence of NF1 is estimated at between one in 2,500 to one in 3,000.3 The age at presentation varies but is usually in childhood and earlier than NF2.
NF1 affects multiple systems within the body.
Typical features of NF1 include cafe au lait macules, Lisch nodules in the iris and fibromatous tumours of the skin. It is associated with orthopaedic problems, such as scoliosis, congenital pseudoarthrosis and osteoporosis, cardiovascular problems, such as congenital heart disease, sarcomas, GI stromal tumours, cognitive as well as behavioural difficulties and neurological complications, such as epilepsy.
LIsch nodules are melanocytic iris hamartomas assessed by slit-lamp examination
NF2 occurs in around one in 25,000 people and presentation is at around 24 years.4 Features include bilateral acoustic neuromas and spinal tumours.
It is due to mutation of the NF2 gene located on chromosome 22.5 This gene encodes a protein called merlin, which also acts a tumour suppressor.
Section 2: Making the diagnosis
The diagnosis of NF1 or NF2 remains a clinical one. A comprehensive history and examination are crucial in the evaluation of suspected NF.
The diagnosis is based on a set of criteria established in the US in 1987 at the National Institutes of Health Consensus Development Conference.6 If there is any suspicion of NF prompt referral to a team specialist in the care of NF is essential.
Cafe au lait macules
There must be at least six cafe au lait macules. These are entirely benign, hyperpigmented macules varying in size from 1-3cm.
They may be present from birth and/or become more prominent during the first two years of life.
Freckling of the axilla or groin
Freckles are usually small (less or equal to 5mm) and appear between the ages of three and five years.
As well as the axillary and inguinal areas, freckling may be around the eyelids, the nape of the neck, under the chin or the submammary area.
Cutaneous and subcutaneous neurofibromas arise from tissue surrounding a peripheral nerve sheath and are generally benign.
They usually develop in the teens or early twenties and may present with localised pruritus.
Paraspinal neurofibromas may lead to spinal cord compression.
Plexiform neurofibromas are usually congenital. They involve multiple nerve bundles and may extend into surrounding structures while having the potential to transform into malignant peripheral nerve sheath tumours (MPNST).
MPNSTs tend to present with new onset pain in an existing plexiform neurofibroma or with neurological deficit.
Optic glioma may occur in the optic pathway of children with NF1. Gliomas may lead to proptosis or precocious puberty if there is extension into the hypothalamus.
Lisch nodules are melanocytic iris hamartomas, which occur in children aged between five and 10 years. They are assessed by slit-lamp examination.
NF1 patients may be of short stature and have bony problems including bowing of long bones, pathological fractures, scoliosis and sphenoid wing dysplasia. Plain X-rays may be required.
Other clinical features
Cognitive and behavioural difficulties tend to occur in children with NF1. They may have a lower than average IQ and problems with working memory, visuo-spatial tasks and autistic spectrum disorders.
In addition, NF1 patients are susceptible to congenital heart defects, renal artery stenosis and malignancies including phaeochromocytoma, sarcomas, leukaemia, GI stromal tumours and duodenal carcinoid.
Bilateral acoustic neuromas are commonly seen in children with NF2. They are almost always benign and usually present with hearing loss, tinnitus or imbalance, or a combination of all three.
Up to 30 per cent of NF2 cases present with symptoms from an intracranial meningioma (headaches, seizures), spinal tumour (pain, muscle weakness) or cutaneous tumour.
Cutaneous features are more subtle than those seen in NF1 and include plaque-like lesions with excess hair and subcutaneous nodular tumours on major peripheral nerves.
Cataracts are a major cause of sight impairment in patients with NF2 and often requires surgical correction.
Congenital cataract in a relative of a known NF2 patient should prompt a thorough evaluation for other signs of NF2.
Section 3: Managing the condition
The main principles of management in NF are patient education, regular surveillance for disease manifestations and genetic counselling.
