Are café‑au‑lait macules normal, and at what size, number, or features do they become pathological (e.g., indicative of neurofibromatosis type 1)?

Café-au-Lait Spots: Normal vs. Pathological

Isolated café-au-lait macules (CALMs) are normal in up to 25% of healthy children, but become pathological when ≥6 spots are present with each measuring ≥5mm in prepubertal children or ≥15mm postpubertal, which meets diagnostic criteria for neurofibromatosis type 1 (NF1) and carries an 8-15 year reduction in life expectancy. 1, 2

When CALMs Are Normal

• 1-2 isolated CALMs without other features are considered low-risk and benign, occurring in up to 25% of preschool-aged children 1, 3, 4
• Fair-skinned children with red or blond hair may have 5-15 feathery, irregular CALMs with no other NF1 features and appear unlikely to develop pathological conditions 5
• Solitary CALMs are common birthmarks in up to 2.5% of normal neonates 4

When CALMs Become Pathological

Primary Diagnostic Threshold: Neurofibromatosis Type 1

The critical threshold is ≥6 CALMs meeting size criteria (≥5mm prepubertal, ≥15mm postpubertal), which is one of the NIH diagnostic criteria for NF1 1, 2. NF1 affects 1 in 2,000-3,000 people and requires lifelong surveillance due to:

• 8.5% risk of malignant peripheral nerve sheath tumor (MPNST) by age 30, rising to 15.8% by age 85 2
• 15-20% risk of optic pathway gliomas in young children 1
• Significantly increased breast cancer risk requiring mammography starting at age 30 2

Additional Pathological Features to Assess

Perform a comprehensive skin and systemic examination looking for:

• Axillary or inguinal freckling (Crowe's sign) - highly specific for NF1, typically appears within first 3 years of life 1, 2
• Cutaneous or subcutaneous neurofibromas - diagnostic for NF1 1, 2
• Lisch nodules on slit-lamp examination (iris hamartomas) - diagnostic for NF1 1, 2
• Plexiform neurofibromas - may be congenital but subtle in infancy 1

Alternative Genetic Syndromes to Consider

CALMs plus specific associated features suggest non-NF1 syndromes:

• RASopathies (Noonan, Costello, CBL syndromes): CALMs + dysmorphic facial features + congenital heart defects + short stature + cryptorchidism 1, 2
• Legius syndrome: CALMs + freckling but NO neurofibromas, NO optic gliomas, NO tumor risk - requires SPRED1 genetic testing to distinguish from NF1 2
• Constitutional Mismatch Repair Deficiency (CMMRD): CALMs + hypopigmented spots + pilomatrixomas + childhood cancers (leukemia, brain tumors, GI malignancies) - carries extremely high cancer risk 6, 1, 2, 3
• McCune-Albright syndrome: Large segmental CALMs + precocious puberty + fibrous dysplasia 3

Clinical Management Algorithm

For Children with Multiple CALMs (≥3 spots):

1. Document exact number and measure size of each CALM to determine if ≥6 spots meet size criteria 1, 2

2. Examine for NF1-associated features:

   • Axillary/inguinal freckling 1, 2
   • Any neurofibromas (cutaneous, subcutaneous, or plexiform) 1, 2
   • Slit-lamp examination for Lisch nodules 1, 2
   • Visual assessment for optic pathway gliomas 1

3. Screen for alternative syndromes:

   • Dysmorphic features, heart defects, short stature (RASopathies) 1, 2
   • Hypopigmented spots, pilomatrixomas, family history of childhood cancers (CMMRD) 1, 2

4. Obtain detailed three-generation family history examining for CALMs, neurofibromatosis, childhood cancers, learning disabilities, unexplained tumors 1

Referral Criteria to Genetics

Immediate referral is warranted for: 1, 2

• ≥2 NIH diagnostic criteria for NF1 met
• CALMs + developmental delays, hypotonia, or neurologic symptoms (high-risk for CMMRD or other genetic conditions)
• CALMs + dysmorphic features suggesting RASopathy
• CALMs + family history of childhood cancers
• CALMs + childhood leukemia diagnosed at age <18

Surveillance Protocol

For children with multiple CALMs but <2 NF1 criteria (intermediate-risk): 1

• Clinical examination every 3-6 months during first 3 years of life
• Annual visits after age 3-5 years if no additional features develop
• Monitor for new skin freckling, skin lumps, vision changes, developmental concerns

For confirmed NF1 (≥2 NIH criteria met): 2

• Refer to specialized NF1 clinic for coordinated care
• Annual comprehensive physical examination throughout life
• Blood pressure monitoring for pheochromocytoma and renovascular hypertension
• Neurologic examination for new deficits
• Women: annual mammography starting age 30, consider breast MRI ages 30-50

Critical Pitfalls to Avoid

• Do not confuse Legius syndrome with NF1 - Legius patients have CALMs and freckling but lack tumor risks and require different surveillance; genetic testing (SPRED1 vs. NF1 gene) definitively distinguishes these 2
• Do not delay referral in children with CALMs plus developmental delays, hypotonia, or childhood leukemia - these suggest CMMRD or other syndromic diagnoses requiring immediate specialized care 6, 1, 2
• Do not provide false reassurance about benign nature in fair-skinned children with >6 CALMs - while some fair-skinned children with feathery CALMs may not develop NF1, proper documentation and surveillance are still required 5
• Do not overlook CMMRD - it can mimic NF1 with CALMs, freckling, neurofibromas, and Lisch nodules in up to one-third of patients, but has higher frequency of hypopigmented spots and pilomatrixomas 2

Parent Education Priorities

Instruct parents to urgently report: 1, 2

• New skin freckling in armpits or groin
• Any skin lumps or bumps
• Vision changes or eye problems
• Developmental concerns or learning difficulties
• Rapid growth, bleeding, or severe pain in any skin lesion (suggests MPNST transformation)