What is the diagnosis and management approach for individuals with cafe au lait spots?

Café au Lait Spots: Diagnosis and Management

Initial Assessment

Document the exact number and size of all café au lait macules (CALMs), as ≥6 spots measuring ≥5mm (prepubertal) or ≥15mm (postpubertal) meets one of the NIH diagnostic criteria for neurofibromatosis type 1 (NF1), a condition associated with 8-15 years reduced life expectancy. 1

Critical Physical Examination Findings

• Examine for axillary or inguinal freckling (Crowe's sign), which is highly specific for NF1 1
• Perform slit-lamp examination for Lisch nodules (iris hamartomas), which confirm NF1 diagnosis 1
• Assess for cutaneous or subcutaneous neurofibromas, as these distinguish NF1 from benign familial café au lait spots 1
• Evaluate for dysmorphic facies, congenital heart defects, short stature, and cryptorchidism, which suggest RASopathies (Noonan, Costello, or CBL syndrome) rather than NF1 1

Differential Diagnosis Framework

When to Suspect NF1 vs. Other Conditions

NF1 (most common, 1 in 2,000-3,000): Multiple CALMs plus freckling, Lisch nodules, neurofibromas, optic gliomas, bone dysplasia, or family history of NF1 1, 2

Legius syndrome: CALMs and freckling identical to NF1 but lacks neurofibromas and optic gliomas—critical distinction as cancer surveillance differs 1, 3

Constitutional mismatch repair deficiency: CALMs with NF1-like features but presents with childhood cancers (Lynch syndrome-associated, hematologic malignancies, embryonic tumors) 3

Familial café au lait spots (FCAL): Autosomal dominant multiple CALMs without any other NF1 features across generations—benign condition not linked to NF1 gene 4, 5

Fair-skinned phenotype: Children with red/blond hair and fair complexion often have 5-15 feathery-bordered CALMs without developing NF1 6

Referral Criteria

Refer to genetics immediately if the patient meets ≥2 NIH diagnostic criteria for NF1 (≥6 CALMs of appropriate size, freckling, Lisch nodules, neurofibromas, optic glioma, bone dysplasia, first-degree relative with NF1) 1

Refer for genetic evaluation when:

• Leukemia diagnosed at age <18 with CALMs and/or other NF1 signs 1
• Parent of newly diagnosed child with NF1 1
• Developmental delays, hypotonia, or other syndromic features with CALMs 1

Refer to specialized NF1 clinic for all confirmed or suspected NF1 cases for lifelong care coordination and surveillance 1

Surveillance Protocol for Confirmed NF1

Annual Monitoring Requirements

• Complete physical examination focusing on new or rapidly growing neurofibromas, as progressive severe pain or rapid volume change signals malignant peripheral nerve sheath tumor (MPNST) transformation—risk is 8.5% by age 30,15.8% by age 85 1, 3
• Blood pressure measurement to screen for pheochromocytoma and renovascular hypertension 1
• Neurologic examination for new deficits suggesting MPNST or CNS tumors 1
• Assessment for diaphoresis/palpitations indicating pheochromocytoma 1

Age-Specific Surveillance

• Women with NF1: Begin annual mammograms at age 30 and consider breast MRI with contrast between ages 30-50 1
• Baseline MRI of known or suspected non-superficial plexiform neurofibromas should be considered 1

Patient Education: Red Flag Symptoms Requiring Urgent Evaluation

• Progressive severe pain in existing neurofibroma (MPNST) 1, 3
• Rapid change in tumor volume (MPNST) 1, 3
• New unexplained neurologic symptoms (MPNST, brain tumors) 1, 3
• Diaphoresis, palpitations, or hypertensive episodes (pheochromocytoma) 1

Management of Isolated CALMs Without Other Features

For children with only multiple CALMs at initial presentation, establish annual follow-up with physical and ophthalmologic examinations. Most children who will develop NF1 manifest additional diagnostic features (freckling, Lisch nodules, neurofibromas) within 3 years, usually before age 5. 7

However, 19.5% to 57.1% of patients with isolated CALMs never develop NF1, particularly fair-skinned children with feathery-bordered spots. 2, 6 Genetic testing can guide follow-up intensity but is not mandatory for all cases. 2

Critical Pitfalls to Avoid

Do not diagnose NF1 based solely on CALMs and freckling—this presentation is identical in Legius syndrome, which lacks tumor risks and requires no cancer surveillance 1, 3

Do not confuse familial café au lait spots with NF1—FCAL is autosomal dominant, benign, and not linked to the NF1 gene 4, 5

Do not delay genetics referral in children with CALMs plus developmental delays, hypotonia, or leukemia, as these suggest constitutional mismatch repair deficiency or other syndromic diagnoses requiring specialized care 1, 3

Do not provide false reassurance to families with multiple affected generations—while FCAL exists, genetic testing or prolonged surveillance is needed to exclude NF1 definitively 5