Neurofibromatosis

Neurofibromatosis
Synonyms	N/A
Pronounce
Field	Neurosurgery
Symptoms	Small lumps within the skin, scoliosis, hearing loss, vision loss<ref name=NIH2016/>
Complications
Onset	Birth to early adulthood<ref name=NIH2016/>
Duration	Life long<ref name=NIH2016/>
Types	Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), schwannomatosis<ref name=NIH2016/>
Causes	Genetic<ref name=NIH2016/>
Risks
Diagnosis	Symptoms, genetic testing<ref name=Gen2016/>
Differential diagnosis
Prevention
Treatment	Surgery, radiation therapy<ref name=Gen2016/>
Medication
Prognosis	NF1: normal life expectancy<ref name=NIH2016/> NF2: shortened life expectancy<ref name=NIH2016/>
Frequency	1 in 3,000 people (United States)<ref name=NIH2016/>
Deaths

Neurofibromatosis (NF) is a group of three conditions in which tumors grow in the nervous system.<ref name="NIH2016">

Neurofibromatosis Fact Sheet(link). NINDS.

3 February 2016.

This article incorporates text from this source, which is in the public domain.</ref> The three types are neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis.<ref name=NIH2016/> In NF1 symptoms include light brown spots on the skin, freckles in the armpit and groin, small bumps within nerves, and scoliosis.<ref name=Gen2016/> In NF2, there may be hearing loss, cataracts at a young age, balance problems, flesh colored skin flaps, and muscle wasting.<ref name=Gen2016>

Learning about Neurofibromatosis(link). National Human Genome Research Institute (NHGRI).

16 August 2016.

This article incorporates text from this source, which is in the public domain.</ref> In schwannomatosis there may be pain either in one location or in wide areas of the body.<ref name=Gene2019/> The tumors in NF are generally non-cancerous.<ref name=NIH2016 />

The cause is a genetic mutation in certain genes.<ref name=NIH2016/> These can be inherited from a person's parents, or in about half of cases spontaneously occur during early development.<ref name=NIH2016/> Different mutations result in the three types of NF.<ref name=Wood2015>,

 Neurofibromatosis, 
 Orthopaedics and Trauma, 
 
 Vol. 29(Issue: 3),
 pp. 206–210,
 DOI: 10.1016/j.mporth.2015.02.004,
 
 
 
 Full text,</ref> The tumors involve the supporting cells of the nervous system rather than the neurons.<ref name=NIH2016/> In NF1 the tumors are neurofibromas (tumors of the peripheral nerves), while in NF2 and schwannomatosis tumors of Schwann cells are more common.<ref name=NIH2016/> Diagnosis is typically based on symptoms, examination, medical imaging, and biopsy.<ref name=Stat2019>, 
 Neurofibromatosis, 
 , 
 
 
 
 
 PMID: 29083784,</ref><ref name=Gene2019>, 
 Schwannomatosis, 
 , 
 
 
 
 
 PMID: 29517885,
 
 
 Full text,</ref> Genetic testing may rarely be done to support the diagnosis.<ref name=Gen2016 />

There is no known prevention or cure.<ref name=NIH2016 /><ref name=Gen2016 /> Surgery may be done to remove tumors that are causing problems or have become cancerous.<ref name=NIH2016 /> Radiation and chemotherapy may also be used if cancer occurs.<ref name=NIH2016 /> A cochlear implant or auditory brainstem implant may help some who have hearing loss due to the condition.<ref name=NIH2016 />

In the United States, about 1 in 3,500 people have NF1 and 1 in 25,000 have NF2.<ref name=NIH2016 /> Males and females are affected equally often.<ref name=Gen2016 /> In NF1, symptoms are often present at birth or develop before 10 years of age.<ref name=NIH2016 /> While the condition typically worsens with time, most people with NF1 have a normal life expectancy.<ref name=NIH2016 /> In NF2, symptoms may not become apparent until early adulthood.<ref name=NIH2016 /> NF2 increases the risk of early death.<ref name=NIH2016/> Descriptions of the condition occur as far back as the 1st century.<ref name = evans>,

 Neurofibromatoses in clinical practice. online version, 
  
 London:Springer, 
  
  
  
 ISBN 978-0-85729-628-3,</ref> It was formally described by Friedrich Daniel von Recklinghausen in 1882, after whom it was previously named.<ref name=Wood2015 />

Signs and symptoms

Lisch nodules as seen in NF1

Person with multiple small neurofibromas in the skin and a "café au lait spot" (bottom of photo, to the right of centre). A biopsy has been taken of one of the lesions.

Neurofibromatosis type 1 in early life may cause learning and behavior problems – about 60% of children who have NF1 have mild difficulty in school.<ref>

Neurofibromatosis(link). NHS Choices. NHS.

</ref> Signs the individual might have are as follows:<ref>

Neurofibromatosis(link). NINDS. NIH.

</ref><ref name="NINDS2">

NINDS Neurofibromatosis Information Page(link). {{{website}}}.

