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Neurofibromatosis (NF) refers to a group of three distinct genetic conditions in which
tumors A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
grow in the
nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...
. The tumors are non-cancerous (
benign Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
) and often involve the skin or surrounding bone. 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 Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...
(side-way curvature of the back), and
headaches A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Head ...
. Neurofibromatosis type II (NF2), on the other hand, may present with early-onset
hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spo ...
,
cataract A cataract is a cloudy area in the lens (anatomy), lens of the eye that leads to a visual impairment, decrease in vision of the eye. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colours, blurry or ...
s,
tinnitus Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...
, difficulty walking or maintaining balance, and
muscle atrophy Muscle atrophy is the loss of skeletal muscle mass. It can be caused by immobility, aging, malnutrition, medications, or a wide range of injuries or diseases that impact the musculoskeletal or nervous system. Muscle atrophy leads to muscle weakne ...
. The third type is called
schwannomatosis Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF). Originally described in Japanese patients, it consists of multiple cutaneous schwannomas, central nervous system tumors, ...
and often presents in early adulthood with widespread pain, numbness, or tingling due to nerve compression. The cause is a
genetic mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis ...
in certain
oncogenes An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
. These can be inherited, or in about half of cases spontaneously occur during early development. Different mutations result in the three types of NF. Neurofibromatosis arise from the supporting cells of the nervous system rather than the
neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
themselves. In NF1, the tumors are neurofibromas (tumors of the peripheral nerves), while in NF2 and schwannomatosis tumors of Schwann cells are more common. Diagnosis is typically based on symptoms, examination,
medical imaging Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to revea ...
, and
biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...
.
Genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
may rarely be done to support the diagnosis. There is no known prevention or cure. Surgery may be done to remove tumors that are causing problems or have become cancerous.
Radiation In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or a material medium. This includes: * ''electromagnetic radiation'' consisting of photons, such as radio waves, microwaves, infr ...
and
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
may also be used if cancer occurs. A
cochlear implant A cochlear implant (CI) is a surgically implanted Neuroprosthetics, neuroprosthesis that provides a person who has moderate-to-profound sensorineural hearing loss with sound perception. With the help of therapy, cochlear implants may allow for imp ...
or auditory brainstem implant may help some who have hearing loss due to the condition. In the United States, about 1 in 3,500 people have NF1 and 1 in 25,000 have NF2. Males and females are affected equally often. In NF1, symptoms are often present at birth or develop before 10 years of age. While the condition typically worsens with time, most people with NF1 have a normal life expectancy. In NF2, symptoms may not become apparent until early adulthood. NF2 increases the risk of early death. Descriptions of the condition occur as far back as the 1st century. It was formally described by Friedrich Daniel von Recklinghausen in 1882, after whom it was previously named.


Signs and symptoms

Neurofibromatosis type 1 in early life may cause learning and
behavior Behavior (American English) or behaviour (British English) is the range of actions of Individual, individuals, organisms, systems or Artificial intelligence, artificial entities in some environment. These systems can include other systems or or ...
problems – about 60% of children who have NF1 have mild difficulty in school. Signs the individual might have are as follows: * 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 Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...
) * 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. Symptoms may include pain due to pressure on nerves,
tinnitus Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...
, weakness in fingers, numbness, headaches. 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. The main symptom of schwannomatosis is localized pain. This pain is due to tissues and nerves experiencing more pressure because of nearby tumors. File:Neurofibromatosis type II tumor types.png, Figure of various morbidities associated with neurofibromatosis type II.


Cause

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. NF2 is caused by a mutation on the NF2 tumor suppressor gene on chromosome 22. Schwannomatosis is caused by various mutations on chromosome 22. Neurofibromatosis is an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
disorder, which means only one copy of the affected
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
is needed for the disorder to develop. 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. The types of neurofibromatosis are: *
Neurofibromatosis type I Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system neurocutaneous disorder caused by a subset of genetic mutations at the neurofibromin 1 (''NF1'') locus. Other conditions associated with mutation of the ...
, in which the nerve tissue grows tumors (neurofibromas) that may be benign, but may cause serious damage by compressing nerves and other tissues. * 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. *
Schwannomatosis Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF). Originally described in Japanese patients, it consists of multiple cutaneous schwannomas, central nervous system tumors, ...
, in which painful schwannomas develop on spinal and peripheral nerves.


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 A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
and therefore serves as a signal regulator of
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. 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. Another function of neurofibromin is to bind to microtubules that play a role in the release of
adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...
and its activity. Adenylyl cyclase plays an essential role in cognition. Neurofibromin's role in the activity of adenylyl cyclase explains why patients with NF experience cognitive impairment. * Neurofibromatosis type II is caused by a mutation on chromosome 22 (22q12). The mutation falls on the NF2 tumor suppressor gene. The gene normally encodes a cytoplasmic protein known as
merlin The Multi-Element Radio Linked Interferometer Network (MERLIN) is an interferometer array of radio telescopes spread across England. The array is run from Jodrell Bank Observatory in Cheshire by the University of Manchester on behalf of UK Re ...
. 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. 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. * Schwannomatosis is caused by a mutation on the
SMARCB1 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 is a protein that in humans is encoded by the ''SMARCB1'' gene. Function The protein encoded by this gene is part of a complex that relieves repress ...
gene. 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. The complex including SMARCB1 plays a role in tumor suppression. The mutation of the SMARCB1 gene causes a loss of function in the complex leading to the formation of tumors indicative of schwannomatosis.


Diagnosis

The neurofibromatoses are considered as RASopathies and as members of the '' neurocutaneous syndromes'' (''phakomatoses''). The diagnosis of neurofibromatosis is done via the following means:


Differential diagnosis

Conditions similar to NF include:


Treatment

Surgical removal of tumors is an option; however, the risks involved should be assessed first. With regard to OPG (optic pathway gliomas), the preferred treatment is chemotherapy. However, radiotherapy is not recommended in children who present with this disorder. 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.


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 Psychology is the scientific study of mind and behavior. Its subject matter includes the behavior of humans and nonhumans, both consciousness, conscious and Unconscious mind, unconscious phenomena, and mental processes such as thoughts, feel ...
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 Cranial nerves are the nerves that emerge directly from the brain (including the brainstem), of which there are conventionally considered twelve pairs. Cranial nerves relay information between the brain and parts of the body, primarily to and f ...
and the
brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...
, can be life-threatening. Most individuals with schwannomatosis have significant pain. In some extreme cases, the pain will be severe and disabling.


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. Males and females are affected equally often in all three conditions. In NF1, symptoms are often present at birth or develop before 10 years of age. While the condition typically worsens with time, most people with NF1 have a normal life expectancy. In NF2, symptoms may not become apparent until early adulthood. NF2 increases the risk of early death. Schwannomatosis symptoms develop in early childhood and can worsen with time. Typically life expectancy is unaffected in those with schwannomatosis.


History

Descriptions of what is believed to be the condition go as far back as the 1st century. The conditions were formally described by Friedrich Daniel von Recklinghausen in 1882, after whom it was previously named.


References


Further reading

*


External links


National Institute of Neurological Disorders and Stroke - information on Neurofibromatosis
{{Authority control Genodermatoses PNS neoplasia Wikipedia medicine articles ready to translate