What is Neurofibromatosis?
Neurofibromatosis is a condition that causes tumors to grow in the nervous system and skin. There are different types of neurofibromatosis, with type 1 and type 2 being the most common (See image: Neurofibromatosis, NF1, NF2, and Schwannomatosis).
Type 1 neurofibromatosis, also known as von Recklinghausen disease, is a type of inherited disease. It brings with it symptoms, like growths called neurofibromas, light brown coffee-colored skin spots called cafe-au-lait macules, freckling, and optic gliomas, which are tumors that grow in the nerve connecting the eye to the brain. Doctors typically diagnose type 1 based on these symptoms.
Neurofibromatosis type 2 (NF2) is identified by vestibular schwannomas, which are tumors that develop on the nerve inside the ear responsible for balance and hearing, and meningiomas, which are tumors that occur in the membranes surrounding the brain and spinal cord. NF2 is also an inherited disease.
Treatment for both types 1 and 2 of neurofibromatosis typically involves closely monitoring the symptoms and medical treatment when needed.
What Causes Neurofibromatosis?
Neurofibromatosis type 1 is a condition caused by a change in a specific gene called the neurofibromin 1 (NF1) gene. This change can either be new (not inherited) or can be passed on from a parent. The NF1 gene is located in a specific spot, called 17q11.2, inside your cells. This gene is responsible for creating a protein known as neurofibromin, which helps stop tumors from growing. This happens through its role in the RAS/MAPK and mTOR pathways, which are basically routes that information takes within a cell to trigger certain actions.
Sometimes, changes can occur where you only have this alteration in the NF1 gene in certain parts of your body. This can result in three types of Neurofibromatosis type 1: segmental, generalized, or gonadal. Segmental means the changes or tumors only show up in certain sections of your body. Generalized Neurofibromatosis appears similar to the typical type but doesn’t have the NF1 gene alteration. Gonadal Neurofibromatosis is when the change only affects your ova (female reproductive cells) or sperm (male reproductive cells).
A similar condition, known as Neurofibromatosis type 2, is due to changes in another gene called the NF2 gene. This gene is found on band 22q12 and makes a protein known as merlin. Like neurofibromin, merlin also helps control the growth of cells and prevent tumors from forming. It accomplishes this through its role in the PI3kinase/Akt, Raf/MEK/ERK, and mTOR pathways. This means merlin also helps transmit information within cells to start or stop certain processes.
Risk Factors and Frequency for Neurofibromatosis
Neurofibromatosis, a genetic disorder, comes in two types: type 1 and type 2. Out of all the cases of neurofibromatosis, about 96% are type 1. The disorder affects one out of every 3000 newborns, and it doesn’t favor any particular gender or race. About half of all patients with this disorder get it due to a spontaneous mutation, while the other half inherit it from one of their parents. Type 1 is fully penetrant, which means if a person inherits the mutation, they will definitely develop the disorder, but how the disorder shows itself can vary widely.
- Neurofibromatosis type 1 makes up about 96% of all neurofibromatosis cases.
- The condition shows up in 1 out of every 3000 births and affects all genders and races equally.
- About 50% of patients develop the condition due to a sudden mutation, while the other 50% inherit it.
- The condition will definitely develop in those who inherit it, but how it presents can vary.
Neurofibromatosis type 2, on the other hand, makes up about 3% of all cases. Its prevalence is between 1 in 33,000 and 1 in 87,410 births. Just like type 1, type 2 doesn’t have a preference for any specific gender or race. This type of neurofibromatosis can present differently among different families. Certain mutations can result in a more severe clinical presentation because they create a shortened protein.
- Neurofibromatosis type 2 makes up about 3% of all neurofibromatosis cases.
- Its occurrence rate is between 1 in 33,000 and 1 in 87,410 births.
- It affects all genders and races equally.
- The way it presents can vary among different families.
- Certain mutations can lead to a more severe form of the disorder.
Signs and Symptoms of Neurofibromatosis
Neurofibromatosis type 1 is a condition that causes both skin and internal problems. Cafe-au-lait spots, which are patches of skin pigmentation, are one of the key signs to diagnose the condition. These spots have a uniform look and sharp edges. The condition also leads to freckles in unusual places like the armpit or groin, which is also known as Crowe sign. The disease can cause the growth of tumors called neurofibromas, which can be on the skin or inside the body. These skin tumors are soft and dome-shaped but can also look like little nodules or plaques. Deeper, internal tumors can appear around your eye or inside your belly or chest.
Neurofibromas often display a characteristic termed the ‘buttonhole sign.’ Plexiform neurofibromas, which grow along nerves, usually appear at birth and can feel like a “bag of worms.” Other skin symptoms include curve in the spine (scoliosis), abnormal bone growth, learning problems, and attention deficit hyperactivity disorder (ADHD). People with this condition can also have brownish spots in the colored part of their eye (iris) known as Lisch nodules that do not impact vision, but may also develop optic glioma, a kind of nerve tumor that can affect vision and is seen in 15% of individuals with neurofibromatosis type 1. Additionally, they may experience generalized darkening of the skin, blue-red patches, juvenile xanthogranuloma (an uncommon skin disorder), glomus tumor, melanoma (a type of skin cancer), nevus anemicus (a type of birthmark), and itchiness. They are also at a higher risk for certain types of cancers including rhabdomyosarcoma, myeloid leukemia, and pheochromocytomas.
