Introduction

Neurofibromatosis is a medical disorder defined by the development of tumours that affect the brain and spinal cord, as well as the nerves that transmit signals 1) between the brain and spinal cord and 2) between the brain/spinal cord and other parts of the body.¹ Most of these tumours are benign (non-cancerous), but in some cases they can become malignant (cancerous).¹

There are three types of neurofibromatosis:

1. Neurofibromatosis type 1 (NF1) (also known as von Recklinghausen disease)
2. Neurofibromatosis type 2 (NF2)
3. Schwannomatosis 

Neurofibromatosis tumours have distinctive characteristics:

• Cell compositions: benign neurofibromatosis tumours contain a mixture of cell types, including Schwann cells, fibroblasts, and perineurial cells²
• Location: neurofibromatosis tumours develop and grow in the nervous system and skin²
• Variable: the clinical symptoms and growth of neurofibromatosis tumours can vary greatly, even within individuals²
• Genetic mutation: neurofibromatosis is associated with genetic mutations which lead to tumour growth

The different types of neurofibromatosis

Neurofibromatosis type 1 (NF1)

NF1 is the most common neurofibromatosis type, making up 96% of all neurofibromatosis cases.^1,2 It is caused by a genetic mutation on the neurofibromin 1 (NF1) gene which codes for neurofibromin.² Neurofibromin is a tumour suppressor gene that inhibits and prevents tumour development.

As such, a mutation in this gene can cause neurofibromin to become dysfunctional and tumours to develop. Approximately 50% of patients with NF1 have a random, spontaneous mutation; the remaining 50% inherit the gene from their parents.²

Patients with NF1 can have a variety of clinical features and symptoms that can change throughout their lives.¹ These can include:

• Six or more flat, light brown spots on the skin (known as ‘cafe au lait spots’).³ These spots are the most common feature of NF1, and are usually seen at birth or develop during childhood¹ 
• Soft, pea-sized bumps on or under the skin.³ These are benign tumours that are often present at birth and become noticeable after a couple of years.¹ More tumours may appear as the patient ages³
• Freckling in the armpits or the groin areas. Freckling usually appears between 3 and 5 years of age. The frecklings are smaller than cafe au lait spots and are usually found in clusters in the skin folds³
• Tiny bumps on the iris of the eye (Lisch nodules). These bumps are harmless and don't affect vision³
• Skeletal deformities, such as scoliosis or bowed lower leg³
• Tumours on the optic nerve. This clinical symptom is only present in early childhood, and rarely in late childhood or adolescence³. It is almost never seen in adults
• Mild learning disabilities are common in children with NF1, with problems in reading or mathematics. ADHD and speech delay are common³
• Larger than average head size³
• Below average in height³

Neurofibromatosis type 2 (NF2)

NF2 is less common than NF1.¹ It is also caused by a genetic mutation in the NF2 gene, which codes for merlin.² Merlin is a tumour suppressor protein, and like NF1, it becomes inactive once mutated. As such, there is nothing preventing cells from proliferating and forming tumours.²

NF2 makes up 3% of neurofibromatosis cases and is found in 1 in 33,000 births.² Similar to NF1, approximately 50% of NF2 cases are inherited from their parents and the other 50% is caused by a random mutation in the NF2 gene. NF2 affects both genders and all races equally. 

Like with NF1, NF2 has variable clinical symptoms.² Symptoms usually appear during late teens and early adulthood and they can vary in severity.³ The symptoms from NF2 are usually caused by the development of slow-growing benign tumours in both ears and these can include:³

• Gradual hearing loss
• Ringing in the ears 
• Poor balance
• Headaches

These symptoms are felt as the tumours grow on the nerves that are responsible for carrying the sounds and balance information to the brain from the inner ear.³ In some cases, NF2 can develop in other nerve cells such as the spinal, visual and cranial nerves and these can lead to the following symptoms:³

• Numbness and weakness in the legs and arms
• Pain 
• Difficulties in balancing
• Vision problems 
• Seizures
• Headaches
• Facial drops

