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Neurofibromatosis Type 1 (NF1, also known as von Recklinghausen disease) is an autosomal dominant disorder characterized by tumor and nontumor manifestations that can involve various organ systems, including pigmentary skin lesions called café au lait macules, ectodermal tumors in the skin and nerve sheaths called neurofibromas, and those involving other organs such as skeletal dysplasias.1


NF1 is a genetic disorder resulting from a mutation in the NF1 tumor suppressor gene located at chromosome 17q11.2, which encodes the guanosine triphosphatase–activating protein neurofibromin. Decreased production of neurofibromin results in the overactivation of the RAS pathway involved in promoting cell growth/division. The mutation may be de novo or inherited, germline or somatic.2 Penetrance, or the likelihood that a person carrying the NF1 mutation will develop clinical features of the disease, is complete. However, the severity of the clinical features can be variable.1

Epidemiology including risk factors and primary prevention

NF1 is a relatively common disorder, with a prevalence of approximately 1 in 2,500 to 3,000 individuals.3 Approximately 50% of cases of NF1 are de novo mutations of the NF1 gene. All ethnicities, races, and sexes are affected with equal frequency.3


Diagnosis of NF1 is usually made clinically, although genetic testing may be required for diagnosis on rare occasions. The National Institutes of Health (NIH) Consensus Development Conference criteria4 require two or more of the following clinical features in an individual without a parent diagnosed with NF1:

  • 6 or more café-au-lait macules present (> 5mm in diameter in prepuberty or > 15mm in diameter post puberty).
  • 2 or more neurofibromas of any type 1 plexiform neurofibroma
  • Skinfold freckling (axillary or inguinal)
  • 2 or more Lisch nodules (iris hamartomas)
  • A distinct bony lesion (such as thinning of long bone cortex and sphenoid wing dysplasia)
  • Optic pathway glioma (OPG)
  • A mutation in the NF1 gene with an allele fraction of 50% occurring in normal tissue

If an individual has a parent diagnosed with NF1, then the individual warrants a diagnosis of NF1 if they meet one or more of the above criteria.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

The first feature to be noted, often evident in early infancy, is café au lait macules with uniform and regular borders. Skinfold freckling, usually in the axillary and inguinal regions, typically develops around 3 to 5 years of age.

Optic pathway gliomas (OPGs) typically develop prior to age 6. Iris hamartomas (Lisch nodules) often appear in children by school age and are present in most teenagers.

Cutaneous neurofibromas usually first appear on the trunk in the teenage years and can increase in number and extend distally as the individual ages. Although they are benign tumors, they can cause significant pain and disfiguration, which impacts quality of life.

Plexiform neurofibromas arise from nerve trunks or branches; they often arise early in childhood and are found in up to 50% of individuals with NF1. Plexiform neurofibromas can occur in any area of the body, including head and neck, orbit, extremities, thorax, paraspinal nerve roots, abdomen, and pelvis. The most common related symptoms are pain and motor dysfunction, with other morbidities related to direct impact of the tumor on surrounding structures. Depending on their location, functional impact may include visual or hearing impairments, airway obstruction, speech and swallowing difficulties, motor dysfunction, and bowel or bladder dysfunction, among others.5 Plexiform neurofibromas are benign but there is a 10% chance of transformation to malignant peripheral nerve sheath tumors (MPNST), usually during or after young adulthood. Malignant transformation should be suspected in patients with known plexiform neurofibromas that undergo rapid growth, consistency change, or cause increased pain. MPNST and vascular complications are the major causes of reduced life expectancy (by ~8 to 15 years) in NF1 patients.6

Specific secondary or associated conditions and complications

In addition to malignant peripheral nerve sheath tumors, NF1 is associated with skeletal abnormalities, including scoliosis (dystrophic and non-dystrophic), long bone pseudoarthrosis, sphenoid wing dysplasia, and osteopenia. Dystrophic scoliosis is characterized by a sharply angulated curve associated with vertebral dysplasia (e.g., vertebral scalloping, rib penciling, among others) that progresses rapidly and often requires surgical management. Tibial dysplasia is the most common type of bone dysplasia in patients with NF1.6

In children, NF1 may be associated with learning disabilities, including attention deficit hyperactivity disorder (ADHD), which occurs in at least 50% of individuals with NF1. Some individuals with NF1 demonstrate difficulty with social pragmatics that impact communication skills, and it has been suggested that NF1 increases susceptibility to autism spectrum disorder (ASD).6 

Patients with NF1 also demonstrate a higher incidence of pain, with studies reporting that 29% to 70% of these patients experience pain.7 This has been shown to negatively impact quality of life. The mechanism is thought to be multifactorial, from secondary pain from tumors to changes in pain pathways.

NF1 can also be associated with vascular abnormalities, such as renal artery stenosis and hypertension secondary to renovascular disease or pheochromocytoma. It is also associated with precocious puberty. Other non-tumor associated neurologic symptoms include headaches and seizures.8

Essentials of Assessment


Children with NF1 may exhibit both physical and cognitive impairments related to the disorder. A thorough history including developmental milestones, pain, current function across functional domains, school performance, and behavior with peers and adults may help to direct an appropriate workup to identify tumor or nontumor impairments. History of any prior or current receipt of rehabilitation therapies, early intervention, or school services or accommodations should be elicited. It is also helpful to screen for any treatment for tumors to assess for any treatment-related complications such as chemotherapy-induced neuropathy.

