Neuro Fibroma to Ses

REVIEW

82 Ferner

10.1136/jnnp.2010.206532

Pract Neurol 2010; 10: 82–93

The neurofibromatosesRosalie E Ferner

• Axillary or groin freckling

• Two or more neurofbromas or one plexi-

form neurofi broma

• Lisch nodules in the Iris

• Optic pathway glioma

• Bony dysplasia of the sphenoid wing

• Pseudarthrosis of the long bones

In practice, the diagnosis is straightforward on

clinical inspection in most adults, but note:

• Although café au lait patches are present

in 99% of patients by the age of 5 years,

they fade in some older people or become

obscured in individuals with many cuta-

neous neurofi bromas.

• Café au lait patches may be the only

sign in young children, even without

a family history of NF1, because other

symptoms develop later in childhood or

adolescence.

• About 10% of the general population

have one to two café au lait patches.

• In mosaic NF1, the mutation occurs after

fertilisation in contrast with classical NF1

where the mutation is already present in

the sperm or egg before fertilisation. The

proportion of the body that is affected is

determined by the timing of the mutation.

Neurofi bromatosis 1 (NF1) and neurofi bromatosis 2 (NF2) are inherited autosomal

dominant disorders that have a signifi cant impact on the nervous system and

predispose to tumour formation. The current nomenclature makes NF1 and NF2

awkward bedfellows because they are clinically and genetically separate disorders.

Neurofi bromas are characteristic of NF1, a common condition with major skin

involvement and many clinical complications. By contrast, schwannomas are the

distinctive lesions in NF2, cutaneous signs are less prominent in this rarer disorder

and clinical manifestations are largely restricted to the nervous system and eye.

The current aim of neurofi bromatosis specialists is to provide cohesive standards

of care for everyone with neurofi bromatosis and to devise standardised protocols

for assessment and management within a multidisciplinary setting.

Correspondence to

Dr RE Ferner, Consultant

Neurologist and Lead Clinician for

Neurofi bromatosis Service, Guy’s

and St Thomas’ Hospitals NHS

Trust, and

Honorary Senior Lecturer in

Neurology King’s College London,

Department of Neurology, Guy’s

Hospital, Great Maze Pond, London

SE1 9RT, UK; rosalie.ferner@

kcl.ac.uk

INTRODUCTIONIncreasing cooperation between clinicians

and scientists in recent years has led to a bet-

ter understanding of the clinical and genetic

characteristics of neurofi bromatosis 1 (NF1)

and neurofi bromatosis 2 (NF2). The neurofi -

bromatoses fall fi rmly within the sphere of the

neurologist who is ideally placed to coordinate

the care of these complex disorders.

NEUROFIBROMATOSIS 1Diagnosis and differential diagnosesIn 1882 von Recklinghausen described benign

tumours arising from the peripheral nerve

sheath as ‘neurofi bromas’.1 The condition was

then named after him until the 1987 National

Institutes of Health Consensus Development

Conference formulated the current diagnostic

criteria and proposed that it should be called

NF1.2 The clinical diagnosis is based on the

presence of at least two major disease fea-

tures2 3 out of the following:

• A fi rst degree relative with NF1

• Six or more café au lait patches which

may be present at birth or, if not, they

appear in the fi rst few years of life

04_pn206532.indd 8204_pn206532.indd 82 3/6/2010 4:56:04 PM3/6/2010 4:56:04 PM

83Ferner

www.practical-neurology.com

Mutations occurring early in embryonic

development produce mild generalised

disease indistinguishable from classical

NF1. Later mutations result in disease

manifestations that are restricted to

one segment of the body. For instance,

an individual with segmental NF1 might

present with café au lait patches, neuro-

fi bromas or freckling but only in one body

segment.4 The importance of mosaicism is

that NF1 complications are infrequent in

individuals with mosaic disease and the

risk of passing on classical NF1 is low (see

section on genetic counselling below).

• Patients with the recently reported Legius

syndrome also present with café au lait

patches and axillary freckling in asso-

ciation with mild cognitive problems and

macrocephaly.5 Affected individuals have

no neurofi bromas or other NF1 compli-

cations (this syndrome is associated with

SPRED1 mutations on chromosome 15,5

a member of the SPROUTY/SPRED family

of tumour suppressor proteins). Although

there is clinical overlap between NF1 and

Legius syndrome, they are genetically

separate and Legius syndrome has a sig-

nifi cantly milder phenotype than NF1.

