NF Type 2 Related Schwannomatosis

Overview

NF2-Related Schwannomatosis (NF2-SWN), formerly known as neurofibromatosis type 2 or NF2, is the most common type of schwannomatosis (SWN) affecting about 1 in 25,000 people worldwide. It is named after the schwannoma tumors that grow on nerves throughout the body that is specifically caused by genetic changes in the NF2 gene. These tumors are usually benign, meaning they are not cancerous, but they can cause various health problems depending on their size and location. Similar to NF1, about 50% of NF2-SWN patients inherit the disease-causing variant or change in the NF2 gene from a parent, while 50% will be the first person in their family to have the variant or change in the NF2 gene.

NF2-SWN is a highly unpredictable disorder that varies widely in severity from one person to the next, even among family members. Some individuals with NF2-SWN may experience minimal symptoms, such as minor hearing loss or balance issues, while others may face significant challenges due to the growth of multiple tumors. These tumors can lead to serious medical or cosmetic problems. Despite the unpredictability of NF2-SWN, many individuals with the condition display remarkable resilience and spirit. With proper management and support, NF2-SWN should not limit the future or aspirations of those affected, allowing them to lead fulfilling and active lives.

The upcoming content will contain information to help you understand some of the manifestations, updated diagnostic criteria, treatments, genetics, and other helpful resources.

Manifestations

Below are the potential symptoms of NF2-SWN

Tumor

  • Vestibular schwannomas – tumors particularly affecting the acoustic (cochlear), vestibular nerves, or the cranial nerves
  • Schwannomas in the central/peripheral nervous system
  • Meningiomas – tumors of the membranes surrounding the brain and spina cord
  • Ependymomas – tumors that develop from cells lining the ventricles of the brain and center of the spinal cord

Hearing

  • Can be partial or complete hearing loss; often progressive
  • Tinnitus – ringing or buzzing in the ears
  • Often occurs in both ears due to the VS tumors on the nerves that control hearing and balance.

Balance

  • Dizziness
  • Unsteadiness
  • Caused by tumors affecting the balance nerves.

Visual

  • Juvenile cataracts
  • Dry eye
  • Eyelid closing problems
  • Loss of sensation in the eye
  • Double vision
  • Partial or complete blindness

Mobility

  • Tingling, numbness, or weakness in the arms or legs due to tumors pressing on nerves.
  • Drooping or weakness of facial muscles (facial palsy), resulting from tumors affecting facial nerves.
  • Foot drop
  • Muscle wasting

Speech

  • Slurring due to loss of mobility of tongue or facial muscles

Pain

  • Discomfort or pain in various parts of the body due to nerve tumors.
  • Frequent or severe headaches caused by tumor growth or pressure in the brain.

Seizures

  • Some individuals may experience seizures, which are sudden, uncontrolled electrical disturbances in the brain.

Diagnostic Criteria

DIAGNOSTIC CRITERIA FOR NF2-RELATED SCHWANNOMATOSIS (Plotkin et al., 2022)

A diagnosis of NF2-SWN can be made when an individual has one of the following:

  1. Bilateral vestibular schwannomas (VS)
  2. An identical NF2 pathogenic variant in at least 2 anatomically distinct NF2-related tumors (schwannoma, meningioma (tumor that arises from the meninges — the membranes that surround your brain and spinal cord), and/or ependymoma (intramedullary spinal cord tumors)).
  3. Either 2 major or 1 major and 2 minor criteria as described in the following:

Major criteria:

  • Unilateral vestibular schwannoma
  • First-degree relative other than sibling with NF2-related schwannomatosis
  • 2 or more meningiomas (Note: single meningioma qualifies as minor criteria).
  • NF2 pathogenic variant* in an unaffected tissue such as blood (Note: if the VAF is clearly <50%, the diagnosis is mosaic NF2-related schwannomatosis)

Minor criteria:

Can count >1 of a type (eg, 2 distinct schwannomas would count as 2 minor criteria)

  • Ependymoma, meningioma (Note: multiple meningiomas qualify as a major criteria), schwannoma (Note: if the major criterion is unilateral VS, at least 1 schwannoma must be dermal in location)

