Introduction

Neurofibromatosis refers to a collection of conditions where tumours, called neurofibromas, develop along nerves within the nervous system. This can affect the functioning of the brain and spinal cord, which are responsible for how the body reacts to stimuli. The tumours that form can either be non-cancerous, also known as benign tumours, but some may become cancerous, known as malignant tumours.¹

Neurofibromatosis 1

Overview

Neurofibromatosis 1 (NF1) is the most common neurofibromatosis. This form of neurofibromatosis is caused by a genetic mutation in the NF1 gene, located on chromosome 17. The NF1 gene produces neurofibromin within nerves and other specialised cells, functioning as a tumour suppressor.⁴ Tumour suppressor proteins target cells that divide too rapidly or uncontrollably, similar to how tumours form and develop, and regulate how these cells divide.⁵ A mutation within the NF1 gene produces a non-functional version of neurofibromin that cannot regulate cell division, causing neurofibromas to form, primarily in the skin and around large nerves within the body. 

Causes and inheritance

Roughly half of all cases of NF1 are inherited from a parent, where the mutated gene is passed onto their children. The gene is passed on through autosomal dominant inheritance, which means that only one copy of a gene is needed to cause the condition. When an autosomal dominant gene is passed onto a child, they have a 50% chance of inheriting the mutated gene and this chance is equal between those assigned male at birth (AMAB) and those assigned female at birth (AFAB).⁶ In the other half of cases, the mutations develop without any known reason, referred to as spontaneous mutations. 

Symptoms

Generally, the symptoms of NF1 are mild but may be severe in rare cases:

• ‘Café au lait’ spots (coffee-coloured patches on the skin roughly 5mm in size that typically present in childhood)
• Freckles in unusual places (armpits, groin, breast area)
• Bumps under skin
• Learning difficulties
• Hyperactivity
• Below average height in children
• Bone deformities

Neurofibromatosis 2

Overview

Neurofibromatosis 2 (NF2) is less common than NF1 and also involves the development of neurofibromas within the nervous system. However, NF2 is differentiated by the presence of benign tumours within the central nervous system (CNS). The tumours in NF2 form along the nerves that control balance and hearing and cause issues within these areas, known as vestibular schwannomas.

Causes

Much like NF1, NF2 is caused by a mutation within a gene. However, in the case of NF2, the NF2 gene is located on chromosome 22. The NF2 gene is responsible for producing a protein called merlin (also known as neurofibromin 2 or schwannoma) within Schwann cells, which play an important role in the development, maintenance and insulation of peripheral nerves. Merlin functions as a tumour suppressor just like neurofibromin and prevents the development of neurofibromas.⁷

Mutations in the NF2 gene cause the production of a non-functioning version of Merlin which can cause cells, such as Schwann cells, to divide rapidly and can cause tumours to form. Like NF1, the mutation in NF2 is considered autosomal dominant and can be genetically passed on from a parent to their child. New mutations can also arise in people with no known history in the family. 

Symptoms

The symptoms of NF2 may present from birth to adulthood. NF2 symptoms are most common in people in their late teens or 20s:

• Dizziness
• Hearing problems or loss
• Ringing in the ears (tinnitus)
• Balance issues
• Issues when walking

Schwannomatosis

Overview

Schwannomatosis is the rarest form of neurofibromatosis affecting roughly 1 in 40,000 people. In schwannomatosis, benign tumours called schwannomas grow on the coverings of peripheral nerves. Schwannomas are composed solely of Schwann cells, while neurofibromas can be made of a mixture of cells.⁸

Causes

Like NF1 and NF2, genetic mutations are one of the causes of schwannomatosis. In the case of schwannomatosis, 2 genes are involved called SMARCB1 and LZTR1. The SMARCB1 gene produces a protein subunit involved in SWI/SNF protein complexes that regulate gene activity. The LZTR1 gene is thought to act as a tumour suppressor to prevent the growth of tumours. Changes in one of either gene are thought to cause schwannomatosis and can be passed from a parent to their children.⁹

Symptoms

The symptoms of schwannomatosis normally develop in early adulthood and depend on the location of the schwannoma:

• Chronic pain is the most common symptom and can affect any part of the body. It can be intense at times
• Numbness
• Weakness
• Issues with urination
• Headaches
• Vision problems

Bone abnormalities in neurofibromatosis

While the tumours are typically non-cancerous, the pressure caused by the presence of tumours can negatively impact the areas surrounding the nerves such as the underlying bone structures. Some bone abnormalities can be age-related and can be identified during a person’s early years. Bone deformities are most documented in NF1 due to how common the condition is, but could also manifest in NF2 and schwannomatosis. 

