Neurofibromatosis

Historically, descriptions of individuals thought now to have neurofibromatosis (NF) have been found in manuscripts dating back to 1000 AD. Von Recklinghausen coined the term 'neurofibroma' in 1881 to describe a benign tumour arising from the peripheral nerve sheath. Consequently, type 1 neurofibromatosis (NF1) is also known as Von Recklinghausen's disease.

Introduction

It is a genetic disorder causing lesions in the skin, nervous system and skeleton. There are two main types of neurofibromatosis (NF).

• Type 1 is the more common form and caused by a defect in the gene, NF1, situated at chromosome 17q11.2. Neurofibromin, the gene product, is a ubiquitous nervous system protein and is believed to act as a tumour suppressor.
  • Loss of neurofibromin leads to an increased risk of developing benign and malignant tumours but effects of a mutation are highly variable between sufferers and can appear at any age due to a variety of mutations, differing penetration and mosaicism.
  • Watson's syndrome is the only subtype of NF1 to have a uniform phenotype in families and is characterised by pulmonary stenosis, cognitive impairment, café au lait patches and few cutaneous neurofibromas.
• Type 2 is a central form with CNS tumours rather than skin lesions. There are inherited schwannomas (vestibular tumours), typically bilateral, but also meningiomas and ependymomas. It may be considered to be a type of schwannomatosis rather than NF. The implicated mutation is on chromosome 22 at gene locus 22q12.2.

There are several other rarer types including type 3 (NF3), type 4 (NF4) and neurofibromatosis-Noonan syndrome (NFNS), (not to be confused with Noonan's syndrome).

Epidemiology

Both type 1 and 2 of neurofibromatosis (NF) are inherited as autosomal dominant conditions but, for both types, there is no family history in about 50%, reflecting the incidence of new mutations.

• The birth incidence of type 1 is given as 1 in 2,500-3,000 but may be slightly higher because of failure to diagnose milder cases.
• NF type 2 has a prevalence of about 1 in 25,000.

The sex ratio is equal. It appears to be more common in white races.

Presentation

Diagnostic criteria for type 1 neurofibromatosis (NF1)

There are diagnostic criteria for NF1 that require at least 2 of 7 criteria. Some of these do not appear until later childhood or adolescence, and so confirmation of the diagnosis may be delayed and children should be followed up.

• At least six café au lait spots or hyperpigmented macules. They must be at least 5 mm wide in children younger than 10 years and 15 mm in adults.
• Axillary or inguinal freckles.
• Two or more typical neurofibromas or one plexiform neurofibroma.
• Optic nerve glioma.
• Two or more iris hamartomas. They are called Lisch nodules and are seen by slit-lamp examination.
• Sphenoid dysplasia or typical long-bone abnormalities such as arthrosis.
• Having a first-degree relative with NF1.

Diagnostic criteria for type 2 neurofibromatosis (NF2)

At least one of the following three is required for diagnosis of NF2:

• Bilateral 8th nerve masses on MRI scan.
• A first-degree relative with NF2 for a unilateral 8th nerve mass.
• A first-degree relative with NF2 for an individual with at least two of the following:
  • Meningioma
  • Glioma
  • Schwannoma
  • Juvenile cataracts

  • Dermal features

    • Café au lait spots are often the first findings in NF1. They may be present at birth or may appear with time. They usually increase in size and number during childhood. 1-2 café au lait patches occur in 10% of the general population. Children with 3-5 café au lait patches, but no other signs of NF1, should be followed up, as they might have mosaic NF1 or NF2.
    • Axillary or inguinal freckles are rare at birth but appear throughout childhood and adolescence.
    • Café au lait patches and skin-fold freckling do not usually cause complications; however, some patients are distressed by the appearance of this pigmentation and may be helped by skin camouflage advice. There is no evidence to support the routine use of laser treatment for café au lait patches.
    • Hypopigmented macules may co-exist with café au lait spots in NF1 and are found in a similar distribution.
    • Urticaria pigmentosa may be seen in a small subset of infants. It is a collection of mast cells within the dermis.
    • Naevus anaemicus and benign cherry angiomas (Campbell de Morgan spots) are observed more frequently in NF1 than in the general population.
    • Juvenile xanthogranulomas are benign orange papules that appear transiently on the head and trunk in 1% of young children. The suggestion of an increased risk of chronic myeloid leukaemia in children with NF1 and xanthogranulomas has not been borne out and routine haematological testing is not recommended in this group.

