When are cafe au lait (CAL) spots significant in children?

When Café au Lait Spots Are Significant in Children

Café au lait macules (CALMs) become clinically significant when a child has ≥6 spots measuring ≥5mm in prepubertal children or ≥15mm in postpubertal individuals, as this meets one of the NIH diagnostic criteria for neurofibromatosis type 1 (NF1), a condition associated with 8-15 years reduced life expectancy. 1

Immediate Red Flags Requiring Urgent Evaluation

The following presentations warrant immediate referral to genetics or specialized evaluation:

• ≥6 CALMs meeting size criteria (≥5mm prepubertal, ≥15mm postpubertal) 1
• CALMs plus axillary or inguinal freckling (Crowe's sign), which is highly specific for NF1 1
• CALMs with leukemia diagnosed before age 18, suggesting constitutional mismatch repair deficiency syndrome or CBL syndrome 1
• CALMs with developmental delays, hypotonia, or neurologic symptoms, raising concern for biallelic mismatch repair deficiency syndrome 2
• CALMs with dysmorphic facial features, congenital heart defects, or short stature, suggesting RASopathies (Noonan, Costello, or CBL syndromes) 2, 1

Algorithmic Approach to Evaluation

Step 1: Document and Measure

Count and measure every single CALM precisely. The exact number and size determine whether NIH criteria are met. 1 This is not optional—documentation must be meticulous.

Step 2: Complete Physical Examination

Look specifically for:

• Axillary or inguinal freckling (appears typically ages 4-5 years in NF1) 1
• Cutaneous or subcutaneous neurofibromas (may not appear until later childhood/adolescence) 1
• Dysmorphic facial features (widely spaced eyes, ptosis, low-set ears suggest RASopathies) 2
• Segmental distribution of CALMs (suggests segmental neurofibromatosis or mosaic RASopathy) 3

Step 3: Ophthalmologic Examination

Slit-lamp examination for Lisch nodules (iris hamartomas) is essential, as these are pathognomonic for NF1 and often appear before other diagnostic features. 1, 3

Step 4: Risk Stratification

High-Risk (Refer to Genetics Immediately):

• ≥6 CALMs meeting size criteria 1
• Any CALMs plus freckling 1
• Any CALMs plus Lisch nodules 1
• Any CALMs plus neurofibromas 1
• CALMs plus developmental delays or hypotonia 2
• CALMs plus leukemia or other childhood cancers 1

Intermediate-Risk (Close Follow-up, Consider Genetics Referral):

• 3-5 CALMs meeting size criteria 3
• Multiple CALMs with dysmorphic features but no clear syndrome 2
• Segmental CALMs (may represent segmental NF1 or mosaic conditions) 3

Low-Risk (Routine Follow-up):

• 1-2 isolated CALMs in otherwise healthy child 2
• Multiple feathery-bordered CALMs in fair-skinned, red/blond-haired children without other features (often benign variant) 4

Critical Diagnostic Distinctions

Neurofibromatosis Type 1 vs. Legius Syndrome

Legius syndrome mimics NF1 with CALMs and freckling but lacks neurofibromas, optic gliomas, and tumor risks. 2, 1 This distinction is crucial because Legius patients do not require the intensive cancer surveillance needed for NF1. Genetic testing (SPRED1 vs. NF1 gene) definitively distinguishes these conditions. 2, 1

Constitutional Mismatch Repair Deficiency Syndrome

CALMs plus childhood leukemia, brain tumors, or GI malignancies suggest biallelic mismatch repair deficiency syndrome, which carries extremely high cancer risk. 2 These children typically have café au lait spots that may be mistaken for NF1, but the presence of hematologic malignancies or brain tumors in early childhood is the distinguishing feature. 2

RASopathies (Noonan, Costello, CBL Syndromes)

CALMs with congenital heart defects, short stature, cryptorchidism, or characteristic facies suggest RASopathies rather than NF1. 2 Costello syndrome carries 15% cumulative cancer risk by age 20, primarily embryonal rhabdomyosarcoma and neuroblastoma, requiring specific surveillance protocols. 2

Natural History and Follow-Up Timing

Most children with multiple CALMs who will develop NF1 show additional diagnostic features within 3 years of initial evaluation, usually before age 5. 3 The most common confirmatory feature to appear is skin-fold freckling (occurred in 75% of cases in one longitudinal study), followed by Lisch nodules and neurofibromas. 3

Annual follow-up is mandatory for children with multiple CALMs until diagnosis is established or excluded. 1, 3 Each visit must include:

• Complete skin examination for new freckling or neurofibromas 1
• Ophthalmologic examination for Lisch nodules 1, 3
• Developmental and neurologic assessment 1
• Blood pressure measurement (renovascular hypertension risk in NF1) 1

Common Pitfalls to Avoid

Do not dismiss multiple CALMs in fair-skinned children with feathery borders as automatically benign. While this phenotype may represent a benign variant 4, these children still require initial comprehensive evaluation and at least short-term follow-up to ensure no additional features emerge. 4, 3

Do not confuse isolated CALMs with high-risk cutaneous markers for spinal dysraphism. Isolated CALMs are classified as low-risk for underlying spinal cord malformations, unlike hypertrichosis, infantile hemangiomas, or subcutaneous lipomas overlying the spine. 2 However, this classification applies only to spinal dysraphism risk, not to systemic genetic syndromes.

Do not delay genetics referral waiting for "more features to develop." Any child meeting ≥2 NIH diagnostic criteria for NF1 should be referred immediately, as early diagnosis enables appropriate surveillance for life-threatening complications including malignant peripheral nerve sheath tumors (8.5% risk by age 30,15.8% by age 85). 1

Do not assume normal initial evaluation excludes NF1. Freckling typically appears ages 4-5 years, Lisch nodules may not be present in early childhood, and neurofibromas often don't develop until adolescence. 2, 1, 3 This is why longitudinal follow-up is essential.

When Isolated CALMs Are Truly Insignificant

1-2 isolated CALMs in an otherwise healthy child with normal development, no dysmorphic features, and no family history of genetic syndromes are clinically insignificant. 2, 5 These occur in the general population and do not warrant genetic evaluation or specialized follow-up beyond routine pediatric care. 2, 5