"Neurofibromatosis Type 1" – What Is It?
Neurofibromatosis Type 1 (NF1), also known as Recklinghausen’s disease, is a genetic, i.e., hereditary disease that manifests itself (becomes noticeable) in childhood and affects various organs differently. NF1 requires coordinated care by doctors from different specialties. People with NF1 are characterized by the development of tumors, mostly benign nerve sheath tumors, and so-called neurofibromas, but there is also an increased risk of malignant tumors. This makes NF1 one of the tumor-predisposition diseases.
How Is "Neurofibromatosis Type 1" Diagnosed?
NF1 can be clinically diagnosed based on the following criteria, which develop according to age. At least two criteria must be met.
Diagnostic Criteria for NF1
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- 6 or more café-au-lait spots (CALF, irregularly limited milk-coffee-colored spots at skin level), the largest diameter >5mm before puberty and >15 mm after puberty
- 2 or more neurofibromas of any type or a plexiform neurofibroma (benign nerve sheath tumors)
- Freckling (freckle-like skin folds on the axilla and/or in the groin region)
- Optic pathway tumor (optic glioma, tumor along the optic nerve)
- 2 or more Lisch nodules (benign changes on the iris)
- Typical bone changes (sphenoid wing dysplasia, tibial pseudarthrosis)
- NF1-affected person in first-degree relatives (parents, children)
- If only the NF1-typical skin characteristics are present, a certain degree of diagnostic uncertainty remains, which should be resolved by genetic testing.
The probability of developing neurofibromas of the skin (small benign nerve sheath tumors) is almost 100%. Predicting the number and size of neurofibromas that will develop is impossible. Sometimes, it can happen that a previously known neurofibroma suddenly changes, starts to hurt, grows faster, or feels different. This requires further clarification, e.g., through imaging and/or sampling. The reason for this is the risk of neurofibromas degenerating and developing into malignant peripheral nerve sheath tumors (MPNST).
Further Clinical Features
The clinical symptoms vary, and their development depends on age. In addition to the main skin symptoms, such as CALF and neurofibromas (see diagnostic criteria), other findings are listed below:
- Macrocephalus (large head)
- Short stature
- So-called non-ossifying fibromas
- Scoliosis (curvature of the spine)
- Osteoporosis
- So-called vertebral scalloping
- Rib penciling (thinning of the ribs, visible in the X-ray)
- High blood pressure
- Blood vessel changes
- Learning difficulties
What Is the Risk of Cancer?
Although the risk of developing cancer is not usually a priority for individual patients with neurofibromatosis in everyday life, it is increased compared to the general population. Subsequent tumors occur more frequently in NF1:
- Malignant peripheral nerve sheath tumors (MPNST) usually arise from plexiform or deeper neurofibromas; the lifetime risk is between 8-12%.
- Visual pathway tumors, so-called optic gliomas, are pilocytic astrocytomas that only require treatment if symptoms occur. The peak age of onset is between 0 and 6 years. The risk of developing an optic glioma is around 15%.
- High-grade CNS tumors (brain stem gliomas) are rare at <1% but are often observed together with optic gliomas.
- JMML=Juvenile myelomonocytic leukemia. This is a sporadic form of leukemia, i.e., blood cancer. The risk of this disease is 1:300.
- Embryonal rhabdomyosarcoma (eRMS) is a soft tissue tumor, usually in the urogenital area. The age of onset is between 0-5 years, and the risk is <1%.
- For endocrine tumors, i.e., pheochromocytomas (tumors of the adrenal medulla), carcinoid tumors, or medullary thyroid carcinomas, the risk is <1%.
- Glomus tumors are small, painful nodules on the fingertips.
- Gastrointestinal stromal tumor (GIST) is a malignant tumor of the gastrointestinal tract. The risk of developing such a tumor is 2%.
- For breast cancer, the risk is 4-5 times higher, with a moderate lifetime risk of 20%.
What Is Known About the Development of "Neurofibromatosis Type 1"?
Neurofibromatosis is a genetic disease caused by a pathogenic variant, i.e., a change in the genetic material. The affected gene codes for neurofibromin, a protein important in tumor suppression. It counteracts the development of tumors. The absence of neurofibromin, therefore, increases the risk of cancer.
At around 1 in 3000 people, NF1 is the most common neurofibromatosis. Around half of the diseases are inherited and passed on from parents to their children; the inheritance is autosomal dominant. However, there is no good genotype-phenotype correlation with almost complete penetrance – the disease certainly appears clinically. This means that the manifestation of the disease can be very different, even within a family with the same mutation. It is, therefore, impossible to predict the disease’s severity. A spontaneous or new pathogenic variant causes the other half of the disease, called a de novo mutation.
