About Neurofibromatosis type 1 (NF1)
Neurofibromatosis type 1 (NF1), formerly known as von Recklinghausen’s disease or Peripheral NF is the most common type of NF and also one of the most commonly inherited neurological conditions, affecting about 1 in 2500 people throughout the world.
NF1 is more prevalent than Cystic Fibrosis, Duchenne Muscular Dystrophy, Huntington's Disease and Tay Sachs.
It is most often diagnosed in childhood and characterised by brown skin spots called café-au-lait marks, freckling in the groin and armpits and benign tumours known as neurofibromas.
NF1 is an extremely variable condition. The majority of people with NF1 will never be impacted by major medical complications and will live a long, fulfilling life. For others the condition can be severe, debilitating and life-threatening.
In some cases, signs of NF1 may not appear until later in life, often around puberty.
More complex health issues include learning and behavioural difficulties, softening and curving of bones and curvature of the spine (scoliosis). Tumours may also develop on nerves in the brain (optic or cranial nerves), and along the spinal cord nerves.
NF1 tumours are generally not cancerous, however, depending on their size and location may cause health problems by pressing on the nerves, nearby organs, and tissues.
These tumours develop from a mixture of two types of nerve sheath cells; Schwann and mast cells, to cause a thickening of the nerve.
NF1 affects many different systems of the body, and a person with NF1 may require the involvement of multiple doctors and specialists in their care and ongoing management. These include, but are not limited to, dermatologists, neurologists, neurosurgeons, ophthalmologists, orthopaedic surgeons, plastic surgeons, endocrinologists, psychologists, oncologists, cardiologists, geneticists and genetic counsellors.
STORIES OF NF1 HEROES
Watch this simple animated video about Neurofibromatosis Type 1 (NF1) that has been produced by Health Sketch to help explain why NF occurs, the main signs, the complications to be aware of, and how it is managed.
You can find more comprehensive detail of each of these elements below.
signs and symptoms
NF1 is caused by a single gene change, but it can lead to variable signs and symptoms anywhere there are nerves in the body. Currently there is no cure for NF. However, there are some ways in which symptoms can be managed to alleviate the burden of the condition, although much of NF1 management consists of monitoring and surveillance.
To find out more about specific areas of concern, click to expand.
These are flat brown spots on the skin, often oval shaped with well-defined edges. People with NF1 usually have 6 or more café-au-lait (CAL) marks. They can often look like lighter patches on darker skin. They do not cause any harm.
While café-au-lait marks are harmless, sometimes they can appear in exposed areas causing cosmetic distress. In these instances, laser treatment may be beneficial, however, this has been shown to have very mixed results.
For most people affected by NF1, freckling appears in skin folds which would not normally be exposed to the sun like under the arms and in the groin.
Freckles, like Café-au-lait marks and Lisch nodules do not cause any medical concerns.
These are lumps that are very typical of NF1. They most often begin appearing around the time of puberty and increase in number with age.
They appear usually as mobile pea-sized lumps either on (cutaneous) or under (subcutaneous) the skin, and while they typically appear skin-coloured they can sometimes have a red or purplish tinge.
These tumours are benign, and while they do not cause any serious medical issues, they can cause pain and itching along with having a cosmetic impact.
Most neurofibromas can be removed. You may choose to remove those that cause pain, itching and/or cosmetic distress.
There are many ways in which neurofibromas can be removed. A dermatologist may be able to remove some of the smaller cutaneous neurofibromas under a local anaesthetic with a laser.
However, a plastic surgeon with knowledge of NF is often best placed to remove neurofibromas. This is because neurofibromas can include a lot of blood vessels, which means they often bleed a lot more than other benign tumours. They also often have a deeper root making them more difficult to remove.
The removal technique will depend on the number of neurofibromas to be removed, their type, location and size.
A plastic surgeon may cut out (excise) or destroy (using electrodessication or cryosurgery among other techniques). When a plexiform or larger neurofibroma is involved they will be debulked or removed via excision and then closed with stitches.
Plexiform neurofibromas are more complex, involving more than one nerve root. These tumours are less common than their dermal counterparts and are estimated to affect 30-50% of individuals impacted by NF1.
They can appear anywhere around the body: on the surface of the skin or deep within tissues. They may grow large and impinge on surrounding tissues and organs resulting in limited function.
