Course:MEDG550/Student Activities/Neurofibromatosis

Neurofibromatosis (NF) is a genetic condition that affects multiple tissues and organs throughout the body. There are three main types of NF: Neurofibromatosis Type 1, Neurofibromatosis Type 2 and schwannomatosis. All three are characterized by the growth of tumours that, while non-cancerous, can cause significant medical problems for people living with the condition.

Clinical Features

Neurofibromatosis type 1 (NF1)

About 1 in every 3,000 people is born with NF1. The condition is highly variable in terms of its symptoms and severity, ranging from very mildly to severely affected. Features can include:

• Freckling and darker patches of skin, known as café au lait spots
• Benign tumours called neurofibromas (in adults)
• Benign tumours, known as optic gliomas, that grow along the optic nerve and can lead to vision impairment
• Benign growths, known as Lisch nodules, in the irises of the eyes
• Normal intelligence, but learning disabilities
• Features of autism spectrum disorder
• High blood pressure
• Short stature
• A larger than typical head size
• Skeletal abnormalities such as scoliosis

Café au lait spots can be present from birth and the other features of NF1 will typically be seen by about 8 years of age. The age at diagnosis largely depends on if there is a family history of NF1, in which case the diagnosis can typically be made earlier.

Neurofibromatosis type 2 (NF2)

Schwannoma in NF2. From https://en.wikipedia.org/wiki/Vestibular_schwannoma, Creative Commons License: https://commons.wikimedia.org/wiki/File:Akustikusneurinom_Mrt.jpg

About 1 in every 33,000 people is born with NF2. Its main features include:

• Benign tumours, known as schwannomas, on the nerves that transmit sound into the brain (vestibular nerve)
• Tinnitus, progressive hearing loss, and/or poor balance
• Schwannomas on other nerves in the central and peripheral nervous system
• Cloudy areas on the lenses of the eyes

The average age of onset of NF2 ranges from 18-24 years, with almost all affected individuals developing schwannomas by 30 years of age.

Schwannomatosis

Schwannomatosis is characterized by benign tumours of the skin and schwannomas on the spinal cord, without the tumours on auditory nerves and hearing loss that are characteristic of NF2. The prevalence of this condition is unknown, but it is believed to be much less common than NF1 or NF2.

Genetics

The three types of neurofibromatosis are all caused by mutations (changes) in genes called tumour suppressors. These genes are involved in controlling cell division, and when they are not functioning properly, cells begin to divide uncontrollably creating tumours.

Genetics of NF1

NF1 is caused by mutations in the neurofibromin 1 (NF1) gene . The condition is inherited in an autosomal dominant manner, meaning that a person only needs one mutated copy of the NF1 gene to develop the disease. The loss of a working copy of NF1 leads to the growth of the benign tumours that are characteristic of NF1. About half of NF1 cases are inherited, meaning that one of an affected person's parents also has a mutated copy of "NF1" and half are due to new, random mutations, making that person the first in their family to have NF1. NF1 is considered to be fully penetrant, meaning that anyone who inherits the mutation will go on to develop the disease.

Genetics of NF2

NF2 is caused by mutations in the neurofibromin 2 (NF2) gene . As with NF1, it can be inherited in an autosomal dominant manner, but half of cases are caused by random mutations. It is also fully penetrant.

Genetics of Schwannomatosis

The genetics of schwannomatosis are complex and not fully understood. The condition can be caused by mutations in the SMARCB1 gene. Some tumours in people with schwannomatosis also contain mutations in NF2, but these mutations are not thought to be responsible for forms of the condition that run in families. The condition is not considered to be fully penetrant. There is no genetic test for schwannomatosis.

Diagnosis

All three types of neurofibromatosis are typically diagnosed by a medical exam, while keeping in mind the individual's family history . The U.S. National Institutes of Health (NIH) has established diagnostic criteria for both NF1 and NF2 . Even though there are genetic tests available for NF1, it isn't necessary to identify a mutation to diagnose the condition in a patient. However, genetic testing may be offered to people who are suspected to have the condition, but who do not meet the NIH’s diagnostic criteria . Several groups have proposed clinical diagnostic criteria for NF2, however genetic testing plays an important role in definitively identifying people with this condition . Because both NF2 and schwannomatosis are characterized by the presence of schwannomas, medical imaging techniques such as MRI play an important role in diagnosing and distinguishing the two syndromes. A diagnosis of schwannomatosis is only made after NF2 has been ruled out. .

