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A 6-year-old has multiple café-au-lait macules, axillary freckling, and Lisch nodules on slit-lamp exam. His father has similar skin findings and multiple dermal neurofibromas.
AD; NF1 gene (neurofibromin, tumor suppressor). 50% de novo
Diagnostic criteria (≥2 required):
- ≥6 café-au-lait macules (>5mm prepubertal, >15mm postpubertal)
- ≥2 neurofibromas OR 1 plexiform neurofibroma
- Axillary or inguinal freckling (Crowe sign)
- Optic nerve glioma
- ≥2 Lisch nodules (iris hamartomas)
- Distinctive bony lesions (sphenoid dysplasia, tibial pseudoarthrosis)
- First-degree relative with NF1
Complications:
- Precocious puberty (refer to endocrinology)
- Plexiform neurofibromas → malignant peripheral nerve sheath tumor (MPNST)
- Learning disabilities (~50%)
- Hypertension (renal artery stenosis, pheochromocytoma)
- Primarily a clinical diagnosis: ≥2 of the consensus criteria above (a heterozygous pathogenic NF1 variant now also counts as a criterion)
- Slit-lamp exam for Lisch nodules; brain/orbital MRI when optic pathway glioma is suspected
- Molecular testing of NF1 confirms the diagnosis, aids when criteria are incomplete (young children), and enables prenatal/preimplantation testing
- Consider Legius syndrome (SPRED1) in the differential when only café-au-lait macules and freckling are present
- Regular ophthalmologic screening in children until age 7 for optic nerve gliomas.
- Breast cancer screening in women (start at age 30 years)
- Surgical removal of painful or bothersome neurofibromas
- Tibial pseudoarthroses may require limb amputation
NF1 is not the only disorder that has café au lait macules! Legius, McCune-Albright, Noonan, Russell-Silver, and PTEN-hamartoma tumor syndrome can all present with cafe-au-lait macules.