What Is Neurofibromatosis Type 2?

Introduction

Neurofibromatosis type 2 (NF2) is a rare genetic condition that specifically affects the central nervous system. It causes the formation of non-cancerous tumours on nerves, even though the term itself may be difficult to understand. These tumours can pose significant health risks, particularly when they are numerous and located in or near the brain.¹ There are also other types of tumours that can develop in the nervous system, such as schwannomas, which affect peripheral nerves, and meningiomas, which are slow-growing tumours typically found on the cerebral cortex. Another type, gliomas, encompasses ependymomas that are located in either the brain or spinal cord. Although less common than type 1, neurofibromatosis type 2 still presents its unique challenges and symptoms that profoundly affect individuals who have the condition.

Fig. 1. The clinical presentations associated in individuals with NF2.

Asthagiri AR, Parry DM, Butman JA, H Jeffrey Kim, Tsilou ET, Zhuang Z, et al. Neurofibromatosis type 2. The Lancet [Internet]. Elsevier BV; 2009 [cited 2024 Apr 2]; 373(9679):1974–86. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748851/#S3title.

Causes and risk factors

Neurofibromatosis type 2 is predominantly caused by genetic mutations in the NF2 gene located on chromosome 22q. This gene is responsible for producing a protein called merlin, also known as schwannoma, which acts as a tumour suppressor. Merlin plays a crucial role in regulating tumour growth within the nervous system by enveloping and protecting neurons in the brain and spinal cord. When mutations occur in the NF2 gene, the production of merlin is reduced, leading to the uncontrolled spread of tumours.^1,2 NF2 follows an autosomal dominant inheritance pattern, meaning it only takes one mutated copy of the gene from either parent for the condition to develop. However, it is worth noting that more than half of all NF2 cases arise from spontaneous mutations, with no previous family history of the disorder.¹

Symptoms and clinical presentation

The way NF2 is presented in individuals can vary greatly depending on factors such as the size, location, and severity of the tumours that are present. One key characteristic of NF2 is the appearance of vestibular schwannomas, which can result in symptoms like - problems with hearing, a persistent ringing in the ears known as tinnitus, and balance issues. Other clinical signs may be observed, including:^2,3

• Visual impairments like cataracts or a decline in vision due to tumours on the optic nerve 
• Headaches
• Facial weakness or paralysis
• Numbness in the limbs 
• Difficulties with speech or swallowing
• Back pain caused by tumours on the spinal cord

Diagnosis

• Diagnostic evaluation:^1,4
  • DNA testing and other cutting-edge imaging methods, like MRIs, are used in diagnosis.
  • Specific symptoms, such as tumours affecting the nerves, brain, or eyes, are included, taking into consideration family history and tumour occurrence.
  • Consider other disorders, such as schwannomatosis, with specific diagnostic criteria to prevent misdiagnosis.
• Genetic counselling and testing:⁴
  • The autosomal dominant inheritance of NF2 highlights the importance of genetic counselling since it has a 50% transmission risk.
  • Genetic testing is useful in identifying mutations, predicting transmission risks, and confirming a diagnosis, especially among individuals who do not have a family history.
• Screening protocol:¹
  • Children of affected individuals are screened from birth for early signs such as cataracts and meningiomas.
  • Formal screening for vestibular schwannomas starts at age ten, with the frequency of MRI examinations varying according to the individual's age and tumour status.
• Confirmation of diagnosis:⁴
  • Confirmation of the diagnosis is critical, and genetic testing is recommended for those with symptoms suggestive of NF2.

Management and treatment options

An approved cure for NF2 remains elusive, managing the illness requires a comprehensive approach that focuses on symptom relief, neurological preservation, and tumour development control.^1,5