• Symmetrical multiple spinal nerve root

neurofi bromas and café au lait patches

characterise the rare hereditary spinal

neurofi bromatosis in which NF1 muta-

tions have been identifi ed but there are

no other NF1 disease features.

• NF1 can also be confused with syndromes

causing localised tissue overgrowth, and

with different forms of pigmentation.3 For

example, clinicians should be wary when

a patient is referred with ‘nerve sheath

tumours’ without any other neurocutane-

ous problems because multiple lipomas

can be inherited in an autosomal dominant

fashion. Firm, occasionally painful subcu-

taneous lumps develop in the late twen-

ties or early thirties on the distal arms,

trunk and proximal thighs; the diagnosis is

confi rmed by excision and histology.

Epidemiology and geneticsNF1 has a birth frequency of 1 in 2500–3000,

a minimum prevalence of 1 in 4–5000 and

about 50% of affected individuals have new

mutations.6 The gene was cloned on chro-

mosome 17q11.2 in 1990. Neurofi bromin, the

protein product, is widely expressed with high

levels in the nervous system.7–9 It acts as a

tumour suppressor which explains why NF1

Figure 1Cutaneous neurofi bromas in an adult male with neurofi bromatosis 1.

Figure 2Subcutaneous neurofi bromas in an adult male with neurofi bromatosis 1.


84 Practical Neurology

10.1136/jnnp.2010.206532

patients are prone to developing benign and

malignant tumours. It also reduces cell growth

and proliferation by negative regulation of

the cellular proto-oncogene p21RAS and by

control of the serine threonine kinase MTOR

(mammalian target of rapamycin).10 11

Table 1 Clinical manifestations of neurofi bromatosis 1

Skin Café au lait patchesAxillary and groin frecklingFreckling under breasts and around neck

Hypopigmented macules

Cutaneous angiomas

Xanthogranulomas—orange papules (occur

transiently in childhood)

Cutaneous neurofi bromasSubcutaneous neurofi bromas

Glomus tumour

Nervous system Plexiform neurofi bromasMalignant peripheral nerve sheath tumour

Neurofi bromatous neuropathy

Aqueduct stenosis

Chiari 1 malformation

Sphenoid wing dysplasia

Macrocephaly

EpilepsyCognitive impairmentMultiple sclerosis

Cerebrovascular disease

Brain tumours (astrocytomas)

Optic pathway gliomaThe eye Lisch nodules

Bilateral congenital ptosis

Glaucoma

Choroidal abnormalitiesBone Scoliosis—idiopathic and dystrophic

Pseudarthrosis of a long bone

Osteoporosis

Short stature

Cardiovascular disease Congenital heart disease—pulmonary

stenosis

HypertensionRenal artery stenosis

Respiratory disease Compression from neurofi broma causing

restrictive lung defect

Pulmonary metastases from malignant

peripheral nerve sheath tumour

Gastrointestinal disease Gastrointestinal stromal tumour

Dysplasia

Duodenal carcinoid tumour

Other tumours Breast carcinoma

Phaeochromocytoma

Common clinical features are in bold typeface.

Clinical featuresThe complications of NF1 vary between individ-

uals, involve many of the body systems and are

unpredictable within families.3 Many of the seri-

ous complications occur in childhood, including

orthopaedic problems, disfi guring plexiform

neurofi bromas, optic pathway gliomas, renal

artery stenosis and cognitive impairment.

The skinSkin manifestations are listed in table 1.

Recently, glomus tumours have been described

in association with NF1 but their frequency is

unknown. Glomus bodies are the normal small

dermal arteriovenous anastomoses that control

body temperature, found mostly in the skin of

the fi ngers and toes. The tumours can be sin-

gle or multiple and are located under the nail

bed. They cause pain, sensitivity to cold and

exquisite localised tenderness.12 Sometimes a

bluish discolouration is noticeable under the

nail bed. MRI can be helpful in showing the

lesions. If there is a high index of suspicion,

surgical exploration should be considered

because removal alleviates the symptoms

Neurological complicationsNeurological complications affect both the

peripheral and central nervous systems, account-

ing for signifi cant morbidity and mortality in NF1.

