What is Neurocutaneous Syndromes?
Neurocutaneous syndromes, as the name suggests, are conditions that affect both the nervous system and the skin. It’s very important, especially for children’s doctors (pediatricians), to identify any changes or problems with the skin linked to neurocutaneous syndromes. This can help in monitoring the condition and managing any potential complications.
Two disorders that are often seen in this category, also called phacomatoses, are neurofibromatosis (a disease causing tumors to form on nerve tissue) and tuberous sclerosis complex (a condition leading to noncancerous growths in the brain and other organs). It’s crucial to highlight and manage these conditions early on for the best outcome.
What Causes Neurocutaneous Syndromes?
In the condition known as NF, tumours can develop on the protective layers of the nerves. These tumours are associated with a change or ‘mutation’ in a particular gene, known as the NF1 gene. This gene, located on a specific region of chromosome 17, is responsible for producing a protein called neurofibromin. Neurofibromin normally acts to keep cell growth in check, but if the NF1 gene is mutated, neurofibromin function is impaired, leading to uncontrolled cell growth and tumour development. NF can be passed on from parent to child, but half of the time, the mutation arises spontaneously in an individual.
There’s also a second type of NF, caused by a mutation in the NF2 gene, which is located on a different chromosome, chromosome 22. This gene produces a protein known as merlin or schwannomin. Just like with NF1, NF2 can be passed on from parent to child, but approximately half of the cases are due to a spontaneous mutation.
In another condition called TSC, either the TSC1 gene or the TSC2 gene has a mutation. These genes are positioned on two different chromosomes. TSC, like NF, has an inheritance pattern that can be passed on from parent to child. However, this doesn’t mean everyone with the gene will experience the same symptoms – they can be wide-ranging. Again, half of TSC cases occur due to a spontaneous mutation, meaning it can affect individuals with no family history of the condition.
Risk Factors and Frequency for Neurocutaneous Syndromes
Neurofibromatosis type 1 (NF1) is the most common condition among diseases that affect both the skin and the nervous system. While NF1 affects 1 in 3,000 people, Neurofibromatosis type 2 (NF2) is less common, affecting 1 in 25,000 people. Another related disease, Tuberous Sclerosis Complex (TSC), affects 1 in 6,000 people worldwide. Importantly, none of these diseases are more common in a particular ethnic group, gender, race, or geographic location.
Signs and Symptoms of Neurocutaneous Syndromes
Neurofibromatosis type 1 (NF1) often begins with spots on the skin called café-au-lait macules. If a child has six or more of these spots, doctors should look for other signs of NF1. As they grow older, they may develop freckles in their armpits, groin, neck, and mouth. Benign tumors, or neurofibromas, can also emerge, particular in or around the eyes, neck or limbs. The critical point is that these usually start to appear early in life, around the ages of 3-5 years.
There are more signs to watch out for that don’t involve the skin. For example, some NF1 patients may develop an optic glioma, a tumor near the eye that can cause vision loss. However, it’s important to note these tumors often cause no symptoms. Another sign of NF1 is the presence of Lisch nodules in the eyes, which can be seen in almost all patients by the time they reach 21. If a patient begins to stand, and their tibia or shin bone doesn’t form properly, it could also indicate NF1.
Neurofibromatosis type 2 (NF2) is less common and mainly presents as tinnitus (ringing in the ears), hearing loss, balance issues, and sometimes facial paralysis due to tumors on both sides of the ear nerve. Less often, NF2 patients have café-au-lait macules, and don’t usually develop freckling or skin tumors. However, they may develop skin growths called schwannomas.
Another condition with specific skin symptoms is tuberous sclerosis complex (TSC). One of its early signs are white-colored spots referred to as “ash-leaf” spots. The spots might not be apparent at birth but can be detected using a special light in a dimly lit room. Red nodules and an orange peel-like thickened patch could also appear on the skin.
- Café-au-lait macules
- Freckles in certain areas
- Benign tumors or neurofibromas
- Optic glioma
- Lisch nodules
- Abnormal tibia formation
- Tinnitus, hearing loss, balance issues, facial paralysis
- Skin growths called schwannomas
- Ash-leaf spots
- Red nodules and orange peel-like skin patches
Non-skin symptoms of TSC include heart tumors in newborns that can disrupt the heart’s functioning but usually shrink on their own. Furthermore, infants could experience muscle spasms or seizures typically beginning just before their second birthday. This is a significant symptom requiring quick medical attention to prevent severe intellectual disability.
Testing for Neurocutaneous Syndromes
When a doctor notices certain signs during an examination, they may suspect you have a specific health condition called a neurocutaneous disorder. To diagnose these disorders, doctors rely primarily on their observations during a physical exam. They will often also use test results to confirm the diagnosis and provide appropriate advice to the patient’s family.
One such disorder is Neurofibromatosis type 1 (NF1). To determine if someone has NF1, doctors look for two or more specific signs. These signs may include six or more “café-au-lait” skin spots larger than 5 mm in young children (or greater than 15 mm in teenagers and adults), skinfold freckling, two or more skin growths known as neurofibromas, or a large, complex skin growth called a plexiform neurofibroma. Another sign might be a bone deformation in a long bone or the wing of the sphenoid bone in the skull, which helps support the eye socket. Doctors may also look for a tumor in the optic nerve, distinctive pigmented areas in the eye known as Lisch nodules, or a close relative with NF1.
Children who may be at risk for another condition, Neurofibromatosis type 2 (NF2), due to a family history of this disorder, should have their hearing tested by an audiologist. If any hearing issues are observed, the child should then have a brain scan using magnetic resonance imaging (MRI). In general, a child diagnosed with NF2 should have a brain MRI by their teen years.
