What are the management options for neurofibromatosis (NF)?

Management Options for Neurofibromatosis

The management of neurofibromatosis requires a multidisciplinary approach coordinated through specialized NF clinics, with regular monitoring and targeted interventions including MEK inhibitors for symptomatic plexiform neurofibromas in children ≥2 years and surgical approaches when indicated. 1

Diagnostic Approach

• Comprehensive evaluation should include:

  • Dermatologic examination for café-au-lait spots, freckling, and neurofibromas
  • Ophthalmologic examination for Lisch nodules and optic pathway gliomas
  • Neurologic assessment for central or peripheral nervous system involvement
  • Skeletal evaluation including assessment for scoliosis
  • Blood pressure measurement to detect hypertension 1

• Imaging:

  • MRI brain and orbits with high-resolution sequences is recommended
  • Baseline MRI of known or suspected plexiform neurofibromas
  • Avoid CT scans due to radiation exposure, especially in children 1

• Genetic testing:

  • NF1 gene sequencing can identify pathogenic variants in ~95% of individuals
  • Particularly valuable in young children, atypical presentations, and family planning 1

Monitoring Protocol

• Regular monitoring includes:

  • Annual physical examination by a physician familiar with NF1
  • Regular ophthalmologic examinations
  • Developmental assessment in children
  • Regular blood pressure monitoring
  • MRI follow-up of clinically suspected internal tumors 1

• Cancer surveillance:

  • Annual mammogram starting at age 30 and breast MRI with contrast between ages 30-50 for women with NF1
  • Follow general population age- and gender-specific health screening guidelines 1

Treatment Options

Pharmacological Management

• MEK inhibitors:
  • Selumetinib is FDA-approved for symptomatic, inoperable plexiform neurofibromas in pediatric patients ≥2 years 1
  • Trametinib can be effective where selumetinib is not available 2
  • Cabozantinib has shown activity in treating patients ≥16 years with NF1 plexiform neurofibromas 2

Surgical Approaches

• Consider for:

  • Symptomatic neurofibromas
  • Cosmetic concerns
  • Suspected malignant transformation 1

• Limitations:

  • Complete resection often impossible due to infiltrative nature of tumors
  • Risk of neurological deficit 1

Management of Specific Complications

Central Nervous System Tumors

• Optic pathway gliomas (OPGs):

  • Most common in children <8 years (median: 4-5 years)
  • 15-20% progress requiring intervention
  • Chemotherapy is traditional mainstay of therapy
  • MEK inhibitors showing promising results 2

• Brainstem gliomas:

  • Occur in <10% of individuals with NF1
  • <5% require treatment
  • Treatment indicated for neurological deterioration 2

Peripheral Nerve Sheath Tumors

• Plexiform neurofibromas:
  • Present in ~50% of NF1 patients
  • Faster growth in young children
  • Indications for intervention: visual decline, progressive tumor growth, new/worsening functional deficit, progressive disfigurement 1
  • MEK inhibitors are first-line therapy for inoperable symptomatic lesions 2, 1

Special Considerations

Reproductive Health

• Genetic counseling regarding 50% offspring recurrence risk
• Discussion of prenatal diagnosis and preimplantation genetic diagnosis options
• Pregnant women with NF1 should be referred to high-risk obstetricians 1

Quality of Life Management

• Regular quality of life assessments using validated questionnaires
• Patient education about concerning symptoms:
  • Progressive severe pain
  • Changes in tumor volume
  • New unexplained neurologic symptoms
  • Diaphoresis/palpitations 1

Common Pitfalls and Caveats

• Avoid radiation therapy for NF1-associated gliomas due to risk of vascular and other complications 2
• Distinguish between NF1 and NF2, which are distinct disorders with different management approaches 3, 4
• Be vigilant for malignant transformation of tumors, which contributes significantly to mortality 4
• NF1 is associated with an 8-15 year reduction in life expectancy, primarily due to malignant neoplasms and cardiovascular causes 1
• The disease has variable expression, even within families, requiring individualized monitoring 5, 6