Neurofi bromas

Neurofi bromas are the cardinal manifestation

of NF1. These benign peripheral nerve sheath

tumours contain a mixture of Schwann cells,

fi broblasts, perineurial cells, mast cells and

axons embedded in an extracellular matrix.13

The distinction between the different types of

neurofi bromas produces heated debate among

‘neurofi bromatologists’; this stems from the

importance of identifying the neurofi bromas

that cause signifi cant neurological defi cit or have

malignant potential. Neurofi bromas can form as

localised cutaneous (fi gure 1) or subcutaneous

(fi gure 2) growths, spinal nerve root tumours, or

plexiform lesions (fi gure 3) that involve multi-

ple fascicles or large nerves, frequently infi ltrat-

ing surrounding tissue and blood vessels.3 They

should be distinguished from schwannomas.

Cutaneous neurofi bromas develop in 99% of

patients, usually in early adulthood, but they

can appear in childhood. They increase in size

and number during pregnancy but are unaf-

fected by hormonal contraceptives. Emerging

lesions have a purplish colour, and itching and


85Ferner


MRI can show the site and extent of the

tumour but 18[F] 2-fl uoro-2-deoxy-D-glucose

positron emission computerised tomography

with delayed imaging and targeted biopsy

is the most sensitive and specifi c diagnostic

strategy.20 The goal of treatment is complete

removal of the tumour with clear margins.

Radiotherapy is administered for high grade or

incompletely excised lesions, and chemother-

apy with ifosfamide and doxorubicin provides

palliation for patients with extensive disease.15

Spinal nerve root neurofi bromas

These can be asymptomatic or cause pressure

on the adjacent spinal nerve root or spinal

cord.3 High cervical nerve root neurofi bromas

are prone to compress the cord but the neuro-

logical defi cit is frequently mild in comparison

with the neuroimaging appearances. Patients

require careful evaluation by a multidisciplin-

ary team conversant with the variable natural

history of these neurofi bromas and the risks of

NF1 related surgery.

Axonal symmetrical neurofi bromatous

neuropathy

This affects as least 1% of NF1 adults. They

present with mild distal sensory and motor

symptoms. Thickened peripheral nerves are

infi ltrated with neurofi bromatous tissue.18

Although NF1 neurofi bromatous neuropathy

is not progressive, affected individuals require

assiduous monitoring because they are at

risk of developing malignant peripheral nerve

sheath tumours.18

Cerebral malformations

Chiari 1 malformation and aqueduct stenosis

due to subependymal glial cell proliferation are

encountered in 1.5% of NF1 patients. Sphenoid

wing dysplasia is noticeable as pulsating

exophthalmos without visual compromise; the

absent sphenoid wing allows the temporal lobe

to prolapse forwards into the orbit but surgical

correction is not usually undertaken.3

Epilepsy

Epilepsy is diagnosed in about 6% of NF1

patients, it is frequently mild and it tends to

start between childhood and middle age.3 There

are several underlying causes, including brain

trauma and infection unrelated to NF1 as well

as mesial temporal sclerosis, NF1 related glio-

mas and anecdotal reports of dysembryoblas-

tic neuroepithelial tumours. All seizure types

stinging unresponsive to antihistamines are

common symptoms. Excision, albeit with a risk

of thickened scarring, is the usual treatment

but laser treatment is helpful for small lesions.

Cutaneous neurofi bromas are a major source

of psychological distress but unlike subcutane-

ous and plexiform neurofi bromas, they do not

undergo malignant change.

Subcutaneous neurofi bromas are fi rm periph-

eral nerve tumours that frequently cause pain,

neurological symptoms and defi cit. They can

be mistaken for glomus tumours because the

symptoms are misinterpreted as arising from

a neurofi broma. Women with subcutaneous

breast lumps should be referred to a specialist

breast unit because carcinoma cannot be dis-

tinguished clinically from a neurofi broma. NF1

females have an 8% cumulative risk of devel-

oping breast cancer before the age of 50 years

compared with 2% in the general population.14

About 60% of NF1 individuals have plexiform

neurofi bromas. The period of maximum growth

is in childhood and adolescence. Extensive

plexiform neurofi bromas can cause neurologi-

cal defi cit and disfi gurement. They are diffi cult

to remove, and indeed surgery can cause disas-

trous bleeding and delayed wound healing.3

Malignant peripheral nerve sheath

tumours

These usually arise from pre-existing focal

subcutaneous neurofi bromas or plexiform

neurofi bromas but they can develop de novo.15

People with NF1 have about a 10% lifetime

risk of developing one and most present in

the second and third decades.16 Risk factors

include a personal history or a family history

of cancer, prior treatment with radiotherapy,

deep seated plexiform neurofi bromas, neuro-

fi bromas involving the brachial and lumbosa-

cral plexuses, neurofi bromatous neuropathy

and microdeletion of the NF1 gene.15 17–19

Malignant peripheral nerve sheath tumours

are diffi cult to diagnose because they arise

in individuals who are accustomed to devel-

oping lumps, and the symptoms can overlap

with benign tumours. Urgent referral to a spe-

cialist neurofi bromatosis unit is imperative

when patients complain of one or more of the

following:

