View source for Neurofibromatosis type I

{{short description|Type of neurofibromatosis disease}}
{{for|Von Recklinghausen's disease of bone, a disorder seen with hyperparathyroidism|osteitis fibrosa cystica}}
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{{Infobox medical condition (new)
| name = Neurofibromatosis type 1
| image = 
| caption = Main symptoms of neurofibromatosis type I.<ref>- Source for main symptoms: {{cite web|url=https://www.mayoclinic.org/diseases-conditions/neurofibromatosis/symptoms-causes/syc-20350490|title=Neurofibromatosis|website=Mayo Clinic|date=2021-01-21}}<br>- Image by
Mikael Häggström, MD, using [[Commons:File:Symptoms of neurofibromatosis type 1.png#Summary|source images by various authors]].</ref>
| pronounce = 
| field = [[Neurosurgery]], [[dermatology]], [[ophthalmology]]
| synonyms = {{cslist|von Recklinghausen disease | morbus Recklinghausen | NF1}}
| symptoms = 
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| onset = At birth
| duration = 
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'''Neurofibromatosis type I''' ('''NF-1'''), or '''von Recklinghausen syndrome''', is a complex multi-system neurocutaneous disorder caused by a [[Allele|subset]] of [[Mutation|genetic mutations]] at the [[neurofibromin 1]] (''NF1'') locus. Other conditions associated with mutation of the ''NF1'' gene include [[Watson syndrome]].<ref>{{Cite journal |last=Boxel-Woolf |first=Tom Van |last2=McCarthy |first2=Kathleen M. |title=Speech and language skills in a case of Watson syndrome |url=https://www.tandfonline.com/doi/full/10.1080/02699206.2025.2472051 |journal=Clinical Linguistics & Phonetics |volume=0 |issue=0 |pages=1–24 |doi=10.1080/02699206.2025.2472051 |issn=0269-9206 |pmid=40077991|doi-access=free }}</ref> NF-1 is a [[gene]] on [[chromosome 17]] that is responsible for production of a protein (neurofibromin) which is needed for normal function in many human cell types. {{Nowrap|NF-1}} causes tumors along the nervous system that can grow anywhere on the body. {{Nowrap|NF-1}} is one of the most common genetic disorders and is not limited to any person's race or sex. NF-1 is an [[autosomal dominant]] disorder, which means that mutation or deletion of one copy (or allele) of the {{Nowrap|NF-1 gene}} is sufficient for the development of {{Nowrap|NF-1}}, although presentation varies widely and is often different even between relatives affected by {{Nowrap|NF-1}}.<ref name="ReferenceA">{{cite journal | vauthors = Kunc V, Venkatramani H, Sabapathy SR | title = Neurofibromatosis 1 Diagnosed in Mother Only after a Follow-up of Her Daughter | journal = Indian Journal of Plastic Surgery | volume = 52 | issue = 2 | pages = 260 | date = May 2019 | pmid = 31602150 | pmc = 6785427 | doi = 10.1055/s-0039-1693503 | doi-access = free }}</ref>

{{As of|2015}}, there are at least 100,000 people in the U.S. and about 25,000 people in the UK who have been diagnosed with NF. Common symptoms of {{Nowrap|NF-1}} include brownish-red spots in the colored part of the eye called [[Lisch nodule]]s, benign skin tumors called [[neurofibromas]], and larger benign tumors of nerves called [[plexiform neurofibroma]]s, [[scoliosis]] (curvature of the spine), [[learning disability|learning disabilities]], [[vision disorder]]s, mental disabilities, multiple [[Café au lait spot|café au lait]] spots and [[epilepsy]]. While some people have major complications, others with the condition can lead productive and full lives.

NF-1 is a developmental syndrome caused by [[germline mutations]] in [[neurofibromin 1|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 {{Nowrap|NF-1}} was in some cases confused with [[Legius syndrome]], another syndrome with vaguely similar symptoms, including cafe-au-lait spots.<ref>{{Cite web|title = About Neurofibromatosis – The University of Chicago Medicine|url = http://www.uchospitals.edu/specialties/neurology/neurofibromatosis/about.html|website = www.uchospitals.edu|access-date = 2015-10-27|archive-date = 2015-09-07|archive-url = https://web.archive.org/web/20150907101337/http://www.uchospitals.edu/specialties/neurology/neurofibromatosis/about.html|url-status = dead}}</ref>

NF-1 is an age-specific disease; most signs of NF-1 are visible after birth (during infancy), but many symptoms of {{Nowrap|NF-1}} occur as the person ages and has hormonal changes. {{Nowrap|NF-1}} was formerly known as von Recklinghausen disease, after the researcher who first documented the disorder, [[Friedrich Daniel von Recklinghausen]].<ref>{{cite journal | vauthors = Costa RM, Silva AJ | title = Molecular and cellular mechanisms underlying the cognitive deficits associated with neurofibromatosis 1 | journal = Journal of Child Neurology | volume = 17 | issue = 8 | pages = 622–626; discussion 626–9, 626–51 | date = August 2002 | pmid = 12403561 | doi = 10.1177/088307380201700813 | s2cid = 20385802 }}</ref>

The severity of NF-1 varies widely, and little is known about what causes a person to have more severe or less severe symptoms. 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.<ref name="ReferenceA"/> 60% of people with {{Nowrap|NF-1}} have mild cases, with few symptoms that have very little effect in their day-to-day lives. About 20% of people with NF-1 have what are considered moderate cases, with several symptoms that usually have a few cosmetic effects. The other 20% have severe cases, with several symptoms that affect the person's quality of life. Even in this last group, symptoms are rarely life-threatening.<ref>{{Cite web|url=http://www.ctf.org/understanding-nf/nf1|title=NF1 &#124; Children's Tumor Foundation|access-date=2016-10-25|archive-date=2021-10-21|archive-url=https://web.archive.org/web/20211021213659/https://www.ctf.org/understanding-nf/nf1|url-status=dead}}</ref>

