Introduction

Neurofibromatosis is a debilitating medical disorder. Individuals often find themselves facing new health complications their bodies present every day; different aspects of their lives are often adversely affected. While the complications are profound, there have been persistent pursuits of understanding this health implication to improve a person’s quality of life. 

Definition of Neurofibromatosis (NF)

This genetic disorder involves tumour growth in the brain, spinal cord or nerves, causing various widespread complications including the impairment of one’s senses, movement and learning abilities.¹ The tumour developed is usually benign and non-cancerous, but some may become malignant. However, some people who carry this genetic disorder may remain asymptomatic, and can still live a normal life.²

Types of Neurofibromatosis

Neurofibromatosis is a medical term encompassing three distinct genetic conditions that cause tumour growth in body regions as discussed above. Depending on the affected body part, the tumours can be classified into 2 groups – neurofibromas or schwannomas.³ Neurofibromas refer to the benign tumours that originate from connecting tissue of peripheral nerve cells while schwannomas derive from the Schwann cells of peripheral nerves.⁴ To diagnose a patient, healthcare professionals will either perform genetic testing or analyse data from biopsies and imaging studies like magnetic resonance imaging (MRI). Different disorders will result in distinct symptoms.³

NF1 (Neurofibromatosis Type 1)

Neurofibromatosis Type 1 is the most common condition among the three, affecting children and adults. As it is an autosomal dominant disorder, children have a 50% probability of inheriting the mutated NF1 gene if one of their parents is affected. Patients may have inherited the mutated gene from their parents or spontaneous mutation may have occurred.¹ The mutated gene is located on chromosome 17, resulting in a mutation in the tumour suppressor protein called neurofibromin. Patients are born with NF1, but some symptoms may gradually develop over the years throughout one’s life span. The different organs affected by NF1 include the skin, nerves and bones, resulting in a myriad of symptoms with varying severity among patients. Overall, symptoms are usually mild and do not cause severe health complications.⁵

NF2 (Neurofibromatosis Type 2)

Neurofibromatosis Type 2 is also caused by neurofibromatosis but is much less common compared to NF1. It is caused by an autosomal dominant mutation in the NF2 gene, also causing tumour growth in the nervous system. This genetic disorder is classified separately as patients will display different symptoms than the ones observed in NF1 patients. Similar to NF1, symptoms may appear from birth; some may appear later in life.⁶  Mutation in the NF2 gene can be inherited by one’s parents or it may spontaneously appear throughout one’s life.⁷ The NF2 gene is located on chromosome 22, and the presence of a mutation results in a lack of Merlin protein, which has tumour suppressor properties.⁸

Schwannomatosis

Schwannomatosis is another class of neurofibromatosis, characterised by slow-growing tumours derived from Schwann cells. Although the tumours are usually non-cancerous, patients may experience symptoms like hearing loss, headaches and trouble with balance. Schwannomatosis is a rare genetic condition with several subcategories. If the tumours grow on auditory nerves in both ears, it is classified as NF2-related schwannomatosis. Other classes include SMARCB1- and LZTR1-related schwannomatosis. Besides affecting the nerves in the ears, brain, spine, and eyes, the tumour also grows on peripheral nerves.⁹

Complications of NF1

Dermatological Complications

Café-au-lait spots 

The most distinct symptom exhibited is the appearance of flat, light brown spots on the skin known as “cafe au lait” spots. These harmless birthmarks appear at birth or in the first few years after birth. NF1 is relatively easy to diagnose as symptoms are observable and recognisable by the naked eye. The key feature is that these spots are more than 5mm in children and more than 15 mm in adults.¹ However, the presence of these brown spots alone does not confirm whether someone has NF1, as they also appear in other medical conditions like Legius syndrome.¹⁰

Neurofibromas

Patients with NF1 often develop pea-sized tumours that appear as small bumps on the skin. However, there is a possibility that the bumps grow larger as the disease progresses over the years. This is due to the growth of benign tumours along the peripheral nerves in adolescents or young adults.¹⁰ These tumours may continue growing to become malignant or cancerous.¹¹ Neurofibromas can be categorised depending on their location of growth. They can be differentiated through histological stains and electron microscopy. Cutaneous neurofibromas are almost undetectable at birth as they produce tiny bumps on the skin. On the other hand, plexiform neurofibromas are caused by the development of tumour masses around the area where nerves integrate, resulting in large swellings. Individuals may experience pain, stinging and weakness. Plexiform neurofibromas can become malignant.¹²

Skeletal Complications

Scoliosis

Besides the dermatological complications, NF1 is also known to result in skeletal symptoms including scoliosis, which is the curvature of the spine among small children. Scoliosis is a condition where the spine is curved from the left to right. There are two types of scoliosis– dystrophic and non-dystrophic scoliosis. Patients with dystrophic scoliosis have thin ribs and abnormal vertebrae rotation. If there is a forward tilt of the spine, patients will also be diagnosed with kyphosis.¹³ Depending on the degree of spine curvature, different interventions will be recommended by doctors.¹⁴

Bone dysplasia

Patients with NF1 may also experience abnormal bone development, known as bone dysplasia, whereby normal bone is replaced with fibrous tissue. The impairment of bone development results in symptoms like short stature, shorter limbs, and brittle bones in children from early infancy. Deformation of the bone usually involves the tibia.¹⁵ This causes the anterolateral bending of the tibia and the growth of thick bands of dense fibrous tissue at the bone ends. Due to plexiform neurofibromas, the growth of the tumour and its enlargement will exert pressure on the underlying bone, causing deformities.¹⁴