Physical examination

Pediatric NF1 patients should undergo routine ophthalmic examinations at least annually from the time of diagnosis to screen for OPGs. Skin should be inspected for macules and neurofibromas. Careful central and peripheral nervous system examination should be performed. Assessment of range of motion, inspection for and measurement of any long bone asymmetry, and spine examination are important for identifying and monitoring musculoskeletal impairments. Findings derived from observation of the child’s speech and behavior should be noted. Growth curves should be monitored and vitals taken with special attention to blood pressure values. 

Functional assessment

Fine motor coordination pertaining to age-appropriate self-care skills, gross motor balance, bed mobility, transfers, and gait symmetry and pattern should be a part of the assessment at each visit. Brief assessments of age-appropriate verbal and emotional/behavioral skills can help identify need for more formal assessment to rule out ADHD and ASD and other potential cognitive-behavioral conditions.

Laboratory studies

No specific routine laboratory studies for NF1 are required, although monitoring for bone health, including checking Vitamin D levels, may be considered.


Routine neuroimaging (brain) with magnetic-resonance imaging (MRI) to screen for OPG is controversial. One supporting argument for routine surveillance is that patients younger than 6 years of age have difficulty reporting visual symptoms. The NF1 Optic Pathway Glioma Task Force has recommended against the use of screening MRI, recommending it to be done only if there are findings on the ophthalmological examination.

Whole body MRI with volumetric assessment of plexiform neurofibromas is a way to determine tumor burden, which is useful if using a treatment which slows progress of plexiform tumor growth. Dedicated imaging of specific areas of the body, such as scoliosis series or long bone films, should be ordered based on the history and examination obtained during each clinic visit.

Supplemental assessment tools

While genetic testing is usually not necessary to diagnose NF1, it can be considered in certain instances. For example, it can confirm a suspected diagnosis before a clinical diagnosis is possible (i.e., prior to a second feature appearing). In addition, some genotypic-phenotypic correlations do exist, and genetic testing may provide prognostic information and help determine whether certain organ system surveillance would be important to managing certain morbidities.6

Early predictions of outcomes

Greater disease severity is associated with reduced quality of life, including physical function, bodily pain, general health perception, and vitality. Patients with more visible features of NF1 also report significant emotional effects.9



Social role and social support system

Children with evidence of cognitive-behavioral impairments require in-depth neuropsychological evaluation to identify challenges and strengths, as a diagnosis of NF1 does not result in a predictable pattern of learning disability. Treatment may include medically prescribed psychological and/or rehabilitation therapies and school-based services and accommodations (such as a 504 or an individualized education plan) provided in compliance with the Individuals with Disabilities Education Act. Pharmacologic therapy may be considered as a part of a more comprehensive treatment program. 

Professional issues


Rehabilitation Management and Treatments

Available or current treatment guidelines

The American Academy of Pediatrics Committee on Genetics provides guidelines for monitoring and for intervention to optimize the health, growth, and development of children with NF1.6

At different disease stages

Longitudinal care and anticipatory guidance for patients with NF1 are important to detect and treat problems or complications as they occur, which can improve outcomes when addressed in a timely fashion. Management in families with a known history of NF1 may begin with genetic counseling as part of family planning, including education about NF1 and its possible course.

From birth to 1 month of age, examination for cutaneous lesions and presence of plexiform neurofibromas should be performed. Some experts also suggest imaging by MRI to evaluate for OPGs or other intracranial tumors. During infancy, growth and development should be tracked, and physical examinations should look for cutaneous and skeletal abnormalities, particularly in the spine and the legs. Monitoring of achievement of developmental milestones should prompt additional cognitive/behavioral, neurological, and/or musculoskeletal assessments. Ophthalmologic evaluation continues during this time.

In early childhood, the presence of skinfold freckling and dermal neurofibromas should be documented for reference. Routine visual examination should continue, as should blood pressure and cognitive-behavioral assessments. Known functional findings should inform ongoing assessment. Inspection of signs of plexiform tumors and their growth should be performed, and careful neuro-musculoskeletal-functional evaluations of the body parts where the plexiform tumors are located must be done.

During late childhood, in addition to the above, sexual maturity should be evaluated, as precocity may indicate intracranial tumor. From adolescence to adulthood, in addition to the aforementioned, ophthalmologic examination is recommended. Progression of neurofibromas may result in pain and loss of joint mobility and/or muscular weakness, resulting in disabilities in self-care, eating, communication, and/or mobility. 

Because of the protean range of type and degree of impairment and disability, there is no standard protocol for rehabilitation in NF1 at any age. Rehabilitation interventions should focus on minimizing the specific impairments identified and compensating for those disabilities that remain. A comprehensive, coordinated interdisciplinary approach (in a specialty clinic format, if available) may include exercises for strength, coordination, endurance, and/or range of motion, upper and/or lower limb orthoses (including shoe orthoses and lifts), adaptive equipment, gait aids and wheelchairs, non-pharmacologic and pharmacologic pain management techniques, behavioral management programs, and adaptive/augmented communication systems. The physiatrist needs to enlist their knowledge of the science of rehabilitation modalities and their organizational skills as the leader of a rehabilitation team. 

