Neurofibromatosis is a genetic disorder that causes the formation of tumors on top of nerve tissues, which comprises large growth of masses of tissues due to the collection of cells. These extraneous tumor growths can be found anywhere along the nervous system, including the brain, nerves, and even the spinal cord. The implications of this disease range in severity, as tumors are often not cancer-causing, but can later become cancerous due to complications. Because of the expansive nature of the disease’s effects on the entire nervous system, neurofibromatosis is classified into two types - neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2) - based on their differing implications and causes. This article will explore Neurofibromatosis 2 (NF2), the much rarer form of neurofibromatosis whose tumor growth spans across nerves connected to the brain, leading to prolonged neurological and nervous system damage.
Types of Tumors
NF2 is primarily caused by the growth of slow-growing, non-cancerous tumors that affect “the cranial, spinal, and peripheral nerves” and consequently cover the brain and the spinal cord . The three main types of tumors seen in NF2 correspond with the signs and symptoms experienced by individuals with the condition.
Figure 1. This diagram of the brain indicates the position of the vestibulocochlear (shown by the two purple branches), or eighth cranial nerve .
The first and most common type of tumor is known as schwannoma tumors. These are made up of accumulated Schwann cells, whose function is producing myelin, the protective insulating layer surrounding nerve cells. Schwannomas are most frequently seen on the eighth cranial nerves, also known as vestibulocochlear nerves, in the brain (see fig. 1) . These nerves have two main branches: the acoustic and the vestibular branches. The acoustic branch is responsible for carrying signals for hearing and comprehension into the brain, while the vestibular branch is responsible for maintaining one’s sense of position and balance. As such, people with NF2 often have a compromised sense of balance, high rates of hearing loss, and an inability to balance themselves properly. It is notable that while vestibular schwannomas are the most common in cases of NF2, schwannoma tumors can grow on any cranial or peripheral nerve. Hence, people with NF2 often experience symptoms that are directly related to a variety of sensational abilities and feel strong sensations of pain or numbness in such areas. For example, they experience losses in vision, dizziness, etc . Like other tumors, schwannomas may also be seen on the skin as “bumps” underneath the surface. While these tumors are usually non-cancerous, their severity is variable and may require treatment if the tumor growth becomes uncontrollable .
The second type of tumor is called a meningioma, a type of slow-growing tumor that grows on the tissue enclosing the brain and the spinal cord. Notably, people with NF2 have a significantly higher incidence of meningiomas, as they are able to grow multiple tumors on the brain and spinal cord . As these tumors continue to grow, they pose the risk of compromising one’s nervous system capacity and risks of seizures, vision loss, smell loss, etc., as a result of heightened pressure caused by the growths on the central nervous system . As a result, medical professionals aim to intervene earlier in a patient’s childhood when meningioma tumors are detected, in order to prevent future suppression of the individual’s bodily capabilities and brain function.
Figure 2. This MRI scan shows the growth of an ependymoma tumor within the ventricles of a child’s brain .
The last main tumor that is observed in cases of NF2 are the ependymoma tumors. These tumors grow within the brain or the spinal cord as opposed to on its surface. Additionally, the tumours only spread within these parts of the nervous system and not outside of it. For example, certain ependymoma tumors in the brain are found growing in the ventricles of the brain (see figure 2) as opposed to on the skull’s surface . Therefore, in severe cases, these tumors can lead to headaches, dizziness, or nausea, due to their interference with the brain’s composition . In children, ependymomas are more likely to occur in the lower half of the brain, while in adults, they are more frequently found in the spinal cord . This is also shown in figure 2, where the ependymoma found in the brain is noted as being in a “pediatric patient.” In cases where these tumors become cancerous or pose significant implications on the patient, they can be removed surgically or by means of chemotherapy.
Signs, Symptoms, and Diagnostic Methodology
Often, NF2 symptoms are detected only in adulthood. Early-onset NF2 in children is usually only noticed through the presence of tumors in the central nervous system. Later, immediate treatment or intervention is encouraged to prevent the intensification of symptoms.
Among all symptoms of NF2, the most common is hearing loss or excessive ringing sounds in one’s ears. This is caused by vestibular schwannomas that prevent signals from being adequately transmitted through the acoustic branches of the eighth cranial nerves. Other symptoms also include issues with bodily balance (another direct result of vestibular schwannomas), seizures, loss of eyesight, or growth of tumors beneath the skin.
