Overview of neurofibromatosis

What is neurofibromatosis?

Neurofibromatosis (NFB) refers to three separate medical conditions that cause tumour development in the brain, spinal cord and nerves leading to these body regions.¹ The different types are:

• Neurofibromatosis type 1 (NF1)
• Neurofibromatosis type 1 (NF2)
• Schwannomatosis (SWN)

Although most tumours are benign they can become malignant (cancerous).¹ This article will focus on the two main NFB types (NF1 & NF2).

Prevalence and genetic aspects

NF1 is the predominant form of NFB, affecting 1 in 3000 live births and accounting for 96% of all NFB cases.² It arises from mutations in the neurofibromin 1 gene (NF1), which can be either inherited or occur spontaneously, with spontaneous mutations representing 30-50% of NF1 cases.^1,2 

Comparitively, NF2, although less prevalent - occurring in 1 in 33,000 live births and comprising 3% of NFB cases - is caused by a loss of function mutation in the Merlin protein found in cell membranes.² Both NF1 and NF2 mutations have a 50% inheritance risk if one parent is affected, illustrating the significant genetic component of these conditions.¹ 

Overview of hearing loss

The hearing system consists of the outer, middle and inner ear connected to the auditory nerve that sends the sound signals to the brain pathways to be processed.³ According to the World Health Organisation (WHO), hearing loss affects 5% of the global population, ranging from mild to complete hearing loss.⁴

Types and causes

Hearing loss refers to a person unable to hear normally compared to an individual with healthy hearing. The thresholds according to WHO for normal hearing are 20dB or more in each ear.⁵ Hearing loss can be mild, severe or profound and affects one or both ears leading to difficulty understanding conversations and reacting to surrounding noise in the environment. Individuals can develop hearing loss during their lifetime or be born with it. Types of hearing loss include:³

• Conductive (something is stopping sound from getting through the outer or middle ear)
• Sensorineural (a problem in the inner ear or hearing nerve)
• Mixed (both conductive and sensorineural)
• Auditory neuropathy spectrum disorder (an issue in how the brain processes sound)

Impact on quality of life

Hearing loss negatively impacts quality of life and is linked with psychological distress, cognitive impairment and social isolation.⁴ Depending on the severity, hearing loss may require social support or medical intervention. 

Raising awareness of NFB and how it can cause hearing loss will increase public understanding of the impact of these conditions, driving curative research and encouraging preventative health. 

Understanding neurofibromatosis

Neurofibromatosis type 1 (NF1)

Genetic causes

NF1 (also known as von Recklinghausen’s disease) results from a mutation in the NF1 gene which is a key regulator in cell growth and proliferation pathways.⁶ Non-functional neurofibromin protein influences the uncontrolled growth of tumours in the nerves.⁶ Neurofibromin is produced in nerve cells, oligodendrocytes and Schwann cells.⁶

Common symptoms and complications

NF1 can cause learning disabilities and has been associated with a decreased life expectancy of ~15 years.⁶ This condition is also linked with malignant peripheral nerve sheath tumours (cancer).⁷ Other symptoms include:⁷

• Café au lait spots (light or dark brown birthmarks)
• Soft, non-cancerous tissues under the skin (neurofibromas)
• Freckle clusters (armpits, groin and under the breast)
• Bone, eyes or nervous system issues

Neurofibromatosis type 2 (NF2)

Distinction from NF1

NF2 is caused by a different faulty gene (NF2) that regulates multiple proliferation pathways.⁶ 50% of patients inherit the gene whilst a spontaneous mutation occurs in the remainder of individuals.¹ Patients diagnosed with NF2 experience benign, slow-growing tumours affecting the brain, spine, the tissue surrounding these areas (meninges) and peripheral nerves.¹ These tumours are referred to as vestibular schwannomas.⁸

Key symptoms

The most common first symptom is hearing loss or ringing (tinnitus).¹ Roughly 2 in 3 individuals with neurofibrosis develop vision problems such as cataracts (cloudy patches) which can develop from an early age.^1,8 In some cases, symptoms in children may be overlooked and present during the second decade of life.¹ Tumours may grow larger over time resulting in other symptoms including:⁸

• Balance problems
• Vertigo
• Numbness
• Facial pain
• Weakness of tongue (slurred speech or difficulty swallowing)

Additionally, some patients diagnosed with NF2 will develop a condition called peripheral neuropathy or issues with nerve function which can cause pins and needles, muscle weakness and reduced ability to feel temperature (especially in the feet).⁸ 

Diagnosing hearing loss in neurofibromatosis

Screening and early detection

Importance of regular auditory examinations

Regular monitoring is essential for NFB diagnosis and treatment. A family history of NFB will increase the risk of inheriting the condition. Auditory examinations are crucial to test for abnormal changes in hearing health which may indicate NFB development. 

