Overview

Neurofibromatosis is a condition that affects the nervous system. The condition has three subtypes each with a different genetic basis. It can lead to tumours in the nerves of the brain, spinal cord and other parts of the body. This article explores neurofibromatosis in adults, describing the three subtypes, symptoms, diagnosis, management and future research directions.

Neurofibromatosis

Neurofibromatosis is a genetic disorder which has three distinct types each with specific symptoms and genetic origin.

• Neurofibromatosis type 1 (also referred to as NF1)
• Neurofibromatosis type 2 (also referred to as NF2)
• Schwannomatosis 

Neurofibromatosis type 1

Neurofibromatosis type 1 is the commonest type of neurofibromatosis. It is estimated to affect approximately 1 in 3000 to 1 in 4500 people.¹ It presents with multiple benign tumours called neurofibromas on or under the skin. 

Neurofibromatosis type 1 is caused by mutations in the NF1 gene. This provides the genetic code to make a protein called neurofibromin that helps control cell growth. When the NF1 gene mutates, cell growth increases, resulting in tumours. 

Clinical features of neurofibromatosis type 1 in adults

Neurofibromatosis type 1 can affect various body systems, including:

• Skin
• Nervous system
• Skeleton

NF1 is also associated with an increased risk of cancer.

Skin manifestations

Adults with Neurofibromatosis type 1 often have skin problems which can include:

• Café-au-lait spots 
• Neurofibromas 
• Lisch nodules 

Neurological manifestations

Neurological complications in neurofibromatosis type 1 may include:

• learning disabilities
• attention deficits
• seizures
• headaches 
• tumour growth 

Skeletal abnormalities

Neurofibromatosis type 1 may also cause joint and skeletal problems including:

• scoliosis 
• pseudarthrosis 

Increased risk of cancer

In NF1, there is an increased risk of developing tumours including:

• malignant nerve sheath tumours
• optic gliomas  
• other cancers 

Neurofibromatosis type 2

Neurofibromatosis type 2 is less common than neurofibromatosis type 1 and occurs in approximately 1 in 25,000 individuals.¹ 

Neurofibromatosis type 2 manifests with the formation of benign tumours in the nervous system, particularly bilateral vestibular schwannomas, which affect hearing and balance. 

Neurofibromatosis type 2 is linked to mutations in the NF2 gene on chromosome 22. This is responsible for producing a protein called merlin (also known as schwannomin) which acts as a tumour suppressor.

Clinical features of neurofibromatosis type 2 

Individuals affected by neurofibromatosis type 2 typically develop schwannomas involving both vestibular nerves leading to hearing loss and eventual deafness. 

Neurofibromatosis type 2 is linked to morbidity and a reduced life expectancy. Surgery is the primary management strategy for complicating tumours. Tailored drug therapies aimed at the genetic level may provide improvements for this life-limiting condition in the future.² Psychological support should also be provided to individuals with the condition.³ 

Bilateral vestibular schwannomas

Bilateral vestibular schwannomas are tumours associated with the auditory nerves that cause: 

• hearing loss
• tinnitus
• balance issues

Many people with neurofibromatosis type 2 develop complete hearing loss.¹ 

Meningiomas

Meningiomas are tumours that form on the membranes covering the brain and spinal cord.

Ependymomas

Ependymomas are tumours that develop in the ependymal cells lining the ventricles of the brain and the centre of the spinal cord.

Other symptoms

Other symptoms of neurofibromatosis type 2 include:

• facial weakness
• visual problems 
• coordination issues 

Schwannomatosis

Schwannomatosis is the rarest form of neurofibromatosis. Multiple schwannomas develop without vestibular schwannomas – unlike in neurofibromatosis type 2. Schwannomatosis is thought to be due to mutations in the SMARCB1 or LZTR1 genes. Pain is one of the most significant and debilitating symptoms.

Clinical features of schwannomatosis

Schwannomatosis has some overlap with neurofibromatosis type 2 but they are distinct conditions.⁴ 

Painful schwannomas

These painful tumours can develop on the spinal and peripheral nerves. The pain can be severe and affect quality of life.

Absence of vestibular schwannomas

Schwannomatosis does not typically manifest with vestibular schwannomas, a feature which helps distinguish it from neurofibromatosis type 2.

Diagnosis of neurofibromatosis in adults

Diagnosing neurofibromatosis involves a combination of clinical assessment, imaging and genetic testing.

Clinical criteria

Diagnosis of neurofibromatosis type 1 

The National Institutes of Health diagnostic criteria for neurofibromatosis type 1 includes the presence of: 

• café-au-lait spots
• neurofibromas 
• Lisch nodules 
• skeletal abnormalities 

Diagnosis of neurofibromatosis type 2 

The criteria for diagnosis of NF2 includes the presence of the following: 

• bilateral vestibular schwannomas 
• family history of NF2 combined with other related tumours

Imaging studies

MRI and CT scans help to detect and monitor tumours in neurofibromatosis. These scans can assess the size, location and growth rate of tumours and help guide treatment decisions.

Genetic testing

Genetic testing can confirm a diagnosis of neurofibromatosis, particularly when clinical features are not clear or overlap. Testing for mutations in the specific genes can provide definitive evidence of the disorder. 