• Persistent or nocturnal pain associated with

a plexiform/subcutaneous neurofi broma

• Rapid increase in size of a neurofi broma

• New or unexplained neurological defi cit

• Neurofi broma changes to hard texture15



10.1136/jnnp.2010.206532

Figure 3Plexiform neurofi broma of the abdominal wall in an adult male with neurofi bromatosis 1.

Figure 4MR T2 hyperintensities in the globus pallidi in a young child with neurofi bromatosis 1.

occur but complex partial seizures predomi-

nate and usually respond to carbamazepine or

lamotrigine. When considering whether to use,

and which antiepileptic drugs to use, neurolo-

gists should remember that NF1 patients have

an increased risk of developing osteoporosis

and cognitive impairment (see sections on

cognitive problems and bone below).

Cognitive problems

Cognitive impairment is the commonest neu-

rological manifestation and is characterised by

an IQ in the low average range, specifi c learn-

ing diffi culties and behavioural problems.3 21

About 5% of patients have an IQ less than 70,

and learning problems occur in at least 60%

of children. Visual spatial diffi culties, impaired

attention, inability to interpret non-verbal

cues, reduced working memory, speech and

language defi cits and disordered executive

function are all documented. These cognitive

problems do not appear to worsen with age and

severe intellectual disability is unusual, occur-

ring in about 5% of patients.21 Asymptomatic

hyperintense lesions on T2 weighted brain MRI

are evident in most children with NF1, pre-

dominantly in the basal ganglia, brainstem and

cerebellum, they usually resolve in early adult-

hood and probably refl ect delayed myelination

(fi gure 4).21 They are not thought to play a key

role in the pathogenesis of NF1 related learn-

ing problems which remain unexplained

Learning problems improve with learning

support, and attention defi cit hyperactivity

disorder responds to judicious use of methyl-

phenidate.21 Statins reverse p21RAS activity and

hippocampal learning defi cits in an NF1 mouse

model. Short term trials of these drugs have

shown a good safety profi le in NF1 children, and

their effect on attention, working memory and

visual spatial problems is being evaluated.22

Multiple sclerosis

Primary progressive multiple sclerosis occurs

with increased frequency in NF1 and relaps-

ing remitting disease has also been reported.23

Although NF1 is a tumour suppressor condi-

tion, immunosuppressant therapy is not con-

traindicated and so far there is no evidence of

an increase in malignancy in NF1 patients with

multiple sclerosis.

Cerebrovascular disease

Cerebrovascular disease is part of the spectrum

of the NF1 vasculopathy. Moya moya syndrome,


87Ferner


The eyeAsymptomatic iris Lisch nodules can be seen

reliably on slit lamp examination and are

found in most NF1 individuals.2 3 We have also

encountered families with bilateral congenital

ptosis of uncertain aetiology, congenital and

acquired glaucoma, and choroidal abnormal-

ities. Neurofi bromas of the eyelid and orbit

have been reported.3

BoneBone abnormalities are a prominent prob-

lem in NF1 due to defects in the mainte-

nance of bone structure, bony overgrowth,

and erosion by plexiform neurofi bromas.3 26

Approximately 30% of NF1 patients have

short stature between the 10th and 25th cen-

tiles that affects the limbs and axial skeleton

in proportion.3 About half of NF1 individuals

have reduced bone mineral density but it is

uncertain whether there is an increased risk of

fracture and indeed whether specifi c preven-

tative treatment is warranted in every patient.

Pseudarthrosis of the long bones presents

in infancy as bowing of the affected limb

or spontaneous fracture with delayed heal-

ing, and formation of a false joint (fi gure 6).3

Meticulous assessment is required to avoid an

erroneous diagnosis of non-accidental injury.