    Neurofibromas

    • They may be in the skin or subcutaneous tissues. Deep lesions may require palpation for detection but cutaneous lesions may appear initially as small papules on the trunk, extremities, scalp, or face.
    • Cutaneous neurofibromas are found in the majority of NF1 individuals, are rare in early childhood but tend to develop in the late teens or early twenties. There may be an increase in numbers and a growth of existing lesions at puberty or in pregnancy.
    • Cutaneous neurofibromas rarely appear to undergo malignant transformation. However, they may catch on clothing and/or cause cosmetic embarrassment, stinging or itching.
    • Subcutaneous neurofibromas may be tender to touch and cause tingling in the distribution of the affected nerve. Malignant change occasionally occurs: if rapid growth occurs, refer to a specialist, as removal may result in nerve damage.
    • Plexiform neurofibromas are more diffuse growths that can be locally invasive and quite deep. There may be bony erosion and pain. They may also be accompanied by hyperpigmentation or hypertrichosis over the lesions. Risk of disfigurement from facial plexiform neurofibromas appears to be greatest during the first three years of life.
    • In NF2, sensorimotor polyneuropathy may be seen and there may be identifiable tumours along the relevant peripheral nerves.

    Ocular problems

    • Tumours of the optic nerve (gliomas) occur in about 15% of children with NF1.
    • They are often asymptomatic but, over time, tumours may cause visual acuity loss, abnormal colour vision, visual field loss, squint, pupillary abnormalities, pale optic disc, proptosis and hypothalamic dysfunction. Risk is highest in those aged under 7 years. Young children rarely complain of early visual impairment and sometimes it is not picked up until it is advanced, with bilateral visual loss. Parents should be aware to look out for potential indicators of problems - failure to pick up small toys or bumping into things.
    • The most common presentation is asymmetrical visual field defects. Optic nerve gliomas occasionally start to cause symptoms in older children or even adults. They can also undergo spontaneous regression.
    • Lisch nodules are usually only seen by slit lamp. Occasionally, they can be visible via the ophthalmoscope.
    • Patchy choroidal abnormalities and corkscrew retinal vessels are sometimes seen in patients with NF1.
    • In NF2, posterior subcapsular or juvenile cataracts can precede CNS symptoms. These cataracts may progress over time, impairing visual acuity. Some have retinal hamartomas or epiretinal membranes that are not always significant to vision.

    Skeletal problems

    • Sphenoid dysplasia usually causes no problem but can cause herniation through the bony defect. Patients with plexiform neurofibroma of the eyelid or temporal region often have ipsilateral sphenoid dysplasia.
    • Congenital pseudoarthrosis may be apparent at birth. Bowing of the tibia is the most common presentation and occurs in about 2% of those with NF1. Thinning and angulation of long bones with prominence of the anterior tibia and progressive deformity can occur throughout early childhood. Bowing of the forearm is less common. Fracture can occur spontaneously or after trivial injury, and NF should be considered as a differential for non-accidental injury.
    • The thoracic cage may be asymmetrical with flaring or prominence of the inferior ribs. It affects some children with NF1 but rarely requires surgical correction.
    • Scoliosis may occur with or without kyphosis. This may become evident in childhood or adolescence and adolescent girls are affected rather more often than boys. If it starts before the age of 10 years, scoliosis has a poor prognosis and is likely to be rapidly progressive. Scoliosis detected in adolescence should be followed, but is less likely to require orthopaedic intervention.
    • NF1 causes disruption of bone maintenance and reduced bone mineral density. Be vigilant about the possibility of osteoporosis.

