Comprehensive Management Plan for Neurofibromatosis Type 1 (NF1)
The management of neurofibromatosis type 1 (NF1) requires a specialized multidisciplinary approach coordinated through NF1 clinics to effectively address the diverse manifestations and prevent life-threatening complications that contribute to the 8-15 year reduction in life expectancy. 1
Diagnosis and Initial Evaluation
- Diagnosis based on meeting 2 or more of 7 criteria:
- ≥6 café-au-lait spots (>5mm pre-puberty, >15mm post-puberty)
- ≥2 neurofibromas or 1 plexiform neurofibroma
- Axillary/inguinal freckling
- Optic glioma
- ≥2 Lisch nodules
- Bone abnormalities (tibia pseudarthrosis or sphenoid wing dysplasia)
- First-degree relative with NF1 2
Annual Surveillance Protocol
Medical History Assessment
- Screen for symptoms of:
- Malignant peripheral nerve sheath tumor (MPNST)
- Pheochromocytoma
- Neuropathy
- Depression
- Chronic pain and pruritus
- Fingertip pain
- Bothersome/symptomatic cutaneous neurofibromas 3
Physical Examination
- Blood pressure measurement (essential hypertension, pheochromocytoma, renal artery stenosis)
- Clinical evaluation for scoliosis using Adam's forward bend test
- Thorough skin examination for café-au-lait spots and neurofibromas 3, 1
Laboratory Investigations
- Consider serum vitamin D concentrations and supplementation based on clinical context 3
Imaging Recommendations
- Consider baseline MRI of known or suspected nonsuperficial plexiform neurofibromas
- For women:
- Annual mammogram starting at age 30
- Consider breast MRI with contrast between ages 30-50
- Consider dual-energy X-ray absorptiometry for bone density assessment 3
- Avoid CT scans due to radiation exposure, especially in children 1
Management of Specific Complications
Plexiform Neurofibromas
- Close observation with serial evaluations for newly diagnosed lesions
- Indications for intervention:
- Visual decline
- Progressive tumor growth
- New/worsening functional deficit
- Progressive disfigurement 1
- Consider surgical intervention when feasible, recognizing complete resection is often impossible due to infiltrative nature 1
- For unresectable plexiform neurofibromas, consider MEK inhibitors (selumetinib FDA-approved for children) 4
Vascular Complications
- Monitor for NF1-associated vasculopathy (affects 0.4-6.4% of patients)
- Types include arterial stenosis, moyamoya arteriopathy, aneurysms, arteriovenous malformations
- Consider contrast-enhanced MRA for patients with GFR >30mL/min if renal artery stenosis is suspected 3
Malignancy Surveillance
- Educate patients about concerning symptoms:
- Progressive severe pain (MPNST)
- Changes in tumor volume (MPNST)
- New, unexplained neurologic symptoms (MPNST, CNS tumors)
- Diaphoresis/palpitations (pheochromocytoma) 3
- Monitor for malignancies associated with NF1:
- Malignant gliomas
- Gastrointestinal stromal tumors (GISTs)
- Rhabdomyosarcoma
- Thyroid cancer
- Malignant fibrous histiocytoma
- Pheochromocytoma
- Somatostatinomas
- Juvenile myelomonocytic leukemia 3
Bone Health
- Monitor for decreased bone mineral density and osteoporosis
- Address focal skeletal manifestations (long bone dysplasia/pseudarthrosis, dystrophic scoliosis, sphenoid wing dysplasia) 3
Special Considerations
Pregnancy Management
- Use contraception if pregnancy not desired
- Refer to high-risk obstetrician for pregnant women with NF1
- Monitor for increased risk of:
- Gestational hypertension
- Preeclampsia
- Intrauterine growth restriction
- Cerebrovascular disease
- Preterm labor
- Need for cesarean delivery 3
- Preanesthesia neuraxial imaging is generally not needed; spinal anesthesia may be considered if concerns exist 3
Genetic Counseling
- Educate about 50% offspring recurrence risk
- Discuss availability of prenatal diagnosis and preimplantation genetic diagnosis (PGD)
- Note limitations of PGD for individuals with de novo mutations, somatic mosaicism, and large genomic rearrangements 3, 1
Common Pitfalls and Caveats
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 3
Plexiform neurofibromas are highly vascular and can spontaneously bleed, sometimes seriously enough to be life-threatening. Hemorrhage may present as a rapidly growing tumor 3
Surgical removal of plexiform neurofibromas may require significant intra-operative transfusions due to challenges with hemostasis 3
Avoid overreliance on imaging without clinical correlation, as this may lead to unnecessary procedures and anxiety 1