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==Signs and symptoms==
[[File:NF-1-Tache_cafe-au-lait.jpg|thumb|[[Café au lait spot]] characteristic of NF1]]
[[File:Diagnostic criteria of neurofibromatosis type I.jpg|thumb|Diagnostic criteria of neurofibromatosis type I, requiring at least 2 of the mentioned items.<ref>Graphical abstract from: {{cite journal | vauthors = Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, Blakeley J, Babovic-Vuksanovic D, Cunha KS, Ferner R, Fisher MJ, Friedman JM, Gutmann DH, Kehrer-Sawatzki H, Korf BR, Mautner VF, Peltonen S, Rauen KA, Riccardi V, Schorry E, Stemmer-Rachamimov A, Stevenson DA, Tadini G, Ullrich NJ, Viskochil D, Wimmer K, Yohay K, Huson SM, Evans DG, Plotkin SR | title = Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation | journal = Genetics in Medicine | volume = 23 | issue = 8 | pages = 1506–1513 | date = August 2021 | pmid = 34012067 | pmc = 8354850 | doi = 10.1038/s41436-021-01170-5 }}<br>- "User License: Creative Commons Attribution (CC BY 4.0)"</ref>]]
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.<ref>{{Cite web |url=http://www.mostgene.org/2010_conference/neurofibro_Viskochil.pdf |title= Neurofibromatosis 1: Current Issues in Diagnosis, Therapy, and Patient Management | vauthors = Viskochil D | work = Mountain States Genetic Foundation | location = Denver | date = 2010 |access-date= 2011-05-15 |archive-date=2015-11-06 |archive-url= https://web.archive.org/web/20151106033238/http://www.mostgene.org/2010_conference/neurofibro_Viskochil.pdf |url-status=dead }}</ref><ref>{{Cite web |url=http://www.mostgene.org/2010_conference/current_ther_neuro_klesse.pdf |title= Current Therapies for Neurofibromatosis Type 1 | vauthors = Klesse L | work = Mountain States Genetic Foundation | location = Denver | date = 2010 |access-date=2011-05-15 |archive-url=https://web.archive.org/web/20120309091045/http://www.mostgene.org/2010_conference/current_ther_neuro_klesse.pdf |archive-date=2012-03-09 |url-status=dead }}</ref> 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. Also, Lisch Nodules may grow on the iris, but these are harmless.
# Learning disabilities may arise in preschool children
# Neurofibromas may occur and can sometimes 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, in 8-13% of cases, transition into cancer, which can be fatal<ref>{{cite journal | vauthors = Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A | title = Malignant peripheral nerve sheath tumours in neurofibromatosis 1 | journal = Journal of Medical Genetics | volume = 39 | issue = 5 | pages = 311–314 | date = May 2002 | pmid = 12011145 | pmc = 1735122 | doi = 10.1136/jmg.39.5.311 }}</ref>

===Musculoskeletal disorder===
[[Musculoskeletal disorder|Musculoskeletal abnormalities]] affecting the [[skull]] include [[sphenoid bone]] dysplasia, congenital [[hydrocephalus]] and associated neurologic impairment.

Disorders affecting the [[Vertebral column|spine]] include:
* In NF-1, there can be a generalized abnormality of the soft tissues in the [[fetus]], which is referred to as [[mesoderm]]al [[dysplasia]], resulting in maldevelopment of skeletal structures.
* [[Spina bifida#Meningocele|Meningoceles]] and formation of cystic diverticula of the dura of the spine, unrelated to [[Spina bifida]]
* Radiographically, [[#Dural ectasia|dural ectasia]] can lead to scalloping of the posterior vertebral bodies and to the formation of cystic [[diverticula]] of the dura of the spine. This may result in temporary or permanent loss of lower extremity sensorimotor function.<ref name="Mutua e0165">{{Cite journal| vauthors = Mutua V, Mong'are N, Bundi B, von Csefalvay C, Oriko D, Kitunguu P |date=September 2021|title=Sudden bilateral lower limb paralysis with dural ectasia in Neurofibromatosis type 1: A case report|journal=Medicine: Case Reports and Study Protocols|language=en-US|volume=2|issue=9|pages=e0165|doi=10.1097/MD9.0000000000000165|issn=2691-3895|doi-access=free}}</ref>
* Focal [[scoliosis]] and/or [[kyphosis]] are the most common skeletal manifestation of NF-1, occurring in 20% of affected patients. Approximately 25% of patients will require corrective surgery.

'''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 a primary problem in muscle function (myopathy).<ref name="Summers 161–170">{{cite journal | vauthors = Summers MA, Quinlan KG, Payne JM, Little DG, North KN, Schindeler A | title = Skeletal muscle and motor deficits in Neurofibromatosis Type 1 | journal = Journal of Musculoskeletal & Neuronal Interactions | volume = 15 | issue = 2 | pages = 161–170 | date = June 2015 | pmid = 26032208 | pmc = 5133719 }}</ref>

Clinical findings in people with NF-1 include:
* Reduced skeletal muscle size
* Reduced exercise capacity
* Muscle weakness (The most recent study reports between 30–50% reduced upper and lower limb muscle strength in NF-1 children compare with matched controls<ref>{{cite journal | vauthors = Cornett KM, North KN, Rose KJ, Burns J | title = Muscle weakness in children with neurofibromatosis type 1 | journal = Developmental Medicine and Child Neurology | volume = 57 | issue = 8 | pages = 733–736 | date = August 2015 | pmid = 25913846 | doi = 10.1111/dmcn.12777 | s2cid = 38835893 | doi-access = free }}</ref>).
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.<ref name="Summers 161–170"/><ref>{{cite journal | vauthors = Sullivan K, El-Hoss J, Quinlan KG, Deo N, Garton F, Seto JT, Gdalevitch M, Turner N, Cooney GJ, Kolanczyk M, North KN, Little DG, Schindeler A | title = NF1 is a critical regulator of muscle development and metabolism | journal = Human Molecular Genetics | volume = 23 | issue = 5 | pages = 1250–1259 | date = March 2014 | pmid = 24163128 | pmc = 3954124 | doi = 10.1093/hmg/ddt515 }}</ref>

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.<ref>{{cite journal | vauthors = Stevenson DA, Allen S, Tidyman WE, Carey JC, Viskochil DH, Stevens A, Hanson H, Sheng X, Thompson BA, Okumura MJ, Reinker K, Johnson B, Rauen KA | title = Peripheral muscle weakness in RASopathies | journal = Muscle & Nerve | volume = 46 | issue = 3 | pages = 394–399 | date = September 2012 | pmid = 22907230 | doi = 10.1002/mus.23324 | s2cid = 21120799 }}</ref> It is likely that impaired muscle function in these disorders is linked to altered Ras/MAPK signalling, however, the precise molecular mechanisms remain unknown.<ref name="Summers 161–170"/>

====Facial bones and limbs====
{{See also|List of radiographic findings associated with cutaneous conditions}}
* Bowing of a long bone with a tendency to fracture and not heal, yielding a [[pseudarthrosis]]. 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 or correction by [[Ilizarov apparatus|Ilizarov method]] as a [[limb-sparing techniques|limb-sparing technique]].
* 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 [[epiphysiodesis]], 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.

