Neurofibromatosis type I

For Von Recklinghausen's disease of bone, a disorder seen with hyperparathyroidism, see osteitis fibrosa cystica.
Neurofibromatosis type 1
Synonyms von Recklinghausen disease
morbus Recklinghausen
café au lait spot characteristic of NF1.
Classification and external resources
Specialty Neurosurgery, dermatology
ICD-10 Q85.0 (ILDS Q85.010)
ICD-9-CM 237.71
OMIM 162200
DiseasesDB 8937
MedlinePlus 000847
eMedicine derm/287 neuro/248 oph/338 radio/474
MeSH D009456

Neurofibromatosis type I (NF-1) is a tumor disorder that is caused by the mutation of a gene on chromosome 17 that is responsible for control of cell division. NF-1 causes tumors along the nervous system and can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any person's race or sex. Currently (2015), there are at least 100,000 people in the U.S. and about 150,000 people in the UK who have been diagnosed with NF. Common symptoms of NF-1 include brownish-red spots in the colored part of the eye called Lisch nodules, benign skin tumors called neurofibromas, and larger benign tumors of nerves called plexiform neurofibromas, scoliosis (curvature of the spine), learning disabilities, vision disorders, mental disabilities, multiple café au lait (TCL, name of specifics spots) spots and epilepsy.

NF-1 is a developmental syndrome caused by germline mutations in neurofibromin, a gene that is involved in the RAS pathway (RASopathy). Due to its rarity and to the fact that genetic diagnosis has been used only in recent years, in the past NF-1 was in same cases confused with another syndrome with vaguely similar symptoms, the Legius syndrome.[1]

NF-1 is an age specific disease; most signs of NF-1 are visible after birth (during infancy), but many symptoms of NF-1 occur as the person ages and has hormonal changes. NF-1 was formerly known as von Recklinghausen disease after the researcher (Friedrich Daniel von Recklinghausen) who first documented the disorder.[2]

The severity of NF-1 varies widely, and little is known about what causes a person to have a more severe or less severe case. Even within the same family (as there is a 50% chance that a parent will pass their condition to their offspring) levels of severity can vary enormously. However, 60% of people with NF-1 have mild cases, with few symptoms that have very little effect in their day-to-day lives. 20% of NF-1 patients have moderate cases, with several symptoms that have little more than cosmetic effects. The other 20% have severe cases with several symptoms that effect the person's quality of life. Even in this last group, symptoms are rarely life-threatening.[3]

Signs and symptoms

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.
Back of an elderly woman with NF-1

The following is a list of 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.[4][5] The progression of the condition is roughly as follows:

  1. Congenital musculoskeletal disorders may or may not be present
  2. Cutaneous conditions may be observed in early infancy
  3. Small tumors may arise in the retina which can eventually lead to blindness. Also, Lisch Nodules may grow on the iris, but these are harmless.
  4. Learning disabilities may arise in preschool children
  5. Neurofibromas may occur and can sometimes cause many dependent neurological conditions and cutaneous and skeletal disfigurement.
  6. Depression and social anxiety may occur as a result of disabilities caused by the condition
  7. Neurofibromas may, in rare and extreme cases, transition into cancer, which can be fatal

The NF Clinical Program at St. Louis Children's Hospital maintains a comprehensive list of current NF research studies.

Musculoskeletal disorder

Musculoskeletal abnormalities affecting the skull include Sphenoid bone dysplasia, Congenital Hydrocephalus and associated neurologic impairment. These abnormalities are non-progressive and may be diagnosed in the fetus or at birth.

