How is neurofibromatosis (NF) diagnosed?

Diagnosis of Neurofibromatosis

Neurofibromatosis is primarily diagnosed through clinical evaluation using established diagnostic criteria, with genetic testing serving as a confirmatory tool when clinical findings are insufficient or ambiguous.

Clinical Diagnostic Criteria for NF1

NF1 is diagnosed based on the following clinical features 1:

• Café-au-lait spots: Six or more café-au-lait macules >5mm in prepubertal individuals or >15mm in postpubertal individuals
• Axillary or inguinal freckling
• Multiple cutaneous neurofibromas (typically appear in adolescence or adulthood)
• Iris Lisch nodules (identified through ophthalmologic examination)
• Plexiform neurofibromas (subcutaneous or deep lesions involving nerve plexuses)
• Optic pathway gliomas
• Distinctive osseous lesions (such as sphenoid dysplasia or tibial pseudarthrosis)
• First-degree relative with NF1

The presence of two or more of these features is sufficient for diagnosis 2.

Diagnostic Imaging

Imaging studies play a crucial role in diagnosis and monitoring:

• MRI brain and orbits with high-resolution sequences is recommended for patients with suspected neurofibromatosis 1
• MRI of known or suspected plexiform neurofibromas should be considered as a baseline 3
• CT scans should be avoided when possible due to radiation exposure, especially in children 1

Genetic Testing

Molecular genetic testing has become increasingly important in diagnosis:

• NF1 gene sequencing can identify pathogenic variants in approximately 95% of individuals with NF1 1
• Genetic testing is particularly valuable in:
  • Young children who don't yet meet clinical criteria
  • Individuals with atypical presentations
  • Cases requiring differentiation from other conditions (e.g., Legius syndrome)
  • Family planning contexts 3, 1

Special Diagnostic Considerations

Mosaic/Segmental NF1

• Characterized by clinical features limited to one body segment or region
• May require more extensive genetic testing, including tissue sampling from affected areas 2

Atypical Presentations

• Some genetic variants are associated with specific phenotypes
• For example, the c.2970_2972delAAT mutation is associated with typical pigmentary features but absence of neurofibromas 4
• In patients with suggestive features but not meeting full criteria, targeted genetic testing may be warranted 4

Differentiating NF1 from NF2 and Schwannomatosis

• NF2 is characterized primarily by bilateral vestibular schwannomas, rather than cutaneous findings 5
• Genetic testing can definitively differentiate between these conditions when clinical overlap exists 5

Multidisciplinary Assessment

A comprehensive diagnostic approach should include:

• Dermatologic examination for café-au-lait spots, freckling, and neurofibromas
• Ophthalmologic examination for Lisch nodules and optic pathway gliomas
• Neurologic assessment for signs of central or peripheral nervous system involvement
• Skeletal evaluation including clinical assessment for scoliosis using Adam's forward bend test 3, 1
• Blood pressure measurement to detect hypertension, which may indicate pheochromocytoma or renal artery stenosis 1

Follow-up After Diagnosis

Once diagnosed, regular monitoring is essential:

• Annual physical examination by a physician familiar with NF1 6
• Regular ophthalmologic examinations (annually in children, less frequently in adults) 6
• Developmental assessment in children 6
• Regular blood pressure monitoring 1
• MRI for follow-up of clinically suspected internal tumors 6

Common Pitfalls in Diagnosis

• Delayed diagnosis in mild cases or those without obvious cutaneous manifestations
• Misdiagnosis between NF1 and NF2 due to overlapping features
• Failure to recognize mosaic forms of the condition
• Overlooking NF1 in young children before development of all clinical features

For optimal management, evaluation by and care coordination with specialized NF1 clinics is strongly recommended, as a multidisciplinary team approach is essential for managing this complex disorder 3, 1.