Can count only once (eg, bilateral cortical cataracts count as a single minor criterion)

  • Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person aged <40 years, meningioma
  • When the variant is present at significantly less than 50%, the diagnosis is mosaic NF2-related schwannomatosis

DIAGNOSTIC CRITERIA FOR MOSAIC SCHWANNOMATOSIS:

Mosaicism in NF2-related schwannomatosis is a condition where the body has two different cell populations, one with normal NF2 genes and one with abnormal NF2 genes from which tumors can arise. This can happen when the pathogenic changes in the NF2 gene are acquired only by certain cells after fertilization and is carried onwards throughout the lifespan. Mosaicism is confirmed for NF2-related schwannomatosis by either of the following:

  • Clearly less than 50% pathogenic variant allele fraction (VAF) in blood or saliva

OR

  • Pathogenic variant not detected in blood or saliva but shared pathogenic variant in two or more anatomically unrelated tumors

ADDITIONAL GENETIC CRITERIA UPDATES:

  • Genetic analysis in blood or saliva may identify pathogenic NF2 variants in 66%–90% of individuals
  • Genetic analysis is NOT required for diagnosis for NF2-related schwannomatosis if clinical criteria are met
  • Genetic analysis with family history is sufficient to diagnose NF2-related schwannomatosis

(no requirement to have clinical manifestations)

Treatments

While there is currently no cure for NF2-SWN, various treatment options are available to manage symptoms, improve quality of life, and slow the progression of the disease. Here are the primary treatment options for NF2-SWN:

  • Surgical Interventions:
    • Tumor Removal: Surgery to remove benign tumors such as vestibular schwannomas, meningiomas, and ependymomas to alleviate symptoms and prevent complications.
  • Medications
    • Bevacizumab: An angiogenesis inhibitor used to shrink vestibular schwannomas and improve hearing.
    • Steroids: Used to reduce inflammation and edema around tumors.
    • Pain Management: Medications to manage chronic pain associated with NF2-SWN.
  • Hearing Restoration:
    • Cochlear Implants: Devices implanted to improve hearing in individuals with severe hearing loss.
    • Auditory Brainstem Implants (ABI): Devices used when cochlear implants are not an option due to damaged auditory nerves.
  • Radiation Therapy:
    • Delivers radiation in small, precise doses to control tumor growth while minimizing damage to surrounding tissues.
    • Fractionated Stereotactic Radiotherapy (FSRT)
    • Gamma knife radiosurgery
  • Gene Therapy and Experimental Treatments:
    • Gene Therapy: Emerging treatments aiming to correct the genetic mutation causing NF2-SWN.
    • Clinical Trials: Participation in trials for new medications and therapies targeting NF2-SWN.
  • Supportive Therapies:
    • Physical Therapy: To manage muscle weakness and improve mobility.
    • Occupational Therapy: To assist with daily activities and enhance quality of life.
    • Speech Therapy: For individuals experiencing speech difficulties due to tumors affecting cranial nerves.
  • Regular Monitoring:
    • MRI and CT Scans: Regular imaging to monitor tumor growth and adjust treatment plans accordingly.
    • Audiological Evaluations: Regular hearing tests to track any changes in hearing ability.

POTENTIAL NF SPECIALISTS

Due to the diverse ways NF2-SWN can affect the body, individuals with this condition often require care from a variety of healthcare specialists. The most comprehensive care is typically available at an NF clinic, which offers a wide range of essential services. A list of NF specialty clinics can be found here (provide link). It is important to seek out facilities with expertise in NF2-SWN, as they understand the complexities of the condition and are well-versed in its treatment and management. Ideally, these specialists will work together, coordinating and communicating effectively to provide the best possible care and treatment plans.