These are benign tumours, but in a small number of instances (approximately 10%) can become malignant.
The size and location of the plexiform neurofibroma of concern will determine who is involved with its treatment.
Some plexiform neurofibromas are visible on the skin and can be cut out (excised) completely by a plastic surgeon while others will only be able to be debulked due to their size, location and tissue involvement. For those that have developed alongside bone or other organs other specialists may need to be involved in surgery to remove all or part of the tumour.
For those plexiform neurofibromas that are considered inoperable may respond to a chemotherapy drug called a MEK inhibitor. As this treatment is still under investigation they can only be accessed under very limited and life-threatening circumstances via an oncologist through compassionate access grants from the drug companies that produce them.
Skin itch can be bothersome for some people impacted by NF1. It has been found that this is a type of nerve pain and is thought likely to have something to do with the increased number of mast cells people with NF1 have. Exactly what causes the itching is not yet known. A recent study at Sydney’s Royal North Shore Hospital indicated that itch could be a concern for as many as 62% of people with NF1 and can have a significant impact on quality of life.
Contact the CTF Support Team for more information if this is a concern for you.
Itching can be managed in several ways depending on the severity, and the effectiveness of treatment for everyone.
Emollient creams or antihistamine, which can be purchased at your local pharmacy and applied or taken daily may assist with relieving itch.
Recently it has been found that itch is a form of neuropathic pain. For many people, a local or general medication including Gabapentin and Pregabalin, which are oral medications usually taken to assist with nerve pain, assist in relieving itch. Amitriptyline, Doxepin and other tricyclic antidepressant medications have also proven successful for some people with NF-related itch. Medication and dosage will need to be discussed with your NF specialist or treating doctor.
BRAIN AND SPEECH
Learning and Behaviour
Between 50-80% of people with NF1 will have learning difficulties. While intelligence is usually within the normal range, children may need extra help at school.
Some children will struggle with:
- Absorbing information
- Processing both written and verbal information (e.g. following instructions)
- Retrieving information (memory)
- Communicating information verbally or in writing
- Misperception of auditory and visual information
- Attention and impulse control
- Executive functioning (e.g. following the steps to get through a task)
- Social skills
- Autism Spectrum Disorder (ASD)
Early intervention can be beneficial in ensuring habits, routines and supports are in place to ensure the child can reach their full potential.
Contact our Support Team to access a copy of our teacher’s toolkit.
There are a range of strategies and supports that can be put in place to assist with cognitive difficulties. These include structured routines, program modification, classroom support and medication, depending on the issues a child is impacted with.
Cognitive and learning assessments can be completed by neuropsychologists or educational psychologists.
Many people with NF1 experience headaches, and some experience migraines. In many cases these headaches are not indicative of an underlying cause.
Headaches, where there is no indication of an underlying cause, are often treated with over the counter medication, but depending on the severity and frequency your doctor may recommend a preventative medication to assist in allowing you to continue with daily routines and tasks.
It may be beneficial to keep a record of your headaches in the weeks prior to your doctor’s appointment so that you can are armed with as much information about the frequency, severity, symptoms and medication required. This will help your doctor make decisions about what the best course of action is.
Please contact our support team if you would like a downloadable version of the headache diary.
In 60-70% of children, an MRI will reveal areas of increased brightness on the brain scan. These are referred to as T2 hyperintensities (formerly unidentified bright objects (UBOs), and in general do not cause learning or developmental impairment.
They have been described as “birthmarks on the brain”.
Seizures / Epilepsy
Around 5% of people with NF1 will at some stage experience seizures, and only a small proportion of those will have epilepsy.
In most cases, the reason behind the seizures is unknown, but in a few instances may be caused by a tumour or other changes seen on MRI.
There are now numerous medications on the market that can assist with managing seizures. These include medications such as Keppra and Trileptal among many others. The type of medication prescribed will depend upon someone’s age and the type of seizures they have been experiencing.
Not everyone who has a seizure(s) will need treatment via medication.
Speech and language impairments are thought to be common in children with NF1 but is likely still under-identified.
Challenges with speech and language can significantly impact upon learning.
Speech therapy can be beneficial and may be accessed through the NDIS (including ECEI), privately or via a Chronic Disease Management Plan through your GP. Some schools also have access to speech therapy.
High blood pressure is common, but a small number of people with NF1 have serious complications that underly their hypertension. It is recommended that people with NF1 have their blood pressure checked annually.