Disorders affecting the spine include:

Skeletal muscle weakness and motor control deficits

Deficits in motor function in NF-1 have been long recognised and have been historically attributed to nerve dysfunction. In recent years however, studies suggest NF-1 is associated with an primary problem in muscle function (myopathy).[6]

Clinical findings in people with NF-1 include:

Studies in genetically modified mice have thus far confirmed that the NF1 gene is vital for normal muscle development and metabolism. Knockout of the NF1 gene in muscle results in deregulated lipid metabolism and muscle weakness.[6][8]

It is interesting to note that NF-1 is a disease in the RASopathy family of diseases, which include Costello Syndrome, Noonan Syndrome, and Cardiofaciocutaneous syndrome. The RASopathies also present with skeletal muscle weakness.[9] It is likely that impaired muscle function in these disorders is linked to altered Ras/MAPK signalling, however, the precise molecular mechanisms remain unknown.[6]

Facial bones and limbs


Eye disease

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.[13] 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.[14] 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. Schwannomatosis is a rare condition defined by the presence of multiple benign tumors of nerves that are frequently very painful. In addition to pain, weakness is a common problem. Symptoms usually begin in young or mid-adult years.

Peripheral neuropathy


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:

Nerve sheath tumor
MRI image showing malignant peripheral nerve sheath tumor in the left tibia in neurofibromatosis type-1.
Other complications

Central nervous system disease

Main article: Epilepsy
Glial tumors
Main article: Glial tumor

Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system, primarily:

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 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.

Dural ectasia
Main article: Dural ectasia

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.

Mental disorder

Children with NF-1 can experience social problems, attention problems, social anxiety, depression, withdrawal, thought problems, somatic complaints, learning disabilities and aggressive behavior.[24] Treatments include psychotherapy, antidepressants and cognitive behavioral therapy.


Cancer can arise in the form of Malignant peripheral nerve sheath tumor resulting from malignant degeneration of a plexiform neurofibroma.[21][25]


Main article: Neurofibromin 1

Neurofibromin 1 gene

NF-1 is a microdeletion syndrome caused by a mutation of a gene located on chromosomal segment 17q11.2 on the long arm of chromosome 17 which encodes a protein known as neurofibromin[27] (not to be confused with the disorder itself) which plays a role in cell signaling.[28][29] 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.

In 1989, through linkage and cross over analyses, neurofibromin was localized to chromosome 17.[30] 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.[30] This exchange of genetic material presumably caused a mutation in the neurofibromin gene, leading to the NF1 phenotype. Two recurrent microdeletion types with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion), are found in most cases.[31]

Structure of the Neurofibromin gene

The Neurofibromin gene was soon sequenced and found to be 350,000 base pairs in length.[32] However, the protein is 2818 amino acids long leading to the concept of splice variants.[33] For example, exon 9a, 23a and 48a are expressed in the neurons of the forebrain, muscle tissues and adult neurons respectively.[33]

Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase Activating Protein (GAP) Family.[32] 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.[34]

Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein adenylyl cyclase,[35] and a second with collapsin response mediator protein.[36] 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.[37]

Inheritance and spontaneous mutation

NF-1 is inherited in an autosomal dominant fashion, although it can also arise due to spontaneous mutation.

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.[38]

Mutations in the NF1 gene have been linked to NF-1, Juvenile myelomonocytic leukemia and Watson syndrome. A condition with a separate gene mutation but similar Café au lait spots is Legius syndrome which has a mutation on the SPRED1 gene.


Prenatal testing and prenatal expectations

Prenatal testing may be used to identify the existence of NF-1 in the fetus. For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis to screen for NF-1.[39]

Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus.[40]

People with NF-1 have a 50% percent chance of passing the disorder on to their kids, but people can have a child born with NF-1 when they themselves do not have it. This is caused in a spontaneous change in the genes during pregnancy.

Post-natal testing

The National Institutes 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.[41] There is practical flowchart to distinguish between NF1, NF2 and schwannomatosis.[42]


NF-1 is a progressive and diverse condition, making the prognosis difficult to predict. The NF-1 gene mutations manifest the disorder differently even amongst people of the same family. This phenomenon is called variable expressivity. 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, although most of them are quite rare. Many NF patients live perfectly normal and uninterrupted lives.


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 Institutes of Health.

See also


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