Neurofibromatosis

Neurofibromatosis Type 1 Causes and
Diagnosis
By Dr Ananya Mandal, MD
Neurofibromatosis type 1 is a congenital condition caused by a mutation in the NF1 gene.
Genes function by providing genetic blue-prints that instruct the development, function,
multiplication and eventually death of cells. When the genetic material contained in the
nucleus is altered, the cell may fail to undergo programmed cell death (apoptosis) and instead
survives when it would not normally do so. These abnormal cells then go on to multiply
uncontrollably and give rise to lumps or tumors.
The NF1 gene, which is found on chromosome 17, normally produces a special protein that
regulates and promotes the growth of nerve tissue. This protein can switch off growth once
the tissue has developed to a certain degree. When the gene is mutated, however, this protein
fails to exert this control over the growth, which continues to occur in an uncontrolled
manner, giving rise to a tumor.
The condition is inherited in an autosomal dominant manner, meaning only one parent needs
to possess the faulty gene for the child to be at risk of developing the condition. In around
50% of cases, the gene is inherited from one of the parents and the remaining cases are
caused by sporadic development of the mutation in people with no family history of the
condition.
The severity of the condition is not inherited and the child of a parent with a severe form of
neurofibromatosis 1 may have only mild symptoms, for example. Patients who have no
family history of the condition and develop the mutation sporadically are also capable of
passing the illness on to their offspring.
Diagnosis
Neurofibromatosis type 1 is commonly diagnosed based on typical clinical features of the
condition. A diagnosis can be confirmed when two or more of the following symptoms are
present:
1. Six or more pale brown caf au lait spots of more than 5 mm diameter in children or
more than 15 mm in adults. Freckles in the armpits or groin.
2. The presence of two or more neurofibromas (lumps that form beneath or on the
surface of the skin) or the presence of one plexiform neurofibroma a growth that
forms at a point where multiple nerve branches meet.
3. Tumors of the optic nerve. An optic glioma does not necessarily affect sight.
4. Two or more small brown spots in the iris called Lisch nodules.
5. Bone abnormalities such as bowing of the leg.
6. A family history of NF1.
Diagnosis
Imaging studies such as X-rays and MRI scans may be performed to check bone development
and look for tumors. An electroencephalogram (EEG) of the brain may be recommended if
the patient has experienced seizures. A skin biopsy may be carried out to check for cancerous
cells. In unconfirmed cases, genetic testing may be performed to check whether the NF1 gene
is mutated.
Reviewed by Sally Robertson, BSc
Sources
1. http://www.nhs.uk/Conditions/Neurofibromatosis/Pages/Introduction.aspx
2. www.nhmrc.gov.au/.../14_neurofibromatosis.pdf
3. http://www.nfnetwork.org/uploads/file/papers/clinical_man._nf1_.pdf
4. http://psyc.jmu.edu/school/documents/Neurofibromatosis%20Complete.pdf
5. http://www.ctf.org/pdf/brochures/NF1-Brochure.pdf
6. www.geneticalliance.org.uk/docs/translations/english/18-nf1-t.pdf
Neurofibromatosis Type 1 Symptoms and

Features
The symptoms of neurofibromatosis vary widely between individuals, with some people only
experiencing mild health problems and others finding they are severely affected on a day-to-
day basis. Some of the symptoms of neurofibromatosis type 1 (NF1) include:
The presence of pale brown skin patches that have smooth outlines, referred to as
caf au lait spots. These are found in 95% of people with NF1. The spots are
usually detected by time a child is around 3 years old and they grow to about 5 mm in
diameter during childhood. In adulthood, they can grow up to 15 mm in diameter.
Freckles are often seen in and around the armpits, groin and underneath the breasts.
Soft, benign tumors called neurofibromas develop on or under the skin as the child
grows into a teenager and then an adult. During childhood, these tumors are usually
pea-sized, but they grow as a person ages. Neurofibromas are not usually painful but
can catch on clothes and or press against other parts of the body, in which case they
may feel sore. One type of neurofibroma that forms at the point where multiple nerve
branches meet can cause large and painful masses. This is called a plexiform
neurofibroma.
Abnormal physical development is a common problem in children with NF1.

