Comprehensive Management of Neurofibromatosis Type 1 (NF1)
The management of neurofibromatosis type 1 (NF1) requires a multidisciplinary approach through specialized NF1 clinics, with regular monitoring for complications including malignancies, vasculopathy, and skeletal abnormalities. 1
Diagnosis
NF1 diagnosis is established when two or more of the following criteria are present:
- Six or more café-au-lait spots (>5mm pre-puberty, >15mm post-puberty)
- Two or more neurofibromas or one plexiform neurofibroma
- Axillary or inguinal freckling
- Optic glioma
- Two or more Lisch nodules
- Bone abnormalities (tibia pseudarthrosis or sphenoid wing dysplasia)
- First-degree relative with NF1 2
Screening and Monitoring Protocol
Regular Clinical Evaluations
- Annual comprehensive medical evaluation 1
- Blood pressure measurement to detect hypertension, pheochromocytoma, and renal artery stenosis 1
- Thorough skin examination for café-au-lait spots and neurofibromas 1
- Clinical evaluation for scoliosis using Adam's forward bend test 1
- Age- and gender-specific health screening (cholesterol, colonoscopy, cervical cancer screening) 1
Imaging and Laboratory Studies
- Baseline MRI of known or suspected nonsuperficial plexiform neurofibromas 1
- For orbital/periorbital plexiform neurofibromas: MRI brain and orbits with high-resolution sequences every 3-6 months until stability confirmed 1
- Contrast-enhanced MRA for suspected renal artery stenosis (if GFR >30mL/min) 1
- Serum vitamin D concentrations and supplementation as needed 1
- Dual-energy X-ray absorptiometry for bone density assessment 1
- Avoid CT scans due to radiation exposure risk, especially in children 1
Cancer Screening
- Annual mammogram starting at age 30 and breast MRI with contrast between ages 30-50 for women 1
- Vigilant monitoring for malignant peripheral nerve sheath tumors (MPNSTs), which have a lifetime risk of 15.8% 1
- Monitor for other NF1-associated malignancies: malignant gliomas, gastrointestinal stromal tumors, rhabdomyosarcoma, thyroid cancer, pheochromocytoma, and others 1
Treatment Approaches
Plexiform Neurofibromas
- 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
- Selumetinib is FDA-approved for symptomatic, inoperable plexiform neurofibromas in pediatric patients ≥2 years 1, 3
- For adults with plexiform neurofibromas, surgical approaches may be considered, though complete resection is often impossible due to tumor infiltration 1
- Alternative MEK inhibitors and mixed tyrosine kinase inhibitors may have better efficacy in adults 3
Orthopedic Management
- ~50% of patients have significant musculoskeletal manifestations, with scoliosis and congenital pseudarthrosis of tibia being most common 2
- Orthopedic manifestations often require specialized management strategies 2
Emerging Therapies
- Targeted therapies at the genetic and molecular level are being developed, including:
Special Considerations
Pregnancy and Contraception
- Pregnant women with NF1 should be referred to a high-risk obstetrician 1
- Monitor for pregnancy complications: gestational hypertension, preeclampsia, intrauterine growth restriction 1
- Provide genetic counseling regarding 50% offspring recurrence risk 1
- Discuss prenatal diagnosis and preimplantation genetic diagnosis (PGD) options 1
- Discuss limitations of PGD for individuals with de novo mutations, somatic mosaicism, and large genomic rearrangements 1
Patient Education
- Educate patients about concerning symptoms requiring immediate medical attention:
- Progressive severe pain
- Changes in tumor volume
- New unexplained neurologic symptoms
- Diaphoresis/palpitations 1
Prognosis and Long-term Monitoring
NF1 is associated with an 8-15 year reduction in life expectancy, primarily due to malignant neoplasms and cardiovascular causes 1. MPNSTs contribute significantly to NF1 mortality with a standardized mortality ratio >2,000 1.
Common Pitfalls and Caveats
- Avoid CT scans due to radiation exposure risk, especially in children 1
- Complete surgical resection of plexiform neurofibromas is often impossible due to their infiltrative nature 1
- NF1 has variable expressivity, even within families, requiring individualized monitoring 1
- Most targeted molecular therapies are still in preclinical stages, with limited approved options 4