About 10% of children with NF1 develop

idiopathic or dystrophic scoliosis that pre-

dominantly involves the lower cervical and

upper thoracic spine. Idiopathic scoliosis has

the same natural history in NF1 as in the gen-

eral population. Dystrophic scoliosis manifests

at a younger age than the idiopathic type,

characteristically involves only a few verte-

brae, producing a short, sharply angulated

curve with distortion of the vertebral bodies

Figure 5Optic pathway gliomas in a child with

neurofi bromatosis 1 involving both

optic nerves which are grossly enlarged

(arrowed)—axial MR scan.

cerebral aneurysm, internal carotid and cerebral

artery stenosis/occlusion have all been reported

and can be exacerbated by radiotherapy.3 13

Brain and optic pathway tumours

Gliomas can develop in any part of the cen-

tral nervous system, generally in the optic

pathways, cerebellum and brainstem.3 24 Most

slow growing gliomas are pilocytic astrocyto-

mas but gliomas outside the optic pathways,

tumours diagnosed in adulthood and symp-

tomatic lesions are higher grade astrocytomas

and have a more aggressive course.

About 15% of NF1 children have optic path-

way gliomas but only 5% develop symptoms

or signs (fi gure 5). They usually present before

the age of 6 years and can cause impaired

visual acuity and colour vision, squint, prop-

tosis, afferent pupillary defect, optic atrophy,

visual fi eld defects and precocious puberty.24

Adult onset or tumour progression are unusual

and visual screening is not required in adult-

hood.24 Young children rarely complain of visual

loss and the best method of diagnosis is regu-

lar visual screening, at least until the age of 7

years. Ideally visual acuity, colour vision, visual

fi elds and fundoscopy should be performed at

6 monthly intervals but many children are not

able to cooperate with such full visual testing.3 24

MR screening is unhelpful because young chil-

dren need to be anaesthetised and neuroimag-

ing does not identify optic pathway gliomas that

will necessarily progress and require treatment.

Children with diagnosed optic pathway glio-

mas should have regular MRI and visual assess-

ment by ophthalmologists conversant with NF1.

There is still debate about when to treat but

decline in visual acuity (greater than two lines) is

usually the main deciding factor in combination

with tumour progression on MRI.25 Radiotherapy

is contraindicated in NF1 children because of the

risk of a second malignancy, neuroendocrine and

neuropsychological sequelae and moya moya.24

Current fi rstline therapy is with vincristine and

carboplatin but the long term visual outcome is

uncertain and a retrospective multicentre study

is investigating this issue.24

Drugs that block RAS (farnesyl transferase

inhibitors) and MTOR pathways are of poten-

tial benefi t for NF1 plexiform neurofi bromas,

malignant peripheral nerve sheath tumours as

well as for optic pathway gliomas. Clinical tri-

als are underway but it is premature to predict

the outcome.3



10.1136/jnnp.2010.206532

Respiratory complicationsRespiratory compromise can arise as a conse-

quence of severe scoliosis and from restrictive

defect caused by compression by plexiform

neurofi bromas. The lung is the principal site of

metastatic spread from malignant peripheral

nerve sheath tumours.15

Gastrointestinal problemsMesenchymal gastrointestinal stromal tumours

occur mainly in the small bowel and are more

indolent than their sporadic counterparts.25

They can be confused with malignant periph-

eral nerve sheath tumours as both are positive

on 18[F] 2-fl uoro-2-deoxy-D-glucose positron

emission computerised tomography. They

cause gastrointestinal bleeding and anaemia,

some require excision and imatinib therapy is

being evaluated.

Dysplasia of the colon can cause consti-

pation, and duodenal carcinoid tumours have

been encountered in NF1 patients, occasion-

ally coexisting with phaeochromocytomas.3

PhaeochromocytomaPhaeochromocytoma is detected in 0.7%

of NF1 individuals but routine screening is

unrewarding; NF1 patients should be advised

to start a 24 h urinary catecholamine col-

lection only when they are symptomatic.

Clinicians should evaluate NF1 individuals

with unexplained paroxysmal palpitations

associated with headache, dizziness and

sweating.3

Genetic counsellingGenetic counselling is advised for everyone

with NF1 before they attempt to have chil-

dren; both prenatal mutation testing and pre-

implantation genetic diagnosis are available.

There is a one in two chance of transmitting

NF1 to an offspring and the risk of having a

severely affected child is 1 in 12.3 People with

mosaic NF1 have a small but unquantifi able

risk of passing on generalised NF1 to an infant

(we have encountered a patient with unilateral

groin freckling who produced a child with gen-

eralised NF1).