Patients and their family should be aware of potentially significant symptoms, for example changes in vision, persistent pain in a plexiform neurofibroma or sphincter disturbance and focal weakness.
Patients may be distressed by the cosmetic appearance of multiple cafe au lait macules and this may be helped by skin camouflage. There is no evidence at present to suggest laser therapy should be used to treat macular lesions.7
Cutaneous neurofibromas are often irritating as they catch on clothing and are painful and itchy. Antihistamines do not usually alleviate the itch and emollients are advised.
Cutaneous neurofibromas may be painful or itchy
If necessary, the neurofibromas may be removed by a dermatologist or plastic surgeon but there is a risk of hypertrophic scarring and recurrence in the affected area. Similarly, removal of subcutaneous neurofibromas should be left to expert hands and the patient should be aware of the risk of permanent nerve damage post-resection.
If there is any suspicion of malignant transformation of a plexiform neurofibroma the patient should be referred for assessment immediately.
Fluorodeoxyglucose positron emission tomography is a useful diagnostic tool in differentiating benign from malignant lesions.8
If an MPNST is present, complete resection with tumour-free margins and adjuvant radiotherapy is the treatment of choice. Angiogenesis inhibitors have shown promise in the treatment of MPNSTs and are undergoing clinical trials in the treatment of plexiform neurofibromas and spinal neurofibromas.9
Children with NF1 aged seven years or younger should have an annual ophthalmology review as they are at highest risk of developing optic gliomas.10
Their visual acuity should be measured and fundoscopy performed to look for disc pallor. A change in acuity would necessitate a brain MRI and regular neuro-ophthalmology and endocrine review.
Chemotherapy is used in some cases but radiotherapy is relatively contraindicated due to the associated increased risk of consequent CNS malignancy. There is no specific treatment for Lisch nodules seen on slit-lamp examination.
Children with NF1 need annual assessment of the spine. Any evidence of scoliosis should precipitate referral to an orthopaedic surgeon who may recommend a brace or corrective surgery.
Patients with severe scoliosis require regular pulmonary function tests.
Bowing of the long bones may be apparent from birth and can lead to pathological fractures. These often require surgical correction and amputation in some cases.
As a bare minimum, NF1 patients should have annual BP measurement. If there is any hypertension, renal arteriography and a 24-hour urinary excretion for catecholamines should be arranged to exclude renal artery stenosis and phaemochromocytoma, respectively.
Patients with a murmur should be referred to a cardiologist.
Patients with NF1 often have a lower than average IQ and learning difficulties. In order to maximise their potential, a detailed developmental assessment should be performed and this should continue throughout school years.
Teachers, educational psychologists, community paediatricians and occupational therapists should be involved.
If the child has ADHD, methylphenidate and CBT may be of use.11 Recent studies in mice have suggested a role for statins in the reversal of cognitive deficits.12
Anxiety and depression commonly respond to antidepressants and counselling. Psychiatrists experienced in handling NF1 cases can be called upon in recalcitrant cases.
Individuals with known NF2 should have at least biannual craniospinal MRI, and annual audiology, cutaneous and ophthalmological evaluations.
Treatment is indicated where there is a risk of brainstem compression, or a change in hearing or facial nerve paresis. These tumours are generally managed surgically and patients should be aware of the risk of permanent facial nerve damage intraoperatively.
The role of radiotherapy is controversial and there is much concern about an increased risk of secondary malignancy.
These are managed surgically; radiotherapy is used if the tumours are anatomically inaccessible or only partially resected.
Intramedullary spinal tumours
It is relatively uncommon for these tumours to require intervention but treatment is generally surgical resection rather than radiotherapy.
Section 4: Prognosis and follow up
NF1 and NF2 are both chronic diseases associated with significant morbidity and a shortened life expectancy. Analysis of more than 32 million deaths in the US revealed that NF1 patients had a mean age of death of 54.4 years compared with 70.1 years for the general population that year.13
Those under 30 years with NF1 are more likely to have a malignant neoplasm or vascular disease documented as a cause of death.
