What are the diagnostic criteria for neurofibromatosis (NF)?

Diagnostic Criteria for Neurofibromatosis

The diagnosis of neurofibromatosis type 1 (NF1) should be established using the revised diagnostic criteria which incorporate both clinical features and genetic testing, while neurofibromatosis type 2 (NF2) requires distinct criteria focused on vestibular schwannomas and other central nervous system tumors. 1, 2, 3

Neurofibromatosis Type 1 (NF1) Diagnostic Criteria

NF1 is diagnosed when a patient meets at least one of the following criteria:

Clinical Diagnostic Criteria

• ≥6 café-au-lait macules (>5mm in prepubertal individuals, >15mm in postpubertal individuals)
• ≥2 neurofibromas of any type OR ≥1 plexiform neurofibroma
• Freckling in axillary or inguinal regions
• Optic pathway glioma
• ≥2 Lisch nodules (iris hamartomas)
• Distinctive osseous lesion (sphenoid dysplasia, tibial pseudarthrosis)
• First-degree relative with NF1 diagnosed by above criteria

Genetic Testing Criteria

• Heterozygous pathogenic NF1 gene variant with or without clinical features 1, 2

Neurofibromatosis Type 2 (NF2) Diagnostic Criteria

NF2 is diagnosed when a patient meets at least one of the following criteria:

• Bilateral vestibular schwannomas
• First-degree relative with NF2 AND unilateral vestibular schwannoma OR any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
• Unilateral vestibular schwannoma AND any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
• Multiple meningiomas AND unilateral vestibular schwannoma OR any two of: schwannoma, glioma, neurofibroma, cataract
• Heterozygous pathogenic NF2 gene variant in blood or tumor tissue 1, 3

Comprehensive Diagnostic Approach

1. Clinical Assessment

• Detailed dermatologic examination for café-au-lait macules, neurofibromas, and axillary/inguinal freckling
• Ophthalmologic examination for Lisch nodules, optic pathway gliomas, and posterior subcapsular cataracts
• Neurologic assessment for focal deficits, signs of increased intracranial pressure
• Skeletal evaluation for scoliosis and bone dysplasia
• Blood pressure measurement to detect hypertension (potential pheochromocytoma) 1

2. Imaging Studies

• MRI of known or suspected plexiform neurofibromas
• Brain and spine MRI when NF2 is suspected
• Mammogram starting at age 30 for women with NF1
• Breast MRI with contrast between ages 30-50 for women with NF1 1

3. Genetic Testing

• NF1 gene sequencing can identify pathogenic variants in ~95% of individuals with NF1
• NF2 gene testing for suspected NF2 cases
• SPRED1 gene testing to differentiate Legius syndrome from NF1 1, 2

4. Biopsy and Histological Assessment (when malignancy suspected)

• Use 14-18G biopsy needles with at least 6 core biopsies
• Assess for:
  • Cytologic atypia
  • Loss of neurofibromatous architecture
  • Hypercellularity
  • Mitotic count
  • Necrosis 4, 1

5. Molecular Assessment (for suspicious lesions)

• Check for:
  • Reduced SOX10/S100 immunoreactivity
  • Absence of CD34-positive lattice-like network
  • Complete loss of p16 expression
  • Complete H3K27me3 loss
  • Increased p53 immunoreactivity
  • Increased Ki-67 labeling index 4, 1

Important Considerations

Mosaic Forms

• Segmental or mosaic forms of NF1 and NF2 should be considered in patients with localized disease
• May require testing of affected tissue rather than blood 2, 3

Differentiating NF1 from Legius Syndrome

• Both present with café-au-lait macules and axillary/inguinal freckling
• Legius syndrome lacks neurofibromas, Lisch nodules, and CNS tumors
• Genetic testing for SPRED1 mutations helps differentiate 2

Common Pitfalls to Avoid

1. Failing to differentiate NF1 from NF2 - these are distinct genetic conditions with different causative genes and clinical manifestations
2. Missing mosaic forms - may present with localized findings and negative blood genetic testing
3. Overlooking malignant transformation - regular monitoring for changes in neurofibroma size, pain, or neurologic symptoms is essential
4. Inadequate follow-up - patients require lifelong monitoring for complications
5. Incomplete family screening - first-degree relatives should be evaluated due to autosomal dominant inheritance 1

For optimal care, evaluation by and coordination with a specialized NF clinic is strongly recommended, along with regular primary care physician follow-up 1.