Neurofibromatosis type I
Encyclopedia
Neurofibromatosis
type I (NF-1), formerly known as von Recklinghausen
disease after the researcher (Friedrich Daniel von Recklinghausen) who first documented the disorder, is a human genetic disorder
. It is possibly the most common inherited disorder caused by a single gene. NF-1 is not to be confused with Proteus Syndrome
(the syndrome which may have affected The Elephant Man
), but rather is a separate disorder. It is a RASopathy
. In diagnosis it may also be confused with Legius syndrome
.
on chromosome
17 that is responsible for control of cell division.
NF-1 causes non-cancerous lumps. NF-1 often comes with scoliosis (curvature of the spine), learning difficulties, eye problems, and epilepsy.
of a gene
on the long arm of chromosome 17 which encodes a protein known as neurofibromin
(not to be confused with the disorder itself) which plays a role in cell signaling
. The Neurofibromin 1
gene is a negative regulator of the Ras oncogene
signal transduction
pathway. It stimulates the GTPase
activity of Ras. It shows greater affinity
for RAS p21 protein activator 1
, but lower specific activity. The mRNA
for this gene is subject to RNA editing
(CGA
->UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants
encoding different isoforms
have also been described for this gene.
The mutant gene is transmitted with an autosomal dominant pattern of inheritance, but up to 50% of NF-1 cases arise due to spontaneous mutation. The incidence of NF-1 is about 1 in 3500 live births.
and Watson syndrome
. A condition with a separate gene mutation but similar Café au lait spot
s is Legius syndrome
which has a mutation on the SPRED1 gene
.
Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase Activating Protein (GAP) Family. This homologous sequence is in the central portion of neurofibromin and being similar to the GAP family is recognized as a negative regulator of the Ras kinase.
Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein adenylyl cyclase
, and a second with collapsin response mediator protein
. Together, likely with domains yet to be discovered, neurofibromin regulates many of the pathways responsible for overactive cell proliferation, learning impairments, skeletal defects and plays a role in neuronal development.
, it is possible via preimplantation genetic diagnosis
to screen for NF-1.
For many NF-1 patients, a primary concern is the disfigurement caused by cutaneous/dermal neurofibromas, pigmented lesions, and the occasional limb abnormalities.
However, there are many more severe complications caused by NF-1, but some of them are quite rare and they are listed in the following section.
There is no cure for the disorder itself. Instead, people with neurofibromatosis are followed by a team of specialists to manage symptoms or complications. In progress and recently concluded medical studies on NF-1 can be found by searching the official website of the National Institute of Health.
The St. Louis Children's Hospital Neurofibromatosis Center maintains a comprehensive list of current NF research studies.
Skull
Spine
Cutaneous conditions
Neurobehavioral developmental disorder
The most common complication in patients with NF-1 is cognitive and learning disability. These cognitive problems have been shown to be present in approximately 80% of children with NF-1 and have significant effects on their schooling and everyday life. These cognitive problems have been shown to be stable into adulthood and do not get worse unlike some of the other physical symptoms of NF-1. The most common cognitive problems are with perception, executive functioning and attention. Disorders include:
Nervous system disease
The primary neurologic involvement in NF-1 is of the peripheral nervous system, and secondarily of the central nervous system.
Neurofibroma
A neurofibroma
is a lesion of the peripheral nervous system. Its cellular lineage is uncertain, and may derive from Schwann cells, other perineural cell lines, or fibroblasts. Neurofibromas may arise sporadically, or in association with NF-1. A neurofibroma may arise at any point along a peripheral nerve. A number of drugs have been studied to treat this condition.
Neurofibroma conditions are progressive and include:
Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system, primarily:
Another CNS manifestation of NF-1 is the so-called "unidentified bright object" or UBO, which is a lesion which has increased signal on a T2 weighted sequence of a magnetic resonance imaging
examination of the brain. These UBOs are typically found in the Cerebral peduncle
, pons, midbrain, globus pallidus, thalamus, and optic radiations. Their exact identity remains a bit of a mystery since they disappear over time (usually, by age 16), and they are not typically biopsied or resected. They may represent a focally degenerative bit of myelin
.