Current laboratory techniques can detect

the causative NF1 mutation in 95% of cases

but usually the phenotype cannot be predicted

from the type of mutation. However, families

with café au lait patches and freckling with-

out neurofi bromas have a mild phenotype due

and ribs. Dystrophic scoliosis can be associ-

ated with respiratory impairment, and surgery

is required to fuse the spine in severe rapidly

progressive cases.3

Cardiovascular diseaseNeurofi bromin is expressed in vascular endo-

thelium and smooth muscle. Loss of neurofi -

bromin through gene mutation is thought to

be the basis for an NF1 vasculopathy.27 High

blood pressure and congenital heart disease,

particularly pulmonary stenosis, occur in asso-

ciation with NF1.3 Renal artery stenosis may be

bilateral and is diagnosed in about 1% of NF1

individuals. Cerebrovascular disease is cited

as a cause of early death in NF1 but this has

not been the experience in the large UK neu-

rofi bromatosis services and requires further

verifi cation.

Figure 6Pseudarthrosis of the tibia in a young

child with neurofi bromatosis 1.


89Ferner


can have an earlier age of onset. In children,

the fi rst manifestation is likely to be cranial

or orbital meningioma, spinal schwannoma or

meningioma, cutaneous schwannoma, focal

amyotrophy or cataracts.29

The diagnosis can be made if two of the

following features are present: meningioma,

schwannoma, glioma, neurofi broma, posterior

subcapsular lens opacity plus a unilateral ves-

tibular schwannoma or a fi rst degree relative

with NF2. Alternatively, a unilateral vestibular

schwannoma plus multiple meningiomas or a

fi rst degree relative with NF2 is suffi cient for

diagnosis30

Recent evidence suggests that 20–30% of

NF2 patients without a family history of the

disease are mosaic. Mosaicism can present with

mild generalised NF2 or with any type of NF2

related tumour occurring just on one side of the

body; the NF2 mutation is detected in tumours

but not in the blood of these patients4 29

NF2 should be distinguished from NF1 (see

above) and from schwannomatosis. In this

latter condition, patients develop multiple

schwannomas affecting the peripheral nerves

and spinal nerve roots without vestibular

schwannomas or other NF2 related tumours.31

Schwannomatosis can occur in families and

the predominant symptom is pain. In seg-

mental schwannomatosis the schwannomas

are restricted to one segment of the body. The

gene for schwannomatosis has been identifi ed

either to a specifi c mutation in exon 17 of the

NF1 gene, or to Legius syndrome, and muta-

tion testing will confi rm a good prognosis in

these patients.3 5 It is important to diagnose

patients with Legius syndrome and mosaic

NF1 because they have a milder phenotype

and will not require monitoring for widespread

disease complications.

Genetic testing should be considered in

children with three to fi ve café au lait patches,

no other disease features and no family his-

tory, and in individuals with an unusual phe-

notype. This will ensure that other conditions

with abnormal pigment are not confused with

NF1 (see above).

SurveillanceFor children, the annual visit should include

a developmental assessment, enquiry about

schooling, examination of the skin, long bones

and spine, monitoring of blood pressure and

the heart for congenital heart disease, visual

assessment and measurement of height,

weight, head circumference, and checks for

delayed or precocious puberty.3

In our NF unit we hold transitional clinics

for teenagers with NF1 to provide education,

support and encourage independence, advis-

ing them to know when and where to seek

help in adulthood. Individuals over 25 years

with mild NF1 need to have yearly blood

pressure checks and to be aware of symp-

toms indicating possible malignant change

in a neurofi broma. They require prompt

access to specialist advice if they develop

symptoms suggesting an NF1 complication.

Ideally, NF clinical nurse specialists and the

UK Neurofi bromatosis Association advisors

should facilitate access to the appropriate

clinician. Doctors in the UK caring for adults

with NF1 should discuss complex problems

with the nationally commissioned NF1 units

in London and Manchester (box).

NEUROFIBROMATOSIS 2Diagnosis and differential diagnosisNF2 was fi rst described by Wishart in 1822

and was formerly known as bilateral acoustic

or central neurofi bromatosis.28 The charac-

teristic defi ning feature is bilateral vestibular

schwannomas.29 30 Because these tumours do

not usually develop before adolescence, the

NF2 diagnostic criteria include features that

Box The nationally commissioned complex NF1 Service. Guy’s and St Thomas’ NHS Foundation Trust and St Mary’s Hospital, Manchester

NF1 patients with ‘complex NF1’ have rare complications that cause signifi cant

morbidity and mortality

NF1 complications requiring direct referral to complex NF1 service• Plexiform or subcutaneous neurofi bromas associated with one or more of

the following requires urgent referral: persistent pain, new/unexplained

neurological defi cit, rapid growth, hard texture

• high cervical neurofi bromas causing cord compression

• unusual NF1 phenotypes

NF1 complications requiring liaison with complex NF1 service via a clinical nurse specialist