Examples include scoliosis or curvature of the spine, a large head and a smaller body
size and weight. A form of abnormal bone development called pseudarthrosis affects
about 2% of children with the condition. The condition often leads to fracture of the
tibia, which becomes bowed on healing.
High blood pressure is estimated to occur in around a fifth of those with NF1 and is
thought to be caused by disturbed kidney function. These individuals are at an
increased risk of stroke and heart attacks.
About 60% of children with NF1 develop learning difficulties, although it is not
clear why. The children usually have a normal or slightly low intelligence quotient
(IQ) and most can be taught in school. The learning difficulty is usually specific to
particular subjects such as maths, reading or coordination.
Attention deficit hyperactivity disorder or ADHD is also common, affecting around

50% of children with NF1. ADHD affects the childs ability to pay attention,
concentrate and control impulses.
The eyes are also commonly affected. Nearly 15% of children with NF1 develop
tumors on their optic nerve. This may lead to problems such as blurred vision,
impaired color vision, narrowed field of vision and squinting. Another symptom is the
presence of tiny brown spots in the iris called Lisch nodules, although these do not
usually cause visual difficulties or symptoms.
People with NF1 are at an increased risk of developing a cancer called malignant
peripheral nerve sheath tumour. This is a tumor that develops in a plexiform
neurofibroma, and it occurs in around 10% of individuals with NF1.
Sources
Neurofibromatosis Type 1 Treatment

There is currently no cure available for neurofibromatosis type 1 (NF1). Management of this
condition is primarily focused on continued monitoring and assessment of the disease for
further problems or complications that can be treated if they develop.
Routine monitoring and assessment of the condition

Most children with NF1 are given a detailed examination every year. This examination
includes:
A complete skin assessment to check existing neurofibromas and to look for the
formation of new ones. Neurofibromas are tumors that develop underneath or on the
surface of the skin.
A detailed check of the eyes for vision defects.
Assessment of the bones to check for curved spine or scoliosis and bone fractures.
Assessment of blood pressure.
Measurements of physical development.
Assessment of skills such as reading, writing and comprehension to check for learning
difficulties.
The child is also monitored for signs of any behavioral problems.
Symptomatic management of patients

Caf au lait spots - There is no effective treatment currently available for the coffee colored
patches that typically develop in this condition. Children who are finding them particularly
distressing may benefit from camouflage make up to mask the lesions.
Treatment of neurofibromas - Neurofibromas are not generally painful but can cause
distress due to their unattractive appearance. They can also press on other parts of the body or
get caught in clothes, in which case they may cause pain and irritation. Sometimes, these
growths can be removed with the use of laser surgery but plastic surgery is usually required.
Plexiform neurofibromas - These large, painful growths that occur at nerve junctions can be
more challenging to treat as they have often spread to nearby tissues.
Learning difficulties - Learning difficulties may be addressed by a team of specialists

including a speech and language therapist, an educational psychologist and an occupational
therapist.
Behavioural problems - For those with behavioral problems such as attention deficit
hyperactivity disorder (ADHD), approaches such as counselling and psychotherapy can help
patients find ways to cope with the condition and medications such as methylphenidate can
help improve concentration and attention span.
High blood pressure - Moderate hypertension can usually be brought under control though
lifestyle changes such as reducing salt intake, exercising regularly and maintaining a healthy
body weight. In cases of very high blood pressure, however, medications such as angiotensin-
converting enzyme (ACE) inhibitors may be prescribed.
Bone deformities - While mild scoliosis may correct itself over time, moderate cases may
require a brace to correct the spines position and in severe cases, surgery may even be
required to realign the vertebrae. A condition called pseudoarthrosis refers to fractures in the
tibia, which may lead to abnormal bone movement and bowing of the leg that may require
surgery to correct. A bone graft may be performed to plug the fracture or metal screws and
rods may be used to reconnect pieces of bone.
Epileptic seizures - Various different treatments are available to help reduce epileptic
seizures.
Sources
Neurofibromatosis Type 2
Neurofibromatosis type 2 is the less common form of neurofibromatosis. This condition is

typically characterized by the development of benign tumors called schwannomas that grow
along the eighth cranial nerve, which is responsible for hearing and balance.
This usually causes hearing loss, tinnitus and balance problems, particularly when negotiating
uneven ground or when walking in the dark. Many people with this condition also experience
visual problems.
Features
Another form of neurofibromatosis is the condition schwannomatosis, which has features that
commonly overlap with neurofibromatosis type 2. However, in schwannomatosis, the tumors
develop anywhere in the body apart from the vetsibular branch of the eighth cranial nerve.
Pain is the main symptom, which develops as a schwannoma grows larger and starts to
compress nerves.
In type 2 neurofibromatosis, the symptoms depend on where in the body the tumors develop.
The tumors usually affect one ear at first but may eventually affect both ears. Less
commonly, a person affected by vestibular schwannomas may feel vertigo-like feelings, as if
the environment around them is moving. Eventually the tumors can cause facial numbness,
weakness in the tongue leading to slurring, and facial pain.
Other features of neurofibromatosis type 2 include non-vestibular schwannomas, cataracts