23 February 2015.

</ref>

• Six or more light brown dermatological spots ("café au lait spots")
• At least two neurofibromas
• At least two growths on the eye's iris
• Abnormal growth of the spine (scoliosis)

People with neurofibromatosis type 2 can exhibit the same type of skin symptoms as type 1, but not necessarily in every case.<ref name=":5">Guha, Martin,

 The Gale Encyclopedia of Genetic Disorders (3rd ed.)2011133Edited by Laurie J. Fundukian. The Gale Encyclopedia of Genetic Disorders (3rd ed.). Detroit, MI: Gale 2010. , Template:Text 978 1 4144 7602 5 (print); 978 1 4144 7605 6 (e‐book) $445 (print) 3 vols, 
 Reference Reviews, 
 
 Vol. 25(Issue: 3),
 pp. 40–42,
 DOI: 10.1108/09504121111119022,</ref> The symptom most characteristic of NF2 is hearing loss. The hearing loss occurs due to the pressure of tumors on the acoustic nerve. The same pressure can cause headaches, dizziness, and nausea.<ref name=":5" />

The main symptom of schwannomatosis is localized pain. This pain is due to tissues and nerves experiencing more pressure because of nearby tumors.<ref name=":42"/>

Cause

Diagram of autosomal dominant inheritance pattern.

The three types of Neurofibromatosis are caused by different mutations on chromosomes. NF1 is caused by a mutation on the NF1 gene on the arm of chromosome 17.<ref name=":02">Woodrow, Christopher,

 Neurofibromatosis, 
 Orthopaedics and Trauma, 
 
 Vol. 29(Issue: 3),
 pp. 206–210,
 DOI: 10.1016/j.mporth.2015.02.004,</ref> NF2 is caused by a mutation on the NF2 tumor suppressor gene on chromosome 22.<ref name=":02" /> Schwannomatosis is caused by various mutations on chromosome 22.<ref name=":02" />

Neurofibromatosis is an autosomal dominant disorder, which means only one copy of the affected gene is needed for the disorder to develop.<ref>Woodrow, Christopher,

 Neurofibromatosis, 
 Orthopaedics and Trauma, 
 
 Vol. 29(Issue: 3),
 pp. 206–210,
 DOI: 10.1016/j.mporth.2015.02.004,
 
 
 
 Full text,</ref> If one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. The severity of the parent's condition does not affect the child; the affected child may have mild NF1 even though it was inherited from a parent with a severe form of the disorder.<ref>

Choices, NHS. Neurofibromatosis type 1 - Causes - NHS Choices(link). www.nhs.uk.

</ref> The types of neurofibromatosis are:

• Neurofibromatosis type I, in which the nerve tissue grows tumors (neurofibromas) that may be benign, but may cause serious damage by compressing nerves and other tissues.<ref>

Neurofibromatosis type 1(link). Genetics Home Reference.

5 October 2015.

</ref>

• Neurofibromatosis type II, in which bilateral acoustic neuromas (tumors of the vestibulocochlear nerve or cranial nerve 8 (CN VIII) also known as schwannoma) develop, often leading to hearing loss.<ref>

Neurofibromatosis type 2(link). Genetics Home Reference.

5 October 2015.

</ref>

• Schwannomatosis, in which painful schwannomas develop on spinal and peripheral nerves.<ref>Arie,

 Practical Surgical Neuropathology: A Diagnostic Approach. online version, 
  
 Elsevier Health Sciences, 
  
  
  
 ISBN 978-0443069826,</ref>

Pathophysiology

Neurofibromatosis type I is caused by a mutation on chromosome 17 encoding a cytoplasmic protein known as neurofibromin.<ref>

Orphanet: Neurofibromatosis type 1(link). www.orpha.net.

</ref> This protein is a tumor suppressor and therefore serves as a signal regulator of cell proliferation and differentiation. A dysfunction or lack of neurofibromin can affect regulation, and cause uncontrolled cell proliferation, leading to the tumors (neurofibromas) that characterize NF1. The neurofibromas caused by NF consist of Schwann cells, fibroblasts, perineuronal cells, mast cells and axons embedded in an extracellular matrix.<ref name=":2">Ferner, Rosalie E.,

 Neurofibromatosis 1, 
 European Journal of Human Genetics, 
 
 Vol. 15(Issue: 2),
 pp. 131–138,
 DOI: 10.1038/sj.ejhg.5201676,
 PMID: 16957683,</ref><ref>, 
 Neurofibromatosis type 1, 
 Journal of the American Academy of Dermatology, 
 
 Vol. 61(Issue: 1),
 pp. 1–14,
 DOI: 10.1016/j.jaad.2008.12.051,
 PMID: 19539839,
 PMC: 2716546,</ref> Another function of neurofibromin is to bind to microtubules that play a role in the release of adenylyl cyclase and its activity.<ref name=":2" /> Adenylyl cyclase plays an essential role in cognition.<ref name=":2" /> Neurofibromin's role in the activity of adenylyl cyclase explains why patients with NF experience cognitive impairment.<ref name=":2" />

