Neurofibromatosis
Disease Details
Family Health Simplified
- Description
- Neurofibromatosis is a genetic disorder that causes tumors to form on nerve tissue, leading to potential complications in the skin, bones, and nervous system.
- Type
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Neurofibromatosis is a genetic disorder with two main types:
1. Neurofibromatosis Type 1 (NF1): This type is typically transmitted in an autosomal dominant manner. Mutations in the NF1 gene located on chromosome 17 are responsible for this type.
2. Neurofibromatosis Type 2 (NF2): Similarly, this type is also transmitted in an autosomal dominant manner. Mutations in the NF2 gene on chromosome 22 cause this type.
Both types can occur as a result of new mutations, meaning they can appear in individuals with no family history of the disorder. - Signs And Symptoms
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Neurofibromatosis type 1 in early life may cause learning and behavior problems – about 60% of children who have NF1 have mild difficulty in school. Signs the individual might have are as follows:
Six or more light brown dermatological spots ("café au lait spots")
At least two neurofibromas
At least two growths on the eye's iris
Abnormal growth of the spine (scoliosis)
Lisch nodules
Tumors on the adrenal glands called pheochromocytomasPeople with neurofibromatosis type 2 can exhibit the same type of skin symptoms as type 1, but not necessarily in every case. Symptoms may include pain due to pressure on nerves, tinnitus, weakness in fingers, numbness, headaches. The symptom most characteristic of NF2 is hearing loss. The hearing loss occurs due to the pressure of tumors on the acoustic nerve. The same pressure can cause headaches, dizziness, and nausea.The main symptom of schwannomatosis is localized pain. This pain is due to tissues and nerves experiencing more pressure because of nearby tumors. - Prognosis
- In most cases, symptoms of NF1 are mild, and individuals live normal and productive lives. In some cases, however, NF1 can be severely debilitating and may cause cosmetic and psychological issues. The course of NF2 varies greatly among individuals. In some cases of NF2, the damage to nearby vital structures, such as other cranial nerves and the brain stem, can be life-threatening. Most individuals with schwannomatosis have significant pain. In some extreme cases, the pain will be severe and disabling.
- Onset
- Neurofibromatosis is typically diagnosed in childhood or early adulthood. The onset of symptoms can vary, with many individuals noticing signs like skin changes (café-au-lait spots) or growths (neurofibromas) before the age of 10.
- Prevalence
- Neurofibromatosis type 1 (NF1) has a prevalence of approximately 1 in 3,000 individuals worldwide. Neurofibromatosis type 2 (NF2) is less common, with a prevalence of about 1 in 25,000 to 40,000 individuals.
- Epidemiology
- In the United States, about 1 in 3,500 people have NF1, 1 in 25,000 have NF2, and 1 in 40,000 have schwannomatosis. Males and females are affected equally often in all three conditions. In NF1, symptoms are often present at birth or develop before 10 years of age. While the condition typically worsens with time, most people with NF1 have a normal life expectancy. In NF2, symptoms may not become apparent until early adulthood. NF2 increases the risk of early death. Schwannomatosis symptoms develop in early childhood and can worsen with time. Typically life expectancy is unaffected in those with schwannomatosis.
- Intractability
- Neurofibromatosis is generally considered to be intractable, meaning it cannot be cured. However, treatments are available to manage and alleviate symptoms, such as surgical removal of tumors, medication to control pain and other symptoms, and various therapies to address complications. The disease's progression and impact can vary greatly among individuals.
- Disease Severity
- Neurofibromatosis severity can vary widely among individuals, from mild skin manifestations to severe neurological complications. It is characterized by the growth of non-cancerous tumors on nerve tissue, which can affect the skin, bones, and the nervous system. The condition can range from causing mild symptoms to significant disability, depending on the number and location of tumors.