and meningiomas.
Epidemiology and cause

Neurofibromatosis type 2 is less common than type 1 neurofibromatosis and is seen in only 1
in 35,000 live births. In around half of cases, the condition is caused by a mutated gene that is
passed on from a parent to their child. In the other half of cases, the mutation develops
sporadically in people with no family history of the condition. These patients can also pass
the condition onto their offspring.
Diagnosis
A diagnosis of neurofibromatosis type 2 is based on the presence of clinical features of the
disease, magnetic resonance imaging, hearing tests, vision tests and a genetic test for the NF2
mutation. Prenatal testing can also be performed to check for this mutation and the most
commonly used tests include chorionic villus sampling and amniocentesis.
Sources
1. http://www.nfnetwork.org/uploads/file/pdf/NF2%20Booklet%20FINAL.pdf
2. http://www.ctf.org/pdf/brochures/NF2_Info_for_Patients_Families.pdf
3. http://www.biomedcentral.com/content/pdf/1750-1172-4-16.pdf
4. 91.146.107.207/~wwwacnr/wp-content/uploads/2012/12/Neurosurgery1.pdf
Neurofibromatosis Type 2 Causes and

Diagnosis
Neurofibromatosis type 2 is a genetic disorder characterized by the growth of benign tumors

along nerves.
In around half of cases, the genetic mutation for this condition is inherited by a child from
one of their parents. In the other half of cases, the mutation arises completely sporadically
and cannot be explained by any family history of the condition.
Genes associated with neurofibromatosis type 2

The gene that becomes mutated in the case of neurofibromatosis type 2 (NF2) is a tumour
suppressor gene present on the long arm of chromosome 22(22q12.2). This NF2 gene codes
for a protein called merlin, which is involved in regulating nerve growth. When this gene is
mutated, the merlin protein produced is incomplete or even absent meaning uncontrolled
growth of the nerve tissue ensues.
In cases where the condition is inherited, only one parent needs to carry the mutated gene for
their offspring to be at risk of also developing the condition. If on parent has the condition,
each child is at a 50% risk of developing the illness. This pattern of inheritance is referred to
as autosomal dominant. The risk of developing the condition is equal between both genders.
In sporadic cases, the mutation seems to occur in either the sperm or ovum prior to
conception and it is unclear why this occurs. A person who develops a sporadic NF2 mutation
can also pass the condition onto their offspring.
Diagnosis
Diagnosis is made based on clinical features, magnetic resonance imaging, hearing tests,
vision tests and genetic testing for the NF2 mutation.
Prenatal testing can also be performed to check for this mutation and the most commonly
used tests include chorionic villus sampling and amniocentesis.
Sources
Neurofibromatosis Type 2 Management

Neurofibromatosis is a condition characterized by the growth of benign tumors along nerves

in the body. The tumors can eventually grow large enough to compress surrounding nerves
and other tissues, which causes various different symptoms depending on the tumors
location. The main aim of treatment is to preserve function rather than to cure the condition.
Some of the approaches to managing neurofibromatosis type 2 are described below:
Watchful waiting
In cases of very slow growing or low-grade tumors, an approach called watchful waiting may
be adopted. The patient is carefully monitored on a regular basis to assess tumor growth and
check whether the condition is becoming symptomatic. The monitoring usually involves
magnetic resonance imaging (MRI) scans, eye tests and hearing tests.
Early intervention with surgery

This approach is adopted by certain centres to eliminate the tumor early on, before symptoms
have a chance to develop.
Vestibular schwannoma treatment

The tumors that develop along the nerves that control hearing and balance are called
vestibular schwannomas. If the tumor is small, it may be removed without causing any
damage to the hearing but if a tumor has grown, surgery can be complicated if nerves that
affect the facial movement, balance and hearing are involved. An alternative to conventional
surgery is radiosurgery which may be used to reduce the size of the tumor instead.
Hearing preservation
Several techniques can be used to preserve or improve the hearing including surgical hearing
implants and speech and language therapy, for example. In cases of complete hearing loss
due to damaged cochlear nerves, auditory brain stem implants may be used.
Medication
Some medications that may have beneficial effects in neurofibromatosis type 2 include
lapatinib, a tyrosine kinase that inhibitis EGFR receptors; an immunosuppressant called
everolimus and a monoclonal antibody called bevacizumab that inhibits vascular endothelial
growth factor (VEGF) and therefore tumour angiogenesis (new blood vessel growth within
tumors).
Sources
Neurofibromatosis Type 2 Symptoms