Scoliosis

Scoliosis is characterised by a curvature of the spine, typically towards one side. Around 5% to 10% of people with NF1 experience scoliosis and may not be noticeable until it becomes more severe and painful.¹⁰ People with NF1 either develop dystrophic (bone wasting where neurofibromas affect the curvature of the spine) or non-dystrophic scoliosis (scoliosis that forms from other sources) but a small percentage may be idiopathic and may not present until adulthood. 

The benign tumours that form in neurofibromatosis appear to weaken the spinal cord and the overall strength of the spine, leading to the curvature seen in scoliosis. This scoliosis can become painful and debilitating when the angulation of the spine is roughly 40% off the vertical.

Congenital pseudoarthrosis

Pseudoarthrosis is a condition where a broken bone heals poorly and fails to fuse with another bone, delaying the healing process of an injury. Pseudoarthrosis can be congenital (develops from birth) or occur later in life and congenital pseudoarthrosis of the tibia is most commonly associated with NF1.¹¹ Roughly 5% of children with NF1 may develop congenital pseudoarthrosis. Exactly how neurofibromatosis causes pseudoarthrosis is not completely understood, but the reduced blood flow and soft tissue surrounding the bone may lead to increased bone reabsorption near the fracture site. 

Abnormalities with bone growth

People with neurofibromatosis may experience problems with bone growth. Neurofibromin is believed to be involved in bone development as the neurofibromin gene is expressed in osteoblasts, cells that form new bones and heal existing ones. The lack of neurofibromin found in NF1 could explain the stunted growth of bones in neurofibromatosis.

Those with NF1 can experience issues with the development of bones within the skull. They may also develop issues with the sphenoid bone behind the eyes, known as ​​congenital sphenoid wing dysplasia.¹² 

Some people diagnosed with NF1 may also suffer from a vitamin D deficiency. Vitamin D is necessary for the absorption and mineralisation of calcium which is needed to maintain bone strength. A lack of vitamin D disrupts the mineralisation of bone and can lead to a decrease in bone density. 

Osteoporosis 

In osteoporosis, the framework of bones becomes thinner, less dense and more prone to fractures. Generally, osteoporosis occurs mostly in older patients but people with NF1 are more likely to develop osteoporosis, affecting the strength of their bones. Osteoporosis is found in up to 50% of NF1 patients and is linked to a decrease in vitamin D. 

Management of neurofibromatosis

There is no current treatment for NF1, NF2 or schwannomatosis, but there are several ways to manage the symptoms. 

If the tumours become too prominent or start causing too many issues in NF1 or schwannomatosis, the tumours can be surgically removed to relieve any discomfort. Surgery for NF2 is more risky as it can cause further problems with deafness or facial weakness and must be properly evaluated beforehand. 

The balance problems in NF2 can be easily managed through vestibular and physical therapy. Furthermore, the hearing loss in NF2 can be managed with the use of hearing aids, the learning of sign language or cochlear implants to improve hearing and communication. 

Any general aches and pains can be treated with medication and painkillers. Physiotherapy may help tackle any mobility issues that develop as well. Regular monitoring of symptoms and physical examinations can help manage any issues with neurofibromatosis. 

Conclusion

There are 3 known types of neurofibromatosis - NF1, NF2 and schwannomatosis. Each one presents differently but all involve the formation of tumours alongside nerves within the nervous system. Though the tumours are typically benign and non-cancerous, they can still affect nearby tissues and bone. The bone abnormalities that develop usually stem from a lack of neurofibromin and other molecules involved in bone development. While these bone deformities are most documented in NF1, they have the opportunity to develop in any neurofibromatosis. No current cures are known for any form of neurofibromatosis, but each condition is manageable and is usually not too debilitating.