Neurofibromatosis type II is caused by a mutation on chromosome 22.<ref name=":3">Lin, Andrew,

 Advances in the treatment of neurofibromatosis-associated tumours, 
 Nature Reviews Clinical Oncology, 
 
 Vol. 10(Issue: 11),
 pp. 616–24,
 DOI: 10.1038/nrclinonc.2013.144,
 PMID: 23939548,
 
 
 Full text,</ref> The mutation falls on the NF2 tumor suppressor gene.<ref name=":3" /> The gene normally encodes a cytoplasmic protein known as merlin. The normal function of merlin is to regulate the activity of multiple growth factors, the mutated copy of the gene leads to merlin's loss of function.<ref name=":3" /> The loss of function leads to increased activity of growth factors normally regulated by merlin, leading to the formation of the tumors associated with NF2.<ref name=":3" />

Schwannomatosis is caused by a mutation on the SMARCB1 gene.<ref name=":42">Plotkin, Scott R.,

 Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria, 
 American Journal of Medical Genetics Part A, 
 
 Vol. 161(Issue: 3),
 pp. 405–416,
 DOI: 10.1002/ajmg.a.35760,
 PMID: 23401320,
 PMC: 4020435,</ref> This gene is located near the NF2 tumor suppressor gene leading to the thought that schwannomatosis and NF2 were the same condition. The two conditions show different mutations on two different genes. The normal function of the SMARCB1 gene is to encode a protein called SMARCB1 that is part of a larger protein complex whose function is not completely understood.<ref name=":42" /> The complex including SMARCB1 plays a role in tumor suppression.<ref name=":42" /> The mutation of the SMARCB1 gene causes a loss of function in the complex leading to the formation of tumors indicative of schwannomatosis.<ref name=":42" />

Diagnosis

The neurofibromatoses are considered as RASopathies and as members of the neurocutaneous syndromes (phakomatoses).<ref name=ka>,

 Master the Board USMLE Step 2 CK, 
  
 KAPLAN Medical, 
 2010, 
  
  
 ISBN 978-1-60714-653-7,</ref>

The diagnosis of neurofibromatosis is done via the following means:<ref>

Neurofibromatosis. What is neurofibromatosis? Type 1 (NF1) | Patient(link). Patient.

</ref>

Differential diagnosis

Conditions similar to NF include: ^{(April 2018)}

Treatment

Surgical removal of tumors is an option; however, the risks involved should be assessed first.<ref> Choices, NHS. Neurofibromatosis type 2 - Treatment - NHS Choices(link). www.nhs.uk.

</ref> With regard to OPG (optic pathway gliomas), the preferred treatment is chemotherapy. However, radiotherapy is not recommended in children who present with this disorder.<ref>

Complex Neufibrmatosis type 1(link). NHS.uk. NHS.

</ref> It is recommended that children diagnosed with NF1 at an early age have an examination each year, which allows any potential growths or changes related to the disorder to be monitored.<ref> Choices, NHS. Neurofibromatosis type 1 - Treatment - NHS Choices(link). www.nhs.uk.

</ref>

Prognosis

In most cases, symptoms of NF1 are mild, and individuals live normal and productive lives. In some cases, however, NF1 can be severely debilitating and may cause cosmetic and psychological issues. The course of NF2 varies greatly among individuals. In some cases of NF2, the damage to nearby vital structures, such as other cranial nerves and the brain stem, can be life-threatening. Most individuals with schwannomatosis have significant pain. In some extreme cases the pain will be severe and disabling.<ref name="NINDS2"/>

Epidemiology

In the United States, about 1 in 3,500 people have NF1, 1 in 25,000 have NF2, and 1 in 40,000 have schwannomatosis.<ref name="NIH2016" /> Males and females are affected equally often in all three conditions.<ref name="Gen2016" /> In NF1, symptoms are often present at birth or develop before 10 years of age.<ref name="NIH2016" /> While the condition typically worsens with time, most people with NF1 have a normal life expectancy.<ref name="NIH2016" /> In NF2, symptoms may not become apparent until early adulthood.<ref name="NIH2016" /> NF2 increases the risk of early death.<ref name="NIH2016" /> Schwannomatosis symptoms develop in early childhood and can worsen with time. Typically life expectancy is unaffected in those with schwannomatosis.<ref name="Gene2019" />

History

Descriptions of the condition occur as far back as the 1st century.<ref name = evans/> The conditions were formally described by Friedrich Daniel von Recklinghausen in 1882, after whom it was previously named.<ref name="Wood2015" />

References

Further reading

• Meena,

 Neurofibromatosis Type 1: Molecular and Cellular Biology. online version, 
  
 Springer Science & Business Media, 
  
  
  
 ISBN 9783642328640,

External links

• National Institute of Neurological Disorders and Stroke - information on Neurofibromatosis