What is the management and evaluation approach for significant café au lait (caffeine with milk spots) spots?

Management and Evaluation of Significant Café au Lait Spots

When a patient presents with significant café au lait macules (CALMs), immediately evaluate for neurofibromatosis type 1 (NF1) using the NIH diagnostic criteria, and if ≥6 CALMs are present (≥5mm prepubertal or ≥15mm postpubertal), refer to genetics and a specialized NF1 clinic for comprehensive assessment and surveillance, as NF1 reduces life expectancy by 8-15 years primarily from malignant peripheral nerve sheath tumors and cardiovascular disease. 1, 2

Initial Diagnostic Evaluation

Count and Measure CALMs

• Document the exact number and size of all CALMs - ≥6 spots meeting size criteria (≥5mm prepubertal, ≥15mm postpubertal) is one of the NIH diagnostic criteria for NF1 1, 3
• Examine for axillary or inguinal freckling (Crowe's sign), which is highly specific for NF1 1
• Look for Lisch nodules on slit-lamp examination (iris hamartomas) 1
• Assess for cutaneous or subcutaneous neurofibromas 1

Distinguish NF1 from Other Conditions

• Fair-skinned children with red/blond hair and feathery-bordered CALMs (5-15 spots) often do not develop NF1 and may represent a benign variant 4
• Familial café au lait spots (FCAL) can present as isolated autosomal dominant CALMs without other NF1 features, though some families show linkage to NF1 gene while others do not 5, 6
• RASopathies (Noonan syndrome, Costello syndrome, CBL syndrome) present with CALMs plus dysmorphic facies, congenital heart defects, short stature, and cryptorchidism 1
• Legius syndrome (SPRED1 mutations) mimics NF1 with CALMs and freckling but lacks neurofibromas and optic gliomas 1

Referral and Genetic Testing

When to Refer to Genetics

• Any patient meeting ≥2 NIH diagnostic criteria for NF1 1
• Diagnostic evaluation of parents when a child is newly diagnosed with NF1 1
• Leukemia diagnosed at age <18 with café au lait macules and/or other signs of NF1 1
• Genetic testing can establish diagnosis and guide surveillance, though phenotypic severity varies even within families 1

Specialized NF1 Clinic Referral

• Strongly recommended for all confirmed or suspected NF1 cases for care coordination and surveillance 1, 2
• NF1 requires lifelong monitoring for life-threatening complications including MPNST (risk 8.5% by age 30,15.8% by age 85) 1, 2

Surveillance Protocol for Confirmed NF1

Annual Clinical Assessments

• Complete physical examination focusing on new or changing neurofibromas, particularly rapid growth or severe pain suggesting MPNST transformation 1
• 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 (pheochromocytoma) 1
• Screen for depression, chronic pain, and neuropathy 2

Cancer Surveillance

• Women with NF1: Begin annual mammography at age 30 and consider breast MRI with contrast between ages 30-50 2
• Baseline MRI of known or suspected non-superficial plexiform neurofibromas should be considered for monitoring 2
• Optic pathway gliomas occur in 15-20% of NF1 patients, typically in young children - monitor for vision changes 2

Pregnancy Management

• Refer pregnant women with NF1 to high-risk obstetrics due to increased cardiovascular and obstetric complications 2

Patient Education Priorities

Warning Signs Requiring Urgent Evaluation

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

Common Pitfalls to Avoid

• Do not dismiss multiple CALMs as benign without systematic evaluation - while isolated CALMs are common in the general population, ≥6 meeting size criteria warrant NF1 assessment 3, 7
• Do not assume all familial CALMs represent NF1 - some families have isolated FCAL without NF1 linkage, though others are NF1 variants 5, 6
• Do not confuse Legius syndrome with NF1 - Legius patients have CALMs but lack tumor risks and require different surveillance 1
• Do not delay referral in children with CALMs plus other concerning features (developmental delays, hypotonia, leukemia) as these suggest syndromic diagnoses requiring specialized care 1