A sudden spike in blood pressure should always be investigated to rule out any underlying cause. If none is found, then essential hypertension will be managed in the same way as it is for people without NF1 - with monitoring and medication as required.
While rare, blood vessel abnormalities can take several forms for people affected by NF1. This includes:
- High blood pressure (mentioned separately)
- Pheochromocytoma (a tumour on the adrenal gland of the kidneys)
- Artery stenosis (narrowing of the arteries) and aneurysms
Congenital Heart Defects
For some children with NF1 congenital heart defects occur, most often affecting the heart valves, in particular the pulmonary valve. These defects are often detected in early childhood if a heart murmur is heard during routine examination.
If a heart murmur is detected a referral should be made to a paediatric cardiologist for further investigation.
These are elevated dome-shaped pigment changes on the iris. They are a common marker for NF1 in adults and occur in up to 95% of adults with NF1. They do not result in any changes to vision or have any impact on eye function.
Lisch nodules often develop during childhood and are diagnosed by an ophthalmologist using a special light called a Slit Lamp.
Optic Pathway Glioma (OPG)
An optic pathway glioma (OPG) is a benign tumour that develops anywhere along the optic nerve, which controls vision.
These tumours most commonly develop in children before the age of 6 years, however, annual screening is generally recommended up until early adulthood.
While as many as 20% of children may develop an OPG, most do not cause any visual symptoms and only about a third of them will require treatment with chemotherapy.
Optic Pathway Gliomas don’t often require treatment, but when they do there are effective chemotherapy treatments that can be used to manage symptoms with the aim of preserving vision. Surgery is generally not considered.
Carboplatin and vincristine are generally well tolerated in children with minimal side effects.
SPINE AND BONES
Curvature of the spine (scoliosis) is common in NF1. Often appearing during the teenage growth spurt it is typically mild, not requiring treatment. In more severe cases it appears during childhood and will require monitoring and in some cases intervention through bracing or surgery.
Scoliosis, when mild may not require any treatment, but rather be monitored for any change.
For more severe scoliosis a brace or surgery may be required.
Thinning and bowing of the long bones, most commonly the tibia, is quite specific to children with NF1 and is generally first seen in infancy.
These bowed bones are more prone to fracture, resulting in a further complication – pseudoarthrosis. This involves the development of a false joint through repeated breakage of the bone which does not completely heal each time.
A small bone in the eye socket, the sphenoid wing, can also be affected.
In children with bowing of the long bones, particularly that in the lower leg (tibia), bracing is used to avoid fracture. Surgery may then be required later in childhood to correct the condition with a bone graft or plate.
Puberty can sometimes begin early (precocious puberty) or be delayed. In most instances this is linked with other complications of the condition.
When puberty begins too early (precocious puberty) medication can be prescribed to halt its progression until an age where it is more appropriate to go through this change.
Many people affected by NF1 are shorter than average, but this does not cause any medical concerns. In rare instances this may be treated by growth hormone.
Short stature can be treated with growth hormone. However, when used to treat children with NF1 this approach has only had limited success.
A large head circumference (macrocephaly) is often seen in both children and adults with NF1. This is not usually indicative of any underlying medical concerns.
Further investigation may be warranted only when there is a significant increase in size over a short period of time, at a rate which crosses percentiles on the growth chart.
NF1 can impact appearance in several ways.
Neurofibromas on the skin may be in exposed places or on the face, and plexiform neurofibromas may grow anywhere, impacting appearance. Café-au-lait marks may also be on visible areas of the body.
These changes can impact the way you think and feel about yourself. For some people it makes them feel self-conscious and stops them doing things.
Constipation is frequently seen in people with NF1 and in general does not have an underlying cause.
Diarrhoea on the other hand can occur as the result of a tumour along the digestive tract, and further investigation may be worthwhile.High blood pressure (mentioned separately)
Pain and Vomiting
Pain and vomiting should always be checked out for someone with a background of NF1. If common causes are ruled out, further investigation should be undertaken to search for any underlying NF1-related tumours or other causes.
OTHER TUMOUR TYPES
The symptoms below are generally considered rare, but are not a complete list of all tumour types.
Malignant Peripheral Nerve Sheath Tumour (MPNST)
In NF1, a malignant peripheral nerve sheath tumour (MPNST) is a soft tissue tumour (or sarcoma), which most often develops from a pre-existing plexiform neurofibroma.
