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Disease/ Disorder


Neurofibromatosis Type 1 (NF-1) is an autosomal dominant disorder that is characterized by tumor and nontumor manifestations including pigmentary skin lesions called café au lait macules, ectodermal tumors in the skin and nerve sheaths called neurofibromas, and skinfold freckling. NF-1 may result in a number of both physical and cognitive impairments.


NF-1 is a genetic disorder resulting from dysfunction of the guanosine triphosphatase–activating protein neurofibromin, resulting in overactivation of the RAS pathway involved in promoting cell growth/division.  The mutation may be de novo or inherited, germline or somatic.

Epidemiology including risk factors and primary prevention

NF-1 (also known as von Recklinghausen disease) is a relatively common disorder, with a prevalence of approximately 1 in 2,000 to 4,000 individuals. Approximately 42% of cases of NF-1 are de novo mutations of the NF-1 gene. All ethnicities, races, and sexes are affected with equal frequency.


Diagnosis of NF-1 is usually made clinically, although genetic testing may be required for diagnosis on rare occasion. National Institutes of Health (NIH) Consensus Development Conference criteria requires two or more of the following clinical features:

  • 6 or more café-au-lait macules present (> 5mm in diameter in prepuberty or > 15 mm 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)
  • First-degree relative with diagnosis of NF-1 based on 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. Characteristic bony abnormalities and skinfold freckling are often first observed in early childhood, between ages 5 and 8. Optic pathway gliomas (OPGs) develop usually prior to age 7. Iris hamartomas (Lisch nodules) will appear between ages 5 -10 years; over 90% of persons with NF1 will have them by adulthood. Dermal neurofibromas usually begin to appear around puberty. Plexiform neurofibromas occur in up to 50% of persons with NF1.  They are benign but often progressive, with most rapid progression during childhood and adolescence.  They can cause substantial morbidity. Life expectancy of those with NF-1 is thought to be reduced by around 8 to 10 years.  Survival is significantly reduced when plexiform neurofibromata mutate to malignant peripheral nerve sheath tumors.

Specific secondary or associated conditions and complications

In addition to malignant peripheral nerve sheath tumors, NF-1 is associated with scoliosis, long bone pseudoarthrosis, vasculopathy such as renal artery stenosis, and hypertension secondary to renovascular disease or pheochromocytoma. In children, NF-1 may be associated with learning disabilities, attention deficit hyperactivity disorder, and other cognitive delay, precocious puberty, seizures, and pain.

Essentials of Assessment


Children with NF-1 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, behavior with peers and adults may help to direct 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.

Physical examination

Pediatric NF-1 patients need regular ophthalmologic examination, through age 12, 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 on blood pressure values. 

Functional assessment

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

Laboratory studies

No specific routine laboratory studies for NF-1 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 not recommended; it is done only if there are findings on the ophthalmological examination.

Whole body MRI with volumetric assessment of plexiform neurofibromata 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 on the basis of the history and examination obtained during each clinic visit.

Supplemental assessment tools

Genetic testing is usually not necessary to diagnose the condition of NF-1; rather, it is a clinical diagnosis. 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.

Early predictions of outcomes

Greater disease severity is associated with reduced quality of life (QOL). Pain is inversely proportional to QOL scores. Affective-emotional functioning, as reported through depressed mood, anxiety, and social stress impacts QOL scores.



Social role and social support system

Children with evidence of cognitive-behavioral impairments requires in depth neuropsychological evaluation to identify challenges and strengths.  Treatment may include medically prescribed psychological and/or rehabilitation therapies and school-based services and accommodations provided in compliance with the Individuals with Disabilities Education Act. Pharmacologic therapy should be considered only 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 (AAP) Committee on Genetics provides guidelines for monitoring and for intervention to optimize the health, growth, and development of children with NF-1 (see Bibliography for the reference).

At different disease stages

Longitudinal care and anticipatory guidance for patients with NF-1 is important to detect and to treat problems or complications as they occur over time, 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 NF-1 and its possible course.

From birth to 1 month of age, examination for cutaneous lesions and presence of plexiform neurofibromas should be taken. Some experts also suggest imaging (by MRI) to evaluate for OPGs or other intracranial tumors. During infancy, growth and development should be tracked, physical examination 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, and blood pressure and cognitive-behavioral assessment should continue. 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 every 2 years, until the age of 18. Progression of neurofibromas may result in pain, 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 NF-1 at any age.  Rehabilitation interventions should focus 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-pharmacological pain management techniques, behavioral management programs, and adaptive/augmented communication systems.  The physiatrist needs to enlist her knowledge of the science of rehabilitation modalities and his organizational skills as the leader of a rehabilitation team. 

Coordination of care

Due to multiorgan involvement and associated complications seen in NF-1, 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 a NF-1 specialty clinic is available within reasonable distance of the family’s home, consideration of utilizing that clinic, perhaps 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 NF-1. It is appropriate to include discussion about expected evaluation steps and interventional considerations, including surgical, for complications of NF-1.

Measurement of treatment outcomes

There are no NF-1 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 MMT and dynamometers can be considered as well as goniometric measurements of range of motion.  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 presentation 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 NF-1 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 a interdisciplinary team approach offers the best chance for improving clinical outcomes, not only from a standpoint of physical well-being, 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.  The first of these biologicals, the Mitogen-activated Protein Kinase (MEK) inhibitor, selumetinib, has been shown to slow the progression of growth of plexiform neurofibromata and been approved by the FDA to treat plexiform neurofibromas in children.  Clinical research is ongoing in the use of MEK inhibition to treat plexiform neurofibroma in adults.

Gaps in the Evidence- Based Knowledge




Gross AM, et. al., Selumetinib in Children with Inoperable Plexiform Neurofibromas, N Engl J Med 2020;382:1430-42.

Ly, KI, Blakeley JO, The Diagnosis and Management of Neurofibromatosis Type 1, Med Clin N Am 103 (2019) 1035–1054

Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Pri 2017; 3: 1-17.

Anderson JL, Gutmann DH. Neurofibromatosis type 1. Handbook of Clinical Neurology 2015; 132: 75-86.

Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care 2014; 13: 834-843.

Hersh JH, Committee on Genetics. Health Supervision for Children with Neurofibromatosis. Pediatrics 2008; 121: 633-648.

Originally Published

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

Author Disclosure

Scott M. Paul, MD
Nothing to Disclose