Yet another type of disorder is Tuberous sclerosis complex (TSC), which is diagnosed based on clinical findings. For a doctor to diagnose TSC, the patient should meet two major criteria or have one major and two or more minor signs. Major signs can include having three or more light-coloured spots on the skin (each spot being 5 mm or larger), three or more raised red skin lesions called angiofibromas, or a fibrous plaque (lump) on the forehead area. Additional signs include rough, raised skin patches known as shagreen patches, multiple harmless tumors in the eye(s) (retinal hamartomas), abnormal brain formation (cortical dysplasias), benign brain tissue growths (subependymal nodules), large brain cell growth (a subependymal giant cell astrocytoma), heart muscle tumors (cardiac rhabdomyosarcoma), lymphatic system tumors, and having two or more fat-rich benign kidney tumors (angiomyolipomas). Minor signs include many small light-colored spots grouped together on the skin (called “confetti” skin lesions), three or more pits in tooth enamel, two or more small benign tumors inside the mouth, an achromic (colorless) patch in the retina, multiple kidney cysts, and nonrenal benign growths, or hamartomas.
Treatment Options for Neurocutaneous Syndromes
If you’ve been diagnosed with Neurofibromatosis type 1 (NF1), a genetic disorder that causes tumors to form on nerve tissue, the most crucial part of your treatment plan will be monitoring for complications related to this condition. This monitoring process can only be effective if we understand how NF1 naturally progresses over time and its potential side effects. For example, complex neurofibromas, a type of growth common in people with NF1, can increase in size and cause problems by compressing the spinal cord or airway. If these become troublesome, you may need to see a surgeon.
Another potential complication includes optic glioma, a tumor that affects the optic nerves. This is why regular eye exams are critical, at least until you’re around 6-7 years old, as the condition rarely develops beyond this age. If it does emerge, the usual treatment is chemotherapy.
Regular checks of your blood pressure are also essential, as conditions such as renal artery stenosis (narrowing of the arteries in your kidneys) or pheochromocytoma (a rare tumor that can cause high blood pressure) are possible complications of NF1.
Once you start to stand or walk, around 10 to 12 months of age, you might reveal signs of long bone dysplasia, a condition that can affect bone development, particularly in the tibia, one of the bones in the lower leg. Early detection via radiographs (x-rays) is key so we can refer you to a specialist in bones and joints (an orthopedist) for more treatment and management if needed.
It’s crucial to diagnose NF1 early because at least 2 out of every 4 patients can experience neurocognitive dysfunction, most commonly experiencing learning disabilities. Early detection and intervention provide the best chance for positive progress, helping you to function effectively into adulthood.
Additionally, if you have NF1 you might also have a slightly increased risk of developing other conditions like pheochromocytoma, rhabdomyosarcoma (a rare cancer), leukemia, and Wilms tumor, when compared to the general public. Yearly checks for scoliosis (curvature of the spine) are recommended because of this.
In the case of another condition called Neurofibromatosis type 2 (NF2), treatment is usually required only when the tumors cause symptoms, and surgery tends to be the primary treatment option.
Early detection is similarly critical for Tuberous sclerosis complex (TSC), another genetic disorder that causes benign tumors to grow in the brain and other vital organs. This is due to the potential for patients to develop infantile spasms or seizures, which need timely and appropriate treatment to prevent severe cognitive impairment.
Ongoing monitoring and managing complications is the mainstay of care for patients with TSC. Regular brain and kidney scans are usually advised around every 1-3 years. If you show signs of increased pressure inside your skull, this could suggest a blockage caused by a specific type of brain tumor. In this situation, immediate brain scans would be carried out, and you might need to see a neurosurgeon for further management.
In simpler terms, even though these conditions can seem overwhelming, early detection, ongoing checks, and timely management of symptoms play a vital role in navigating these complex conditions effectively.
What else can Neurocutaneous Syndromes be?
Neurocutaneous syndromes refer to a group of conditions that affect both the nervous system and the skin. Some of these conditions, which can be quite varied, are:
- Neurofibromatosis
- Schwannomatosis
- Sturge-Weber syndrome
- Tuberous sclerosis complex
- Von Hippel-Lindau disease
What to expect with Neurocutaneous Syndromes
The outlook for a patient can change depending on how old they are when they start showing symptoms, and what other diseases or conditions they have when they see the doctor. This includes serious conditions like cancer.
Possible Complications When Diagnosed with Neurocutaneous Syndromes
People who have a condition called neurofibromatosis type 1 may develop different types of tumors. These include malignant peripheral nerve sheath tumor, gastrointestinal stromal tumor, optic pathway glioma, pheochromocytoma, and juvenile myelomonocytic leukemia. Similarly, individuals with another condition called tuberous sclerosis can develop a build-up of fluid in the brain, known as hydrocephalus, due to a type of tumor called subependymal giant cell astrocytoma. They are also prone to experience seizures.
Potential Health Risks for those with Neurofibromatosis Type 1:
- Malignant peripheral nerve sheath tumor
- Gastrointestinal stromal tumor
- Optic pathway glioma
- Pheochromocytoma
- Juvenile myelomonocytic leukemia
Potential Health Risks for those with Tuberous Sclerosis:
- Hydrocephalus due to subependymal giant cell astrocytoma
- Seizures
Preventing Neurocutaneous Syndromes
Patients who have these conditions should know that we don’t have a cure yet, but we can help manage their symptoms. It’s also wise to seek advice about the inherited nature of these conditions through something known as genetic counseling before attempting to have a baby. This means talking with a healthcare professional about the chances of passing the condition to their children.
