What is Neurofibromatosis Type 1 (Von Recklinghausen Disease)?
Neurofibromatosis type 1 (NF-1), also known as Von Recklinghausen disease, is a hereditary condition affecting the brain, skin, and bones. It’s also associated with a risk of developing abnormal bone structure, blood vessel problems, and learning difficulties. NF-1 is a genetic disorder that can be passed down from one generation to the next.
On top of that, it’s the most frequently occurring condition among a group of disorders called hamartoma neoplastic syndromes. These include syndromes like tuberous sclerosis, Gardner, and Cowden syndromes. Other types of neurofibromatosis exist, such as Neurofibromatosis type 2 (NF2) and schwannomatosis.
People with NF1 often have distinctive skin markings, called Cafe-au-lait macules, and a type of non-malignant tumour known as neurofibromas. NF2 shares similar skin features with NF1. However, the defining features for NF2 are the development of particular types of tumors such as schwannoma, meningioma, and ependymoma.
What Causes Neurofibromatosis Type 1 (Von Recklinghausen Disease)?
NF-1, or Neurofibromatosis type 1, is a genetic disorder that’s passed down in families. The gene responsible for NF-1 is located on the 17th chromosome, and it produces a type of protein named ‘neurofibromin.’ This protein is found in many different parts of the body, and it normally helps in controlling cell growth by turning off a pathway known as the rat sarcoma (RAS) pathway.
However, when there are changes or deletions in the NF-1 gene, it leads to the physical and genetic signals of this disorder. Since NF-1 is an autosomal dominant disorder, it means if only one parent has this gene, there’s a chance it can pass it along to their child. The disorder affects every generation without skipping any, but the symptoms can vary from one family member to another or even between individuals within the same family.
Risk Factors and Frequency for Neurofibromatosis Type 1 (Von Recklinghausen Disease)
NF-1 is a genetic disorder that can be passed down from a parent to all their children. This disorder is not specific to any gender and affects roughly 1 in 2,600 to 3,000 people. Of all cases, about half are inherited within families, while the other half occur randomly. These random occurrences, also known as sporadic mutations, are more likely to happen as the father’s age increases. There’s also a specific kind of NF-1, called segmental NF-1, which mostly affects the skin. This is less common, impacting about 1 in every 36,000 to 40,000 individuals.
- NF-1 is a genetically inherited disorder that affects all children of an affected parent.
- The condition affects 1 out of every 2,600 to 3,000 individuals.
- Both males and females can have NF-1, the condition does not favour any gender.
- Half of all NF-1 cases are inherited within families.
- The other half of the cases happen randomly, and are more likely as the father ages.
- Segmental NF-1, a type of NF-1 that primarily affects the skin, affects 1 out of every 36,000 to 40,000 individuals.
Signs and Symptoms of Neurofibromatosis Type 1 (Von Recklinghausen Disease)
Neurofibromatosis type 1 (NF-1), a disease condition, appears differently in each patient but generally takes a harmless course without causing serious complications. A patient might have a mild form of the disease affecting only a specific body part – called segmental NF-1 – or a more widespread form affecting the entire body – called generalized NF-1.
The early signs of NF-1 include specific skin changes like cafe-au-lait macules (light brown skin patches), freckling in the armpits or groin, Lisch nodules (growths on the iris of the eye), and neurofibromas (skin tumors). Bone abnormalities and optic glioma (an eye tumor) often appear when the patient is between 1 and 3 years old. Patients with NF-1 have an increased risk of developing various tumors, both benign (non-cancerous) and malignant (cancerous), throughout their lives.
For understanding, here are some detailed symptoms:
- Cafe-au-lait macules: These are clearly defined light brown patches that vary in size. They are the first sign of NF-1 and are seen in all children with the condition.
- Neurofibromas: These are tumors that can be found in the skin (cutaneous), under the skin (nodular), and along nerve roots (plexiform).
- Freckling: Small, grouped freckles in the armpits or groin area, known as Crowe’s sign, are generally considered a diagnostic sign of NF-1.
- Lisch nodules: These are dome-shaped lesions around the iris that appear on slit-lamp-examination and are usually asymptomatic.
