Neurofibromatosis type I

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Neurofibromatosis type 1
Classification and external resources

Café au lait spot characteristic of NF1.
ICD-10Q85.0 (ILDS Q85.010)
eMedicinederm/287 neuro/248 oph/338 radio/474
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Neurofibromatosis type 1
Classification and external resources

Café au lait spot characteristic of NF1.
ICD-10Q85.0 (ILDS Q85.010)
eMedicinederm/287 neuro/248 oph/338 radio/474

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. It is a separate disorder, although significant confusion remains in both the media and medical community regarding this fact.[1]. It is a RASopathy. In diagnosis it may also be confused with Legius syndrome.


Simple explanation

NF-1 is a tumor disorder that is caused by the malfunction of a gene 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.


The neurofibromin 1 gene

NF-1 is caused by a mutation 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.[2][3] 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.

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.[4]

Related medical conditions

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.

Discovery of the Neurofibromin gene

In 1989, through linkage and cross over analyses, neurofibromin was localized to chromosome 17.[5] 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.[5] 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.[6] However, the protein is 2818 amino acids long leading to the concept of splice variants.[7] For example, exon 9a, 23a and 48a are expressed in the neurons of the forebrain, muscle tissues and adult neurons respectively.[7]

Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase Activating Protein (GAP) Family.[6] 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.[8]

Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein adenylyl cyclase,[9] and a second with collapsin response mediator protein.[10] 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.[11]


Prenatal testing


For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis to screen for NF-1.[12]


Chorionic villus sampling or amniocentesis can be used to detect NF-1.[13]

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.[14]


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.[15]


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.[16][17] 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
  4. Learning disabilities may arise in preschool children
  5. Neurofibromas may occur and 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 transition into cancer which can be fatal

The St. Louis Children's Hospital Neurofibromatosis Center maintains a comprehensive list of current NF research studies.

Musculoskeletal disorder



Facial bones and limbs

Cutaneous conditions

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.[19] 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.[20] 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.

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
Other complications

Central nervous system disease

Glial tumors

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

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, and aggressive behavior.[25] Treatments include psychotherapy, antidepressants and cognitive behavioral therapy.


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

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

Patient registry

Washington University Neurofibromatosis Center maintains a patient registry.

External links


  1. ^ Legendre, Claire-Marie; Catherine Charpentier-Côté, Régen Drouin, and Chantal Bouffard (February 9). "Neurofibromatosis Type 1 and the “Elephant Man's” Disease: The Confusion Persists: An Ethnographic Study". PLoS One. Retrieved 17 August 2012. 
  2. ^ "neurofibromin 1" GeneCards
  3. ^ "Human Gene NF1 (uc002hgf.1) Description and Page Index"
  4. ^ Online 'Mendelian Inheritance in Man' (OMIM) 162200
  5. ^ a b Goldberg NS, Collins FS (November 1991). "The hunt for the neurofibromatosis gene". Arch Dermatol 127 (11): 1705–7. PMID 1952978. 
  6. ^ a b Marchuk DA, Saulino AM, Tavakkol R, et al. (December 1991). "cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product". Genomics 11 (4): 931–40. doi:10.1016/0888-7543(91)90017-9. PMID 1783401. 
  7. ^ a b Gutmann DH, Giovannini M (2002). "Mouse models of neurofibromatosis 1 and 2". Neoplasia 4 (4): 279–90. doi:10.1038/sj.neo.7900249. PMC 1531708. PMID 12082543. 
  8. ^ Feldkamp MM, Angelov L, Guha A (February 1999). "Neurofibromatosis type 1 peripheral nerve tumors: aberrant activation of the Ras pathway". Surg Neurol 51 (2): 211–8. doi:10.1016/S0090-3019(97)00356-X. PMID 10029430. 
  9. ^ Hannan F, Ho I, Tong JJ, Zhu Y, Nurnberg P, Zhong Y (April 2006). "Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras". Hum. Mol. Genet. 15 (7): 1087–98. doi:10.1093/hmg/ddl023. PMC 1866217. PMID 16513807. 
  10. ^ Ozawa T, Araki N, Yunoue S, et al. (November 2005). "The neurofibromatosis type 1 gene product neurofibromin enhances cell motility by regulating actin filament dynamics via the Rho-ROCK-LIMK2-cofilin pathway". J. Biol. Chem. 280 (47): 39524–33. doi:10.1074/jbc.M503707200. PMID 16169856. 
  11. ^ Le LQ, Parada LF (July 2007). "Tumor microenvironment and neurofibromatosis type I: connecting the GAPs". Oncogene 26 (32): 4609–16. doi:10.1038/sj.onc.1210261. PMC 2760340. PMID 17297459. // 
  12. ^ "British couple successfully screens out genetic disorder using NHS-funded PGD" by Antony Blackburn-Starza, June 9, 2008, BioNews 461
  13. ^ "Are there any prenatal tests for the neurofibromatoses?"
  14. ^ Huson SM, Hughes RAC. The Neurofibromatoses. London, UK: Chapman and Hall; 1994;1.3.2:9
  15. ^ National Institute of Healthwebsite
  16. ^ "Neurofibromatosis 1: Current Issues in Diagnosis, Therapy, and Patient Management", by David Viskochil MD PhD, Mountain States Genetic Foundation, Denver 2010
  17. ^ "Current Therapies for Neurofibromatosis Type 1", by Laura Klesse MD PhD, Mountain States Genetic Foundation, Denver 2010
  18. ^ "Neurofibromatosis, giant cafe-au-lait spot". Health. Retrieved 2010-07-27. 
  19. ^ Hyman SL, Shores A, North KN (October 2005). "The nature and frequency of cognitive deficits in children with neurofibromatosis type 1". Neurology 65 (7): 1037–44. doi:10.1212/01.wnl.0000179303.72345.ce. PMID 16217056. 
  20. ^ Hyman SL, Gill DS, Shores EA, et al. (April 2003). "Natural history of cognitive deficits and their relationship to MRI T2-hyperintensities in NF1". Neurology 60 (7): 1139–45. PMID 12682321. 
  21. ^ Thompson HL, Viskochil DH, Stevenson DA, Chapman KL (February 2010). "Speech-language characteristics of children with neurofibromatosis type 1". Am. J. Med. Genet. A 152A (2): 284–90. doi:10.1002/ajmg.a.33235. PMID 20101681. 
  22. ^ van der Vaart T, van Woerden GM, Elgersma Y, de Zeeuw CI, Schonewille M (June 2011). "Motor deficits in neurofibromatosis type 1 mice: the role of the cerebellum". Genes Brain Behav. 10 (4): 404–9. doi:10.1111/j.1601-183X.2011.00685.x. PMID 21352477. 
  23. ^ "Trial to Evaluate the Safety of Lovastatin in Individuals With Neurofibromatosis Type I (NF1)"
  24. ^ Vivarelli R, Grosso S, Calabrese F, et al. (May 2003). "Epilepsy in neurofibromatosis 1". J. Child Neurol. 18 (5): 338–42. PMID 12822818. 
  25. ^ Johnson NS, Saal HM, Lovell AM, Schorry EK (June 1999). "Social and emotional problems in children with neurofibromatosis type 1: evidence and proposed interventions". J. Pediatr. 134 (6): 767–72. doi:10.1016/S0022-3476(99)70296-9. PMID 10356149. 
  26. ^ "Mortality Associated with Neurofibromatosis 1: A Cohort Study of 1895 Patients in 1980-2006 in France ", May 4, 2011