  • Neurology – conditions affecting the brain and spine
  • Otolaryngology (ENT) – surgeons for ear, nose, throat, and vestibular (inner-ear balance) systems
  • Neurotology – surgery for ear problems related to the nerves
  • Audiology – evaluations for hearing, hearing aids, cochlear and auditory brainstem implants
  • Neurosurgery – surgery for the brain and spinal cord
  • Oncology and neuro-oncology – management and treatment for benign and malignant tumors
  • Ophthalmology – monitoring and treatment of eyes and vision
  • Orthopedics – surgery to remove schwannoma tumors
  • Neuro-ophthalmology – monitoring and treatment of visual problems related to nerves
  • Genetics – diagnosis and family risk assessment
  • Pediatric and adult primary care – routine medical care
  • Physical, occupational, or speech therapy – improve function and treat pain and disability

Treatments for neurofibromatosis are symptomatic, meaning that they treat the symptoms but do not cure the disease. Individuals with neurofibromatosis may be treated with medicine, pain management techniques, various therapies, and surgery, as symptoms arise.

The NF Network offers a tool to help find an experienced NF clinical team. Our office is available for consultation if the need arises.

Find A Doctor

If access to an NF Clinic is not available in your area our Clinical Care Options publication may help bridge the gap of care between your local physician and an experienced practitioner. We have published a comprehensive scientific publication created for the express purpose of improved clinical care. Designed for both the patient and the local physician, often with limited NF knowledge, it includes information on the diagnosis and development of NF, specific tumor types, and a list of Neurofibromatosis Clinical Trials Consortium clinics whose practitioners, collectively are up to date on available treatments and who have agreed to be contacted by physicians to learn more about NF or to refer a patient.

Download the Clinical Care Options Guide

Genetics

NF2-Related Schwannomatosis (NF2-SWN) is a hereditary disorder caused by a change in the NF2 gene, which is located on chromosome 22. Scientists have identified more than 400 mutations in the NF2 gene that lead to the development of NF2-SWN.

The NF2 gene produces a protein called merlin (which stands for Moesin-Ezrin-Radixin-Like protein; also called schwannomin) This protein helps regulate cell growth by acting as a molecular brake and aids in preventing cells from multiplying too many times, particularly in the nervous system. When the NF2 gene is mutated, merlin’s function is disrupted, leading to the growth of tumors on nerves.

Current basic and clinical research focuses not only on understanding how genetic mutations cause the wide range of symptoms seen in NF2-SWN, but also on predicting which symptoms will occur in each individual (personalized or precision medicine). This approach aims to tailor treatments and interventions to each person’s unique genetic makeup and disease presentation.

Familial vs Sporadic

We each carry two copies of most genes in our body, one inherited from each parent, and this includes the NF2 gene. NF2-related schwannomatosis is inherited in an autosomal dominant manner, meaning only one mutated copy is needed for a person to develop the disorder. Therefore, a parent with NF2-SWN has a 50% chance of passing the mutated gene to their child, and any child who inherits the altered gene will also have NF2-SWN.

While about half of the cases of NF2-SWN are inherited from a parent, the other 50% of NF2-SWN cases are the first in their family to be diagnosed with the disorder. These cases result from new genetic alterations or mutations in the sperm or egg cell that formed the child. This event  is called a spontaneous, or de novo mutation. Individuals with sporadic NF2-SWN also have a pathogenic variant in the gene, which means they can pass it on to their children, just like those with familial NF2-SWN.

Parents often worry if something they did caused their child’s NF2 gene mutation, such as exposure to radiation, certain medications, alcohol, or other environmental factors. However, the exact cause of the NF2 gene mutation is currently unknown, and no environmental factors have been linked to it. Genetic mutations happen regularly as cells divide and replicate vast amounts of genetic information. Random errors can occur in this process, leading to mutations like those seen in NF2-SWN.

Mosaicism

Over half of individuals with sporadic (but not familial) NF2-SWN have the pathogenic NF2 variant in only some parts of their body, a condition known as genetic mosaicism. This means that the person has two genetically distinct cell types within their body. People with mosaicism often experience a milder form of NF2-SWN because the disease-causing variant is not present in every cell. For example, they may develop hearing problems in only one ear.  In individuals with mosaic NF2-SWN, the risk of passing the condition to their child is usually less than 50%. To better understand this risk, specialized genetic testing may be necessary for people with mosaic NF2-SWN.

Segmental NF2-SWN

Individuals with segmental NF2-SWN have some of the tumors associated with NF2-SWN confined to a restricted region, such as only one side of the body.