What is neurofibromatosis type 1?

Neurofibromatosis type 1 (NF1), also called Recklinghausen’s disease, is a genetic – or hereditary – disease that manifests (becomes evident) already during childhood, and affects various organs in very different ways. NF1 is a disease that requires coordinated care from doctors of different specialist disciplines. What is characteristic of people with NF1 is the development of tumors, usually benign nerve sheath tumors, called neurofibromas, although the risk of malignant tumors is also higher. NF1 is therefore classified as a tumor predisposition disease.

How is neurofibromatosis type 1 diagnosed?

NF1 can be clinically diagnosed on the basis of the following criteria, the development of which depends on age. At least two of the criteria need to be met.

Diagnostic Criteria for NF1

  • 6 or more café au lait spots (irregularly limited latte-colored spots at skin level), with the largest diameter > 5 mm before puberty and > 15 mm after puberty

  • 2 or more neurofibromas of any kind or a plexiform neurofibroma (benign nerve sheath tumors)

  • Freckling (freckle-like skin fold mottling in the armpit and/or groin region)

  • Optic nerve tumor (optic glioma, tumor along the optic nerve)

  • 2 or more Lisch nodules (benign changes in the iris)

  • Typical bone changes (sphenoidal wing dysplasia, tibial pseudarthrosis)

  • An NF1 first-degree relative (parent, child)

If only skin features typical of NF1 are present, there is still a certain amount of uncertainty concerning the diagnosis that will need to be resolved by a genetic examination.

The probability of developing neurofibromas of the skin (small, benign nerve sheath tumors) is nearly 100%. It is impossible to predict how many and how large they will be. It can sometimes happen that a known neurofibroma will suddenly change by starting to cause pain, growing faster, or feeling different. This will then need to be explored further, such as with an MRI and/or by taking a sample. The reason for this is that there is a risk that neurofibromas will progress and lead to the development of malignant peripheral nerve sheath tumors (MPNST).

Other Clinical Features

There is a wide variety of clinical symptoms, the development of which depends on age. Listed below are both the primary skin-related symptoms such as café-au-lait spots and neurofibromas (see the diagnostic criteria) as well as other findings:

  • Macrocephaly (large head)

  • Dwarfism (short stature)

  • Non-ossifying fibromas

  • Scoliosis (spinal curvature)

  • Osteoporosis

  • Vertebral scalloping

  • Rib penciling (thinning of the ribs, visible on the X-ray)

  • High blood pressure

  • Changes in the blood vessels

  • Learning difficulties

What is the risk of cancer?

Even though the risk of developing a malignant disease usually is not something that individual patients with neurofibromatosis worry about on a daily basis, this risk is nevertheless higher compared to that of the general population. The following tumors occur more frequently with NF1:

  • Malignant peripheral nerve sheath tumors (MPNST) usually develop from plexiform or deeper lying neurofibromas; the lifetime risk is between 8% and 12%.

  • Optic nerve tumors, called optic gliomas, are pilocytic astrocytomas that only require treatment if symptoms manifest. The peak time of onset is between 0-6 years of age. The risk of developing an optic glioma is around 15%.

  • High-grade CNS tumors (brain stem gliomas) are rare (< 1%), yet they are often observed together with optic gliomas.

  • JMML = juvenile myelomonocytic leukemia. This is a particularly rare form of leukemia, or blood cancer. The risk of developing it is 1:300.

  • Embryonal rhabdomyosarcoma (ERMS) is a soft tissue tumor that usually occurs 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, which are small, painful nodules in the fingertips.

  • A gastrointestinal stromal tumor (GIST) is a malignant tumor of the gastrointestinal tract. The risk of developing this kind of tumor is 2%.

  • For breast cancer, the risk is 4-5 times higher, with a moderate lifetime risk of 20%.

What causes neurofibromatosis type 1?

Neurofibromatosis is a genetic disease caused by a mutation, i.e. a change in the genetic material. The affected gene encodes for neurofibromin, which is a protein important for suppressing tumors. In other words, it counteracts the development of tumors. For this reason, the risk of cancer goes up when neurofibromin is lacking.