Coordination of care

Due to multiorgan involvement and associated complications seen in NF1, a care team that includes genetic counselors, oncologists, ophthalmologists, orthopedists, neurologists, neurosurgeons, pediatricians, physiatrists, psychologists and psychiatrists, therapists, and surgical specialists can provide valuable multidisciplinary clinical management. If an NF1 specialty clinic is available within a reasonable distance of the family’s home, utilizing that clinic in coordination with more nearby specialists should be considered.

Patient & family education

Both the patient and family members need education about the genetics, clinical features, potential symptoms, and possible course of NF1. It is appropriate to include discussion about expected evaluation steps and interventional considerations, including surgical management, for complications of NF1.

Measurement of treatment outcomes

There are no NF1 specific functional outcome tools. Age-appropriate normed generic outcome measures can and should be used to track progress to adjust the treatment plan. Measurements of strength, including manual muscle testing and dynamometers, as well as goniometric measurements of range of motion, can be considered. Timed tests of mobility may be helpful as well as normed tests of fine motor coordination. Burden of care functional assessment tools may be useful in persons with more involved presentations but may not be useful, due to ceiling effect, in less involved persons with NF1.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Clinical management of patients with NF1 requires age-appropriate examination, anticipatory guidance, and treatment, from infancy to adulthood. Involvement and education of family throughout the child’s development is essential, and an interdisciplinary team approach offers the best chance for improving clinical outcomes, not only from a standpoint of physical health, but also from a standpoint of psychosocial well-being.

Cutting Edge/Emerging and Unique Concepts and Practice

The signaling pathways controlled by neurofibromin protein are better understood, and biological targets have been identified with potential for treatment of the tumors. Targeted inhibition of the RAS pathway via mitogen-activated protein kinase (MEK) inhibition has been successful. Specifically, the oral biologic, selumetinib, has been shown to slow the progression of growth of plexiform neurofibromas and improve pain and overall function. However, side effects can include nausea, vomiting, and diarrhea.10 It was approved by the FDA to treat symptomatic, inoperable plexiform neurofibromas in pediatric patients who are 2 years of age and older.11 Clinical research is ongoing in the use of MEK inhibition to treat plexiform neurofibroma in adults. The MEK inhibitor mirdametinib has shown promising results in adolescents and adults, and trials are ongoing.12

Gaps in the Evidence-Based Knowledge



  1. Friedman JM. Neurofibromatosis 1. GeneReviews. Updated April 21, 2022. Accessed April 13, 2024. https://www.ncbi.nlm.nih.gov/books/NBK1109/
  2. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014;13(8), 834-843.
  3. Neurofibromatosis 1. National Organization for Rare Disorders. Updated April 25, 2022. Accessed April 13, 2024. https://rarediseases.org/rare-diseases/neurofibromatosis-type-1-nf1/
  4. Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23(8):1506-1513.
  5. Fisher MJ, Blakeley JO, Weiss BD, et al. Management of neurofibromatosis type 1-associated plexiform neurofibromas. Neuro Oncol. 2022;24(11):1827-1844.
  6. Miller DT, Freedenberg D, Schorry E, et al. Health supervision for children with neurofibromatosis type 1. Pediatrics 2019;143(5), 1-16.
  7. Bellampalli SS, Khanna R. Towards a neurobiological understanding of pain in neurofibromatosis type 1: mechanisms and implications for treatment. Pain. 2019;160(5):1007-1018.
  8. Ferner RE, Gutmann DH. Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol. 2013;115, 939-55.
  9. Wolkenstein P, Zeller J, Revus J, et al. Quality-of-life impairment in neurofibromatosis type 1. Arch Dermatol 2001;137(11), 1421-1425.
  10. Gross AM, Wolters PL, Dombi E, et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med 2020;382, 1430-1442
  11. Casey D, Demko S, Sinha A, et al. FDA approval summary: selumetinib for plexiform neurofibroma. Clin Cancer Res 2021;27(15), 4142-4146.
  12. Weiss BD, Wolters PL, Plotkin SR, et al. NF106: A neurofibromatosis clinical trials consortium phase II trial of the MEK inhibitor mirdametinib in adolescents and adults with NF1-related plexiform neurofibromas. J Clin Oncol 2021; 39(7), 797-806.

Originally Version of the Topic

Thomas Chai, MD, Girish S Shroff MD, Sheetal Shroff MD, Siddarth Thakur MD, Carlos J Roldan MD. Neurofibromatosis: Type 1. 8/1/2017

Previous Revision(s) of the Topic

Scott M. Paul, MD. Neurofibromatosis: Type 1. 4/20/2021

Author Disclosure

Mi Ran Shin, MD, MPH
Nothing to Disclose

Sarah Hour, MD
Nothing to Disclose

Annie Abraham, MD
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Justin Burton, MD
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