- Skeletal abnormalities: Curvature of the spine, pseudoarthrosis (false joints), sphenoid wing dysplasia (a facial abnormality), and other bone abnormalities are prevalent.
- Neurological abnormalities: Cognitive dysfunction, learning disability, developmental delay, macrocephaly (large head size), and dural ectasia (ballooning of the dural sac around the spinal nerves) are reported.
- Malignancies: Various types of tumors, including optic nerve glioma, astrocytoma, brainstem glioma, and schwannomas, can occur.
- Other presentations: Issues like hypertension, congenital heart disease, annoying bowel syndrome, and constipation could be encountered.
Upon conducting a whole-body MRI during initial evaluations for patients, researchers found common features like areas with abnormal signal intensity, optic pathway glioma, bone dysplasia, spinal dura ectasia, and plexiform neurofibroma, etc. Typical NF-1-related signs like cafe-au-lait macules, macrocephaly, axillary freckling, Lisch nodules, and cutaneous neurofibromas dominate.
Evidence suggests differences between familial cases of NF-1 and other ones, with the former more likely to show developmental delays and certain types of neurofibroma.
Testing for Neurofibromatosis Type 1 (Von Recklinghausen Disease)
The National Institute of Health (NIH) and the Revised diagnostic criteria are used to diagnose Neurofibromatosis Type 1 (NF-1), a genetic disorder often characterized by changes in skin coloring and growth of tumors along nerves in the skin, brain, and other parts of the body. The NIH criteria requires two or more of the following conditions to be confirmed:
- Six or more Café-au-lait macules, which are flat, brown skin spots larger than 5 to 15 mm in diameter under normal light
- Two or more neurofibromas, which are non-cancerous nerve tissue growths, or one plexiform neurofibroma, which is a large cluster of these growths
- Freckling in the armpit or groin area
- Optic gliomas, which are tumors on the nerve that connects the eye to the brain
- Two or more Lisch nodules, or small harmless areas of melanin on the iris of the eye
- Certain bone abnormalities, such as sphenoid dysplasia (a misshapen skull bone), pseudoarthrosis (a “false joint” that forms at a fracture site), and others
- A first-degree relative, such as a parent or sibling, with the same condition
The NIH criteria are highly accurate, but for young children, more detailed assessments of symptoms and physical exams, especially of the skin, eyes, bones, and nervous system, may be necessary.
The Revised diagnostic criteria published in 2021 included similar but slightly different criteria. For someone with no family history of NF-1, two or more of the listed conditions should be present. For a child with a positive family history, just one or more of the same conditions are necessary.
Mosaic NF1, a less severe form of NF-1, should be suspected if the skin changes are only on one side of the body. In such cases, either the presence of Lisch nodules or a genetic test can lead to a diagnosis.
Neurofibromatosis, bright spots on brain MRI images, and larger than normal brain size are common in those with NF-1, but these findings aren’t necessary for diagnosis. However, they may suggest a risk for cognitive difficulties.
The manifestation of NF1 can also include other symptoms like focal areas of signal intensity, other forms of cancer, lung disease, stomach tumors, and scoliosis.
While genetic testing isn’t always necessary for NF-1 diagnosis, it may be helpful in uncertain cases or for screening family members or unborn children. It’s important to remember, a negative genetic test doesn’t completely rule out NF1, as some milder forms of the condition may still exist. Care for those affected by NF-1 often involves a team of healthcare professionals including geneticists, pediatricians, neurologists, ophthalmologists, psychiatrists, and psychologists. They work together to identify the disorder and related complications, provide treatment and offer emotional support and guidance.
Search algorithms and diagnostic codes are available to assist doctors in diagnosing and managing NF-1.
Treatment Options for Neurofibromatosis Type 1 (Von Recklinghausen Disease)
NF-1, which is a genetic disorder with many different symptoms, does not have a definitive treatment. The conventional way to treat the different symptoms of NF-1 largely involves managing the symptoms as they arise. For a specific type of tumor seen in NF-1, called plexiform neurofibromas, the only treatment option is surgical removal.
When it comes to treating the tumors associated with NF-1, decisions are made based on the type of tumor, whether it is affecting other parts of the body, and any complications that could arise. Radiation therapy, which is the use of high-energy particles or waves to eliminate cancer cells, is not commonly used as it can often lead to additional tumors. However, it can be used when deemed necessary.
