Criteria

Neurofibromatosis (NIH consensus development conference statement)[34][3][15]

The NIH inclusive criteria are met if ≥2 of the following are present:

  • ≥6 café au lait spots >5 mm in diameter in prepubertal patients and >15 mm in diameter in postpubertal patients

  • ≥2 neurofibromas of any type or 1 plexiform neurofibroma; severity is a function of the timing, the number, and the nature of the various NF1 features

  • Freckling in the axillary or inguinal regions

  • Optic pathway glioma

  • ≥2 Lisch nodules (iris hamartomas) identified by slit lamp examination or ≥2 choroidal abnormalities - defined as bright, patchy nodules imaged by optical coherence tomography (OCT)/near-infrared reflectance (NIR) imaging

  • A distinctive osseous lesion such as sphenoid wing dysplasia (which is not a separate criterion in case of an ipsilateral orbital plexiform neurofibroma) or anterolateral bowing of tibia; or pseudarthrosis of a long bone

  • A heterozygous pathogenic NF1 variant in 100% of cells from unaffected tissue

  • A parent with NF1 by the above criteria.

Mosaic NF1 can be confirmed if a pathogenic variant is identified in less than 100% of cells with an allele frequency usually below 40%.

If only café-au-lait macules (CALMs) and freckling are present, the diagnosis is most likely NF1 but exceptionally the person might have another diagnosis such as Legius syndrome. At least one of the two pigmentary findings (CALMs or freckling) should be bilateral.

True severity can be determined only with the use of neuroimaging, although many NF1 specialty clinicians recommend being satisfied with only an expert clinical assessment that includes slit-lamp ophthalmoscopy and visual field testing.[35] Patients with deletion of the entire NF1 gene may have more severe disease than patients with other types of mutation.

The discovery that SPRED1 gene mutations cause NF1-like syndrome/Legius syndrome has; however, introduced substantial heterogeneity to the NIH criteria. Legius syndrome is a condition that, like NF1, is characterised by café au lait spots, freckling, and learning difficulties. An RNA analysis of patients with NF1 defined by the NIH criteria found that out of 71 familial and de novo cases with pigmentary-only criteria, 6 (8%) had SPRED1 gene mutations/Legius syndrome, and 18 (25%) had no constitutional mutation in either NF1 or SPRED1.[36]

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