===Skin===
{{See also|List of conditions associated with café au lait macules}}
* Flat pigmented lesions of the skin called [[Café au lait spot|''café au lait'' spots]], are hyper pigmented lesions that may vary in color from light brown to dark brown; this is reflected by the name of the condition, which means "coffee with milk". The borders may be smooth or irregular. These spots can grow from birth and can continue to grow throughout the person's lifetime. They can increase in size and numbers during puberty and during pregnancies. They are present in about 99% of patients of European origin and in about 93% of patients of Indian origin.<ref>{{cite journal | vauthors = Lakshmanan A, Bubna A, Sankarasubramaniam A, Veeraraghavan M, Rangarajan S, Sundaram M |title=A clinical study of neurofibromatosis-1 at a tertiary health care centre in south India |journal=Pigment International |date=2016 |volume=3 |issue=2 |pages=102 |doi=10.4103/2349-5847.196302 |doi-access=free }}</ref>
* [[Freckle|Freckling]] of the [[axilla]]e or [[Groin|inguinal region]]s.
* [[Neurofibroma#Dermal neurofibroma|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 [[Neurofibroma#CO2 Laser|CO<sub>2</sub> lasers]] or by removal by a plastic surgeon specialized in NF1.<ref>{{Cite web|title = Northwestern Health Sciences University ~ Diagnosis and Discussion|url = https://www.nwhealth.edu/conted/distlear/unknown/unknown4/diaguk4.html|website = www.nwhealth.edu|access-date = 2015-10-27|archive-url = https://web.archive.org/web/20160304090203/https://www.nwhealth.edu/conted/distlear/unknown/unknown4/diaguk4.html|archive-date = 2016-03-04|url-status = dead}}</ref><ref>Piersall, Linda, [[David H. Gutmann]], & [[Rosalie Ferner]]. ''Living with Neurofibromatosis Type 1: A Guide for Adults''. New York, NY: The National Neurofibromatosis Foundation, Inc. Print.</ref>

===Eye disease===
* [[Lisch nodule]]s in the [[iris (anatomy)|iris]].
* [[Optic nerve glioma]]s along one or both [[optic nerves]] or the [[optic chiasm]] can cause bulging of the eyes, involuntary eye movement, squinting, and / or vision loss.  Treatment may include surgery, radiation +/- steroids, or chemotherapy (in children).<ref>{{MedlinePlusEncyclopedia|001024|Optic glioma}}</ref>

===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 90% of children and adults with NF-1 and have significant effects on their schooling and everyday life.<ref>{{cite journal | vauthors = Hyman SL, Shores A, North KN | title = The nature and frequency of cognitive deficits in children with neurofibromatosis type 1 | journal = Neurology | volume = 65 | issue = 7 | pages = 1037–1044 | date = October 2005 | pmid = 16217056 | doi = 10.1212/01.wnl.0000179303.72345.ce | s2cid = 10198510 }}</ref>  These cognitive problems have been shown to be stable into adulthood mainly in the mid 20s to early 30s and do not get worse unlike some of the other physical symptoms of NF-1.<ref>{{cite journal | vauthors = Hyman SL, Gill DS, Shores EA, Steinberg A, Joy P, Gibikote SV, North KN | title = Natural history of cognitive deficits and their relationship to MRI T2-hyperintensities in NF1 | journal = Neurology | volume = 60 | issue = 7 | pages = 1139–1145 | date = April 2003 | pmid = 12682321 | doi = 10.1212/01.WNL.0000055090.78351.C1 | s2cid = 26812237 }}</ref>  The most common cognitive problems are with perception, executive functioning and attention. Disorders include:
* Approximately 42% of children with NF-1 have symptoms of [[autism]], with 36.78% of them being severe cases, 33.33% being mild to moderate cases, and 29.89% of them having both symptoms of autism and ADHD.<ref name="ReferenceB">{{cite journal | vauthors = Garg S, Lehtonen A, Huson SM, Emsley R, Trump D, Evans DG, Green J | title = Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study | journal = Developmental Medicine and Child Neurology | volume = 55 | issue = 2 | pages = 139–145 | date = February 2013 | pmid = 23163236 | doi = 10.1111/dmcn.12043 | s2cid = 11781870 | doi-access = free }}</ref>
* [[Attention deficit hyperactivity disorder]] has been shown to be present in approximately 40% of children with NF-1.<ref name="ReferenceB"/>
* Speech and language delays have also been identified in approximately 68% of preschool children with NF-1.<ref>{{cite journal | vauthors = Thompson HL, Viskochil DH, Stevenson DA, Chapman KL | title = Speech-language characteristics of children with neurofibromatosis type 1 | journal = American Journal of Medical Genetics. Part A | volume = 152A | issue = 2 | pages = 284–290 | date = February 2010 | pmid = 20101681 | doi = 10.1002/ajmg.a.33235 | s2cid = 26650152 }}</ref>
* Motor deficits are common.  Motor deficits due to NF-1 are probably not [[Cerebellum|cerebellar]].<ref>{{cite journal | vauthors = van der Vaart T, van Woerden GM, Elgersma Y, de Zeeuw CI, Schonewille M | title = Motor deficits in neurofibromatosis type 1 mice: the role of the cerebellum | journal = Genes, Brain and Behavior | volume = 10 | issue = 4 | pages = 404–409 | date = June 2011 | pmid = 21352477 | doi = 10.1111/j.1601-183X.2011.00685.x | s2cid = 19609654 | doi-access = free }}</ref>
* [[Spatial visualization ability|Spatial]] deficit.{{citation needed|date=May 2023}}

===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.{{citation needed|date=June 2022}}

====Peripheral neuropathy====

=====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.

Neurofibroma conditions are progressive and include:
* [[Neurofibroma#Plexiform Neurofibroma|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 neurofibroma]], affecting 8–12% of patients with NF-1.  This occurs in a deep nerve trunk. Diagnosis by cross-sectional imaging (e.g., [[computed tomography]] or [[magnetic resonance imaging|magnetic resonance]]) as a [[fusiform]] enlargement of a nerve.
* [[Schwannoma]]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 [[Segmental resection|resected]] while sparing the underlying nerve, whereas resection of a neurofibroma requires the sacrifice of the underlying nerve.
* Nerve root neurofibroma.
* Bones, especially the ribs, can develop chronic erosions (pits) from the constant pressure of adjacent neurofibroma or schwannoma. Similarly, the neural foramen of the [[vertebral column|spine]] can be widened due to the presence of a nerve root neurofibroma or schwannoma. Surgery may be needed when NF-1 related tumors compress organs or other structures.

=====Nerve sheath tumor=====
[[File:MPNST.PNG|thumb|MRI image showing malignant peripheral nerve sheath tumor in the left tibia in neurofibromatosis type-1]]
* Chronic pain, numbness, and/or paralysis due to peripheral [[nerve sheath tumor]].{{citation needed|date=June 2022}}

=====Other complications=====
* Renal artery anomalies or [[pheochromocytoma]] and associated chronic [[hypertension]]
* [[Schwannoma]]
* Plexiform fibromas
* Optic nerve glioma
* Epilepsy

====Central nervous system disease====

=====Epilepsy=====
{{main|Epilepsy}}
* '''Occurrence'''. Epileptic seizures have been reported in up to 7% of {{Nowrap|NF-1}} patients.<ref>{{cite journal | vauthors = Vivarelli R, Grosso S, Calabrese F, Farnetani M, Di Bartolo R, Morgese G, Balestri P | title = Epilepsy in neurofibromatosis 1 | journal = Journal of Child Neurology | volume = 18 | issue = 5 | pages = 338–342 | date = May 2003 | pmid = 12822818 | doi = 10.1177/08830738030180050501 | s2cid = 39229702 }}</ref>
* '''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=====
{{main|Glial tumor}}

Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system, primarily [[optic nerve glioma]]s and associated blindness.<ref>{{cite journal | vauthors = Listernick R, Charrow J, Gutmann DH | title = Intracranial gliomas in neurofibromatosis type 1 | journal = American Journal of Medical Genetics | volume = 89 | issue = 1 | pages = 38–44 | date = March 1999 | pmid = 10469435 | doi = 10.1002/(sici)1096-8628(19990326)89:1<38::aid-ajmg8>3.0.co;2-m }}</ref>

=====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]].{{citation needed|date=March 2023}}

=====Dural ectasia=====
{{main|Dural ectasia}}

Within the CNS, NF-1 manifests as a weakness of the [[dura mater|dura]], which is the tough covering of the brain and spine. Weakness of the dura leads to focal enlargement due to chronic exposure to the pressures of [[Cerebrospinal fluid|CSF]] pulsation, and typically presents as paraesthesia or loss of motor or sensory function.<ref name="Mutua e0165"/> It has been shown that dural ectasia occur near plexiform neurofibromas which may be infiltrative leading to weakening of the dura.<ref name="Dural Ectasia in Neurofibromatosis">{{cite journal | vauthors = Polster SP, Dougherty MC, Zeineddine HA, Lyne SB, Smith HL, MacKenzie C, Pytel P, Yang CW, Tonsgard JH, Warnke PC, Frim DM | title = Dural Ectasia in Neurofibromatosis 1: Case Series, Management, and Review | journal = Neurosurgery | volume = 86 | issue = 5 | pages = 646–655 | date = May 2020 | pmid = 31350851 | doi = 10.1093/neuros/nyz244 }}</ref>

[[Acetazolamide]] has shown promise as a treatment for this condition, and in very few cases do dural ectasia require surgery.<ref name="Dural Ectasia in Neurofibromatosis"/>

===Mental Health===
People with NF1 are at increased risk for experiencing social and emotional difficulties such as; anxiety, depression, low self-esteem and/or body image, social withdrawal, difficulty forming interpersonal relationships, behavioural problems, and difficulties in school.<ref>{{cite journal | vauthors = Cohen JS, Levy HP, Sloan J, Dariotis J, Biesecker BB | title = Depression among adults with neurofibromatosis type 1: prevalence and impact on quality of life | journal = Clinical Genetics | volume = 88 | issue = 5 | pages = 425–430 | date = November 2015 | pmid = 25534182 | pmc = 4573679 | doi = 10.1111/cge.12551 }}</ref> People with NF1 are much more likely to experience suicidal thoughts than the general population. One study found that 45% of people with NF had suicidal thoughts compared to 10% of a healthy control group.<ref>{{cite journal | vauthors = Berardelli I, Maraone A, Belvisi D, Pasquini M, Giustini S, Miraglia E, Iacovino C, Pompili M, Frascarelli M, Fabbrini G | title = The importance of suicide risk assessment in patients affected by neurofibromatosis | journal = International Journal of Psychiatry in Clinical Practice | volume = 25 | issue = 4 | pages = 350–355 | date = November 2021 | pmid = 34270353 | doi = 10.1080/13651501.2021.1921217 | s2cid = 235999769 }}</ref> Another study found that 46.5% were of people with NF1 were found to have at least one psychiatric comorbid diagnosis.<ref>{{cite journal | vauthors = Brar KS, Trivedi C, Kaur N, Adnan M, Patel H, Beg U, Qureshi M, Mansuri Z, Ibrahim A, Zafar MK | title = Prevalence of Psychiatric Comorbidities in Patients With Neurofibromatosis | language = English | journal = The Primary Care Companion for CNS Disorders | volume = 25 | issue = 5 | pages = 49254 | date = October 2023 | pmid = 37816254 | doi = 10.4088/PCC.23m03514 | s2cid = 263240202 }}</ref>

=== Neurodivergence ===
Children and adults with NF-1 often have [[Autism spectrum|Autism]] and/or [[Attention deficit hyperactivity disorder|ADHD]].
* 30 - 50% of people with NF1 also meet the diagnostic criteria for ADHD<ref>{{cite journal | vauthors = Miguel CS, Chaim-Avancini TM, Silva MA, Louzã MR | title = Neurofibromatosis type 1 and attention deficit hyperactivity disorder: a case study and literature review | journal = Neuropsychiatric Disease and Treatment | volume = 11 | pages = 815–821 | date = 2015-03-25 | pmid = 25848279 | pmc = 4378869 | doi = 10.2147/NDT.S75038 | doi-access = free }}</ref>
* 11 - 26% of people with NF1 also have [[Autism spectrum|Autism Spectrum Disorder]]<ref>{{cite journal | vauthors = Chisholm AK, Haebich KM, Pride NA, Walsh KS, Lami F, Ure A, Maloof T, Brignell A, Rouel M, Granader Y, Maier A, Barton B, Darke H, Dabscheck G, Anderson VA, Williams K, North KN, Payne JM | title = Delineating the autistic phenotype in children with neurofibromatosis type 1 | journal = Molecular Autism | volume = 13 | issue = 1 | pages = 3 | date = January 2022 | pmid = 34983638 | pmc = 8729013 | doi = 10.1186/s13229-021-00481-3 | doi-access = free }}</ref>

=== Puberty and height ===
Children diagnosed with NF-1 may experience delayed or precocious puberty. Recent studies have correlated precocious puberty in individuals with NF-1 with the presence of optic pathway tumours.<ref name=":0">{{cite journal | vauthors = Virdis R, Street ME, Bandello MA, Tripodi C, Donadio A, Villani AR, Cagozzi L, Garavelli L, Bernasconi S | title = Growth and pubertal disorders in neurofibromatosis type 1 | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 16 | issue = Suppl 2 | pages = 289–292 | date = March 2003 | pmid = 12729406 | doi = | url = }}</ref> Furthermore, the heights of children affected by NF-1 have been shown to increase normally until puberty, after which increases in height lessen when compared to healthy counterparts.<ref name=":0" /> This eventually causes a shorter stature than expected in individuals with NF-1.