    Neurological problems

    

    • Neurological complications develop from tumours and malformations, including aqueduct stenosis. Skull deformity due to sphenoid wing dysplasia can lead to pulsating exophthalmos.
    • Severe scoliosis can deform the spine, causing cord compression and respiratory compromise.
    • Pressure on peripheral and spinal nerves and the spinal cord will also have neurological sequelae.
    • Epilepsy is usually mild and only occurs in 6-7% of NF1 individuals.
    • Carotid artery stenosis/occlusion and cerebral aneurysm may occur with NF1.
    • Patients should be advised to seek urgent help where they experience acute or progressive sensory disturbance, motor deficit and inco-ordination or sphincter disturbance, which may indicate an intracranial lesion or spinal cord compression.
    • Cognitive problems are the most common neurological complication and usually present as an IQ in the low average range. Specific learning problems occur in one- to two-thirds of children with NF1. The cause of cognitive problems in NF is not known. Children and adolescents with NF are more likely to suffer attention deficit hyperactivity disorder (ADHD); incidence is high, at around 40%.

    • Cardiovascular problems

      • Congenital heart disease (pulmonary stenosis and hypertension) are associated with NF.
      • Renal artery stenosis occurs in approximately 2% of those with NF1, so NF should be a diagnosis considered in hypertensive children, young adults and pregnant women, and refractory hypertension in older individuals and those with an abdominal bruit.
      • Phaeochromocytoma similarly occurs in approximately 2% of those with NF1. About 12% of these tumours are malignant.

      Other clinical problems/complications may include:
      

      • Gastrointestinal (GI) - abdominal bloating, pain, dyspepsia, haemorrhage and constipation may suggest a GI neurofibroma. Carcinoid tumours may give rise to facial flushing, diarrhoea, right-sided cardiac lesions, facial telangiectasiae and bronchoconstriction. GI stromal tumours are also associated with NF1 and may present with anaemia and GI bleeding.
      • Psychological - disfigurement and the unpredictable course of NF may cause anxiety and depression. Parents of children with NF1 report a profound impact of NF on physical, social, behavioural and emotional aspects of their quality of life.Children with NF1 can have difficulties forming friendships and developing social skills.
      • Endocrine - precocious puberty occurs in about 3% and is associated with tumours of the optic chiasma.
      • Obstetric - there appears to be an increased risk of perinatal complications in NF1, with a higher stillbirth rate, intrauterine growth restriction and Caesarean section rate. During pregnancy, neurofibromas may grow in size and number and there is the risk of cord compression if spinal plexiform neurofibromas expand. Obstetricians should also ensure pelvic neurofibromas do not impede delivery of the baby.

      Investigations

      Baseline brain and spinal MRI scanning and routine imaging of the chest and abdomen to identify asymptomatic tumours do not influence management and are not advised.

      Plain X-ray

      • Dural ectasia is often seen on X-rays of the vertebral column. It may suggest future progressive scoliosis.
      • X-rays are required if:
        • There are possible modelling defects of the long bones or ribs.
        • There is concern that a bony lesion may be adjacent to a plexiform neurofibroma.
        • Scoliosis is seen on clinical examination.
        • Bone pain exists.

      Scans

      CT or MRI scanning may be required:
      

      • MRI is preferred for diagnostic head imaging. Hyper-intense lesions on T2-weighted brain MRI are probably caused by aberrant myelination or gliosis and are pathognomonic of NF1. They occur most commonly in children aged 8-16 years but tend to have disappeared by adulthood. They are associated with cognitive impairment. The presence of these lesions can assist in diagnosing NF1 but MRI under anaesthetic is not warranted for this purpose in young children.¹
      • Consider CT or MRI scans to check ventricular size if head circumference in an infant is increasing rapidly. Hydrocephalus is rare in NF1.
      • MRI can evaluate the optic nerves or optic chiasma. It is indicated for optic nerve pallor, visual changes, proptosis, or precocious puberty.
      • Consider MRI scans of the head if headaches increase in frequency or intensity over time. Brain tumours are more common in NF2 than NF1.
      • MRI can also be useful to evaluate mediastinal masses, spinal cord tumours, deep plexiform neurofibromas, abdominal and pelvic lesions and neurofibromas of the brachial or sacral plexus.

