Introduction

Neurofibromatosis refers to the three genetic conditions neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SWN).¹ These conditions can cause tumours to grow along nerves in the brain, spinal cord, and the nerves connecting the brain and spinal cord to the rest of the body.¹ Whilst the majority of these tumours are benign (non-cancerous), there is a possibility for some to become malignant.¹

Neurofibromatosis type 1 (NF1)

Affecting approximately 1/2500 people, NF1 is a relatively common autosomal dominant disorder that causes tumours to grow along your nerves^.2 This condition is caused by an altered NF1 gene found on chromosome 17 that is inherited from parents or de novo genetic changes resulting from mutation upon conception. The mutated gene causes the protein product of the NF1 gene, neurofibromin, to be lost. When neurofibromin can no longer bind to the Ras protein and inhibit the MAP kinase pathway by binding to the Ras protein, regulation of cell growth is impaired and may lead to uncontrolled cell division.

Symptoms

• Café-au-lait macules (CALMs), which are light to dark brown patches on the skin
• Cutaneous neurofibromas, which are rubbery lumps on or under the skin
• Lisch Nodules, which are little bumps on the iris
• Bone changes
• Optic gliomas, which are associated with impeded vision
• Learning disabilities
• Increased brain volume
• Shorter than average height
• Pheochromocytomas

Genotype/phenotype correlations observed in NF1 patients

Figure 1: This diagram is an overview of different NF1 phenotypes associated with NF1 gene mutation or genetic modifiers. Phenotypes are shown in black, NF1 mutations in red, and genetic modifiers in green. Figure 1: Pubmed central image viewer. [Internet]. [cited 2024 Jul 3]

Clinical expressivity, which is the extent to which the genotype exhibits its phenotypic expression, varies among NF1 patients.² This means that patients show differences in the development of symptoms, which is unpredictable and depends on the individual’s age.^2,3 The variance in clinical expressivity can also make a clinical diagnosis in young children, especially with a lack of positive family history, difficult.³ In some cases, genetic counselling is suggested to discuss risks for severe phenotypes or the development of malignant tumours.³

Neurofibromatosis type 2

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder that causes tumours to grow along nerves, particularly those in the central nervous system (CNS). It affects 1 in every 40,000 individuals.⁴ This disorder is caused by a de novo or germline mutation in the NF2 gene on chromosome 22.⁵ Individuals with NF2 have a 50% risk of passing the gene to their offspring.⁵

The NF2 gene is a tumour suppressor gene that codes for the protein merlin, which links transmembrane proteins with the actin cytoskeleton.⁶ The gene is also known to be important in contact inhibition of growth.⁴ When contact inhibition is lost, cells no longer stop proliferation and growth when in contact with one another, leading to uncontrolled cell growth and, eventually, the development of cancer. Although tumours caused by NF2 are usually non-cancerous (benign), they can sometimes become cancerous.⁴

Symptoms

• Acoustic neuroma (vestibular schwannoma), which is associated with ear problems and imbalance
• Juvenile cataracts, which are associated with vision problems
• Meningiomas, which are associated with brain problems
• Ependymomas, which are associated with spinal cord problems
• Schwannomas, which are associated with skin plaques
• Peripheral neuropathy, including symptoms such as muscle weakness

For individuals with a family history of the disorder, presymptomatic genomic testing is an important part of disease management.⁷ This is supported by the fact that onset at an early age negatively impacts the prognosis.⁷ According to a study in Japan from 1986 to 1987, 5-, 10-, and 20-year survival rates for patients <25 years with symptom onset were 85, 67, and 38%, respectively.⁸ On the other hand, patients ≥ 25 years with symptoms onset had rates of 100%, 875, and 62%, respectively.⁸ Most patients with NF2 suffer from significant morbidity and shortened life expectancy, making the disease tricky to manage.⁷

Genotype/phenotype correlations observed in NF2 patients

NF2 patients are known to have a highly variable phenotypic expression. More than 200 different mutations have been found in NF2 patients, including frameshift, nonsense, splice-site, truncating and missense mutation.⁹ Also, the patients’ age at the time of symptom onset can highly vary, which also greatly affects their survival rates.⁸

Nonsense and frameshift mutations of NF2  are the most common types of germline mutations and result in the most severe symptoms; single and multiple exon deletions are also common.⁷ This is supported by comprehensive studies of genotype/phenotype correlations in multiple families.¹⁰ Moreover, splice-site mutations are associated with more variable phenotypes, and mutations in exons 9-15 are associated with milder disease.¹⁰