Within the CNS, NF-1 manifests as a weakness of the dura
, which is the tough covering of the brain and spine. Weakness of the dura leads to focal enlargement terms dural ectasia
due to chronic exposure to the pressures of CSF
pulsation.
Acetazolamide
has shown promise as a treatment for this condition.
, antidepressants and cognitive behavioral therapy.
Cancer
Cancer can arise in the form of Malignant peripheral nerve sheath tumor
resulting from malignant degeneration of a plexiform neurofibroma.
Neurofibromatosis
Neurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...
type I (NF-1), formerly known as von Recklinghausen
Friedrich Daniel von Recklinghausen
Friedrich Daniel von Recklinghausen was a German pathologist who practiced medicine in Würzburg and Strassburg . Born in Gütersloh, Westphalia, he was the father of physiologist Heinrich von Recklinghausen ....
disease after the researcher (Friedrich Daniel von Recklinghausen) who first documented the disorder, is a human genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
. It is possibly the most common inherited disorder caused by a single gene. NF-1 is not to be confused with Proteus Syndrome
Proteus syndrome
Proteus syndrome, also known as Wiedemann's syndrome , is a congenital disorder that causes skin overgrowth and atypical bone development, often accompanied by tumors over half the body....
(the syndrome which may have affected The Elephant Man
Joseph Merrick
Joseph Carey Merrick , sometimes incorrectly referred to as John Merrick, was an English man with severe deformities who was exhibited as a human curiosity named the Elephant Man. He became well known in London society after he went to live at the London Hospital...
), but rather is a separate disorder. It is a RASopathy
RASopathy
The RASopathies are developmental syndromes caused by germline mutations in genes that alter the Ras subfamily and Mitogen-activated protein kinase that control Signal transduction, including:*Capillary malformation-AV malformation syndrome...
. In diagnosis it may also be confused with Legius syndrome
Legius syndrome
Legius syndrome is an autosomal dominant condition characterized by cafe au lait spots. It is often mistaken for Neurofibromatosis type I . It is caused by mutations in the SPRED1 gene. It is also known as Neurofibromatosis Type 1-like syndrome .The syndrome is named after Eric Legius,...
.
Simple explanation
NF-1 is a tumor disorder that is caused by the malfunction of a geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
on chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
17 that is responsible for control of cell division.
NF-1 causes non-cancerous lumps. NF-1 often comes with scoliosis (curvature of the spine), learning difficulties, eye problems, and epilepsy.
The neurofibromin 1 gene
NF-1 is caused by a mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of a gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
on the long arm of chromosome 17 which encodes a protein known as neurofibromin
Neurofibromin 1
Neurofibromin 1 also known as neurofibromatosis-related protein NF-1 is a protein that in humans is encoded by the NF1 gene. Mutations in the NF1 gene are associated with neurofibromatosis type I .- Function :NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the...
(not to be confused with the disorder itself) which plays a role in cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
. The Neurofibromin 1
Neurofibromin 1
Neurofibromin 1 also known as neurofibromatosis-related protein NF-1 is a protein that in humans is encoded by the NF1 gene. Mutations in the NF1 gene are associated with neurofibromatosis type I .- Function :NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the...
gene is a negative regulator of the Ras oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathway. It stimulates the GTPase
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
activity of Ras. It shows greater affinity
Chemical affinity
In chemical physics and physical chemistry, chemical affinity is the electronic property by which dissimilar chemical species are capable of forming chemical compounds...
for RAS p21 protein activator 1
RAS p21 protein activator 1
RAS p21 protein activator 1 or RasGAP , also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:...
, but lower specific activity. The mRNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
for this gene is subject to RNA editing
RNA editing
The term RNA editing describes those molecular processes in which the information content in an RNA molecule is altered through a chemical change in the base makeup. To date, such changes have been observed in tRNA, rRNA, mRNA and microRNA molecules of eukaryotes but not prokaryotes...
(CGA
Chorionic gonadotropin alpha
Glycoprotein hormones alpha chain is a protein that in humans is encoded by the CGA gene.-Further reading:...
->UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
encoding different isoforms
Protein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
have also been described for this gene.
Inheritance and spontaneous mutation
Related medical conditions
Mutations in the NF1 gene have been linked to NF-1, Juvenile myelomonocytic leukemiaJuvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia is a serious chronic leukemia that affects children mostly aged 4 and younger. The average age of patients at diagnosis is 2 years old. The World Health Organization has included JMML in the category of Myelodysplastic and Myeloproliferative disorders...
and Watson syndrome
Watson syndrome
Watson syndrome is an autosomal recessive condition characterized by Lisch nodules, axillary/inguinal freckling, and neurofibromas.Watson syndrome may be allelic to NF1, the same gene associated with Neurofibromatosis type 1.- References :...
. A condition with a separate gene mutation but similar Café au lait spot
Café au lait spot
Café au lait spots or Café au lait macules are pigmented birthmarks. The name café au lait is French for "milky coffee" and refers to their light-brown color...
s is Legius syndrome
Legius syndrome
Legius syndrome is an autosomal dominant condition characterized by cafe au lait spots. It is often mistaken for Neurofibromatosis type I . It is caused by mutations in the SPRED1 gene. It is also known as Neurofibromatosis Type 1-like syndrome .The syndrome is named after Eric Legius,...
which has a mutation on the SPRED1 gene
SPRED1 gene
Sprouty-related, EVH1 domain-containing protein 1 is a protein that in humans is encoded by the SPRED1 gene located on chromosome 15q13.2 and has seven coding exons.- Function :...
.
Discovery of the Neurofibromin gene
In 1989, through linkage and cross over analyzes, neurofibromin was localized to chromosome 17. It was localized to the long arm of chromosome 17 by chance when researchers discovered chromosome exchanges between chromosome 17 with chromosome 1 and 22. It was this exchanging of genetic material that presumably caused a mutation in the neurofibromin gene thus leading to the NF1 phenotype.Structure of the Neurofibromin gene
The Neurofibromin gene was soon sequenced and found to be 350,000 base pairs in length. However, the protein is 2818 amino acids long leading to the concept of splice variants. For example, exon 9a, 23a and 48a are expressed in the neurons of the forebrain, muscle tissues and adult neurons respectively.Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase Activating Protein (GAP) Family. This homologous sequence is in the central portion of neurofibromin and being similar to the GAP family is recognized as a negative regulator of the Ras kinase.
Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein adenylyl cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
, and a second with collapsin response mediator protein
CRMP1
Collapsin response mediator protein 1, encoded by the CRMP1 gene, is a human protein of the CRMP family.This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system...
. Together, likely with domains yet to be discovered, neurofibromin regulates many of the pathways responsible for overactive cell proliferation, learning impairments, skeletal defects and plays a role in neuronal development.
Embryo
For embryos produced via in vitro fertilisationIn vitro fertilisation
In vitro fertilisation is a process by which egg cells are fertilised by sperm outside the body: in vitro. IVF is a major treatment in infertility when other methods of assisted reproductive technology have failed...
, it is possible via preimplantation genetic diagnosis
Preimplantation genetic diagnosis
In medicine and genetics pre-implantation genetic diagnosis refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis...
to screen for NF-1.
Post-natal testing
The National Institute of Health (NIH) has created specific criteria for the diagnosis of NF-1. Two of these seven "Cardinal Clinical Features" are required for positive diagnosis.- 6 or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals. Note that multiple café-au-lait spots alone are not a definitive diagnosis of NF-1 as these spots can be caused by a number of other conditions.
- 2 or more neurofibromas of any type or 1 plexiform neurofibroma
- Freckling in the axillary or inguinal regions
- Optic glioma
- 2 or more Lisch nodulesLisch nodulesA Lisch nodule is a pigmented hamartomatous nodular aggregate of dendritic melanocytes affecting the iris, named after Austrian ophthalmologist Karl Lisch , who first recognized them in 1937....