This ensures a cohesive pattern of care, adherence to national protocols (eg,

for visual screening) and awareness of special needs of NF1 patients

• Optic pathway glioma, brain and spinal cord glioma

• Pseudarthrosis of long bones

• Neurofi bromatous neuropathy

• Multiple sclerosis

Cutaneous

signs are not

conspicuous in NF2



10.1136/jnnp.2010.206532

proximal to the NF2 gene on chromosome 22,

and mutations have been detected in the INI/

SMARB1 tumour suppressor gene in some

families.32

Epidemiology and geneticsThe birth frequency of NF2 is 1 in 25 000 and

recent data show a disease prevalence of 1 in

60 000.6 This high prevalence is due to ear-

lier diagnosis and longer survival because of

improved treatment. The NF2 gene was cloned

on chromosome 22q11.2 and the gene protein

merlin acts as a tumour suppressor, controlling

proliferation of schwann and leptomeningeal

cells by interaction with multiple intercellular

signalling pathways.33 34

Table 2 Clinical manifestations of neurofi bromatosis 2

Skin Café au lait patches mostly just 1–3Cutaneous schwannomas plaque lesionsSubcutaneous schwannomasCutaneous neurofi broma (uncommon)

Nervous system Vestibular schwannomasCranial nerve schwannomas (not 1 and 2)

Spinal schwannomasPeripheral nerve schwannomasCranial meningiomasSpinal meningiomasSpinal/brainstem ependymomas

Spinal/cranial astrocytoma

Focal amyotrophy

Facial mononeuropathy

Neurofi bromatosis 2 neuropathy

Epilepsy

The eye Cataracts subcapsular/wedge

Epiretinal membrane

Retinal hamartoma

Optic nerve meningioma

Common clinical features are in bold typeface.

Figure 7Plaque schwannoma in an adult male

with neurofi bromatosis 2.

Clinical featuresThe skinCutaneous signs are not conspicuous in NF2

(table 2).29 Although 70% of patients have

skin tumours, the majority have fewer than

10 lesions (fi gure 7). Café au lait patches

are reported in 40% of patients but are less

numerous than in NF1.

Neurological complicationsSchwannomas, meningiomas and

ependymomas

Schwannomas are benign tumours arising

from the peripheral nerve sheath and are com-

posed entirely of schwann cells.29 Unlike neu-

rofi bromas, malignant change is rare and 18[F]

2-fl uoro-2-deoxy-D-glucose positron emis-

sion computerised tomography is not helpful

because it is so frequently positive, even wth

benign lesions.

Vestibular schwannomas occur in 95%

of NF2 patients (fi gure 8). They present with

progressive unilateral or bilateral sensorineu-

ral deafness.29 Patients may also complain of

tinnitus and impaired balance, and have signs

of raised intracranial pressure and encroach-

ment on the brainstem. The growth rate varies,

independently of the type of NF2 mutation,

and tends to be maximal in patients less than

30 years of age.29 They are managed differently

from sporadic tumours because NF2 tumours

are often multilobular and occur in the con-

text of multiple nervous system tumours; it is

crucial that management decisions are taken

by a specialist team. The goal of treatment

is preservation of hearing and neurologi-

cal function. Tumours showing progressive

growth, brainstem compression and hearing

loss require removal and there is an option to

insert an auditory brainstem implant at the

time of surgery.35 This electronic device pro-

vides a sense of sound to a person with pro-

found sensorineural hearing loss but patients

do require intensive specialist rehabilitation

to achieve improved lip reading and environ-

mental sound. Some specialist centres are

attempting hearing preservation surgery or

insertion of cochlear implants if there is integ-

rity of the cochlear nerve (these provide supe-

rior hearing to auditory brainstem implants).36

Stereotactic radiosurgery can be considered

for tumours smaller than 3 cm or for patients

who decline surgery or are too frail; the tumour

control rate is about 50%, with 40% retaining


91Ferner


removal and as cortical wedge opacities

(peripheral cortical cataracts). Orbital menin-

giomas and retinal hamartomas can impair

vision, and epiretinal membrane affecting

the macula and of varying severity has been

described.29

Genetic counselling• There is a 50% chance of transmitting

NF2 to an offspring but NF2 mosaics have

a less than one in two chance of passing

on generalised NF2 to a child.4 29

• About 6% of people younger than 30 years

old with unilateral vestibular schwan-

noma will go on to develop other features

of NF2 compared with only 1% who are

over 30 years of age.