By Sally Robertson, BSc
Neurofibromatosis type 2 (NF2) is a rare genetic disorder that affects around 1 in 25,000
individuals. In about half of these people, the condition is inherited, while the other half
develop a spontaneous mutation and there is no family history of the condition. The mutation
that causes NF2 occurs on a single gene located on chromosome 22. A person with NF2 has a
50% chance of passing the illness onto their offspring.
Symptoms
The condition is unpredictable and variable in its progression and therefore affects people in
different ways. People usually start to develop the symptoms and signs of NF2 in late
adolescence or their early 20s, although symptoms can develop at any age. The condition is
characterized by the growth of benign tumors along nerves in the spine and brain, which
leads to a range of neurological symptoms.
Although children with NF2 may present with symptoms, these are often mild and therefore
overlooked. The type and severity of symptoms depends where in the body the benign tumors
start to grow but the most common initial symptom is hearing loss or tinnitus (ringing in the
ears). Less commonly, the initial symptom is visual disturbance, seizure, skin tumor, limb
weakness or disrupted balance. In cases of inherited NF2, the severity is often similar
between family members and the type of mutation is therefore considered a major
determinant of disease severity.
Some symptoms of NF2 are described below:
Development of schwannomas
The majority of patients with this condition develop benign tumors along the nerves that
control hearing and balance. These growths are referred to as vestibular schwannomas (or
acoustic neuromas) and can cause hearing loss, tinnitus and balance problems. Initially, the
tumors usually only affect one ear, but by time a patient reaches the age of 30, tumors have
developed in both ears.
Less often, a person with vestibular schwannomas will experience vertigo-like sensations,
nausea and vomiting. As these tumors grow, facial numbness, a weak tongue and facial pain
are more likely to occur.
Cataracts
Around 60% of NF2 sufferers develop cataracts, cloudy areas in the eye lens that can blur
vision. This symptom often develops during childhood.
Caf-au-lait spots
People with NF2 are at an increased risk of developing light brown pigmentation spots that
are a similar color to white coffee. These are referred to as caf-au-lait spots.
Peripheral neuropathy
This refers to damaged peripheral nerves and depending on which nerves are involved,
symptoms may include pins and needles, numbness, burning sensations and muscle
weakness.
Brain tumors
In around half of cases, patients develop brain tumors called meningiomas, which can cause
vomiting, headaches, convulsions and visual disturbances.
Spinal cord involvement

About 50% of sufferers develop tumors in the spinal cord referred to as gliomas, which can
cause back pain, a skin crawling sensation and muscle weakness.
Assessment of symptoms
As around one half of people who develop this condition have a spontaneous mutation, there
is often no family history of the condition, which complicates diagnosis. To diagnose a
person based on their symptoms, at least one of the following needs to apply:
The patient has a first-degree relative with NF2 and also either has unilateral vestibular
schwannoma or two of the following:
Glioma
Posterior subcapsular lenticular opacities
Schwannoma
Neurofibroma
Meningioma
Bilateral vestibular schwannomas
Multiple meningiomas in addition to either of the following:
Any two of schwannoma, cataract, glioma or neurofibroma

Unilateral vestibular schwannoma
Unilateral vestibular schwannoma in addition to any two of the following:
Neurofibroma
Glioma
Meningioma
Schwannoma
Posterior subcapsular lenticular opacities
Assessment of physical symptoms

People who are at an increased risk of developing NF2 should be screened for signs of visual
disturbances, hearing loss and motor or sensory problems. Although menangiomas in the
optic nerve are rare, they may be a sign of NF2. Cranial nerve palsies may arise due to tumors
forming on the nearby vestibular nerve or due to their direct growth on the cranial nerve.
Differentiating between NF2 and NF1