(iris hamartomas) - A distinctive osseous lesion such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudarthrosis
- A first degree relative (parent, sibling, or offspring) with NF-1 by the above criteria
- Discovered mutations of the NF1 gene, which is located at chromosome 17q11.2
Prognosis
NF-1 is such a progressive and diverse condition that it makes it difficult to predict. The NF-1 gene manifest the disorder differently even amongst members of the same family. For example, some individuals have no symptoms, while others may have a manifestation that is rapidly more progressive and severe.For many NF-1 patients, a primary concern is the disfigurement caused by cutaneous/dermal neurofibromas, pigmented lesions, and the occasional limb abnormalities.
However, there are many more severe complications caused by NF-1, but some of them are quite rare and they are listed in the following section.
There is no cure for the disorder itself. Instead, people with neurofibromatosis are followed by a team of specialists to manage symptoms or complications. In progress and recently concluded medical studies on NF-1 can be found by searching the official website of the National Institute of Health.
Treatment
Here we list conditions and complications associated with NF-1, and, where available, age range of onset and progressive development, occurrence percentage of NF-1 population, method of earliest diagnosis, and treatments and related medical specialties. The progression of the condition is roughly as follows:- Congenital musculoskeletal disorders may or may not be present
- Cutaneous conditions may be observed in early infancy
- Small tumors may arise in the retina which can eventually lead to blindness
- Learning disabilities may arise in preschool children
- Neurofibromas may occur and cause many dependent neurological conditions and cutaneous and skeletal disfigurement
- Depression and social anxiety may occur as a result of disabilities caused by the condition
- Neurofibromas may transition into cancer which can be fatal
The St. Louis Children's Hospital Neurofibromatosis Center maintains a comprehensive list of current NF research studies.
SkullSkullThe skull is a bony structure in the head of many animals that supports the structures of the face and forms a cavity for the brain.The skull is composed of two parts: the cranium and the mandible. A skull without a mandible is only a cranium. Animals that have skulls are called craniates...
- Sphenoid boneSphenoid boneThe sphenoid bone is an unpaired bone situated at the base of the skull in front of the temporal bone and basilar part of the occipital bone.The sphenoid bone is one of the seven bones that articulate to form the orbit...
dysplasiaDysplasiaDysplasia , is a term used in pathology to refer to an abnormality of development. This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells. Dysplasia is often indicative of an early neoplastic process...
. - Congenital HydrocephalusHydrocephalusHydrocephalus , also known as "water in the brain," is a medical condition in which there is an abnormal accumulation of cerebrospinal fluid in the ventricles, or cavities, of the brain. This may cause increased intracranial pressure inside the skull and progressive enlargement of the head,...
and associated neurologic impairment. Diagnose in fetus or at birth. Nonprogressive.
SpineVertebral columnIn human anatomy, the vertebral column is a column usually consisting of 24 articulating vertebrae, and 9 fused vertebrae in the sacrum and the coccyx. It is situated in the dorsal aspect of the torso, separated by intervertebral discs...
- In NF-1, there can be a generalized abnormality of the soft tissues in the fetusFetusA fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
, which is referred to as mesodermMesodermIn all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and...
al dysplasiaDysplasiaDysplasia , is a term used in pathology to refer to an abnormality of development. This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells. Dysplasia is often indicative of an early neoplastic process...
, resulting in maldevelopment of skeletal structures. - Meningoceles and formation of cystic diverticula of the dura of the spine, unrelated to Spina bifidaSpina bifidaSpina bifida is a developmental congenital disorder caused by the incomplete closing of the embryonic neural tube. Some vertebrae overlying the spinal cord are not fully formed and remain unfused and open. If the opening is large enough, this allows a portion of the spinal cord to protrude through...
- Radiographically, Dural ectasia can lead to scalloping of the posterior vertebral bodies and to the formation of cystic diverticula of the dura of the spine (termed meningoceles. This meningocele is not related to spina bifida).
- Focal scoliosisScoliosisScoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
and/or kyphosisKyphosisKyphosis , also called roundback or Kelso's hunchback, is a condition of over-curvature of the thoracic vertebrae...
are the most common skeletal manifestation of NF-1, occurring in 20% of affected patients. Approximately 25% of patients will require corrective surgery.