However, it is notable that the majority of the above symptoms are quite universal, as they may be applicable to a wide range of medical and neurological conditions. As such, in order to accurately diagnose NF2, neurologists adhere to a methodology to standardize and ensure accuracy in diagnosis. Firstly, they will check for the presence of vestibular schwannomas, the most common indicator, often used as the “hallmark” of NF2 . Since the disease is genetic, they will check for any family members who may have had the same or related conditions (from which a plausible mutation could have been passed down). They will also check for the presence of the other types of tumors, including meningiomas and ependymoma tumors, as either could be the cause of NF2-related symptoms . Moreover, to ensure that the symptoms are not one-off occurrences, they will often run clinical tests, including hearing tests, eyesight examinations and MRIs to confirm the presence of suspected tumors or symptoms .
NF2 is a genetic disease and is caused by a faulty or a mutated NF2 gene . The faulty NF2 gene is what leads to the uncontrolled growth of tumors within the brain and spinal cord, as the original gene (neurofibromin 2 merlin) is a tumor suppressor gene . 50% of all NF2 cases arise from the gene passing from parent to child, which is of a relatively high likelihood given that only one parent needs to have the faulty gene in order for the child to be at risk of developing the disorder, meaning that the gene is a dominant gene .
However, there are also cases in which the faulty NF2 gene arises spontaneously without having been passed down in the familial gene pool. The reasons for this are unknown; hence, the cause is listed as a “spontaneous mutation” .
Unfortunately, there is currently no known cure for NF2, and thus, doctors treat the condition on a day-to-day basis, given how its severity can vary unpredictably. As a result, the methodology of “regular monitoring and treating any problems as they occur” has been utilized to provide maximally effective treatments to patients on a case-by-case basis . Surgery or radiation therapy can be used to remove tumors if their growth is uncontrollable and if they pose significant risks to the functioning of the central nervous system. However, this option is known to be quite risky, as there is a high likelihood of surgical processes causing “further injury to nerves and additional neurological problems”, including complete loss of hearing  . As a result, neurologists must carefully weigh the potential benefits of conducting the surgery against the risks based on the severity and individual scenario of the patient.
NF2 is a disease that increases in severity as one ages. This worsening occurs at different rates for different individuals. However, it can be generalized that most NF2 patients will eventually experience complete hearing loss and very limited levels of mobility. As such, it is recommended that in order to offset the impacts of NF2, patients are afforded mobility devices and hearing aides as a form of “treatment” to the disorder .
Currently, research into NF2 is ongoing in order to understand more about the causative factors behind the faulty gene and the tumor growths. For example, the National Institute of Neurological Disorders and Stroke is conducting ongoing studies on patients with NF2 (including MRI, blood collection, and genetic sequencing) with the aims of “identifying imaging biomarkers of hearing loss, attempting to discover the mode of peripheral neuropathy in patients with NF2, as well as attempting to discover previously unknown serum biomarkers associated with high tumor burden” . In other words, this study aims to find tangible processes and phenomena associated with hearing loss, discover how common it is for patients with NF2 to have damaged nerve signal transportation networks (known as peripheral neuropathy), and determine specific proteins or “biomarkers” associated with the high incidence of tumors present in patients with NF2.
Moreover, there is also ongoing research into potential drugs and treatments for NF2, which is important given the high incidence of the disease and the lack of tangible and reliable treatments. For example, there is currently an ongoing study on the potential “effectiveness” and “tolerability” of Icotinib (a growth-inhibiting drug) as an inhibitor of the growth of tumors and vestibular schwannoma, thereby helping to reduce the severe and lasting impacts of continued tumor growth in patients with NF2 .
The above are just two examples of the broad ongoing research into the field of Neurofibromatosis, specifically NF2. The sheer breadth of this disease and the general lack of knowledge regarding its spontaneous causes and possible treatments have been a cause of concern for the neuroscientific research community. As such, ongoing research efforts hope to yield tangible outcomes to mitigate the effects of this disease.
With an incidence rate of 0.0025% (one out of every 40,000 births, NF2 has always been relatively obscure . However, understanding the types of tumor growths and its correlations with the symptoms and diagnosis of NF2 have helped to provide neurologists with a methodology to help understand and monitor the disease in patients, especially given the nature of the disease. However, it is hoped that the increase in research efforts into the causes and potential treatments can help mitigate and minimize the negative impacts of this disease on patients in the future.
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