===Cancer===
[[Cancer]] can arise in the form of [[malignant peripheral nerve sheath tumor]] resulting from malignant degeneration of a plexiform neurofibroma.<ref name="pmid10469434">{{cite journal | vauthors = Korf BR | title = Plexiform neurofibromas | journal = American Journal of Medical Genetics | volume = 89 | issue = 1 | pages = 31–37 | date = March 1999 | pmid = 10469434 | doi = 10.1002/(sici)1096-8628(19990326)89:1<31::aid-ajmg7>3.0.co;2-w }}</ref><ref name="pmid8402499">{{cite journal | vauthors = Matsui I, Tanimura M, Kobayashi N, Sawada T, Nagahara N, Akatsuka J | title = Neurofibromatosis type 1 and childhood cancer | journal = Cancer | volume = 72 | issue = 9 | pages = 2746–2754 | date = November 1993 | pmid = 8402499 | doi = 10.1002/1097-0142(19931101)72:9<2746::AID-CNCR2820720936>3.0.CO;2-W | doi-access = free }}</ref>
* '''Frequency'''. A plexiform neurofibroma has a lifetime risk of 8–12% of transformation into a malignant tumor.
* '''Diagnosis'''. [[Magnetic resonance imaging|MRI]].
* '''Treatment'''.  Surgery (primary), radiation therapy.
* '''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 population.<ref>{{cite journal | vauthors = Duong TA, Sbidian E, Valeyrie-Allanore L, Vialette C, Ferkal S, Hadj-Rabia S, Glorion C, Lyonnet S, Zerah M, Kemlin I, Rodriguez D, Bastuji-Garin S, Wolkenstein P | title = Mortality associated with neurofibromatosis 1: a cohort study of 1895 patients in 1980-2006 in France | journal = Orphanet Journal of Rare Diseases | volume = 6 | pages = 18 | date = May 2011 | pmid = 21542925 | pmc = 3095535 | doi = 10.1186/1750-1172-6-18 | doi-access = free }}</ref>  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.

=== Breast Cancer ===
Biological females with NF also have a five-fold increased risk of [[breast cancer]] and may have an increased breast cancer related mortality. The median survival for breast cancer in people with NF was 5 years vs. the reported median survival of over 20 years in the general population using the SEER database.<ref>{{cite journal | vauthors = Suarez-Kelly LP, Yu L, Kline D, Schneider EB, Agnese DM, Carson WE | title = Increased breast cancer risk in women with neurofibromatosis type 1: a meta-analysis and systematic review of the literature | journal = Hereditary Cancer in Clinical Practice | volume = 17 | issue = 1 | pages = 12 | date = 2019-03-25 | pmid = 30962859 | pmc = 6434896 | doi = 10.1186/s13053-019-0110-z | doi-access = free }}</ref><ref>{{Cite web |title=Cancer Statistics Review, 1975-2012 | work = SEER Cancer Statistics Review |url=https://seer.cancer.gov/archive/csr/1975_2012/index.html |access-date=2023-11-15 |language=en}}</ref>

==Cause==
{{main|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 1|neurofibromin]]<ref name="pmid2134734">{{cite journal | vauthors = Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL | title = Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients | journal = Science | volume = 249 | issue = 4965 | pages = 181–186 | date = July 1990 | pmid = 2134734 | doi = 10.1126/science.2134734 | bibcode = 1990Sci...249..181W }}</ref> (not to be confused with the disorder itself) which plays a role in [[cell signaling]].<ref>[https://www.genecards.org/cgi-bin/carddisp.pl?gene=NF1 "neurofibromin 1"] [[GeneCards]]</ref><ref>[http://genome.ucsc.edu/cgi-bin/hgGene?hgg_gene=uc002hgf.1&org=human "Human Gene NF1 (uc002hgf.1) Description and Page Index"]</ref> The [[Neurofibromin 1]] gene is a negative regulator of the [[Ras (protein)|Ras]] [[oncogene]] [[signal transduction]] pathway. It stimulates the [[GTPase]] activity of [[Ras (protein)|Ras]].

In 1989, through linkage and cross over analyses, neurofibromin was localized to chromosome 17.<ref name=autogenerated1>{{cite journal | vauthors = Goldberg NS, Collins FS | title = The hunt for the neurofibromatosis gene | journal = Archives of Dermatology | volume = 127 | issue = 11 | pages = 1705–1707 | date = November 1991 | pmid = 1952978 | doi = 10.1001/archderm.1991.01680100105014 }}</ref> 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.<ref name=autogenerated1 /> 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.<ref>{{cite journal | vauthors = Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel MJ, Martin L, Barbarot S, Leheup B, Rodriguez D, Lacombe D, Dollfus H, Pasquier L, Isidor B, Ferkal S, Soulier J, Sanson M, Dieux-Coeslier A, Bièche I, Parfait B, Vidaud M, Wolkenstein P, Upadhyaya M, Vidaud D | title = NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype | journal = Human Mutation | volume = 31 | issue = 6 | pages = E1506–E1518 | date = June 2010 | pmid = 20513137 | doi = 10.1002/humu.21271 | s2cid = 24525378 | doi-access = free }}</ref>

==== Structure ====
The neurofibromin gene was soon sequenced and found to be 350,000 base pairs in length.<ref name="autogenerated3">{{cite journal | vauthors = Marchuk DA, Saulino AM, Tavakkol R, Swaroop M, Wallace MR, Andersen LB, Mitchell AL, Gutmann DH, Boguski M, Collins FS | title = cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product | journal = Genomics | volume = 11 | issue = 4 | pages = 931–940 | date = December 1991 | pmid = 1783401 | doi = 10.1016/0888-7543(91)90017-9 | hdl-access = free | hdl = 2027.42/29018 }}</ref> However, the protein is 2818 amino acids long leading to the concept of splice variants.<ref name=autogenerated2>{{cite journal | vauthors = Gutmann DH, Giovannini M | title = Mouse models of neurofibromatosis 1 and 2 | journal = Neoplasia | volume = 4 | issue = 4 | pages = 279–290 | year = 2002 | pmid = 12082543 | pmc = 1531708 | doi = 10.1038/sj.neo.7900249 }}</ref> For example, exon 9a, 23a and 48a are expressed in the neurons of the forebrain, muscle tissues and adult neurons respectively.<ref name="autogenerated2" />

Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase activating protein (GAP) family.<ref name="autogenerated3" /> 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 (protein)|Ras]] kinase.<ref>{{cite journal | vauthors = Feldkamp MM, Angelov L, Guha A | title = Neurofibromatosis type 1 peripheral nerve tumors: aberrant activation of the Ras pathway | journal = Surgical Neurology | volume = 51 | issue = 2 | pages = 211–218 | date = February 1999 | pmid = 10029430 | doi = 10.1016/S0090-3019(97)00356-X }}</ref>

Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein [[Adenylate cyclase|adenylyl cyclase]],<ref>{{cite journal | vauthors = Hannan F, Ho I, Tong JJ, Zhu Y, Nurnberg P, Zhong Y | title = Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras | journal = Human Molecular Genetics | volume = 15 | issue = 7 | pages = 1087–1098 | date = April 2006 | pmid = 16513807 | pmc = 1866217 | doi = 10.1093/hmg/ddl023 }}</ref> and a second with [[CRMP1|collapsin response mediator protein]].<ref>{{cite journal | vauthors = Ozawa T, Araki N, Yunoue S, Tokuo H, Feng L, Patrakitkomjorn S, Hara T, Ichikawa Y, Matsumoto K, Fujii K, Saya H | title = The neurofibromatosis type 1 gene product neurofibromin enhances cell motility by regulating actin filament dynamics via the Rho-ROCK-LIMK2-cofilin pathway | journal = The Journal of Biological Chemistry | volume = 280 | issue = 47 | pages = 39524–39533 | date = November 2005 | pmid = 16169856 | doi = 10.1074/jbc.M503707200 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Le LQ, Parada LF | title = Tumor microenvironment and neurofibromatosis type I: connecting the GAPs | journal = Oncogene | volume = 26 | issue = 32 | pages = 4609–4616 | date = July 2007 | pmid = 17297459 | pmc = 2760340 | doi = 10.1038/sj.onc.1210261 }}</ref>