Neurofibromatosis type 2 mostly leads to the development of schwannomas and meningiomas. Schwannomas are tumors that affect the nerves responsible for balance and hearing, more commonly occurring in the upper part of the eighth cranial nerve. These tumors can also grow on any cranial nerve. When the facial nerve also gets involved along with the balance nerve schwannoma, surgical treatment becomes complex. People with this condition often experience tinnitus (ringing in the ears), hearing loss, and balance issues. Those with a certain protein variation tend to experience the onset of this disease at a younger age and develop a high number of tumors.
Testing for Neurofibromatosis
Neurofibromatosis type 1 is a genetic disorder that causes tumors to grow on nerve tissue. The National Institutes of Health (NIH) has established a list of seven characteristics, with at least two required to make a diagnosis. Regular genetic testing is not commonly conducted for diagnosis.
Below are the seven key characteristics:
1. Six or more flat, brown spots on the skin (cafe-au-lait spots) larger than 5mm in children and over 15mm in adults.
2. Two or more neurofibromas (tumors on nerve tissue) or a type of neurofibroma called a plexiform neurofibroma.
3. Freckles in the armpit or groin area.
4. Optic glioma, a tumor on the nerve that connects the eye and brain.
5. Two or more Lisch nodules, small, benign areas of pigment in the iris of the eye.
6. Bone deformities involving the sphenoid bone in the skull or thinning of the long bone cortex, which is the outer layer of bones.
7. Having a close family member, such as a parent or sibling, with the same condition.
Similar conditions include neurofibromatosis type 1-like syndrome, familial cafe-au-lait spots, and segmental neurofibromatosis type 1. These can present with similar features but lack certain characteristics or genetic mutations common in neurofibromatosis type 1.
Neurofibromatosis type 2 is a different type of genetic disorder and is typically indicated by a bilateral vestibular schwannoma, which are tumors on the nerves responsible for balance and hearing in both ears. However, not all individuals with this condition will have these tumors.
The NIH also has specific criteria for diagnosing neurofibromatosis type 2. Definitively diagnosing this condition involves observing bilateral vestibular schwannomas or that the individual has a close relative with the condition along with tumors related to balance and hearing in one ear before the age of 30. Also, other types of tumors like meningiomas, gliomas, schwannomas, and certain types of eye abnormalities may be used to help with diagnosis. A probable diagnosis for neurofibromatosis type 2 can be made based on other combinations of the characteristics mentioned.
Treatment Options for Neurofibromatosis
“Cafe-au-lait spots and neurofibromas are harmless conditions that generally don’t need treatment. However, if a patient has symptoms from these conditions, a doctor can surgically remove the affected areas, although these might come back later. Plexiform neurofibromas, however, carry a 8% to 13% risk of developing into cancerous tumors. This risk is higher if patients notice pain that goes on for longer than a month, new neurological symptoms, hardening of the neurofibroma, or rapid increases in size. Such cancerous tumors are usually treated by surgically removing them. The drug Imatinib has been shown to help reduce the size of plexiform neurofibromas.
It’s very important to constantly monitor for any new neurological symptoms as these could be signs of tumor development. Patients should have regular eye exams to catch the development of optic gliomas, which are tumors that affect the optic nerve, and are normally treated with chemotherapy.
For children, monitoring for difficulties in learning and behavior issues is key. Therapy can be very helpful for patients, in terms of providing support about the fact that this disease can be inherited from parents to their offspring.
In cases of Neurofibromatosis type 2, patients need to have their hearing assessed. Evaluations by an eye doctor, along with MRI scans, hearing tests, and testing reflexes are all crucial aspects of managing this condition. Surgery typically remains the primary treatment option for tumors that cause symptoms, however, these tumors may return in 44% of cases. Radiation therapy is other method, but this does come with a raised risk of the tumors become malignant (cancerous). Bevacizumab, a type of drug that inhibits blood vessel growth, can be used to medically treat Neurofibromatosis type 2. It was found to reduce tumor size in 53% of cases and improved hearing in 57%. For patients suspected of having Neurofibromatosis type 2, it’s recommended to get an MRI of the head and spine. This is important especially if the tumor is pressing against the brainstem or is causing hearing loss.”
What else can Neurofibromatosis be?
When it comes to diagnosing certain conditions, there are several possibilities a doctor may consider:
- Acoustic neuroma
- Brainstem syndromes
- Café-au-lait spots
- Legius syndrome (SPRED1 -related café-au-lait spots and freckles)
- McCune-Albright syndrome
- Spinal injury