• 10% of individuals with multiple meningi-

omas have NF2.29

Prenatal testing and preimplantation genetic

diagnosis are available. NF2 gene mutation

testing is useful in every patient as there is

a phenotype–genotype correlation.29 Severe

disease is associated with frameshift or non-

sense mutations and a milder phenotype is

linked with large deletions, missense muta-

tions or inframe deletions. Early detection

of tumours aids management of NF2, and

presymptomatic testing is an integral part of

NF2 care in families where the genetic muta-

tion is known. If the NF2 mutation is identifi ed

in two separate tumour specimens, the diag-

nosis can be verifi ed in mosaic patients.

Screening and surveillanceVision assessment, and examination of the

skin and nervous system should be undertaken

Figure 8Bilateral vestibular schwannomas

distorting the brainstem in a

young man with neurofi bromatosis

2—enhanced axial MR scan.

pretreatment hearing for 3 years.29 37 However,

there is a small risk of radiation induced malig-

nancy and surgical removal of a tumour after

radiotherapy is diffi cult with poor facial nerve

preservation. A recent study noted improved

hearing in some patients and reduction in

tumour size with bevacizumab (vascular endo-

thelial growth factor inhibitor).38

Schwannomas on other cranial nerves are

slower growing and do not usually require sur-

gical intervention.

90% of NF2 patients have extramedullary

spinal schwannomas or meningiomas but only

a third cause symptoms (fi gure 9).29

Cranial meningiomas develop in 45% of

patients, are frequently multiple and cause sig-

nifi cant neurological problems and mortality.29

Ependymomas and pilocytic astrocyto-

mas occur predominantly in the upper cervi-

cal cord and brainstem and can be associated

with a syrinx.29 They can remain stable for

many years although some cause progressive

neurological defi cit.

Epilepsy

There has been no systematic study of sei-

zures in NF2 but 10% of our NF2 patients have

epilepsy that is not exclusively related to any

tumours. Cortical dysplasia has been reported

in NF2. Further studies are needed to address

the cause of seizures in this group of patients.

Neuropathy and amyotrophy

NF2 neuropathy is an axonal peripheral neu-

ropathy which can be severe and progres-

sive.39 It has been suggested that it is caused

by compression from multiple schwannn cell

tumourlets arising along the length of periph-

eral nerves on adjacent nerve fi bres. Care

should be taken to ensure that the neurolog-

ical defi cit is not arising from cauda equina

schwannomas, particularly if surgical inter-

vention is contemplated.

Isolated facial mononeuropathy that predates

and is distinct from vestibular schwannoma

onset is due to schwann cell proliferation.

Focal amyotrophy appears as focal wasting

and weakness in the affected limb. The cause

is uncertain but localised schwann cell infi ltra-

tion has been proposed.29 40

EyesCataracts present as posterior subcapsu-

lar lens opacities that do not usually require



10.1136/jnnp.2010.206532

annually from birth in at risk individuals. Brain

MRI should be performed every 2 years from

age 12 until 20 years and every 3–5 years until

age 40 years. Spinal MRI is undertaken every

3 years.29 Patients with symptomatic NF2 are

best managed by specialist multidisciplin-

ary teams. Once vestibular schwannomas are

detected, brain MRI is required at least annu-

ally with concomitant speech and pure tone

audiometry.29 Ongoing psychological support

and access to hearing therapy services are

also crucial for patient welfare.

CONCLUSIONSOptimal care of the neurofi bromatoses

requires a multidisciplinary team of clini-

cians, nurses and therapists in partnership

with the patient and family. The UK National

Commissioning Group has funded specialist

services in London and Manchester for ‘com-

plex NF1’, and from April 2010 there will be

specialist NF2 centres in Manchester, London,

Oxford, Cambridge and Sheffi eld (radiosur-

gery). These exciting developments will facili-

tate a high standard of multidisciplinary care

for patients with neurofi bromatosis through-

out the country. The challenge is to match the

advances in molecular biology with meticu-

lous recording of phenotype, and monitoring

of clinical response to emerging therapies.

ACKNOWLEDGEMENTSThis article was reviewed by Wayne Lam,

Edinburgh.

Provenance and peer review Commissioned and

externally peer reviewed.

Competing interests None.

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