- Healthcare Professionals
- Disease Ontology ID - DOID:8712
- Pathophysiology
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The pathophysiology is varied, and each NF type has a different one:
Neurofibromatosis type I is the most common of the three types and is caused by genetic changes in the NF1 gene located on chromosome 17 (17q11.2). This gene encodes a cytoplasmic protein known the neurofibromin, which functions as a tumor suppressor and therefore serves as a signal regulator of cell proliferation and differentiation. A dysfunction or lack of neurofibromin can affect regulation, and cause uncontrolled cell proliferation, leading to the tumors (neurofibromas) that characterize NF1. The neurofibromas caused by NF consist of Schwann cells, fibroblasts, perineuronal cells, mast cells and axons embedded in an extracellular matrix. Another function of neurofibromin is to bind to microtubules that play a role in the release of adenylyl cyclase and its activity. Adenylyl cyclase plays an essential role in cognition. Neurofibromin's role in the activity of adenylyl cyclase explains why patients with NF experience cognitive impairment.Neurofibromatosis type II is caused by a mutation on chromosome 22 (22q12). The mutation falls on the NF2 tumor suppressor gene. The gene normally encodes a cytoplasmic protein known as merlin. The normal function of merlin is to regulate the activity of multiple growth factors, the mutated copy of the gene leads to merlin's loss of function. The loss of function leads to increased activity of growth factors normally regulated by merlin, leading to the formation of the tumors associated with NF2.Schwannomatosis is caused by a mutation on the SMARCB1 gene. This gene is located near the NF2 tumor suppressor gene leading to the thought that schwannomatosis and NF2 were the same condition. The two conditions show different mutations on two different genes. The normal function of the SMARCB1 gene is to encode a protein called SMARCB1 that is part of a larger protein complex whose function is not completely understood. The complex including SMARCB1 plays a role in tumor suppression. The mutation of the SMARCB1 gene causes a loss of function in the complex leading to the formation of tumors indicative of schwannomatosis. - Carrier Status
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Neurofibromatosis is a genetic disorder with two main types: NF1 and NF2. It is typically inherited in an autosomal dominant manner. This means:
1. **Carrier Status:** For autosomal dominant conditions like neurofibromatosis, the concept of "carrier status" as it applies to recessive conditions doesn't really apply. An individual with one copy of the mutated gene will generally express the condition.
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Individuals with a family history of neurofibromatosis should consider genetic counseling for more personalized information. - Mechanism
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Neurofibromatosis is a genetic disorder characterized by the development of multiple benign tumors along nerves in the skin, brain, and other parts of the body. There are two main types: Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2).
### Mechanism:
- **NF1:** The mechanism involves mutations in the NF1 gene located on chromosome 17. This gene encodes a protein called neurofibromin, which functions as a tumor suppressor by negatively regulating the RAS-mediated cell growth pathway. Mutations in NF1 lead to a loss of neurofibromin function, resulting in uncontrolled cell proliferation and tumor development.
- **NF2:** The mechanism involves mutations in the NF2 gene on chromosome 22. This gene encodes the protein merlin (or schwannomin), which also acts as a tumor suppressor by influencing cell shape, motility, and growth signaling. Loss of functional merlin due to NF2 mutations leads to the formation of tumors, primarily schwannomas.
### Molecular Mechanisms:
- **NF1 Molecular Mechanism:**
- The NF1 gene mutation is often a loss-of-function mutation.
- Neurofibromin normally activates the GTPase activity of RAS, converting it from the active GTP-bound form to the inactive GDP-bound form.
- Without functional neurofibromin, RAS remains in a constitutively active state, leading to continuous cell division and tumor formation.
- The PI3K/AKT and MAPK/ERK pathways downstream of RAS become dysregulated, promoting proliferation and survival of Schwann cells, melanocytes, and other cell types.
- **NF2 Molecular Mechanism:**
- Mutations in the NF2 gene lead to the production of a dysfunctional merlin protein.
- Merlin acts as a linker between the cytoskeleton and cell membrane proteins, helping to organize signaling complexes and maintaining cell contact inhibition.
- Loss of merlin disrupts these processes, leading to increased cell proliferation, altered signaling through pathways such as Hippo and mTORC1, and eventually tumor formation, particularly affecting Schwann cells of the nervous system.
Both types of neurofibromatosis involve crucial tumor suppressor genes whose loss of function leads to dysregulated cellular pathways, resulting in tumor growth. - Treatment
- Surgical removal of tumors is an option; however, the risks involved should be assessed first. With regard to OPG (optic pathway gliomas), the preferred treatment is chemotherapy. However, radiotherapy is not recommended in children who present with this disorder. It is recommended that children diagnosed with NF1 at an early age have an examination each year, which allows any potential growths or changes related to the disorder to be monitored.
- Compassionate Use Treatment
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Neurofibromatosis, particularly Neurofibromatosis Type 1 (NF1) and Neurofibromatosis Type 2 (NF2), can benefit from compassionate use treatments and off-label or experimental treatments under certain conditions.
1. **Compassionate Use Treatments**:
Compassionate use programs allow patients with serious or life-threatening conditions access to experimental drugs outside of clinical trials when no other treatments are available. For neurofibromatosis:
- **Selumetinib**: Recently received FDA approval for use in pediatric patients with symptomatic, inoperable plexiform neurofibromas. While it is now approved, it may have previously been accessed through compassionate use.
- **Sirolimus**: Sometimes requested for compassionate use for patients with severe symptoms, as it shows promise in reducing tumor growth.