Genetic counselling

Genetic counselling is recommended for patients and families to understand the implications of test results and inheritance patterns. 

Management and treatment of neurofibromatosis 

Managing neurofibromatosis requires a multidisciplinary approach due to the variety of symptoms and complications associated with the disorder.

Multidisciplinary approach

Various clinicians can be involved in treatment and management of neurofibromatosis and include:

• Neurologists
• Dermatologists
• Geneticists
• Pain specialists
• Neurosurgeons
• Other healthcare professionals

Neurologists

Neurologists are doctors who can monitor and treat neurological symptoms such as seizures, headaches and balance issues.

Dermatologists

Dermatologists are doctors who manage and treat skin symptoms such as neurofibromas.

Geneticists

Geneticists are doctors who are involved in the genetic testing for diagnosis of neurofibromatosis. They may also also provide genetic counselling to give important information on inheritance patterns, genetic testing and family planning.

Pain specialists

Pain specialists are doctors, often anaesthetists, who can use medication and other therapies to manage pain. Adequate pain management can improve physical functioning, mental health, quality of life and reduce pain.⁵ As pain can be a debilitating aspect of neurofibromatosis, adequate pain management should be integral to treatment. 

Neurosurgeons

Neurosurgeons, and other specialist surgeons, will be involved where surgery is required for neurofibromatosis, such as where tumours arise in the brain or for correction of scoliosis.

Other healthcare professionals

Other healthcare professionals such as specialist nurses, occupational therapists, physiotherapists and psychologists will be involved in ensuring adequate management of symptoms and achieving optimal quality of life in day-to-day activities. 

Medical management

Pain management

Chronic pain is a significant issue in neurofibromatosis, especially in schwannomatosis. Pain management includes medication, physiotherapy and surgical intervention. Psychological therapies, such as CBT and mindfulness, may also be helpful.⁶

Anticonvulsants

Anticonvulsants are prescribed by specialists for seizures that may be caused by neurofibromatosis.

Learning disabilities

Educational support and therapy are important for adults with learning disabilities due to neurofibromatosis.

Surgical treatment

Surgery is often required to remove tumours that are causing pain, physical disability or have the potential to become malignant. Surgical treatment options include:

• Tumour removal for symptomatic neurofibromas, vestibular schwannomas and other tumours
• Corrective surgery to correct skeletal abnormalities such as scoliosis

Rehabilitation

Rehabilitation may include physiotherapy and occupational therapy to help maintain or improve function and teach compensatory techniques in activities of daily living.

Psychosocial support

Neurofibromatosis can significantly impact an individual's psychological well-being and quality of life. Comprehensive care includes:

• Psychological counselling
• Therapies, such as mindfulness and meditation, can promote quality of life in adults with neurofibromatosis⁷ 
• Support groups

Psychological counselling 

Psychological counselling may be important to help individuals and their carers deal with the emotional and mental health challenges of the disorder.

Support groups 

Connecting with others who have neurofibromatosis can provide valuable emotional support and practical advice. These can be accessed in person or online through support groups such as ChangingFaces. The NF Registry is a way for individuals to become involved in research, be a part of a community and learn more about new NF treatments. The data they provide allows researchers to better understand NF.⁸ 

Emerging therapies

Advancements in molecular biology and genetics have led to the development of targeted therapies for neurofibromatosis. These therapies aim to inhibit specific pathways involved in tumour growth.

Targeted molecular therapies

Drugs such as Selumetinib have shown promise in treating NF1-related plexiform neurofibromas.⁹ 

Prognosis in neurofibromatosis

The prognosis for individuals with neurofibromatosis varies by the subtype of the condition, the severity of symptoms and the presence of malignant growths. Early diagnosis and treatment can significantly improve outcomes. Neurofibromatosis type 1 generally has a better prognosis than neurofibromatosis type 2, which is associated with more severe neurological complications.

The extent of tumour growth and associated complications play a role in prognosis. The development of malignant peripheral nerve sheath tumours, and other cancers, negatively impacts on life expectancy and quality of life.

While life expectancy can be almost normal for many with neurofibromatosis 1, those with NF2 may have a reduced life expectancy.³ 

Quality of life

Multidisciplinary care and emerging therapies aim to improve the quality of life for individuals with neurofibromatosis. Pain management and surgery may improve quality of life.

Current research and future directions

Research into neurofibromatosis is ongoing, with several promising areas of investigation. Current research is focused on finding new treatments and improving existing ones. In the future, the development of tailored drug therapies aimed at the genetic level are likely to provide huge improvements for this devastating condition.¹⁰ 

Summary

Neurofibromatosis is a genetic disorder with three distinct subtypes, presenting with a wide range of symptoms, that requires a multidisciplinary approach to management. 

Life expectancy and quality of life are affected by the subtype of the condition, the degree of symptoms and the impact of effective treatment and support. Surgery is currently still the mainstay of treatment but personalised treatments can also deal with specific symptoms. Early diagnosis, personalised treatment plans and psychosocial support are vital.

Progress has been made in understanding and treating this disorder but ongoing research is essential to develop more effective therapies and ultimately improve the life expectancy and quality of life for affected individuals.