Around 10% of people impacted by NF1 will develop an MPNST during their lifetime, but the highest risk period is between 30 – 50 years.
Regardless, of whether there is a known plexiform neurofibroma, the below symptoms should always be checked by a doctor with NF knowledge:
- The tumour becomes hard
- There is persistent pain in the area (for more than a couple of days)
- It grows rapidly
- There is tingling, numbness or other odd sensations in the limbs.
To see whether a plexiform neurofibroma has ‘transformed’, a doctor may order an MRI and a PET scan to understand how it is changing. A biopsy and surgery to remove the tumour may be required if concern for MPNST is warranted.
Like neurofibromas on the skin other tumours can sometimes, depending on their location, size and impact on other tissues or organs, be surgically removed or reduced in size (debulked).
Malignancies are generally managed through surgery or chemotherapy. Radiotherapy is generally not recommended for people with NF1, although there are exceptions.
A pheochromocytoma (PHEO) is usually a benign tumour that develops on the adrenal glands on the kidneys, which produce an adrenaline-like substance causing blood pressure and heart rate to rise.
Only around 1-4 in every 100 people (approximately 1-4%) affected by NF1 will develop one of these tumours. Only a very small portion of these becomes malignant.
Symptoms to look out for include:
- High blood pressure
- Headaches associated with high blood pressure
These most often arise in adulthood, over the age of 30, but can occur at any age.
Pregnant women with NF1 with and a pheochromocytoma can have very serious complications and require immediate medical attention
They are usually easily diagnosed with a CT scan and by measuring the levels of adrenaline substances in the urine.
Surgery to remove a PHEO is very successful when caught early.
A diagnosis of NF1 for women brings with it a moderately increased risk of breast cancer before age 40. Due to this risk the guidelines recommend monitoring from the age of 35 via ultrasound, MRI and mammogram.
The recommended screening method changes with age as the risk decreases back to that of the general population later in life and due to the change in breast tissue density.
Lumps discovered on imaging may need to be biopsied (a sample taken) or excised (removed) to determine whether the lump is a neurofibroma or breast cancer. Specialists will look at family history, as well as NF diagnosis when making screening and treatment recommendations.
To learn more click here.
Other Tumours and Cancers
Several other tumours and cancer have been linked to NF1, but by comparison are relatively rare. These include:
Monitoring and surveillance for these types of tumours/cancer is not routine in NF1 when symptoms are not present because they are very rare. Always discuss new symptoms and concerns with your General Practitioner (GP) and NF specialist.
DIAGNOSTIC CRITERIA OF NF1
Diagnosis of NF1 is usually made clinically through medical examination of the body as this is considered most reliable. However, more and more frequently diagnosis is made through a blood test in which the NF1 gene is analysed for changes (for more information head to Causes of NF)
To receive a clinical diagnosis of NF1 an individual must have at least two of the following diagnostic criteria:
- A first degree relative with NF1 (mum, dad, brother or sister).
- 6 or more Café-au-lait marks (CALM) which are 5 mm or larger in pre-pubertal children, or 15 mm or larger for anyone who has passed through puberty.
- Freckling under the arms (axillary) or in the groin area (inguinal).
- Presence of two or more neurofibromas of any type or one or more plexiform neurofibromas.
- Two or more benign pigmented lumps on the iris (Lisch Nodules).
- A distinctive bony lesion: long bone or sphenoid wing dysplasia.
- Optic pathway glioma (OPG).
- A pathogenic NF1 gene variant through genetic analysis.
management and treatment
The cornerstone of NF1 management is surveillance. This is because the condition affects everyone so differently and the signs and symptoms that can be experienced are so varied.
Surveillance may consist of:
Not everyone who has NF1 will need an MRI. Many people will only have scans if symptoms appear. One reason for this is because often these scans give incidental findings of tumours or other abnormalities that nothing needs to be done about (i.e. the risks and side effects of treatment outweighs any benefit having the treatment would result in).
This then requires monitoring over a period of time, which can cause additional stress in an already stressful situation.
Disclaimer: We have taken all reasonable steps and care to ensure that the information on this page is medically accurate and up-to-date at the time of writing. The Children's Tumour Foundation cannot be liable should this information change with new research. Please always consult your individual healthcare specialist for advice about your specific condition and needs.