Cutaneous and nodular neurofibromas, which are types of tumors present in NF-1, are treated when they cause painful symptoms, increase in size, cause weakness or loss of vision, or lead to concerns about physical appearance. The treatment involves surgery, laser treatment, or burning off the tumors using a high-frequency electric current (electrodesiccation). General itchiness and nerve pain may be managed with a type of medication called gabapentin.
In the case of plexiform neurofibromas, which are associated with severe illness and a higher chance of becoming cancerous compared to cutaneous and nodular neurofibromas, common reasons for their removal are if they are causing breathing problems, spinal cord compression, or disfiguration. For children aged three years and older who cannot undergo surgery for plexiform neurofibromas despite having symptoms or if it is growing, a drug called Selumetinib is often recommended. Selumetinib is a drug that helps block certain proteins that let cancer cells grow.
There are some new treatments being researched and tested that include using cells to carry therapeutic genes, using viruses to kill cancer cells, gene therapy, and targeted treatment that kills cancer cells while sparing healthy cells.
Optic pathway gliomas and other slow-growing cancerous tumors should be closely monitored for any symptoms, changes in vision, and size. For children, chemotherapy with a combination of drugs is typically used for treatment. In adults, treatment is not as precise. Surgery is usually reserved for evaluating high-grade gliomas, which are more cancerous and aggressive tumors.
For people with NF-1, surgery can enhance their appearance when they have cutaneous neurofibromas. Other therapies such as CO2 laser, photocoagulation, and radiofrequency ablation are also used, but these can result in skin pigmentation or scarring.
People with this condition who are presenting seizures or epilepsy may benefit from a neurosurgical intervention. Children with learning or cognitive issues should receive special therapy services to assist them.
Some skeletal abnormalities like the malformation of tissues or a false joint may require orthopedic treatment. Dietary supplements, like Vitamin-D and calcium, are recommended for people with weakened and brittle bones. Psychologists and counselors can provide support for socialization and offer emotional support.
It is important to follow-up every year to monitor the different complications of the disease. All infants should undergo an MRI scan to look for any neurological abnormalities.
Lastly, talking with a professional about the genetic nature of this condition can greatly benefit the patient’s management of the disorder. It is important to remember and share with others that a child of a person with NF-1 has a 50% chance of also having the disorder, and potentially, more severe symptoms. Blood relatives without any signs of the disease are less likely to carry the gene. Their children also have a diminished risk, but the chance is not completely absent.
What else can Neurofibromatosis Type 1 (Von Recklinghausen Disease) be?
Legius syndrome is a disorder similar to NF-1, where it is passed down through generations. But, it doesn’t affect the nervous system or result in nerve tissue tumors. Symptoms include spots of light brown skin and freckling. This syndrome arises from certain mutations in the SPRED1 protein.
Next, there’s Neurofibromatosis type 2. People affected by this don’t have more light-brown skin spots like in NF-1. There are also no signs of tan-colored patches in the iris, cognitive problems, or peripheral nerve cancer. What’s common in this condition are meningiomas (a type of brain tumor) and tumors on the balance nerves in the inner ear. It’s caused by mutations in a gene located on the 22q chromosome that’s supposed to prevent tumor formation.
Noonan syndrome can also lead to light-brown skin spots, alongside other physical traits like low-set ears, widely spaced eyes, a webbed neck, short stature, and heart issues. Genetic mutations involving certain signaling pathways inside cells lead to this syndrome.
Constitutional mismatch repair deficiency (CMMR-D) syndrome is another disorder that can cause light-brown skin spots, freckling, and tan-colored iris patches. This condition typically ties to brain tumors, colorectal cancer, and certain blood cancers. It’s not as frequently associated with eye nerve gliomas and a type of cancer affecting skeletal muscle cells, as seen in NF-1. This syndrome is caused by mutations in any one of the four genes responsible for correcting mistakes when DNA is copied.
Some other conditions to consider include McCune-Albright syndrome, Silver-Russell syndrome, phosphatase and tensin homolog (PTEN) hamartoma syndrome, Carney syndrome, ataxia-telangiectasia, Klippel-Trenaunay-Weber syndrome, Turner syndrome, and tuberous sclerosis.
