Diagnostic and Management Approach for Neurofibromatosis (NF)
For optimal diagnosis and management of neurofibromatosis, evaluation by and care coordination with a specialized NF clinic is strongly recommended, as this multidisciplinary approach significantly reduces morbidity and mortality. 1
Diagnostic Approach
Clinical Diagnostic Criteria
- Diagnosis of NF1 is primarily clinical, with the following key features to assess:
- Café-au-lait spots (≥6 spots >5mm in prepubertal individuals or >15mm in postpubertal individuals) 2, 3
- Axillary and inguinal freckling 2, 3
- Multiple cutaneous neurofibromas 2, 3
- Iris Lisch nodules (hamartomas of the iris) 2, 3
- Optic pathway gliomas 3
- Distinctive osseous lesions (sphenoid dysplasia, tibial pseudarthrosis) 4
- First-degree relative with NF1 3
Imaging and Laboratory Assessment
- Ultrasound serves as an excellent initial imaging modality for suspected neurofibromas due to its non-invasive nature 5
- MRI is warranted for neurofibromas with atypical features on ultrasound 5
- For suspicious lesions, biopsy sampling should target radiologically concerning but surgically accessible areas, using 14-18G needles with at least 6 core biopsies 5
- Molecular genetic testing is available but infrequently needed for diagnosis 3
Management Approach
Regular Monitoring and Surveillance
- Annual general medical evaluation should include: 1
- Assessment for signs/symptoms of malignant peripheral nerve sheath tumor (MPNST)
- Evaluation for pheochromocytoma
- Screening for neuropathy
- Assessment for depression
- Evaluation of chronic pain and pruritus
- Blood pressure measurement
- Clinical evaluation for scoliosis with Adam's forward bend test
Cancer Screening
- For women with NF1: 1
- Annual mammogram starting at age 30
- Consider breast MRI with contrast between ages 30-50
- Consider baseline MRI of known or suspected non-superficial plexiform neurofibromas 1
Warning Signs Requiring Urgent Evaluation
- Progressive severe pain (concerning for MPNST) 1
- Changes in tumor volume (concerning for MPNST) 1
- New, unexplained neurologic symptoms (concerning for MPNST or CNS tumors) 1
- Diaphoresis/palpitations (concerning for pheochromocytoma) 1
Treatment Considerations
- Indications for intervention in plexiform neurofibromas include: 6
- Visual decline or risk to vision
- Progressive tumor growth
- New or worsening functional deficits
- Progressive disfigurement
- MEK inhibitor selumetinib has shown promising results for plexiform neurofibromas 6
- Surgical removal of both benign and malignant tumors may be warranted 3
Pregnancy and Family Planning
- Referral to a high-risk obstetrician is recommended for pregnant women with NF1 1
- Patients should be educated about the 50% offspring recurrence risk 1
- Preimplantation genetic diagnosis and prenatal diagnosis are available options 1
Special Considerations
Malignant Transformation
- MPNST is clinically aggressive and tends to metastasize early 1
- The risk of NF1-associated MPNST to ages 30,50, and 85 years is 8.5%, 12.3%, and 15.8% respectively 1
- High-grade MPNSTs are usually fatal, contributing significantly to NF1 mortality 1
Common Pitfalls
- Not all symptoms in NF1 patients are due to the disease - common explanations remain common (e.g., most hypertension is essential and not pheochromocytoma-related) 1
- Penetrance of the NF1 gene is complete by age 5, so diagnosis may be difficult in early childhood and made during follow-up 2
- Annual clinical examination is sufficient for follow-up; excessive screening investigations are not useful for rare complications 2
- Life expectancy in NF1 is reduced by 8-15 years compared to the general population, primarily due to malignant neoplasms and cardiovascular causes 1
NF2 vs. NF1
- NF2 is a distinct condition characterized primarily by bilateral vestibular schwannomas and requires different management approaches 7
- When evaluating a patient with suspected neurofibromatosis, it's crucial to distinguish between NF1 and NF2 as they have different clinical manifestations and management strategies 7