With around 1 in 3000 people affected, NF1 is the most common type of neurofibromatosis. Around half of the cases are passed down by parents to their children; heredity is therefore autosomal dominant. Penetrance is nearly complete; in other words, the disease always manifests with clinical symptoms, though without a good genotype-phenotype correlation. This means that the symptoms of the disease may be very different even within a family that has the same mutation. It is therefore impossible to predict the severity of the disease. The other half of the cases are due to a spontaneous or new mutation, called a de novo mutation.

In addition, there is also segmental NF1, where the disease is restricted to just a certain part of the body, such as a leg. This is also called a mosaic form of NF1. In such cases, the mutation does not affect all of the cells in the body, but only some. This means that healthy and affected cells are found side-by-side.

A genetic examination is generally possible and is recommended to confirm the diagnosis, especially in children, in whom the disease is only apparent through the characteristic skin changes. The mutation can be found with a clinically confirmed diagnosis in 95% of those affected. If this is not the case, it is recommended to conduct further genetic diagnostics to check for the presence of a disease similar to NF1.

Is there a treatment?

Treatment is orientated towards the symptoms. Any complaints or complications that develop are treated. It is necessary to consider chemotherapy if an optic glioma causes vision loss and/or protrusion of the eyeball. Radiation should not be regarded as an option. Currently, a new treatment option using what are called MEK inhibitors (selumetinib and cobimetinib) for inoperable plexiform neurofibromas is receiving a lot of attention. However, these drugs have not yet been approved in Germany for this diagnosis.

Please ask the doctor who is treating you whether there are open clinical studies in which you could take part.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

The goal is to detect developing complications early on in order to achieve the best possible treatment results. To this end, regular visits to the doctor are recommended:

Examination recommendations from AACR 2016

  • Following diagnosis, molecular genetic testing to verify or confirm the diagnosis

  • Annual clinical checkup with a medical history and clinical examination. The main focus is on the skin and neurological changes, blood pressure measurement (to rule out renal artery stenosis and pheochromocytoma), and a developmental assessment of size, weight, and puberty stage.

  • Every 6-12 months, supplementary ophthalmological examinations until the age of 8 (vision, visual fields, pupillary reflexes, fundus) and then once or twice a year until the age of 20

  • One-time examination to check for color vision and visual fields as soon as the child’s development allows

  • If available, OCT (optical coherence tomography) at every ophthalmological examination

  • A checkup is recommended after 2 weeks when there is a loss of vision during screening to rule out other causes (refractive error, cataract); an MRI is justified if findings are confirmed.

  • Annual physical examination for MPNST, which are rapidly growing and/or painful, non-dermal neurofibromas that can lead to neurological deficits and the loss of function and/or exhibit changes in quality)

  • During the transition to young adulthood (between the ages of 16 and 20), it is worth considering a whole-body MRI, as it is well known that there is a higher risk of developing MPNST if there are a lot of internal tumors.

  • Patient education concerning the fact that the risk of developing breast cancer is 4-5 times as high; offer of breast screening for women 30-50 years of age

  • During adulthood, annual checkups with blood pressure measurement and access to all special outpatient clinics depending on the health problems

  • No routine MRI if there are no symptoms

Self-Care and Support

What should I pay special attention to?

The risk of developing an optic nerve tumor (optic glioma) is greatest at 3-4 years of age (0-6 years). There are typical symptoms that parents can observe if their child is suffering from increasing visual impairment, namely:

  • Clumsiness when grabbing small objects

  • Increasingly striking against corners and edges, bruises

  • Protrusion of the eyeball (proptosis)

If you see these signs increasing in your child, please set up an appointment with your attending ophthalmologist or pediatrician or at a special NF1 clinic.

The risk of developing MPNST increases in early adulthood. Increased attentiveness is needed starting in puberty:

  • Pain that disturbs sleep at night

  • Local neurological changes or a loss of function

  • Rapid growth of known changes/tumors

  • Hard and/or painful neurofibromas of the skin

  • Skin areas previously exposed to radiation

  • Known atypical neurofibromas (called ANNUBP = atypical neurofibromatous neoplasms of uncertain biologic potential)

  • Known high number of internal neurofibromas in the full-body MRI

Please contact the doctor who is treating you or any neurofibromatosis center and set up an appointment if there are any uncertainties.

Support Groups and Additional Information