Neurological Complications

Optic gliomas

NF1 poses implications for the central nervous system as tumour growth may involve the glioma of the optic pathway. A glioma refers to cell growth that originates in the brain or spinal cord. This complication affects 20% of people with NF1, especially among children. The probability of developing optic gliomas as one gets older decreases. Some patients may experience vision loss, but most cases remain asymptomatic.¹⁶ Although many interventions aim to control tumour growth, research is still ongoing to identify solutions to reverse visual loss. For early diagnosis of optic gliomas, young children at risk of being affected by NF1 should undergo ophthalmological exams.¹¹

Learning disabilities

Children with NF1 may experience poor academic performance and achievement due to impaired cognitive abilities. They may find it challenging to solve numerical problems or read. NF1 is known to be closely associated with behavioural problems such as ADHD where those affected have poor concentration and short attention span, leading to lower intellectual ability.¹ Although the reason for NF1’s link to learning disabilities is still unknown, it can be said the loss of NF1 gene leads to abnormal maturation of the brain.¹⁷

Complications of NF2

Neurological Complications

Bilateral vestibular schwannomas (acoustic neuromas)

The majority of people with NF2 develop vestibular schwannomas which is a health condition wherebenign tumour growth occurs in the nerves of both ears. Compared to NF1, the tumour growth in NF2 usually affects auditory nerves. This causes several implications including hearing loss, tinnitus (ringing in the ears), and balance issues that can impede one’s quality of life.⁷ The average onset age is around 18 to 24 years old.¹⁸  

Central Nervous System (CNS) Tumors

Meningiomas

Another symptom of NF2 is tumour growth that stems from the meninges, which is the membrane surrounding the brain and spinal cord. This can exert pressure on the surrounding tissue, blood vessels and nerves in the brain region. Symptoms usually progress slowly and differ depending on the location of the meningioma in the brain. Individuals with NF2 may experience changes in vision, loss of hearing and seizures.²⁰

Ependymomas

Unlike meningiomas that grow along the brain and spine, ependymomas are tumours that develop inside the spine. This is because the mutated NF2 gene results in a loss of cell cycle regulation. This symptom is prevalent in about 20% of individuals with NF2 and can be detected by MRI scans. Similar to meningiomas, symptoms will vary depending on the location of the tumour growth, but are commonly characterised by pain, weakness and numbness.⁷

Ocular Complications

Cataracts

Cataracts occur when the protein in the lens of our eyes breaks down and accumulates over time. This means the eye lens becomes cloudy, impeding one’s vision and eventually leading to vision loss. Cataracts are very common as one gets older.²⁰ There has been evidence that cataracts are linked to NF2. Different categories of cataracts including subcapsular and cortical wedge are the most common ocular complications in those with NF2.⁸ Subcapsular cataracts grow at the back of the lens, reducing vision in bright light, whereas congenital cataracts affect the edges of the lens but will spread to the centre of the lens.²¹

Complications of Schwannomatosis

Pain

Chronic pain due to schwannomas

The pain experienced by patients with schwannomatosis can be debilitating, as schwannomas exert pressure on surrounding nerves or tissues throughout the body, depending on the location of its growth. If the tumour presses on the spinal cord, patients may experience numbness and weakness.²²

Neurological Complications

Muscle weakness

Schwannomatosis can also lead to muscle weakness in the affected body part. For example, schwannomas by the facial nerve can cause sensation loss and facial paralysis while sciatic nerve schwannomas can result in lower back pain that spreads to the legs.²³

Treatment and Management

Medical Management

Tumour growth management

There is currently no cure for neurofibromatosis, but different approaches can be used to slow down symptom progression with standard cancer therapies. The FDA has approved the use of a drug called selumetinib in chemotherapy that aims to stop tumour growth among children as young as 2 years old with NF1. This method can be used to treat optic pathway or other brain gliomas in neurofibromatosis. It also aims to prevent potential malignancies involving peripheral nerves.¹

Surgical Interventions

Tumour removal

Affected individuals would be recommended to resort to surgery to remove the tumour if it is rapidly growing or affecting other organs. However, it cannot be completely removed. The risk level of the surgical procedure will depend on the part of the nerve that is affected. For instance, as schwannomas derive from the sheath around the nerves, it can be removed easily without causing nerve damage. However, in NF2 patients with vestibular schwannomas, the intervention will very likely cause permanent hearing loss due to potential nerve damage.²³

Corrective surgeries for skeletal abnormalities

As discussed earlier, some individuals with neurofibromatosis have skeletal deformations like scoliosis. In these cases, bone malformations can be corrected by surgery or by wearing braces depending on the severity of the curvature.¹

Therapies

Physical therapy and Occupational therapy

Since neurofibromatosis is associated with muscle weakness, postural abnormalities and headaches, an affected individual’s daily life is impacted. While physical therapy aims to improve mobility, occupational therapy aims to restore the ability to perform daily tasks. With physical therapy, individuals can manage symptoms related to musculoskeletal dysfunction and live a normal life. A study showed that a 17-year-old NF1 patient demonstrated improved cervical motion and muscle strength after undergoing 13 weeks of physical therapy. Unlike before, she could now drive, study and participate in recreational activities.²⁴           

Summary

Overall, the complications of neurofibromatosis include dermatological symptoms, neurological disorders, and musculoskeletal dysfunctions. Hence, it is important for patients to have early diagnosis and regular monitoring to manage symptoms to improve quality of life. Recent clinical research aims to not only understand the effect of genetic defects on people with neurofibromatosis but also to predict when and which conditions will arise in each person. This will help doctors understand the link between symptoms and anticipate any loss of physiological functions for early intervention.¹