Facial bones and limbs
- Bowing of a long bone with a tendency to fracture and not heal, yielding a pseudarthrosisPseudarthrosisPseudarthrosis is the movement of a bone at the location of a fracture resulting from inadequate healing of the fracture.Pseudarthrosis can also result from a developmental failure.-Etymology:...
. The most common bone to be affected is the tibia, causing congenital pseudarthrosis of the tibia or CPT. CPT occurs in 2-4% of individuals with NF-1. Treatment includes limb amputation. - Malformation of the facial bones or of the eye sockets (lambdoid suture defects, sphenoid dysplasia)
- Unilateral overgrowth of a limb. When a plexiform neurofibroma manifests on a leg or arm, it will cause extra blood circulation, and may thus accelerate the growth of the limb. This may cause considerable difference in length between left and right limbs. To equalize the difference during childhood, there is an orthopedic surgery called epiphysiodesisEpiphysiodesisEpiphysiodesis is a Pediatric surgical procedure in which the epiphyseal plate of a bone is either removed, or a cube containing part of it rotated 90° and reinserted.This procedure is used to:*Lengthen an abnormally short leg...
, where growth at the epiphyseal (growth) plate is halted. It can be performed on one side of the bone to help correct an angular deformity, or on both sides to stop growth of that bone completely. The surgery must also be carefully planned with regard to timing, as it is non-reversible. The goal is that the limbs are at near-equal length at end of growth.
Cutaneous conditionsCutaneous conditionsThere are many conditions of or affecting the human integumentary system—the organ system that comprises the entire surface of the body and includes skin, hair, nails, and related muscle and glands.- Diseases :...
- Flat pigmented lesions of the skin called café au lait spotsCafé au lait spotCafé au lait spots or Café au lait macules are pigmented birthmarks. The name café au lait is French for "milky coffee" and refers to their light-brown color...
. These spots can grow from birth to 16 years and are nonprogressive after that. - FrecklingFreckleFor other uses of the word, see Freckles .Freckles are clusters of concentrated melanin which are most often visible on people with a fair complexion. A freckle is also called an "ephelis". Freckles do not have an increased number of melanin producing cells...
of the axillae or inguinal regions. - Dermal neurofibroma, manifested as single or multiple firm, rubbery bumps of varying sizes on a person's skin. Age of onset is puberty. Progressive in number and size. Not malignant. Can be treated with CO2 lasers.
Neurobehavioral developmental disorderDevelopmental disorderDevelopmental disorders occur at some stage in a child's development, often retarding the development. These may include,psychological or physical disorders. The disorder is an impairment in the normal development of motor or cognitive skills that are developed before age 18 in which they are...
The most common complication in patients with NF-1 is cognitive and learning disability. These cognitive problems have been shown to be present in approximately 80% of children with NF-1 and have significant effects on their schooling and everyday life. These cognitive problems have been shown to be stable into adulthood and do not get worse unlike some of the other physical symptoms of NF-1. The most common cognitive problems are with perception, executive functioning and attention. Disorders include:
- Attention deficit hyperactivity disorder has been shown to be present in approximately 38% of children with NF-1.
- Speech and language delays have also been identified in approximately 68% of preschool children with NF1.
- Math deficits.
- Motor deficits are common. Motor deficits due to NF-1 are probably not cerebellarCerebellumThe cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
. - Spatial deficit. LovastatinLovastatinLovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...
, normally used to treat hypercholesterolemiaHypercholesterolemiaHypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
, is currently in phase one of clinical trial (NCT00352599). This drug has been shown to reverse spatial deficits in miceMICE-Fiction:*Mice , alien species in The Hitchhiker's Guide to the Galaxy*The Mice -Acronyms:* "Meetings, Incentives, Conferencing, Exhibitions", facilities terminology for events...
. - Asperger's Syndrome.
Nervous system diseaseNervous system diseaseNervous system disease refers to a general class of medical conditions affecting the nervous system.They can be divided into:* Central nervous system disease in the CNS* Peripheral neuropathy in the PNS...
