Neurofibromatosis

Template:Short description Template:Cs1 config Template:Use dmy dates Template:Infobox medical condition (new) Neurofibromatosis (NF) refers to a group of three distinct genetic conditions in which tumors grow in the nervous system.<ref name="NIH2016">Template:Cite web Template:PD-notice</ref> The tumors are non-cancerous (benign) and often involve the skin or surrounding bone.<ref name="NIH2016" /> Although symptoms are often mild, each condition presents differently. Neurofibromatosis type I (NF1) is typically characterized by café au lait spots (light-brown flat patches of skin), neurofibromas (small bumps in or under the skin), scoliosis (side-way curvature of the back), and headaches.<ref name="Gen2016">Template:Cite webTemplate:PD-notice</ref> Neurofibromatosis type II (NF2), on the other hand, may present with early-onset hearing loss, cataracts, tinnitus, difficulty walking or maintaining balance, and muscle atrophy.<ref name="Gen2016" /> The third type is called schwannomatosis and often presents in early adulthood with widespread pain, numbness, or tingling due to nerve compression.<ref name=Gene2019/>

The cause is a genetic mutation in certain oncogenes.<ref name=NIH2016/> These can be inherited, 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="Woodrow_2015">Template:Cite journal</ref> Neurofibromatosis arise from the supporting cells of the nervous system rather than the neurons themselves.<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">Template:Cite book</ref><ref name="Gene2019">Template:Cite book</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">Template:Cite book</ref> It was formally described by Friedrich Daniel von Recklinghausen in 1882, after whom it was previously named.<ref name="Woodrow_2015" />

Signs and symptoms

File:Lisch nodules.JPG

Lisch nodules as seen in NF1

File:Early neurofibromatosis.jpg

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>Template:Cite web</ref> Signs the individual might have are as follows:<ref>Template:Cite web</ref><ref name="NINDS2">Template:Cite web</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)
• Lisch nodules
• Tumors on the adrenal glands called pheochromocytomas

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">Template:Cite journal</ref> Symptoms may include pain due to pressure on nerves, tinnitus, weakness in fingers, numbness, headaches. The symptom most characteristic of NF2 is hearing loss.<ref>Template:Cite journal</ref> 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" />

• Figure of various morbidities associated with neurofibromatosis type II.<ref name="pmid33445724">Template:Cite journal</ref>
  Figure of various morbidities associated with neurofibromatosis type II.<ref name="pmid33445724">Template:Cite journal</ref>

Cause

File:Autosomal dominant - en.svg

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="Woodrow_2015" /> NF2 is caused by a mutation on the NF2 tumor suppressor gene on chromosome 22.<ref name="Woodrow_2015" /> Schwannomatosis is caused by various mutations on chromosome 22.<ref name="Woodrow_2015" />

Neurofibromatosis is an autosomal dominant disorder, which means only one copy of the affected gene is needed for the disorder to develop.<ref name="Woodrow_2015" /> 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>Template:Cite web</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>Template:Cite web</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>Template:Cite web</ref>
• Schwannomatosis, in which painful schwannomas develop on spinal and peripheral nerves.<ref>Template:Cite book</ref>

Pathophysiology

The pathophysiology is varied, and each NF type has a different one:

• Neurofibromatosis type I is the most common of the three types and is caused by genetic changes in the NF1 gene located on chromosome 17 (17q11.2). This gene encodes a cytoplasmic protein known the neurofibromin, which functions as a tumor suppressor and therefore serves as a signal regulator of cell proliferation and differentiation.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref> 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">Template:Cite journal</ref><ref>Template:Cite journal</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 (22q12).<ref name=":3">Template:Cite journal</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">Template:Cite journal</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">Template:Cite book</ref> The diagnosis of neurofibromatosis is done via the following means:<ref>Template:Cite web</ref>

Differential diagnosis

Conditions similar to NF include:

Treatment

Surgical removal of tumors is an option; however, the risks involved should be assessed first.<ref>Template:Cite web</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>Template:Cite web</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>Template:Cite web</ref>

Prognosis

File:Adam Pearson-64485.jpg

Adam Pearson, a British actor with neurofibromatosis

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 what is believed to be the condition go 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="Woodrow_2015" />

Further reading

• Template:Cite book

External links

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