===Inheritance and spontaneous mutation===
[[Image:Autosomal Dominant Pedigree Chart.svg|thumb|right|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 [[Mutation#Spontaneous mutation|spontaneous mutation]]. The incidence of NF-1 is about 1 in 3500 live births.<ref>{{OMIM|162200|NEUROFIBROMATOSIS, TYPE I; NF1}}</ref>

==Diagnosis==

===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.<ref>{{Cite web |url=http://www.bionews.org.uk/page_13407.asp |title = British couple successfully screens out genetic disorder using NHS-funded PGD | vauthors = Blackburn-Starzan A | date = 9 June 2008 | work = BioNews | volume = 461 |access-date=May 16, 2011 |archive-date=March 30, 2016 |archive-url=https://web.archive.org/web/20160330024658/http://www.bionews.org.uk/page_13407.asp |url-status=dead }}</ref>

While the presence of NF-1 can be identified through prenatal testing the severity with which the condition will be expressed is impossible to determine.<ref>{{Cite web|url=https://www.genome.gov/Genetic-Disorders/Neurofibromatosis|title=About Neurofibromatosis|website=Genome.gov|language=en|access-date=2020-03-05}}</ref>

People with NF-1 have a 50% percent chance of passing the disorder to their offspring, but people can have a child born with NF-1 when they themselves do not have the condition. This is caused by a [[spontaneous mutation]].

===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.<ref>{{cite journal |title=Neurofibromatosis: Conference Statement |journal=Archives of Neurology |date=1 May 1988 |volume=45 |issue=5 |pages=575 |doi=10.1001/archneur.1988.00520290115023 }}</ref><ref>{{cite book | vauthors = Huson SM, Hughes RA  |title=The neurofibromatoses: a pathogenetic and clinical overview |publisher=Chapman & Hall |location=London |year=1994 |isbn=978-0-412-38920-7 |at=1.3.2:9}}</ref> There is practical flowchart to distinguish between NF1, NF2 and schwannomatosis.<ref>{{cite journal | vauthors = Rodrigues LO, Batista PB, Goloni-Bertollo EM, de Souza-Costa D, Eliam L, Eliam M, Cunha KS, Darrigo-Junior LG, Ferraz-Filho JR, Geller M, Gianordoli-Nascimento IF, Madeira LG, Malloy-Diniz LF, Mendes HM, de Miranda DM, Pavarino EC, Baptista-Pereira L, Rezende NA, Rodrigues L, da Silva CM, de Souza JF, de Souza ML, Stangherlin A, Valadares ER, Vidigal PV | title = Neurofibromatoses: part 1 - diagnosis and differential diagnosis | journal = Arquivos de Neuro-Psiquiatria | volume = 72 | issue = 3 | pages = 241–250 | date = March 2014 | pmid = 24676443 | doi = 10.1590/0004-282X20130241 | doi-access = free }}</ref>
* Six or more [[café-au-lait spot]]s over 5&nbsp;mm in greatest diameter in pre-pubertal individuals and over 15&nbsp;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.
* Two or more neurofibromas of any type or 1 plexiform neurofibroma
* Freckling in the [[axillary region|axillary]] ([[Crowe sign]]) or [[Groin|inguinal region]]s
* [[Optic nerve glioma]]
* Two or more [[Lisch nodule]]s (pigmented 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.

==Psychological and Neurodevelopmental Disorders==

In addition to physical manifestations, patients with NF1 are at high risk of developing [[Neurodevelopmental disorder|neurodevelopmental disorders]], which result in learning difficulties, attention problems, and other behavioral or social challenges. <ref name=":12">{{Cite journal|url=https://onlinelibrary.wiley.com/doi/10.1111/dmcn.13526|title=Neurodevelopmental disorders in children with neurofibromatosis type 1|last1=Vogel|first1=Alecia C|last2=Gutmann|first2=David H|date=November 2017 |journal=Developmental Medicine & Child Neurology|volume=59|issue=11|pages=1112–1116|access-date=2024-10-12|language=en|issn=0012-1622|doi=10.1111/dmcn.13526|last3=Morris|first3=Stephanie M|pmid=28845518 }}</ref> Studies have shown that children with NF1 are particularly prone to being affected by conditions such as [[Attention deficit hyperactivity disorder|Attention Deficit Hyperactivity Disorder]] (ADHD) or [[Autism spectrum disorders|Autism Spectrum Disorder]] (ASD), as well as psychological disorders such as anxiety or depression, highlighting the importance of multidisciplinary evaluation and care for these patients. <ref name=":12" />

===Autism spectrum disorder in NF-1===

A significant number of children with NF-1 exhibit symptoms commonly associated with Autism Spectrum Disorder (ASD), which can impact daily functioning.<ref name="NF1Learning">{{Cite web|url=https://www.ctf.org/wp-content/uploads/2023/11/NF1-Learning-brochure.pdf|title=Learning Disabilities in Children with NF1|last=Children’s Tumor Foundation|website=ctf.org|date=November 2023|access-date=12 October 2024}}</ref> These symptoms may include difficulties with flexibility and transitions, repetitive behaviors, challenges in social communication, social awareness, and adaptability.<ref name="NF1Learning" />

Some studies have identified subtle but significant differences between ASD symptomatology in individuals with NF-1 and those with idiopathic autism.<ref name=":11">{{Cite journal|url=https://doi.org/10.1007/s10803-014-2321-5|title=Autism Spectrum Disorder Profile in Neurofibromatosis Type I|last1=Garg|first1=Shruti|last2=Plasschaert|first2=Ellen|date=2015-06-01|journal=Journal of Autism and Developmental Disorders|volume=45|issue=6|pages=1649–1657|access-date=2024-07-23|language=en|issn=1573-3432|doi=10.1007/s10803-014-2321-5|last3=Descheemaeker|first3=Mie-Jef|last4=Huson|first4=Susan|last5=Borghgraef|first5=Martine|last6=Vogels|first6=Annick|last7=Evans|first7=D. Gareth|last8=Legius|first8=Eric|last9=Green|first9=Jonathan|pmid=25475362 |url-access=subscription}}</ref> These differences include stronger eye contact, fewer repetitive behaviors, and more pronounced autistic mannerisms compared to non-syndromic ASD.<ref name=":NF1-TSC">{{Cite journal|title=Autism Symptoms in Children and Young Adults With Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex, and Neurofibromatosis Type 1: A Cross-Syndrome Comparison|last1=Lubbers|first1=Kyra|last2=Stijl|first2=Eefje M.|date=2022-05-16|journal=Frontiers in Psychiatry|volume=13|language=en|issn=1664-0640|doi=10.3389/fpsyt.2022.852208|pmc=9149157|pmid=35651825|last3=Dierckx|first3=Bram|last4=Hagenaar|first4=Doesjka A.|last5=ten Hoopen|first5=Leontine W.|last6=Legerstee|first6=Jeroen S.|last7=de Nijs|first7=Pieter F. A.|last8=Rietman|first8=André B.|last9=Greaves-Lord|first9=Kirstin |doi-access=free}}</ref> Enhanced language skills have also been noted in this population.<ref name=":11" /> More than 90% of children with ASD + NF1 demonstrate clinically significant challenges in interpreting social signals and social communication during interactions.<ref name=":11" />

