Neurofibromatosis type II (NF2) is a rare genetic disorder distinguished by the growth of noncancerous tumors within the nervous system. As a neurocutaneous syndrome, it affects the brain, spinal cord, nerves, and skin. The defining characteristic is the development of tumors on the nerves for hearing and balance, leading to a specific set of symptoms. Although the genetic changes are present from conception, signs typically appear in the late teenage years or early twenties.
Underlying Genetic Causes
The origin of neurofibromatosis type II is a mutation of the NF2 gene on chromosome 22. This gene provides instructions for producing a protein called merlin. Merlin functions as a tumor suppressor, controlling cell growth and preventing cells from multiplying uncontrollably. When the NF2 gene is mutated, it cannot produce a functional merlin protein, allowing tumors to form in the nervous system.
The condition can arise in two ways. Approximately half of all individuals with NF2 inherit the mutated gene from a parent. This inheritance pattern is autosomal dominant, meaning only one copy of the altered gene is needed to cause the disorder. Each child of an affected parent has a 50% chance of inheriting the gene mutation.
The other half of cases result from a new, or “de novo,” mutation in the NF2 gene. This means the genetic change occurs spontaneously in an individual without any previous family history of the disorder. In a smaller subset of these cases, a person may have mosaic NF2, where the mutation is present in some, but not all, cells of the body, which can lead to milder symptoms.
Characteristic Signs and Symptoms
The hallmark of NF2 is the development of bilateral vestibular schwannomas. These are slow-growing tumors on the vestibulocochlear nerve on both sides of the head. This nerve transmits sound and balance information from the inner ear to the brain. As these tumors grow, they compress the nerve, leading to a collection of symptoms.
Progressive hearing loss is often the first and most common symptom, starting in the late teens or early twenties. This may be accompanied by tinnitus, a persistent ringing in the ears, and problems with balance or dizziness. The pressure from these tumors can also affect adjacent nerves, sometimes causing facial weakness or numbness.
Beyond vestibular schwannomas, individuals with NF2 are predisposed to other nervous system tumors. Meningiomas, tumors that arise from the protective layers covering the brain and spinal cord, are found in about half of all patients. Ependymomas are a type of tumor that grows within the fluid-filled spaces of the brain or spinal cord. Schwannomas can also develop on other cranial, spinal, or peripheral nerves, causing pain or weakness depending on their location.
Ocular and skin findings can also occur, though they are less prominent than in neurofibromatosis type 1. Some individuals may develop a specific type of cataract known as a juvenile posterior subcapsular cataract. Skin manifestations are less common but can include a few café-au-lait macules or raised, plaque-like skin schwannomas.
How Neurofibromatosis Type II is Diagnosed
The diagnosis of NF2 is based on clinical criteria that rely on the presence of the condition’s characteristic tumors. The most direct path to diagnosis is identifying bilateral vestibular schwannomas. A diagnosis can also be made if an individual has a first-degree relative with NF2 and develops a unilateral vestibular schwannoma or other specific tumors like meningiomas.
Imaging studies are part of the diagnostic process. Magnetic Resonance Imaging (MRI) with contrast is the preferred method for visualizing tumors in the brain and spinal cord. An MRI can detect the presence, size, and location of vestibular schwannomas. Comprehensive MRI scans of the entire spine are also performed to screen for associated meningiomas or ependymomas.
In addition to imaging, specialized examinations assess function. A comprehensive audiological evaluation is performed to measure the extent of hearing loss. An ophthalmological exam is conducted to check for cataracts or other eye abnormalities associated with NF2.
Genetic testing can confirm the diagnosis. By analyzing a blood sample, a laboratory can identify a mutation in the NF2 gene. While not always necessary if clinical criteria are met, genetic testing can be useful in cases with an uncertain presentation or for family planning purposes.
Management and Treatment Strategies
Management of NF2 focuses on monitoring tumor growth and preserving neurological function, as there is currently no cure. For many individuals with small and asymptomatic tumors, the initial approach is active surveillance. This strategy involves regular follow-up appointments and periodic MRI scans to track any changes in tumor size or the emergence of new tumors.
When tumors grow and cause symptoms, intervention becomes necessary. Surgical removal of tumors is a primary treatment option. The goal is to resect as much of the tumor as is safely possible while aiming to preserve hearing and facial nerve function. Advances in microsurgery have improved outcomes, but the risk of hearing loss remains significant with larger tumors.
Stereotactic radiosurgery offers a less invasive alternative to surgery for controlling tumor growth. This technique uses highly focused radiation beams to target the tumor, damaging its DNA and preventing it from growing further. It is often used for smaller vestibular schwannomas and can be effective in preserving hearing for a longer period compared to surgical resection.
Targeted medical therapies represent an evolving area of treatment. Medications like bevacizumab inhibit the growth of blood vessels that feed tumors and have shown success in shrinking some NF2-related tumors and improving hearing. For managing profound hearing loss, various technological aids are available. These include hearing aids, cochlear implants (CIs), and auditory brainstem implants (ABIs), which can restore a sense of sound when the auditory nerve is no longer functional.