When to Work Up for Neurofibromatosis with a Large Single Café-au-Lait Spot
A single large café-au-lait macule alone does not warrant workup for neurofibromatosis type 1 (NF1), as the NIH diagnostic criteria require ≥6 café-au-lait macules (≥5mm prepubertal or ≥15mm postpubertal) to meet even one criterion for NF1. 1
Key Diagnostic Threshold
- The presence of ≥6 café-au-lait macules meeting size criteria is required as one of the NIH diagnostic criteria for NF1, not a single spot regardless of size 1
- Document the exact number and size of all café-au-lait spots present, as this is crucial for determining if diagnostic criteria are met 1
When to Pursue Further Evaluation
Initiate workup if the patient has a single large café-au-lait spot PLUS any of the following:
- Axillary or inguinal freckling (Crowe's sign), which is highly specific for NF1 1
- Family history of NF1 in a first-degree relative 1
- Cutaneous or subcutaneous neurofibromas on examination 1
- Dysmorphic facial features, congenital heart defects, short stature, or cryptorchidism, suggesting RASopathies (Noonan, Costello, or CBL syndrome) rather than isolated café-au-lait spots 1
- Developmental delays, hypotonia, or leukemia diagnosed at age <18, which warrant genetics referral 1
- Lisch nodules on slit-lamp examination 1
Evidence on Isolated Café-au-Lait Macules
- Among children presenting with isolated café-au-lait macules, 19.5% to 57.1% do not ultimately receive an NF1 diagnosis after follow-up or genetic testing 2
- Children older than 29 months with fewer than 6 café-au-lait macules or atypical macules have only a 0.9% risk for constitutional NF1 3
- In contrast, children younger than 29 months with ≥6 café-au-lait macules have an 80.4% risk for NF1 3
Referral Criteria
Refer to genetics when the patient meets ≥2 NIH diagnostic criteria for NF1:
- This includes ≥6 café-au-lait macules PLUS one additional criterion (freckling, neurofibromas, Lisch nodules, optic glioma, bone dysplasia, or family history) 1
- Genetic testing can establish diagnosis and guide surveillance, though a single café-au-lait spot alone does not meet referral threshold 1
Important Differential Diagnosis
- Legius syndrome (SPRED1 mutations) mimics NF1 with café-au-lait macules and freckling but lacks neurofibromas and optic gliomas—distinguishing this is critical as surveillance requirements differ markedly 4, 1
- Familial multiple café-au-lait spots can occur as an autosomal dominant condition without NF1, even with axillary freckling or Lisch nodules in some families 5
Common Pitfalls to Avoid
- Do not diagnose NF1 based on a single café-au-lait spot, regardless of size—this leads to unnecessary anxiety and inappropriate surveillance 1
- Do not confuse Legius syndrome with NF1—Legius patients lack tumor risks and require different management 1
- Do not delay referral in children with café-au-lait macules plus developmental delays, hypotonia, or leukemia, as these suggest syndromic diagnoses requiring specialized care 1