What Is Neurofibromatosis

Are you familiar with the term "neurofibromatosis"? Despite its intimidating name, it's actually a relatively simple concept. 

Firstly, it's important to understand that neurofibromatosis is not a single medical disorder but a term encompassing three distinct conditions: NF1, NF2, and Schwannomatosis (SWN). These conditions may cause the formation of tumours that can impact the brain, spinal cord, and nerves that send signals throughout the body. While the majority of these tumours are benign, there is a possibility for them to become malignant.

This article will provide further information on neurofibromatosis, including its causes, available treatment options, and diagnosis.

Overview

Neurofibromatosis (NF) is one of the most common genetic disorders, affecting more than 2 million people worldwide. It usually affects people after the age of 20.¹ It refers to 3 different genetic mutations that cause the development of multiple lesions and tumours in the peripheral and central nervous systems, and these are NF1, NF2 and SWN. Some people with NF have barely noticeable neurological problems, while others are affected profoundly.

While there is no known cure, its symptoms can be treated and managed. 

Types of neurofibromatosis

Back in 1882, a pathologist named Friedrich Daniel von Recklinghausen observed a group of patients with skin lesions and tumours in their nervous systems. However, it wasn't until the 20^th century that experts identified these conditions as two separate genetic disorders: neurofibromatosis type 1 (also called Recklinghausen's disease) and neurofibromatosis type 2 (previously known as central neurofibromatosis).² It is debatable if schwannomatosis is NF. Although numerous experts in the field contend that schwannomatosis should be categorised as NF due to the fact that it bears some resemblances to NF1 and NF2, research suggests that it is an independent genetic disorder.

• Neurofibromatosis type 1 (most common)
• Neurofibromatosis type 2 (second most common)
• Schwannomatosis (least common)

Neurofibromatosis type 1

Often referred to as NF1, it is commonly known as the most prevalent condition among the three with an incidence of 1 in 3,500 individuals. Although most individuals acquire genetic defects through inheritance, around 40% of documented cases arise from a spontaneous genetic mutation in the NF1 gene. This mutation can be inherited, which results in a 50% chance of the child inheriting the same genetic mutation.

NF1 can cause a range of symptoms and medical issues that can vary throughout a person's life. Most individuals with NF1 have an average life expectancy. The diagnosis process may take some time due to the fact that certain clinical features may only appear as a person ages. Therefore, it is not rare for a person with NF1 to be misdiagnosed early on.

It is important to note that NF1 is also known by other names, which include:

• Von Recklinghausen’s disease
• Von Recklinghausen’s neurofibromatosis
• Neurofibromatosis-pheochromocytoma-duodenal carcinoid syndrome
• Peripheral neurofibromatosis

NF1 diagnosis and signs

Most of the diagnoses for NF1 can be seen with bare eyes. These are the signs doctors look for:

• Café-au-lait macules (CALMs) - mainly develop in childhood and are found in almost all patients. CALMs are presented as light brown macules of about 10 to 40 mm in diameter with an ovoid shape and poorly circumscribed borders. If an individual presents with six or more spots, it is strongly suggested to be NF1.

• Characteristic axillary freckling - freckling in the armpits or groyne is a common occurrence in patients aged 3 to 5 years. These freckles resemble café-au-lait spots but are smaller. Although freckling can be a symptom of other conditions, it does not accompany other symptoms of NF1. About 90% of patients with NF1 have freckling.³

• Neurofibromas - NF1 can be diagnosed when neurofibromas appear on or around peripheral nerves. Neurofibromas come in two types: cutaneous neurofibromas, which are small pea-sized or larger bumps on the skin, and plexiform neurofibromas, which involve multiple nerves and can be more prominent. While cutaneous neurofibromas generally do not cause significant symptoms, plexiform neurofibromas can grow deep inside the body near nerve roots. They can expand along large segments of affected nerves, so there is a 10% chance they could become malignant.^4,5
• Lisch nodules - pigmented hamartomas of the iris or two or more growths on the eye's iris are usually not present until adolescence, however, they are harmless. These nodules are considered a characteristic ophthalmologic feature of NF1.⁶
• Optic pathway glioma - describes a tumour of the optic pathways. This tumour typically forms prior to the age of six and is uncommon in late childhood or adulthood. Although they may affect eyesight, many do not display any noticeable indications.
• Bone deformities - abnormal development of the eye socket or the tibia.
• Family history of NF1 - even though NF1 can be caused by a spontaneous genetic mutation, if one parent is diagnosed with NF1, there is a 50% chance that their child will inherit the NF1 mutations.

Neurofibromatosis type 2

The clinical features of NF2 were first noted in the late 1800s, but it was initially thought to be a subtype of NF1. It wasn't until nearly a century later that NF2 was acknowledged as its own distinct condition. NF2 is much less common than NF1, with an incidence of 1 in 25,000.²

Around 50% of people with the condition inherit the gene, while in others, it is caused by a spontaneous genetic mutation in the NF2 gene. Each child has a 50% chance of inheriting the abnormal NF2 gene if a parent is affected.  