2. **Off-Label Treatments**:
Certain drugs approved for other conditions may be used off-label for neurofibromatosis treatment:
- **Bevacizumab**: Primarily used for cancer treatment; it has been prescribed off-label for NF2-related vestibular schwannomas to decrease tumor size and improve hearing.
- **Everolimus**: Used for reducing growth in various tumors, it has shown benefit in clinical trials for certain neurofibromatosis-related tumors.
3. **Experimental Treatments**:
Ongoing research aims to identify new therapies for neurofibromatosis. Some drugs still in the experimental phase include:
- **MEK Inhibitors (e.g., Trametinib)**: Research continues into their effectiveness for reducing tumor growth in NF1.
- **AR-42 (HDAC Inhibitor)**: Shows potential effectiveness for patients with NF2.
- **CRISPR-Cas9 Trials**: Gene-editing technologies are being explored to correct genetic mutations associated with neurofibromatosis.
Patients considering these options should discuss them thoroughly with their healthcare providers for the most appropriate and personalized approach. - Lifestyle Recommendations
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For neurofibromatosis, lifestyle recommendations typically include:
1. **Regular Medical Check-ups:** Routine visits to a healthcare provider to monitor the progression of the condition.
2. **Healthy Diet:** Maintain a balanced diet rich in fruits, vegetables, lean proteins, and whole grains to support overall health.
3. **Physical Activity:** Engage in regular exercise tailored to individual abilities and limitations to promote cardiovascular health and overall well-being.
4. **Avoidance of Tobacco and Excessive Alcohol:** Refrain from smoking and limit alcohol intake to reduce additional health risks.
5. **Stress Management:** Practice stress-reducing techniques such as meditation, yoga, or other relaxation methods.
6. **Skin Care:** Protect skin from trauma and excessive sun exposure to prevent complications with neurofibromas.
7. **Support Networks:** Joining support groups for individuals with neurofibromatosis can provide emotional support and valuable information.
8. **Professional Counseling:** Seek psychological support if needed, to cope with the emotional and psychological challenges of the condition.
9. **Educational Support:** For children with neurofibromatosis, work with educators to address learning disabilities or other school-related challenges.
Consult with your healthcare provider for personalized advice based on your specific condition and needs. - Medication
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There is no cure for neurofibromatosis (NF), but treatment focuses on managing symptoms and complications. Medication may include:
1. Pain Relief: Analgesics such as pain relievers (e.g., acetaminophen, ibuprofen) for symptomatic pain management.
2. Anti-cancer Medications: Selumetinib has been approved by the FDA for treating plexiform neurofibromas in children with NF1.
3. Blood Pressure Management: Antihypertensive drugs for patients with associated vascular issues.
Surgery, physical therapy, and monitoring for complications are also important aspects of managing neurofibromatosis. Regular follow-up with healthcare providers is crucial for ongoing care. - Repurposable Drugs
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Research into repurposable drugs for neurofibromatosis, particularly Neurofibromatosis Type 1 (NF1), has identified several candidates. Some of the repurposable drugs under investigation include:
1. **Selumetinib**: Originally developed for cancer treatment, this MEK inhibitor has shown efficacy in shrinking plexiform neurofibromas in NF1 patients.
2. **Everolimus**: An mTOR inhibitor used in cancer therapy, which has been studied for its potential to reduce tumor growth in NF1.
3. **Lovastatin**: A statin typically used for lowering cholesterol, which has been researched for cognitive improvements in NF1 patients.
Studies are ongoing to confirm the effectiveness and safety of these repurposed drugs for managing neurofibromatosis symptoms and complications. - Metabolites
- Neurofibromatosis is a genetic disorder that causes tumors to form on nerve tissue. The specific metabolites associated with neurofibromatosis are not well-characterized, but research has noted alterations in certain metabolic pathways due to tumor development. These include disruptions in glucose metabolism, lipid metabolism, and amino acid pathways. Further research is ongoing to better understand these metabolic changes and their implications for disease progression and treatment.
- Nutraceuticals
- There is limited evidence supporting specific nutraceuticals for the treatment of neurofibromatosis. Standard treatment involves monitoring and managing symptoms, including surgery for tumor removal if necessary. It is important to consult healthcare professionals for appropriate management and treatment options.
- Peptides
- Neurofibromatosis does not currently have a standard treatment involving peptides or nanoparticles (nan). The disorder, which causes tumors to form on nerve tissue, is typically managed through surgical removal of tumors, symptom management, and regular monitoring for complications. Research is ongoing to explore potential treatments, including emerging therapies that might involve peptides or nanotechnology. However, these are not yet established or widely used in clinical practice for managing the condition.