Differential diagnosis between the rare NF2 and the relatively common NF1 can be difficult.
However, patients with NF2 are very unlikely to present with caf-au-lait spots, whereas
these lesions are common in NF1. Furthermore, the benign growths almost never become
cancerous in NF2, whereas their malignant transformation is common in cases of NF1.
Both NF1 and NF2 patients develop subcutaneous lesions but in those with NF2, these are
usually defined histologically as schwannomas, while in NF1 patients, they are defined as
neurofibromas. Subcutaneous neurofibromas are uncommon in people with NF2.
Finally, subcapsular lenticular opacities are features of NF2, while Lisch nodules would
indicate NF1.
Sources
5. http://www.cancer.net/cancer-types/neurofibromatosis-type-2
6. http://www.nfauk.org/what-is-neurofibromatosis/nf-type-2/
7. http://ghr.nlm.nih.gov/condition/neurofibromatosis-type-2
8. http://jmg.bmj.com/content/37/12/897.full
9. www.mayoclinic.org/.../con-20027728
10. http://emedicine.medscape.com/article/1178283-clinical
11. www.ninds.nih.gov/.../detail_neurofibromatosis.htm
What is Neurofibromatosis?
Neurofibromatosis describes a group of genetic conditions that lead to the growth of tumors
along the nerves. In the majority of cases, these tumors are benign but they can become
cancerous in some cases.
Types of neurofibromatosis
There are two main types of neurofibromatosis:
The most common form is neurofibromatosis type 1 (NF1), which occurs in 1 in 3000
births.
Neurofibromatosis type 2 (NF2) is a less common form that is observed in around 1 in
35,000 births.
Although these two conditions share the same name, they are separate illnesses caused by
different gene mutations.
Neurofibromatosis type 1
NF1 is a congenital condition that is present from birth, although some of the symptoms
associated with the illness develop over time. The severity of symptoms varies between
individuals but in the majority of cases, the skin is affected and is typically characterized by:
Pale brown patches with smooth outlines, referred to as caf au lait spots.
Soft, benign tumors underneath or on the surface of the skin. These are called
neurofibromas.
Around a third of people affected by this condition also develop the following
symptoms:
o Scoliosis or curvature of the spine
o High blood pressure
o Learning and behavioural difficulties
The underlying cause of NF1 is a genetic mutation, which causes derangement of the genetic
material that governs the growth and development of the nerve cells. This leads to
uncontrolled and abnormal growth of the nerve tissue. In about 50% of cases, the gene is
inherited, while other cases are sporadic with the mutations developing independently of any
family history of the condition.
Treatment
At present, there is no available cure for NF1. Most people with this condition need to be
routinely monitored for worsening symptoms and treated accordingly. Surgery may be
advised to remove the tumors and correct bone deformities and medication may be prescribed
to help control symptoms such as high blood pressure.
In addition, therapy is available to help people deal with any behavioural difficulties. A large
proportion of people with NF1 manage to lead a fulfilled life with the help of careful
monitoring and treatment but complications such as stroke can mean life expectancy is
reduced by up to 15 years in some individuals.
Sources

Neurofibromatosis

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Neurofibromatosis

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Neurofibromatosis Type 1 Causes and

Neurofibromatosis type 1 is a congenital condition caused by a mutation in the NF1 gene.

Reviewed by Sally Robertson, BSc

Neurofibromatosis Type 1 Symptoms and

Abnormal physical development is a common problem in children with NF1.

Attention deficit hyperactivity disorder or ADHD is also common, affecting around

Reviewed by Sally Robertson, BSc

Neurofibromatosis Type 1 Treatment

Routine monitoring and assessment of the condition

Symptomatic management of patients

Learning difficulties - Learning difficulties may be addressed by a team of specialists

Neurofibromatosis type 2 is the less common form of neurofibromatosis. This condition is

Other features of neurofibromatosis type 2 include non-vestibular schwannomas, cataracts

Epidemiology and cause

Neurofibromatosis Type 2 Causes and

Neurofibromatosis type 2 is a genetic disorder characterized by the growth of benign tumors

Genes associated with neurofibromatosis type 2

Reviewed by Sally Robertson, BSc

Neurofibromatosis Type 2 Management

Neurofibromatosis is a condition characterized by the growth of benign tumors along nerves

Some of the approaches to managing neurofibromatosis type 2 are described below:

Early intervention with surgery

Vestibular schwannoma treatment

Reviewed by Sally Robertson, BSc

Neurofibromatosis Type 2 Symptoms

Some symptoms of NF2 are described below:

Spinal cord involvement

Multiple meningiomas in addition to either of the following:

Any two of schwannoma, cataract, glioma or neurofibroma

Unilateral vestibular schwannoma in addition to any two of the following:

Assessment of physical symptoms

Differentiating between NF2 and NF1

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