The primary neurologic involvement in NF-1 is of the peripheral nervous system, and secondarily of the central nervous system.NeurofibromaNeurofibromaA neurofibroma is a benign nerve sheath tumor in the peripheral nervous system. Usually found in individuals with neurofibromatosis type I , an autosomal dominant genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability...
A neurofibroma
Neurofibroma
A neurofibroma is a benign nerve sheath tumor in the peripheral nervous system. Usually found in individuals with neurofibromatosis type I , an autosomal dominant genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability...
is a lesion of the peripheral nervous system. Its cellular lineage is uncertain, and may derive from Schwann cells, other perineural cell lines, or fibroblasts. Neurofibromas may arise sporadically, or in association with NF-1. A neurofibroma may arise at any point along a peripheral nerve. A number of drugs have been studied to treat this condition.
Neurofibroma conditions are progressive and include:
- Plexiform neurofibroma: Often congenital. Lesions are composed of sheets of neurofibromatous tissue that may infiltrate and encase major nerves, blood vessels, and other vital structures. These lesions are difficult and sometimes impossible to routinely resect without causing any significant damage to surrounding nerves and tissue.
- Solitary neurofibromaSolitary neurofibromaA solitary neurofibroma may be 2 to 20mm in diameter, is soft, flaccid, and pinkish-white, and frequently this soft small tumor can be invaginated, as if through a ring in the skin by pressure with the finger, a maneuver called "button-holing."...
, affecting 8–12% of patients with NF-1. This occur in a deep nerve trunk. Diagnosis by cross-sectional imaging (e.g., computed tomographyComputed tomographyX-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
or magnetic resonanceMagnetic resonance imagingMagnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
) as a fusiform enlargement of a nerve. - SchwannomaSchwannomaA schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....
s, peripheral nerve-sheath tumors which are seen with increased frequency in NF-1. The major distinction between a schwannoma and a solitary neurofibroma is that a schwannoma can be resectedResectionResection may refer to:*Segmental resection , the partial removal of an organ or other body structure*Resection , a means of establishing a location...
while sparing the underlying nerve, whereas resection of a neurofibroma requires the sacrifice of the underlying nerve. - Nerve root neurofibromaNeurofibromaA neurofibroma is a benign nerve sheath tumor in the peripheral nervous system. Usually found in individuals with neurofibromatosis type I , an autosomal dominant genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability...
. - Bones, especially the ribs, can develop chronic erosions (pits) from the constant pressure of adjacent neurofibromaNeurofibromaA neurofibroma is a benign nerve sheath tumor in the peripheral nervous system. Usually found in individuals with neurofibromatosis type I , an autosomal dominant genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability...
or SchwannomaSchwannomaA schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....
. Similarly, the neural foramen of the spineVertebral columnIn human anatomy, the vertebral column is a column usually consisting of 24 articulating vertebrae, and 9 fused vertebrae in the sacrum and the coccyx. It is situated in the dorsal aspect of the torso, separated by intervertebral discs...
can be widened due to the presence of a nerve root neurofibroma or schwannomaSchwannomaA schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....
. Surgery may be needed when NF-1 related tumors compress organs or other structures.
Nerve sheath tumor
- Peripheral nerve sheath tumorNerve sheath tumorA nerve sheath tumor is a type of tumor of the nervous system which is made up primarily of the myelin surrounding nerves.A peripheral nerve sheath tumor is a nerve sheath tumor in the peripheral nervous system....
. - Chronic pain, numbness, and/or paralysis due to peripheral nerve sheath tumorNerve sheath tumorA nerve sheath tumor is a type of tumor of the nervous system which is made up primarily of the myelin surrounding nerves.A peripheral nerve sheath tumor is a nerve sheath tumor in the peripheral nervous system....
.
Other complications
- Renal artery anomalies or pheochromocytomaPheochromocytomaA pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
and associated chronic hypertensionHypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and... - SchwannomaSchwannomaA schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....
Epilepsy
- Occurrence. Epileptic seizures haven been reported in up to 7% of NF-1 patients.