Teenagers and adults are often seen for hearing and balance problems, younger children with NF2 show more vision problems and this means that signs of NF2 in children are often overlooked, especially if there is no NF2 family history.¹

Schwannomatosis

Schwannomatosis is the rarest type of neurofibromatosis and is genetically and clinically distinct from the other types.² The exact genetic mutation responsible for schwannomatosis is not known, but mutation of the SMARCB or LZTR1 gene is associated with the disease.¹ Schwannomatosis causes tumours to develop on the cranial, spinal and peripheral nerves - but very rarely on the inner ear nerves like in NF2.³ 

The clinical symptoms of schwannomatosis are similar to the symptoms of NF2 (as the tumours form on the same nerves) but patients with schwannomatosis don’t experience hearing loss like patients with NF2.³ The symptoms of schwannomatosis most commonly appear between the ages of 25 and 30 and can include:^1,3

• Chronic pain which can appear anywhere in the body
• Numbness and weakness in various parts of the body
• Loss of muscle function

Tumour growth mechanisms in neurofibromatosis

Loss of tumour suppressor function

As discussed earlier, both NF1 and NF2 are caused by a genetic mutation that causes a loss of a tumour suppressor function. 

Role of the NF1 gene in tumour suppression

The NF1 gene is found on chromosome 17 and codes a tumour suppressor protein called neurofibromin. Neurofibromin acts by regulating the Ras cellular proliferation pathway, which controls cell division.^1,4 Normally, neurofibromin negatively regulates the Ras pathway by keeping Ras proteins in their inactive form - meaning that cells only divide when needed.⁵ However, when the NF1 gene becomes mutated and dysfunctional, the Ras proteins become active - causing cells to divide uncontrollably and form tumours.⁵

Role of the NF2 gene in tumour suppression

NF2 is caused by a mutation in the NF2 gene, which is found on chromosome 22 and encodes the tumour suppressor protein Merlin.² Like Neurofibromin, Merlin controls cell division. To this end, Merlin negatively regulates another cell division pathway called the Hippo pathway, which regulates and controls cell proliferation, cell differentiation and cell migration in our organs.⁶ When the NF2 gene becomes mutated, Merlin is not produced, leading to uncontrolled cell growth and division and causing tumours to grow. 

Dysregulated signalling pathway

Tumour growth can be caused by dysregulation in a cell signalling pathway, as described above. As biology is all interconnected, a mutation in any gene can set off a cascade of consequences that can ultimately permit tumour growth.

Diagnosis

Diagnosis will begin with a medical history of the patient and their family and with a physical examination. Other diagnostic tools used include:³

• Examining the skin for cafe au lait spots 
• Eye exam to detect Lisch nodules
• Hearing and balance exams to diagnose NF2 
• Imaging tests such as X-rays, CT scans and MRI scans to detect tumours in the brain or spinal cord
• Genetic testing, especially if there is a family history of neurofibromatosis

Treatment 

Neurofibromatosis cannot be cured, but treatments are available to manage patients’ symptoms.¹ 

NF1

Most patients with NF1 do not need any treatment for their symptoms, but periodic evaluation by a specialist is recommended.¹. Selumetinib is a drug treatment available for children over the age of 2 to help stop more tumours from growing. Surgery is another treatment available to remove tumours that are causing discomfort to patients.¹ 

NF2

NF2 can also be managed by regular check-ups. However, once tumours have grown to the point where they are affecting the patient’s hearing, they can be surgically removed.¹ 

Schwannomatosis

There is currently no treatment available for schwannomatosis.¹ Surgery can be used to remove tumours that are large or causing discomfort to the patient, but nerve damage is a risk that will need to be considered.

Summary

Neurofibromatosis is a medical condition that causes tumours to grow in the brain, spinal cord and nerves. There are three types of neurofibromatosis: NF1, NF2 and schwannomatosis, which differ in their clinical presentation and underlying cause. There is no cure available for neurofibromatosis, but there are treatments available to improve patients’ quality of life. However, most patients will not require any treatments, and there is no change in the average life expectancy for patients with neurofibromatosis.