What is the management plan for patients with neurofibromatosis-1 (NF1)?

Management Plan for Neurofibromatosis Type 1 (NF1)

The management of neurofibromatosis type 1 (NF1) requires a multidisciplinary approach coordinated through specialized NF1 clinics to address the complex and variable manifestations of this disorder, with regular monitoring for complications including malignancies, vasculopathies, and neurological issues. 1

Initial and Ongoing Evaluation

Screening and Monitoring

• Annual comprehensive medical evaluation including:
  • Blood pressure measurement to detect hypertension, pheochromocytoma, and renal artery stenosis 1
  • Clinical evaluation for scoliosis using Adam's forward bend test 1
  • Thorough skin examination for café-au-lait spots and neurofibromas 1
  • Screening for symptoms of malignant peripheral nerve sheath tumor (MPNST), pheochromocytoma, neuropathy, depression, chronic pain, and pruritus 1

Imaging and Diagnostic Tests

• Baseline MRI of known or suspected nonsuperficial plexiform neurofibromas 1
• For women: Annual mammogram starting at age 30 and breast MRI with contrast between ages 30-50 1
• Bone health: Consider dual-energy X-ray absorptiometry for bone density assessment and serum vitamin D concentrations 1
• For suspected renal artery stenosis: Contrast-enhanced MRA for patients with GFR >30mL/min 1
• For orbital/periorbital plexiform neurofibromas: MRI brain and orbits with high-resolution sequences every 3-6 months until stability confirmed 1

Management of Specific Manifestations

Plexiform Neurofibromas

• For symptomatic, inoperable plexiform neurofibromas in pediatric patients ≥2 years: Selumetinib is FDA-approved 2
• For newly diagnosed plexiform neurofibromas: Close observation with serial evaluations 1
• Indications for intervention include:
  • Visual decline
  • Progressive tumor growth
  • New or worsening functional deficit
  • Progressive disfigurement 1
• Surgical approaches may be considered for adults as tumors are less likely to continue growing 1
  • Note that complete resection is often impossible due to infiltrative nature 1
  • Be aware that plexiform neurofibromas are highly vascular and can spontaneously bleed 1

Cutaneous and Subcutaneous Neurofibromas

• High Quantity (HQ) electrosurgical removal is effective for large numbers of tumors (hundreds per session) 3
• This is not cosmetic surgery but restoration of normal appearance from disfigurement 3

Malignancy Surveillance

• Education about concerning symptoms such as:
  • Progressive severe pain
  • Changes in tumor volume
  • New unexplained neurologic symptoms
  • Diaphoresis/palpitations 4, 1
• Monitor for NF1-associated malignancies including:
  • Malignant peripheral nerve sheath tumors (MPNSTs) - lifetime risk of 15.8% 1
  • Malignant gliomas
  • Gastrointestinal stromal tumors
  • Rhabdomyosarcoma
  • Thyroid cancer
  • Pheochromocytoma 1

Vascular Complications

• Monitor for NF1-associated vasculopathy including:
  • Arterial stenosis
  • Moyamoya arteriopathy
  • Aneurysms
  • Arteriovenous malformations 1

Reproductive Health and Genetic Counseling

• Contraception should be used if pregnancy is not desired 1
• Pregnant women with NF1 should be referred to a high-risk obstetrician 1
• Monitor for pregnancy complications including:
  • Gestational hypertension
  • Preeclampsia
  • Intrauterine growth restriction
  • Cerebrovascular disease
  • Preterm labor 1
• Genetic counseling regarding:
  • 50% offspring recurrence risk
  • Availability of prenatal diagnosis and preimplantation genetic diagnosis (PGD)
  • Limitations of PGD for individuals with de novo mutations, somatic mosaicism, and large genomic rearrangements 4, 1

General Health Considerations

• Follow general population age- and gender-specific health screening (e.g., cholesterol, colonoscopy, cervical cancer screening) 4
• Remember that common medical problems remain common in NF1 patients:
  • Most hypertension is essential, not pheochromocytoma-related
  • Most back pain is not MPNST-related
  • Most headaches are not tumor-associated 4, 1
• Be aware of reduced life expectancy (8-15 years shorter than general population) primarily due to malignant neoplasms and cardiovascular causes 1

Care Coordination

• Strong recommendation for evaluation by and care coordination with specialized NF1 clinics 4, 1
• Multidisciplinary team approach is essential for this complex disorder 5
• For some patients, a multidisciplinary NF clinic may serve as a medical home, although all patients should have a primary care physician 4

Emerging Therapies

• Targeted therapies at the genetic and molecular level are being developed, including:
  • Mitogen-activated protein kinase kinase inhibition
  • Mammalian target of Rapamycin inhibition
  • Tyrosine kinase inhibition 6
• Most of these therapies are still in preclinical stages, but represent promising future directions 6

Important Caveats

• Complete resection of plexiform neurofibromas is often impossible due to their infiltrative nature and involvement of critical structures 1
• NF1 has wide phenotypic variability, and the severity of disease cannot be predicted based on specific variants 1
• Avoid CT scans due to radiation exposure, especially in children 1
• Insurance coverage for tumor removal procedures may be challenging, potentially limiting access to care 3