- Diagnosis. Electroencephalograph, magnetic resonance imaging, computed tomographic scan, single-photon emission CT and positron emission tomographic scan.
- Etiology. Due to cerebral tumors, cortical malformation, mesial temporal sclerosis.
- Therapy. Drug therapy (57% amenable) where not resistant (29%).
Glial tumors
Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system, primarily:
- Optic nerve gliomaGliomaA glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
s and associated blindness. - AstrocytomaAstrocytomaAstrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs...
Focally degenerative myelin
Another CNS manifestation of NF-1 is the so-called "unidentified bright object" or UBO, which is a lesion which has increased signal on a T2 weighted sequence of a magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
examination of the brain. These UBOs are typically found in the Cerebral peduncle
Cerebral peduncle
Mainly, the three common areas that give rise to the cerebral peduncles are the cortex, the spinal cord and the cerebellum. The cerebral peduncle, by most classifications, is everything in the mesencephalon except the tectum. The region includes the midbrain tegmentum, crus cerebri and pretectum...
, pons, midbrain, globus pallidus, thalamus, and optic radiations. Their exact identity remains a bit of a mystery since they disappear over time (usually, by age 16), and they are not typically biopsied or resected. They may represent a focally degenerative bit of myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
.
Dural ectasia
Within the CNS, NF-1 manifests as a weakness of the dura
Dura mater
The dura mater , or dura, is the outermost of the three layers of the meninges surrounding the brain and spinal cord. It is derived from Mesoderm. The other two meningeal layers are the pia mater and the arachnoid mater. The dura surrounds the brain and the spinal cord and is responsible for...
, which is the tough covering of the brain and spine. Weakness of the dura leads to focal enlargement terms dural ectasia
Dural ectasia
Dural ectasia is a widening or ballooning of the dural sac surrounding the spinal cord usually at the lumbosacral level. It is one of the major manifestations of Marfan syndrome. It may cause low back pain, headaches and neurological signs such as weakness and loss of bowel and bladder function,...
due to chronic exposure to the pressures of CSF
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
pulsation.
Acetazolamide
Acetazolamide
Acetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, Idiopathic intracranial hypertension , altitude sickness, cystinuria, and dural ectasia...
has shown promise as a treatment for this condition.
Mental disorder
Children with NF-1 can experience social problems, attention problems, social anxiety, depression, withdrawal, thought problems, somatic complaints, and aggressive behavior. Treatments include psychotherapyPsychotherapy
Psychotherapy is a general term referring to any form of therapeutic interaction or treatment contracted between a trained professional and a client or patient; family, couple or group...
, antidepressants and cognitive behavioral therapy.
CancerCancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
Cancer can arise in the form of Malignant peripheral nerve sheath tumorMalignant peripheral nerve sheath tumor
A malignant peripheral nerve sheath tumor is a form of cancer of the connective tissue surrounding nerves. Given its origin and behavior it is classified as a sarcoma...
resulting from malignant degeneration of a plexiform neurofibroma.
- Frequency. A plexiform neurofibroma has a lifetime risk of 8–12% of transformation into a malignant tumor.
- Diagnosis. MRIMagnetic resonance imagingMagnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
. - Treatment. ChemotherapyChemotherapyChemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. - Mortality. Malignant nerve sheath tumor was the main cause of death (60%) in a study of 1895 patients with NF-1 from France in the time period 1980-2006 indicated excess mortality in NF-1 patients compared to the general populaion. The cause of death was available for 58 (86.6 %) patients. The study found excess mortality occurred among patients aged 10 to 40 years. Significant excess mortality was found in both males and females.
External links
- Understanding NF1, Harvard Medical School
- GeneReviews/NCBI/NIH/UW entry on Neurofibromatosis 1
- GeneReviews/NIH/NCBI/UW entry on Legius syndrome SPRED1 Sprouty-related, EVH1 domain-containing protein 1
- NF KONTAKT.be (a nonprofit organization providing information and resources for families, Schools and Health Care workers dealing with NF1, NF2, and tumour-related neurofibromatosis in Belgium and providing awareness and support of Neurofibromatosis in Europe)