If only skin color changes are present, the main conditions to consider are:
- Legius syndrome
- Noonan syndrome, and
- Constitutional mismatch repair deficiency.
What to expect with Neurofibromatosis Type 1 (Von Recklinghausen Disease)
The future for patients with Neurofibromatosis type 1 (NF-1), a genetic disorder that causes tumors to form on nerve tissue, can vary widely. This depends on how severe the disease is, if there is any cancer present, and the extent of the physical changes. Those with mild forms of NF-1 can have a fairly normal lifespan. However, those suffering from moderate to severe forms often struggle with a lower quality of life due to physical disfigurement and other health complications.
Women with NF-1 who also develop breast cancer usually have low survival rates five years after diagnosis and high mortality. Patients with tumors in the central nervous system (the brain and spine) have a heightened risk for second cancers, death, and problems with blood vessels.
A particular type of cancer known as Malignant peripheral nerve sheath tumors (MPNST), which develops in association with NF-1, generally leads to poor survival. It’s noted that certain markers in nerve tumors like S100 protein and SOX10 disappear as the benign tumor transitions into MPNST.
A study of 2467 NF-1 patients from Denmark between 1995 to 2013 found that they had higher chances for several challenges, including more hospitalizations, mental health disorders, struggles in school, difficulties in relationships, higher rates of abortions and stillbirths, poor quality of life, and increased dependency on others.
Doctors recommend regular full-body MRI scans for NF-1 patients to assess the development and progression of their condition. If there are changes in the Gigaxonin-related domain (GRD), an essential protein for nerve function, it can lead to faster disease and radiological progression in NF-1. Brain tumors and MPNSTs contribute most to death in patients with NF-1.
Approximately 45% of recent and ongoing research trials are focusing on Plexiform Neurofibromas (PN), tumors that happen in patients with NF-1.
Possible Complications When Diagnosed with Neurofibromatosis Type 1 (Von Recklinghausen Disease)
: People affected by certain health conditions need regular checks by a team of various medical specialists. This is to spot any symptoms early and treat them as soon as possible. During regular check-ups for children, their height, weight, head size, and blood pressure should be monitored. Also, evaluations of their eyes, skin, bone structure, nervous system, development, and mental abilities should be carried out. It’s also important to check how kids are doing at school and to screen for signs of depression.
It’s recommended to get further tests if there’s a tumor also known as plexiform neurofibroma that changes in size quickly, gets more bumps, becomes more painful or results in new neurological symptoms. These tests may involve the use of an MRI machine. Females with this condition should have a mammogram annually starting at age 30 instead of the usual age of 40 due to the associated risk of breast cancer.
Any of these symptoms should also be evaluated for another type of tumor called pheochromocytoma:
- High blood pressure
- Headaches
- Excessive sweating
- Heart palpitations
Vascular issues associated with this condition occur in roughly 0.4 to 6.4 percent of the cases, appearing as high blood pressure, kidney-associated high blood pressure, bleeding strokes, aneurysms, or abnormal connections between arteries and veins.
Therefore, procedures like Magnetic resonance angiogram, renal angiogram, or computed tomography angiogram should be used to examine the vascular lesions and to guide the necessary medical and surgical treatments to prevent additional complications. Symptoms like toe or fingertip pain may indicate the presence of glomus tumors. Severe vascular blockages, the so-called moyamoya disease, and multiple endocrine neoplasias (additional tumors in the endocrine glands), are often associated with this condition.
Preventing Neurofibromatosis Type 1 (Von Recklinghausen Disease)
People who have this disease, and their families, should understand what this illness is, what its symptoms are, how long it might last, and what complications can arise. It’s also essential to educate them on the need for regular check-ups and ongoing care from a team of healthcare professionals. This care should focus on both physical and mental health.
Additionally, before deciding to start a family, genetic counseling should be provided. This counseling will equip patients and their families with the necessary information they need to make an informed decision. Support from community-based models and support groups, like those of Neurofibromatosis type 1, have proven to be significantly helpful in ensuring continuity of care for these patients.
The lifelong care from a team of different healthcare professionals is very important in treating these patients.