Schwannomatosis

Schwannomatosis is characterised by the development of slow-growing tumours on the tissue that lines nerve cells, which is made up of Schwann cells. It is the rarest form of neurofibromatosis that affects 1/40,000 – 1/70,000 individuals, has a mean age of diagnosis of 41.9 years, and a mean age of death of 76.9.^{13 14} Although these tumours are mostly non-cancerous (benign), in rare cases, they may transform into malignant peripheral nerve sheath tumours.^{11 12}

The different types of schwannomatosis are classified according to their specific gene variant, they can be broadly sorted into NF2-related schwannomatosis and non-NF2-related schwannomatosis. Currently known NF2-related schwannomatosis includes SMARCB1-related schwannomatosis and LZTR1-related schwannomatosis.¹¹

Inactivation via mutations in the related tumour suppressor genes (NF2, SMARCB1 and LZTR1) on chromosome 22 predisposes the development of tumours in patients.¹³ Despite the overlap between schwannomatosis and neurofibromatosis type 2 (NF2), they are considered to be separate clinical entities.¹³

SMARCB1 encodes for a subunit of a protein that is called the SW1/SNF complex. The SW1/SNF gene is involved in gene activity regulation via chromatin remodelling. When there is a pathogenic variant of SMARCB1, it causes the ability of our cells to repair and replicate DNA to be impaired. This affects the control of growth, division, and maturation of our cells. On the other hand, the LZTR1 gene encodes an unknown protein which is known to regulate cell proliferation and prevent the uncontrolled cell division seen in cancer cells. Mutations of SMARCB1 or LZTR1 alone are not enough to account for schwannoma growth.¹³ Studies have shown that accumulated mutations throughout an individual’s lifetime may be needed to form, such as the NF2 gene.¹³

Symptoms of NF2-related schwannomatosis

• Hearing loss or ringing in the ears, which is associated with acoustic neuroma   (vestibular schwannoma) and poor balance
•  Headache and general aching
• Numbness
• Weakness in muscles
• Poor balance.
• Impaired vision, which is associated with cataracts

Symptoms of SMARCB1- and LZTR1-related schwannomatosis

• Localised or diffused pain
• Numbness and tingling
• Weakness
• Muscular dystrophy

Diagnosing neurofibromatosis

Doctors can diagnose neurofibromatosis in several ways, they may provide blood tests, genetic tests, carry out scans for tumours and examine your physical symptoms to make a diagnosis.

Scans to detect tumours:

• Computed tomography (CT) scan
• Magnetic resonance imaging (MRI)
• X-ray

Genetic testing for neurofibromatosis

Based on the patient’s personal and family history, a genetic test may be recommended.  There are three possible results from the genetic test:

• Positive result — a pathological mutation is identified, and the patient receives a diagnosis of the condition
• Negative result: no pathological mutation is identified, and the patient would not receive a genetic diagnosis
• Uncertain result — a mutation is found, but it is unknown if the mutation increases the risk of developing symptoms.

Mosaicism as a possible reason for false-negative results

Neurofibromatosis can occur in mosaic forms.¹⁵  Mosaicism causes two or more populations of cells in an individual’s body with a different genetic makeup, which may cause a negative result even when an individual has a diagnosis of neurofibromatosis.¹⁵ In these cases, it can be difficult to know the extent of affected cells and their risk of developing symptoms or passing on their faulty genes to their children.¹³

FAQs

Is there a cure for NF1, NF2 and schwannomatosis?

There is currently no cure for NF1 and NF2. For schwannomatosis, the relatively compact nature of schwannomas means that it is possible to cure patients by removing the tumour surgically.

Is there a way to prevent or avoid neurofibromatosis?

Currently, there is no known method to prevent or avoid neurofibromatosis. 

Summary

Neurofibromatosis refers to three distinct genetic conditions that are caused by pathological mutations in genes. Among these three conditions, NF1 is the most common, followed by NF2 and schwannomatosis. These mutations predispose individuals to cancer and cause a wide range of symptoms that vary in severity. For example, patients with NF1 and NF2 are known to have a significant variance in the development of symptoms.  Due to the high hereditary nature of neurofibromatosis, genetic counselling is recommended to discuss the risks of the parents passing the faulty gene(s) to their children. Based on a patient’s personal and family history, genetic tests are used to test for the condition and differentiate between the different types of neurofibromatosis. For individuals with a family history of NF2, presymptomatic genomic testing is especially important since the onset at an early age significantly lowers life expectancy.