Tools and tests used in diagnosing hearing loss

NHS healthcare professionals (HCPs) often provide free hearing tests. Sometimes, a patient may be referred to a hearing specialist (audiologist).⁹ Other ways to test your hearing involve online tools that can measure your hearing sensitivity or visiting a local pharmacist or optician for a hearing test.⁹ 

Treatment and management

Medical treatments

Surgery for vestibular schwannomas

NF1 cannot be cured, however the condition can be managed with a treatment plan.¹ NF2 requires regular monitoring to ensure symptoms do not worsen.¹⁰ Magnetic resonance imaging (MRI) is an important tool to measure tumour growth around vestibular nerves.¹ Tumour growth may require surgery with either NF1 or NF2. However, surgery carries a high risk of further hearing damage.

For instance, in NF2 removing tumours from nerve tissue close to the ear could cause irreparable damage to your hearing and lead to facial paralysis.¹⁰ A team of specialist HCPs can weigh the risks against the benefits of a successful surgery keeping their patient informed and ensuring symptom management.¹ 

Medications to manage symptoms

The National Institute for Health and Care Excellence (NICE) has approved the medication selumetinib to help prevent tumour growth in children over the age of 3 diagnosed with NF1.¹ Other methods of treatment involve pain medication to assist with headaches or anti-seizure drugs.¹ HCPs specialising in NF1 treatment can evaluate children for learning disabilities, ADHD and autism for educational support.¹ 

Hearing restoration and rehabilitation

Hearing aids

Hearing aids can provide sound enhancement depending on the severity of hearing loss.¹¹ However, speech discrimination can be poor reducing the individual's quality of life.¹¹ Hearing loss can get progressively worse over time, exceeding the point that a hearing aid can provide effective hearing restoration.¹¹

Cochlear implants and auditory brainstem implants

Patients with hearing loss can benefit from effective hearing restoration using modern science technology.¹¹ Individuals with single-sided deafness may be offered a bone-conduction hearing implant (BCHI).¹¹ This transmits vibrations from auditory signals to the other side (opposite ear) for recognition.¹¹ Alternatively, patients with a non-functioning cochlear nerve may be offered an auditory brainstem implant (ABI).¹¹

Operation of cochlear implants (CIs) and ABIs is similar with a processor receiving an auditory signal and converting it into an electrical signal for the brain to process.¹¹ ABIs are inserted near the brainstem whereas CIs are placed inside the cochlear.¹¹ Implant hearing restoration options can enhance a patient's quality of life to a greater extent compared to hearing aids. 

Support systems and resources

Patient advocacy and support groups

If you are diagnosed with NFB or are coping with a family member’s diagnosis or treatment please seek advice from a HCP. It is important to check your eligibility for government and charitable grants and be able to access health and social care support in your local area.¹² Local support groups can help individuals who feel isolated or emotionally overwhelmed.

Social workers can provide support to families to achieve good health, help with daily treatment and provide emotional and practical assistance.¹² Additionally, charities such as Nerve Tumours UK aim to improve the lives of people diagnosed with NFB.⁷ Please visit their website or call 07939 046 030 for more information. 

Research and future directions

Advances in treatment

Experimental therapies and clinical trials

Surgical resection is the primary treatment for tumour growth as NFB has no cure.¹³ Research into therapeutic strategies such as new drugs being tested in clinical trials, may reveal future treatments to prevent the development of NFB-related tumours.¹³ In some cases, the tumour may be symptomatic and inoperable.¹⁴

Mitogen-activated protein kinase inhibitors (MEKi) offer a targeted therapy of proteins overactivated in growth pathways in NFB extending life expectancy through tumour shrinkage.¹⁴ The National Institute of Neurological Disorders and Stroke (NINDS) aims to support clinical trials and research cognitive impairment in children to enable HCPs to inform early and anticipate cognitive disabilities.¹

Genetic research and potential for gene therapy

Future research will focus on the role of other growth pathways such as the Hippo pathway that may influence tumour growth or the influence of cells in the surrounding tumour microenvironment.¹³ Studies have indicated that oestrogen signalling during puberty is associated with neurofibroma development.¹³ Additional evidence through genetic research will shed light on the mechanisms controlling tumour growth in NFB.

Summary

NF1 and NF2 can cause malignant tumours leading to rapid patient health deterioration. Both conditions can be present at birth with symptoms going unnoticed until later in life. Currently, there is no curative treatment. Depending on the size and severity, tumours in the ear region can cause hearing loss which may progressively worsen over time causing social isolation and emotional distress. Regular auditory examinations are crucial to monitor hearing health, especially in children whose parents carry an NF1 or NF2 mutation. 

Public knowledge of symptoms and signs plays a vital role in early intervention. An NFB diagnosis requires HCPs and specialists whose expertise can advise the patient on the most beneficial and safe course of treatment. Surgical resection of the tumour, medication and tools to aid hearing restoration may be combined to improve patient quality of life and overall well-being. Spreading awareness of NFB will encourage gene therapy advancement and increase public understanding and support.