      Electrophysiology

      • If seizures occur, EEG is required in assessment.
      • Myelography is occasionally helpful to clarify the extent of a spinal cord tumour but, generally, MRI alone is enough.
      • Visual evoked potentials (VEPs) may be helpful in detecting optic nerve gliomas or assessing tumour progression with optic pathway tumours.

      Slit-lamp examination

      This usually requires the expertise of an ophthalmologist.
      

      • Slit-lamp examination may provide essential diagnostic information in older children and adults who present with only one clinical criterion such as multiple café au lait spots.
      • The frequency of Lisch nodules increases with age. They are seen in more than 95% of those with NF1 who are older than 10 years.
      • Slit-lamp examination is valuable to decide if the parents of an affected child carry the NF1 mutation, even in the absence of any other features of the disease.

      Genetic testing

      NF1 mutational analysis may clarify the diagnosis in some ambiguous cases but is not advocated routinely.

      Histology

      Biopsy of asymptomatic cutaneous neurofibromas should not be undertaken for diagnostic purposes in individuals with clear-cut NF1.
      
      Tests for hearing and vestibular function are important in NF2.

      Differential diagnosis

      Type 1 or type 2 neurofibromatosis (NF)?
      

      • Type 1 tends to present in childhood or adolescence, whilst type 2 usually presents in adults aged under 40 years, and mostly in the 20s.
      • Around 45% of type 2 present with hearing problems such as deafness and tinnitus, with or without loss of balance or facial weakness due to vestibular schwannomas.
      • Café au lait spots are the usual, early feature of NF1 but there are rarely more than six spots in NF2. It rarely shows axillary or inguinal freckles.
      • Multiple subcutaneous lesions can be indistinguishable between the two.
      • Posterior subcapsular lenticular opacities, even in childhood, would be suggestive of NF2, whereas Lisch nodules would be diagnostic of NF1.

      Other conditions with café au lait patches include:
      

      • McCune-Albright syndrome.
      • DNA repair syndromes.
      • Hereditary non-polyposis cancer of the colon.

      Other conditions with pigmented macules include:
      

      • Neurocutaneous melanosis.
      • Peutz-Jeghers syndrome.

      Other localised overgrowth syndromes include:
      

      

      • Klippel-Trénaunay syndrome.
      • Proteus' syndrome
      • .

        Management

        Care is largely a matter of monitoring progress and intervening appropriately where tumours produce pressure symptoms or behave in a manner suggestive of malignant change.
        
        All children with uncomplicated disease should be assessed annually, ideally by one paediatrician in each area to facilitate co-ordinated care. Young adults (16-25 years) will need education about NF and its possible complications, including reproductive counselling.
        

        • Height and weight should be charted and abnormal pubertal development assessed.
        • Review visual symptoms. Those aged under 7 years should have annual visual acuity and fundoscopy testing. Baseline assessment of colour vision and visual fields should be undertaken once the child is able to cope with the test.
        • Check the skin for new neurofibromas and progression of existing ones. Irritation does not usually respond to antihistamines and the benefit of mast cell stabilisers is uncertain; advise avoiding excessive heat. Emollients may be helpful. Cutaneous neurofibromas can be removed if they catch in clothing or cause other problems.
        • Plexiform neurofibromas may be locally invasive. Determine the extent of involvement and any evidence of bony erosion or nerve entrapment.
        • Check for skeletal involvement, including scoliosis, hemihypertrophy, and long-bone modelling defects. Check head circumference in the first three years, as rapid increase may indicate tumour or hydrocephalus.
        • Examine the heart, looking for murmurs. Check blood pressure at every visit and take prompt action if there is hypertension. Any unexplained murmur should be referred for a cardiology opinion and echocardiography.
        • Ask about the child's neurodevelopment, to note any learning disabilities and take early action.