It is important to note that NF2 is also known by other names, which include:

• Bilateral acoustic neurofibromatosis
• Vestibular schwannoma neurofibromatosis
• Central neurofibromatosis

NF2 diagnosis and signs

While NF1 diagnosis is straightforward and easy to observe, NF2 can be harder to observe and requires more examinations. These are the signs doctors look for:

• Bi- or unilateral vestibular schwannomas - these tumours occur on or around the vestibular branches of both auditory nerves. Unlike in NF1 patients, tumours in NF2 patients are uniformly benign which often leads to sudden hearing loss,⁷ sudden onset of tinnitus, and imbalance.⁸
• Meningiomas or gliomas - nervous tissue tumours which consist of Schwann cells only. 
• Family history of NF2 - even though NF2 can be caused by a spontaneous genetic mutation, if one parent is diagnosed with NF2, there is a 50% chance that their child will inherit the NF2 mutation.
• Posterior subcapsular opacities - ​​cataracts can cause the lens of your eye to thicken and become slightly opaque, which reduces the amount of light that can pass through to the retina at the back of your eye. This can result in blurry or fuzzy vision.

Schwannomatosis

We will consider schwannomatosis as a related disorder in this article. It is more often diagnosed in adults aged 30 and above. It is characterised by benign tumours called schwannomas that affect the nerve. 

Schwannomatosis diagnosis and signs

• Criteria - individuals who are 30 years or older with no vestibular tumours present in an MRI scan and no known NF2 mutation and who possess two or more schwannomas located within or between layers of the skin (with at least one confirmed by tissue pathology), may exhibit definitive indications of the particular condition.
• Family history of schwannomatosis - if an individual's close family member meets the mentioned criteria, it could indicate that the individual has schwannomatosis.
• Tumours are limited to one part of the body.

Causes of neurofibromatosis

Neurofibromatosis is a genetic disorder. This means that it is caused by genetic defects,  commonly in the form of mutations. 

Cause of NF1

NF1 is a condition that arises from genetic mutations that disrupt the production of a crucial protein known as neurofibromin 1. Scientists believe this protein plays a vital role in preventing tumour growth.⁹ Thus, the absence of neurofibromin 1 frequently results in the development of neurofibromas and gliomas in NF1. In about half of all NF1 cases, the mutations occur spontaneously without any known cause.

Cause of NF2

NF2 is caused by mutations in a specific tumour-suppressing gene called merlin (schwannoma). This is much smaller than neurofibromin, which may explain a significantly lower rate of mutation in NF2 compared to NF1.¹⁰ In some cases, individuals with NF2 may have a gene mutation without known cause.

Cause of schwannomatosis

Schwannomatosis is not fully understood, but it is believed that 85% of cases occur spontaneously without a known cause. In comparison, the remaining 15% are inherited.

Management and treatment for neurofibromatosis

NF1 treatment

Although NF1 cannot be cured, some treatments can help manage its signs and symptoms. It's worth noting that not everyone with NF1 may require extended treatment for any signs or developments relating to the disease during their lifetime. Nevertheless, it's highly recommended that individuals with NF1 should receive periodic evaluations by an NF1 specialist, even if they are not currently experiencing any symptoms. This assessment will aid in determining whether there are any signs or symptoms that may necessitate treatment and provide reassurance that treatment is not needed when appropriate.

The FDA has approved selumetinib (Koselugo) as a treatment for NF1 in children aged two years and above. This medication aids in inhibiting the growth of tumour cells. If a tumour is causing symptoms or is suspected to be cancerous, surgery might be necessary to remove it.

It is worth noting that optic pathways or other brain gliomas can be addressed through chemotherapy. It is essential to mention that the FDA has approved selumetinib for children over the age of 2 who are exhibiting symptoms of inoperable plexiform neurofibromas. Chemotherapy is crucial in treating cancers that may arise in NF1, including malignant peripheral nerve sheath tumours (MPNST) and breast cancer.

NF2 treatment

There has yet to be a consensus among doctors about the best surgical options for NF2. The extent of hearing loss and the tumour size are the main factors determining which surgical option is most appropriate. Before undergoing surgery, individuals should carefully consider each option's benefits and risks and choose the best treatment for them.

Schwannomatosis treatment

Currently, there is no recognised medical treatment or medication for schwannomatosis. In cases where tumours are growing or symptoms are related to specific schwannomas, surgery may be an option to provide relief. However, it is essential to consider the possible risks of nerve damage against the potential advantages of surgery.

Risk factors

The biggest risk factor for neurofibromatosis is a family history of neurofibromatosis.

Complications

The effects of neurofibromatosis can differ among family members. Common complications occur due to tumours that influence nerve tissue or pressure organs within the body.¹¹

Complications of NF1

• Neurological problems
• Anxiety and emotional distress from deformed appearance
• Bone deformations and weakening
• Hormonal changes 
• High blood pressure and blood vessel abnormalities
• Breathing difficulties from a pressured airway
• Cancer
• Benign adrenal gland tumour

Complications of NF2

• Partial or total deafness
• Facial nerve damage
• Vision problems
• Small benign skin tumours
• Weakness or numbness in the extremities
• Multiple benign brain tumours or spinal tumours requiring frequent surgeries

Complications of schwannomatosis

Schwannomatosis can cause severe pain that might need surgical treatment or pain management by a specialist.

FAQs

How can I prevent neurofibromatosis

Neurofibromatosis cannot be prevented.

How common is neurofibromatosis

NF1 - 1 in 3,500 births

NF2 - 1 in 40,000 births

Schwannomatosis - 1 in 70,000 births

When should I see a doctor

Contact your doctor promptly if you notice any changes in signs or symptoms of neurofibromatosis between visits. Many complications of NF1 can be treated effectively if therapy starts early.

Summary

Neurofibromatosis is a common genetic defect that can cause various symptoms including the development of tumours in the brain and spinal cord. While most cases cannot be cured, some surgery techniques and medications can help alleviate severe symptoms.