There is also segmental NF1, which means the disease is limited to a particular body area, e.g., a leg. This is also referred to as a mosaic form of NF1. The pathogenic variant does not affect all but only some of the body cells, so there are healthy and affected cells side by side.
Genetic testing is possible in principle and is recommended to confirm the diagnosis, especially in children who only present with typical skin changes. The pathogenic variant can be found in 95% of cases if the diagnosis is clinically confirmed. If this is not the case, further genetic testing for the presence of an NF1-like disease is recommended.
Is There Any Form of Treatment Available?
The therapy depends on the symptoms. If symptoms or complications arise, these are treated. If there is an optic glioma that causes loss of vision and protrusion of the eyeball, chemotherapy must be considered; radiotherapy should be avoided. A new treatment option with so-called MEK inhibitors (selumetinib, cobimetinib) for inoperable plexiform neurofibromas is attracting much attention. However, there is presently no drug approval for this diagnosis in Germany.
Please ask your attending physician whether any open clinical studies could be considered for you.
Diagnosis of " Neurofibromatosis Type 1" What's Next?
If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.
Diagnosis of "Neurofibromatosis Type 1" What's Next?
If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.
Medical Measures for Early Detection
According to the latest AACR (American Association of Cancer Research) guidelines, the following tests are recommended for the early detection of patients with neurofibromatosis type 1:
Optic nerve glioma
- Comprehensive ophthalmological examination from 6-8 months annually until the age of 8 years, then every2 years until the age of 18 years
- If available, OCT (optical coherence tomography) at eye examination until 8 years of age
- If ophthalmic examination is not possible, unreliable or inconsistent, MRI should be performed from 2 years of age
- If visual impairment is suspected, MRI of the skull and orbit should be performed. An ophthalmological examination should be performed within 3 months
- If a tumour is detected with stable vision, close monitoring without therapeutic intervention is warranted
Plexiform neurofibromas
- One whole-body MRI in late adolescence to detect asymptomatic tumours at risk for ANNUBP and MPNST and to detemine tumour burden (close follow-up for >300 plexiform neurofibromas)
- Whole-body MRI once before treatment with a MEK inhibitor (if whole-body MRI is not possible, consider neck to pelvis MRI as an alternative)
- If surgery is required for scoliosis, one spinal MRI prior to surgery
Other screening measures
- Annual clinical check-ups: Fast growing tumours or changes in their nature? Pain? Functional limitations?
- Regional diffusion-weighted imaging (DWI) MRI and F-FDG PET/MRI or F-FDG PET/CT if there are clinical signs: Neurological impairment, pain, rapid growth of a plexiform neurofibroma in adolescents or young adults
- No specific screening is indicated for other brain tumours. Diagnosis is only made when symptoms appear
- Clinical examination for leukaemia from birth or diagnosis annually
- Blood pressure measurement from birth or yearly at diagnosis to check for renal artery stenosis in the absence of other symptoms suggesting pheochromocytoma
- No specific screening is indicated for rhabdomyosarcoma. Investigation only in the presence of symptoms
- Mammography and possibly MRI of the breast from the age of 30
- No specific screening indicated for GIST. Screening only if symptoms occur.
Neurofibromatosis Type 1 - What You Can Do Yourself
You Should Pay Attention to This
The risk of developing a visual pathway tumor (optic glioma) is highest at the age of 3-4 years (0-6 years). There are typical symptoms that parents may notice as their child’s vision deteriorates. These are
- Manual clumsiness in grasping small things
- Increased bumping on corners and edges
- bruises
- protruding eyeball (proptosis).
If you notice an increase in these signs in your child, please make an appointment with the ophthalmologist, pediatrician, or NF1 outpatient clinic responsible for your child.
The risk of developing MPNST increases in young adulthood. Increased attention is required from puberty onwards:
- Pain that disturbs sleep at night
- Localized neurological changes or loss of function
- Rapid growth of known changes/tumors
- Hard and/or painful neurofibromas of the skin
- Pre-irradiated skin regions
- Known atypical neurofibromas (so-called ANNUBP= Atypical Neurofibromatous Neoplasms of Uncertain Biologic Potential)
- Known high internal neurofibroma burden on whole-body MRI
If you are unsure, please contact your treating doctor or any neurofibromatosis consultation and make an appointment.
Further Information
Neurofibromatosis type 1 is also being researched in our accompanying project Liquid Biopsy, so we encourage patients to register for this in addition to the CPS Registry
Any further questions?
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