1. Observation: Small tumours may be regularly monitored without early treatment, particularly if they do not provoke severe symptoms.
2. Surgery: Tumours are often surgically removed to relieve symptoms or avoid consequences, especially for severe tumours affecting the brain, spine, or peripheral nerves.
3. Radiation therapy: A useful technique for preventing or delaying the growth of tumours that resist surgical intervention, particularly vestibular schwannomas.¹
4. Medications: Certain drugs, such as bevacizumab (a monoclonal antibody against vascular endothelial growth factor) or mTOR inhibitors, may be used to slow tumour development and alleviate symptoms. Bevacizumab has shown potential for causing tumour shrinkage and improving hearing in NF2 patients.
5. Symptomatic management:
   • Vestibular training, physical therapy, and occupational therapy are all options for treating balance issues.
   • Individuals with hearing loss may acquire other communication strategies, such as sign language.
   • Tinnitus may be controlled by tinnitus retraining treatment and behavioural strategies.
   • Medication, meditation, acupuncture, and behavioural techniques may help alleviate NF2-related pain and discomfort.
6. Multidisciplinary care: A comprehensive plan of action comprising oncologists, neurologists, neuroradiologists, ophthalmologists, geneticists, and neurosurgeons, is necessary for the care of NF2.
7. Surveillance: Monitoring tumour development and detecting any changes in neurological state need routine surveillance, usually performed by yearly brain MRI scans.

Prognosis and complications

Patients with NF2 may have different experiences depending on various factors, such as the size, development, and effectiveness of their tumours, as well as the efficacy of their treatments. Although NF2 tumours are typically non-cancerous, their location and size can still have a significant impact on individuals affected by the condition. The symptoms of NF2 can manifest in various ways, including progressive hearing loss, problems with balance, weakness in facial muscles, and even impairment of vision. In rare cases, individuals may also experience spinal cord compression and the growth of malignant tumours.¹ However, it is important to note that with the proper support and care, many people affected by NF2 can overcome these challenges and find fulfilment in their lives.

Coping strategies and support for NF2

Living with NF2 presents various challenges, encompassing both psychological and physical obstacles. The unpredictable nature of the illness and its interference with daily activities can take a toll on mental health. 

It is crucial to establish a robust support system comprising medical experts, family members, and peers who can truly comprehend the journey of living with NF2. 

To manage symptoms and improve overall well-being, maintaining a balanced diet, engaging in regular exercise, and ensuring sufficient sleep are essential aspects of a healthy lifestyle.^4,6 

Additionally, seeking psychological counselling and treatment can be beneficial in addressing the emotional impacts associated with having NF2.

Research and future outcomes

Ongoing research aims to provide more potent therapies and get more insights into the underlying processes of NF2. Targeted medicines that directly block tumour development pathways, gene therapy strategies to restore normal NF2 gene activity, and innovative imaging methods for tumour early identification and monitoring are promising research fields.⁵ Researchers aim to enhance the quality of life and prognosis of those affected by this uncommon condition by expanding our understanding of NF2 and creating novel therapeutic approaches.

FAQs

Does ageing worsen NF2?

The ageing process does not directly worsen NF2, but certain symptoms, like tumour growth, may progress over time.

Do all NF2 patients become deaf?

Most people with NF2 will eventually become completely deaf, while others may use implants or hearing aids to maintain partial hearing.

When is NF2 usually diagnosed?

NF2 symptoms may manifest at any age, but they usually first show up in late adolescence or early adulthood.

How common is NF2?

Rarely, NF2 affects around 1 in 3 people globally. However, since diagnoses might vary, the real number of cases may be greater.

Should individuals with NF2 consider having children?

A person with the faulty NF2 gene may pass it on to their offspring, with a 50% probability of inheritance for every child. There are alternatives for family planning available to those who want to prevent passing on the defective gene.

Summary

Neurofibromatosis type 2 is a rare genetic anomaly that affects the complicated network of the central nervous system. This disease causes benign tumours on nerves to develop; the most common kind of these tumours is vestibular schwannomas, which may cause a variety of neurological symptoms. Although spontaneous mutations may occasionally happen, the main cause of NF2 is mutations in the NF2 gene, which is inherited autosomally dominantly. Clinical evaluation, genetic testing, and imaging methods are combined in the diagnosis process, along with established early detection strategies. While there is no cure, treatment options include medication, radiation therapy, surgery, monitoring, and symptomatic care. However, these generally demand a multidisciplinary approach. NF2 patients have different prognoses based on the size of their tumours and how well their treatments work. Creating a support network and leading a healthy lifestyle are two coping mechanisms. Current investigations aim to improve treatments and understanding of NF2, and there may be future developments in gene therapy, targeted pharmaceuticals, and imaging methods.