Treatment

There is currently no cure for NF, however, patients with NF may require a wide range treatments to manage their condition. For example, patients may need surgical removal of painful or disfiguring neurofibromas, chemotherapy to prevent the progression of optic tumours, or surgery to correct skeletal problems such as scoliosis. While there are no universally-accepted surveillance guidelines for NF1, it is generally recommended that patients have annual medical exams with a physician who is familiar with NF1 to monitor their symptoms.

The management and surveillance recommendations for NF2 and schwannomatosis are very similar. Surgical removal of schwannomas is the primary form of treatment. People with NF2 also need regular hearing tests and may require treatment for hearing loss due to growth of schwannomas on auditory nerves. People with schwannomatosis sometime require pain management. Regular MRI scans are recommended for people living with NF2 or schwannomatosis.

Genetic Counselling

As mentioned above, about 50% of all cases of NF1 are inherited, and the other half occur due to random mutations. If a patient has a parent with NF1 (i.e. if they inherited their NF1 mutation from their mother or father), then each of the patient’s full siblings will have a 50% chance of having NF1 as well. If neither parent has the condition, there is still a very small risk that they could have another child with NF1, due to a phenomenon known as germline mosaicism (when some of an unaffected person's gonads (sperm or egg cells) carry the NF1 mutation). The same risks would apply to a family living with NF2. Even when the specific mutation is known, it is difficult to predict how severe the disease will be, therefore, even within a family, the features of NF can very dramatically from person to person.

If a person with NF1 or NF2 decides to have children, each child will have a 50% chance of inheriting the condition. If the mutation in the family has been identified, the affected individuals can choose to have in vitro fertilization with preimplantation genetic diagnosis to select an embryo that doesn't have the NF-causing mutation . Although prenatal testing is possible for both NF1 and NF2, it is generally not offered for NF1 because the severity of the condition is highly variable and difficult to predict .

Because we don’t know as much about the genetics of schwannomatosis, genetic counselling for this condition is challenging. For people with schwannomatosis who have a family history of the disease, the risk that they will pass the condition on to their child can be up to 50%. However, for affected individuals with no family history of the condition, it is estimated that there is about a 15% chance they will pass the condition on to their child. No preimplantation genetic diagnosis or prenatal testing are available for this condition.

A genetic counsellor may be able to help determine if your NF is inherited or a result of a new mutation. Inherited mutations may also have implications for other member of your family. A genetic counsellor will be able to answer your questions about NF, including risks to your children and other family members. They will also be able to provide support and information after a new diagnosis and talk to you about testing options.

Resources

BC Neurofibromatosis Foundation http://www.bcnf.bc.ca/

Children’s Tumor Foundation: Ending NF Through Research http://www.ctf.org/

Kids Health NF Page http://kidshealth.org/en/parents/nf.html

NF Network http://www.nfnetwork.org/understanding-nf/what-is-nf

Canadian Association of Genetic Counsellors- Find a clinic page https://www.cagc-accg.ca/?page=225

National Society of Genetic Counselors- Find a genetic counselor page http://nsgc.org/p/cm/ld/fid=164

References

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Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number:16220: 6/27/2014. World Wide Web URL: http://www.omim.org/entry/162200

Evans D. G. Neurofibromatosis 2. 1998 Oct 14 [Updated 2011 Aug 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1201/

Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 101000: 10/1/2012. World Wide Web URL: http://www.omim.org/entry/101000

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Rad, E. & Tee, A. R. (2016) Neurofibromatosis type 1: Fundamental insights into cell signalling and cancer. Seminars in Cell & Developmental Biology, Available online 6 February 2016.

MacCollin, M., et al. (2005) Diagnostic criteria for schwannomatosis. Neurology, 64, 11, 1838-1845.

Baser, M. E., et al. (2002) Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology , 59, 11, 1759-1765.