Discrepancies have been noted between parent-report questionnaires, such as the [[Social Responsiveness Scale]] (SRS), and clinical observation tools as in the case of the [[Autism Diagnostic Observation Schedule]] (ADOS), suggesting that restricted repetitive behaviors in NF-1 autism may be qualitatively different or less severe than in idiopathic autism, and therefore may go undetected in ADOS assessments.<ref name=":11" />

Studies indicate that parent-reported scores on the autistic mannerisms subscale of the SRS questionnaire were notably high, with two-thirds of children with NF-1 + ASD scoring in the severe problem range.<ref name=":11" />

Regarding items assessing imagination and creativity, children with NF-1 + ASD exhibit similar levels of impairment as the autism group, while being significantly more affected than children with only ASD. <ref name=":11" /> Furthermore, no differences were observed between the groups on items measuring hyperactivity. Similarly, no evidence of group differences was found for the anxiety item, which is also associated with certain genetic disorders, such as [[Fragile X syndrome]] and [[Cornelia de Lange syndrome]].<ref name=":11" />

Research suggests that Neurofibromatosis Type 1 and [[Tuberous Sclerosis]] (TSC) exhibit similarities in the symptomatology associated with Autism Spectrum Disorder.<ref name=":NF1-TSC" />  These findings may indicate the existence of shared neurobiological characteristics between the two syndromes that influence the presentation of ASD symptoms.

Due to their fewer observed repetitive behaviors and improved eye contact, these children may not exhibit the typical characteristics of idiopathic autism in clinical settings, increasing the likelihood that they will be overlooked by clinicians.<ref name=":11" />

Unlike idiopathic ASD, both males and females seem to be equally affected, indicating a diminished protective effect of gender against ASD symptoms, akin to other syndromic causes of ASD.<ref name=":12" /> 

Other studies do not find a significant association between neurofibromatosis type 1 (NF1) and autism spectrum disorder (ASD).<ref name=":1">{{Cite journal |last1=Morotti |first1=Hadley |last2=Mastel |first2=Sarah |last3=Keller |first3=Kory |last4=Barnard |first4=Rebecca A |last5=Hall |first5=Trevor |last6=O'Roak |first6=Brian J |last7=Fombonne |first7=Eric |date=2021 |title=Autism and attention-deficit/hyperactivity disorders and symptoms in children with neurofibromatosis type 1 |url=https://onlinelibrary.wiley.com/doi/10.1111/dmcn.14558 |journal=Developmental Medicine & Child Neurology |language=en |volume=63 |issue=2 |pages=226–232 |doi=10.1111/dmcn.14558 |pmid=32406525 |issn=1469-8749}}</ref>  While children with NF1 exhibit more autism-related symptoms and behavioral problems compared to typically developing children, these are often explained by the presence of ADHD and other concurrent issues, without reaching clinically significant levels.<ref name=":1" />

=== ADHD in NF-1 ===

Children with NF-1 may experience behavioral difficulties related to inattention, impulsivity, hyperactivity, and inflexibility.<ref name="NF1Learning" /> Studies have shown that clinical criteria for diagnosing ADHD are met by 23% to 50% of children with NF-1.<ref name=":13">{{Cite journal|url=https://journals.sagepub.com/doi/10.1177/1087054717707579|title=Attention and Executive Disorders in Neurofibromatosis 1: Comparison Between NF1 With ADHD Symptomatology (NF-1 + ADHD) and ADHD Per Se|last1=Lion-François|first1=Laurence|last2=Herbillon|first2=Vania|date=November 2020 |journal=Journal of Attention Disorders|volume=24|issue=13|pages=1807–1823|access-date=2024-10-24|language=en|issn=1087-0547|doi=10.1177/1087054717707579|last3=Peyric|first3=Emeline|last4=Mercier|first4=Catherine|last5=Gérard|first5=Daniel|last6=Ginhoux|first6=Tiphanie|last7=Coutinho|first7=Virginie|last8=Kemlin|first8=Isabelle|last9=Kassai|first9=Behrouz|pmid=28587546 |url-access=subscription}}</ref> Children with NF-1 may sometimes have attention difficulties without hyperactivity or behavioral problems. In such cases, attention deficits might go unnoticed without formal cognitive testing, although some children may have attention issues that, while not severe enough for an ADHD diagnosis, would still benefit from support.<ref name="NF1Learning" />

Individuals with neurofibromatosis type 1 often exhibit certain brain abnormalities known as T2 hyperintensities (visible on MRI scans), referred to as Unidentified Bright Objects (UBOs), which are located in specific brain regions such as the cerebellum, brainstem, thalamus, and basal ganglia—areas involved in motor signal processing and cognitive functions.<ref name=":13" /> Some of these brain regions are also connected to attention-related networks, particularly those involved in cognitive flexibility and motor inhibition, which are essential for attention and behavior. It is well established that these networks are impaired in ADHD.<ref name=":13" />

Studies suggest that while ADHD symptoms may partially explain attention problems in NF-1, such as impulsivity, they do not fully account for other deficits like cognitive control.<ref name=":13" /> Children with NF-1 often exhibit impairments in planning, spatial working memory, and response inhibition, independent of ADHD, suggesting that the impact of ADHD on their attention and executive functioning is limited.<ref name=":13" />

Although ADHD prevalence is a key factor in NF-1 cognition studies, comparisons between children with NF-1 and ADHD and those without ADHD have not consistently shown clear differences.<ref name=":13" /> This creates confusion regarding how to differentiate the effects of NF-1 and ADHD on cognition. Moreover, focusing on ADHD symptoms might obscure attention issues that are specifically associated with NF-1.<ref name=":13" />

Results from tasks assigned in studies comparing NF-1 + ADHD groups with children who have only ADHD suggest that NF-1 + ADHD is not simply a combination of both conditions, nor does ADHD merely exacerbate attention problems in NF-1.<ref name=":13" /> These differences are qualitative rather than quantitative, supporting the idea that some deficits are unique to NF-1 and independent of ADHD. Additionally, certain attention issues, such as intrinsic alertness and visual scanning among distractors, may be considered characteristic traits of NF-1.<ref name=":13" />

==Treatment==
Treatment for NF1 is limited, and there is currently no cure.  Pain meds can be prescribed to help with pain. In some cases, growths may be removed surgically or reduced with radiation therapy. Treatment options are limited, given the tumours tendency to regrow following surgery and their propensity to transform into malignant tumours following radiation.<ref>{{cite journal | vauthors = Coltin H, Perreault S, Larouche V, Black K, Wilson B, Vanan MI, Gupta AA, Morgenstern DA, Parkin PC, Bouffet E, Ramaswamy V | title = Selumetinib for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1: A national real-world case series | journal = Pediatric Blood & Cancer | volume = 69 | issue = 8 | pages = e29633 | date = August 2022 | pmid = 35289492 | doi = 10.1002/pbc.29633 | s2cid = 247453317 }}</ref> Although surgery in these areas can cause further injury to nerves and additional neurological problems. The benefits of surgery should always be considered against its risks. Some NF tumours are inoperable.