        Older adults should be offered the opportunity of attending clinic on an annual basis: adults with severe disease will usually already have been identified by this stage and need lifelong monitoring in a dedicated specialist clinic; those with mild disease have a much lower risk of complications, but should have a minimum of annual blood pressure checks and be aware to consult their GP if they encounter unusual symptoms (who can then refer them on if necessary).

        Drugs

        There are no specific drugs for the disorder, although they may be needed for secondary problems such as hypertension, epilepsy or ADHD.

        Surgery

        Neurofibromas

        • Neurofibromas that press on vital structures, obstruct vision, or grow rapidly need urgent attention.
        • Plexiform neurofibromas can be difficult. They often recur after resection because there are residual cell rests deep in soft tissues.
        • Neurofibromas on the scalp, along the hairline, or around the waist where clothes rub can cause irritation and discomfort and are worthy of removal.
        • In NF2, there has been some success with cochlear implants for bilateral acoustic neuroma.

        Spinal cord tumours

        • Prompt attention is required if neurological symptoms appear. Resection of spinal cord tumours is quite difficult but may be necessary to prevent progressive paraplegia or quadriplegia.
        • For some patients, surgical intervention may not cure but it provides valuable palliation.

        Orthopaedic surgery

        • Rapidly progressive scoliosis or severe bony defects need urgent attention.
        • Early referral for scoliosis gives the best results.
        • Long-bone defects can require amputation but mode bracing and casting techniques have reduced the need.

        Vascular surgery

        • Percutaneous transluminal renal artery angioplasty (PTRAA) may be effective in treating some renal artery stenosis due to fibromuscular dysplasia.
        • Others may require surgical repair and anastomosis of the renal artery.

        Complications

        Many complications have already been mentioned.
        Individuals with NF are at an increased risk of brain tumours, leukaemia, and other malignancies of neural crest origin, including neurofibrosarcomas. Brain tumours are rather more common in NF2. Occasionally, peripheral nerve sheath tumours undergo malignant change in NF1 but not NF2. The risk of malignant change is usually rated as quite low but a study from Manchester suggested that the lifetime risk for an individual with NF1 is 8 to 13% with a mean age of diagnosis of 26 and a 5-year survival rate of 21%,giving cause for concern.
        

        
       
     

    Prognosis

    • Type 1, in particular, is so varied in its manifestation, that it is difficult to predict outcome, as phenotype is so variable even within affected families.
    • Most people with NF1 lead relatively long and healthy lives, but it does reduce life expectancy by around 15 years. The major complications are hypertension and malignancy.
    • NF2 generally has a worse prognosis. Much of the morbidity from these tumours results from their treatment. Early detection and prompt attention to complications may reduce overall morbidity and mortality.

    Prevention

    The risk of an affected individual with type 1 neurofibromatosis (NF1) or type 2 neurofibromatosis (NF2) transmitting the disease to their child is 50% but this cannot predict the severity of any inherited disease. When the complications that cause lifelong morbidity or early mortality in NF1 are considered, the risk of having a severely affected child is about 1 in 12.
    
    Where parents have had the first affected child known in a family, they should be examined for cutaneous stigmata or Lisch nodules. They may be found to have a segmental or mosaic form of NF and thus be at risk of having another affected child. Where there are no clinical signs, their affected child's condition will have arisen due to a de novo mutation, and the risk to the parent of having another child with NF1 is extremely small (less than 1%).
    
    The NF1 gene mutation can now be found in 85-95% of cases. Prenatal testing is possible using fetal DNA extracted from chorionic villous sampling or from amniocentesis. Many do not want prenatal assessment because it cannot determine disease severity. Pre-implantation genetic diagnosis is also available. Genetic counselling prior to conception should be advised in all individuals with NF.