These findings were substantiated by a UK study showing the overall cancer risk was 2.7 times higher in the NF1 population, mainly due to an increase in CNS and connective tissue tumours.14 The increased cancer risk was more evident below the age of 50 years.
The mean survival of patients with NF2 in the UK has been estimated to be 62 years.15 There is a correlation between severity of disease and age of death. The risk of mortality increases if the diagnosis is made at a young age and is greater in people with intracranial meningiomas compared with those without meningiomas.16
There is evidence that referral to a specialist centre for regular screening for complications of NF1 and NF2 optimises care and lowers the risk of mortality.16
Patients should have regular follow up with clinicians skilled in the diagnosis and management of NF1 and 2.
Such specialists would include paediatricians, neurologists, dermatologists and geneticists.
Section 5: Case study
A four-year-old girl presents with a painful left ear. She is a new patient to the practice having arrived in the UK from north Africa with her family six months previously.
Routine developmental history revealed delayed gross motor milestones and she had not walked until 30 months.
Although she spoke and interacted, much of the speech was unrecognisable to her family. Her mother gave a history of numerous birth marks that had multiplied from birth and of a lumpy area on the arm.
There was no family history of note and her siblings had normal developmental histories.
Cafe au lait macules
On examination, the left eardrum was bulging and dull and she was diagnosed with otitis media. Examination of the skin revealed 16 cafe au lait macules on the trunk and arms, an indistinct 1x1.5cm mass on left forearm and freckling in the axilla and on the neck.
Her GP suspected NF and referred the girl to paediatric outpatients, where the diagnosis was confirmed. The girl was sent for an ophthalmic and orthopaedic assessment.
Other family members were screened for signs of NF1 and offered genetic counselling.
Occupational therapy has helped improve the patient's life at home. The NF team at a tertiary care centre reviews the girl annually.
Section 6: Evidence base
A number of trials are underway and actively recruiting to establish novel therapeutic strategies for NF1 and NF2.
- Pilot study of imatinib mesylate (STI-571, NSC 716051) in neurofibromatosis (NF1) patient with plexiform neurofibromas - Indiana University.
- This is a trial to use the tyrosine kinase inhibitor imatinib in the treatment of plexiform neurofibromas in NF1.
- Imatinib is an oral preparation best known for the treatment of chronic myeloid leukaemia.
- AZD2171 in treating patients with neurofibromatosis type-1 and plexiform neurofibroma and/or neurofibroma near the spine - Mayo Clinic.
- Angiogenesis inhibitors, which are used to treat metastatic colon cancer and diabetic retinopathy, are being evaluated in the treatment of plexiform neurofibromas in NF1 and in vestibular schwannomas in NF2.
Assessment of the efficacy and safety of drugs to treat the cognitive and behavioural symptoms of NF is also ongoing.
To date there are no formal NICE or SIGN guidelines on the management of neurofibromatosis.
These review papers provide guidance on the diagnosis and management of suspected neurofibromatosis:
- Ferner RE, Huson SM, Thomas N et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007; 44(2): 81-8.
This paper contains a series of useful tables concerning diagnostic criteria and assessment of children with NF1.
- Evans DG, Sainio M, Baser ME. Neurofibromatosis type 2. J Med Genet 2000; 37(12): 897-904.
This sets out the diagnostic criteria and recommended management of NF2 in a clear and concise manner.
- NHS Evidence
An excellent summary of NF1 diagnosis and management with clinical scenarios and useful links. www.library.nhs.uk/geneticconditions/viewresource.aspx?resID=112038
- Neurofibromatosis Association
The UK's leading authority on NF. The website contains invaluable information, practical advice and links to a network of UK advisors on NF for professionals and families. www.nfauk.org/nf/18
- Children's Tumour Foundation
This is a link to a series of podcasts covering topics including behavioural difficulties, pain management, dermal neurofibromas and future directions of research. www.ctf.org/For-Scientists/medical-podcasts.html
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