=== Drug Therapies ===

==== Mirdametinib ====
{{Excerpt|Mirdametinib}}

==== Selumetinib ====
[[Selumetinib]], is a drug produced by [[AstraZeneca|Astra Zeneca]] sold under the brand name Koselugo, and was approved by the FDA in April 2020<ref>{{Cite web | author = Office of the Commissioner|date=2020-04-10|title=FDA Approves First Therapy for Children with Debilitating and Disfiguring Rare Disease|url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-children-debilitating-and-disfiguring-rare-disease|access-date=2020-06-21|website=FDA|language=en}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}</ref> for the treatment of NF-1 in the pediatric population who are two or more years of age. It is a mitogen-activated protein kinase inhibitor (MEKi) and is indicated for use in pediatric patients who are symptomatic and have inoperable plexiform neurofibromas.<ref>AstraZeneca Pharmaceuticals LP. Koselugo(Selumetinib)[package insert]. U.S. Food and Drug Administration website.[https://web.archive.org/web/20200411011927/https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf]. Accessed June 21, 2020.</ref> However, this medication is not curative and is not suitable for all patients.

Side effects of Selumetinib include headache, nausea/vomiting, abdominal pain and other problems of the [[gastrointestinal tract]], fatigue, muscle pain, Constipation,  Paronychia as well as dry skin and other skin and hair problems.<ref>{{Cite web | work = DailyMed | publisher = U.S. National Library of Medicine | title = KOSELUGO- selumetinib capsule |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7d042c61-f28f-4ab5-ab10-d7558c0d49ff |access-date=2023-11-15 }}</ref> The side effects can have a significant impact on a patient's life and may lead to someone having to discontinue treatment.

In an open-label, phase 2 trial of selumetinib with 50 children:
* 35 patients (70%) had a confirmed partial response, 28 of these patients had a durable response (lasting ≥1 year)
* After 1 year of treatment, the mean decrease in child-reported tumour pain-intensity scores was 2 points, which is considered a clinically meaningful improvement

==Prognosis==
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 [[Expressivity (genetics)|variable expressivity]]. For example, some individuals have almost no symptoms, while others may have a manifestation that is rapidly more progressive and can lead to significant disability and death.

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 like increased cancer risk, a plexiform neurofibroma has a 10-15% chance of developing into a MPNST (Malignant Peripheral Nerve Sheath Tumour) Epidemiology NF-1 is estimated to affect around 25,000 people in the [[United Kingdom|UK]].<ref>{{Cite web| vauthors = Ashton R, Crawford H, Morrison P, McKee S, Huson S |date=2012|title=Neurofibromatosis Type 1 (NF1) a Guide for Adults and Families |url= https://nervetumours.org.uk/images/downloads/NTUK_Neurofibromatosis_Type_1_-_a_guide_for_adults_and_families_v1.pdf |access-date=2021-04-27 |website=Nerve Tumours UK}}</ref>

== In popular culture ==
[[Victor Hugo]]'s novel ''[[The Hunchback of Notre-Dame]]'' (1831) is often cited as having influenced popular culture and shaped misunderstandings about neurofibromatosis, as it was assumed that the man who inspired [[Quasimodo|the book's protagonist]] had neurofibromatosis.<ref>{{Cite journal |last1=Valeyrie-Allanore |first1=Laurence |last2=Roujeau |first2=Jean-Christophe |last3=Revuz |first3=Jean |date=2005 |title=Neurofibromatosis type 1: From diagnosis to therapeutic challenges |journal=American Journal of Medical Genetics Part A |volume=137A |issue=1 |pages=12–23 |doi=10.1002/ajmg.a.38486|pmid=29388340 }}</ref>

For many years, it was thought that [[Joseph Merrick]] (popularly known as the Elephant Man) had neurofibromatosis. In 1986, geneticists Tibbles and Cohen theorized that Merrick instead had the much rarer [[Proteus syndrome]].<ref>{{cite journal | vauthors = Legendre CM, Charpentier-Côté C, Drouin R, Bouffard C | title = Neurofibromatosis type 1: persisting misidentification of the "elephant man" disease | journal = Journal of the American Board of Family Medicine | volume = 24 | issue = 1 | pages = 112–114 | date = 2011-01-01 | pmid = 21209351 | doi = 10.3122/jabfm.2011.01.100219 | doi-access = free }}</ref>

In [[Abraham Verghese]]'s novel ''[[The Covenant of Water]]'' (2023), neurofibromatosis is referred to solely as "the condition" and is a key plot point.

In [[Aaron Schimberg]]'s film ''[[A Different Man]]'' (2024), the main characters played by [[Sebastian Stan]] and [[Adam Pearson (actor)|Adam Pearson]] both have neurofibromatosis, which Pearson also has in real life.

== See also ==
* [[Neurofibromatosis type II]]
* [[Characteristics of syndromic ASD conditions]]

== References ==
{{Reflist}}

== External links ==
{{commonscatinline}}
{{Medical resources
|  ICD10          = {{ICD10|Q|85|0|q|80}} ([[ILDS]] Q85.010)
|  ICD9           = {{ICD9|237.71}}
|  ICDO           =
|  OMIM           = 162200
|  DiseasesDB     = 8937
|  MedlinePlus    = 000847
|  eMedicineSubj  = derm
|  eMedicineTopic = 287
|  eMedicine_mult = {{eMedicine2|neuro|248}} {{eMedicine2|oph|338}} {{eMedicine2|radio|474}}
|  MeshID         = D009456
|  GeneReviewsNBK   = NBK1109
|  GeneReviewsName  = Neurofibromatosis 1
}}

{{Autism spectrum}}
{{Phakomatoses}}
{{Central nervous system tumors}}
{{Deficiencies of intracellular signaling peptides and proteins}}

{{DEFAULTSORT:Neurofibromatosis Type I}}
[[Category:Deficiencies of intracellular signaling peptides and proteins]]
[[Category:Neurological disorders]]
[[Category:Neuro-cardio-facial-cutaneous syndromes]]
[[Category:RASopathies]]
[[Category:Syndromic autism]]

[[tr:Nörofibromatoz tip 1]]