What is the best approach protocol for a patient presenting with cafe au lait macules, potentially indicating Neurofibromatosis Type 1 (NF1)?

Best Approach Protocol for Café au Lait Macules

Initial Clinical Assessment

Document the exact number and measure the size of every café au lait macule, as ≥6 CALMs measuring ≥5mm (prepubertal) or ≥15mm (postpubertal) meets one NIH diagnostic criterion for neurofibromatosis type 1 (NF1), a condition that reduces life expectancy by 8-15 years primarily due to malignant peripheral nerve sheath tumors. 1

Critical Physical Examination Findings

Perform a systematic examination looking for:

• Axillary or inguinal freckling (Crowe's sign) - highly specific for NF1 1
• Cutaneous or subcutaneous neurofibromas - palpable skin lumps or bumps 1
• Lisch nodules - requires slit-lamp examination by ophthalmology 1
• Bone abnormalities - leg bowing, scoliosis, or history of pathologic fractures 2
• Dysmorphic facial features - suggests RASopathies rather than isolated NF1 1

Essential History Components

Developmental and neurologic history:

• Developmental delays, hypotonia, or learning disabilities suggest high-risk syndromic diagnoses requiring immediate genetics referral 1, 2
• Vision problems may indicate optic pathway gliomas (occur in 15-20% of NF1 patients) 1
• Seizures or persistent headaches suggest CNS tumors 2

Red flag symptoms requiring urgent evaluation:

• Progressive severe pain in existing skin lumps (suggests malignant transformation with 8.5% risk by age 30) 1, 2
• Rapid tumor growth 1, 2
• New neurologic deficits 1, 2
• Diaphoresis, palpitations, or hypertensive episodes (pheochromocytoma) 1

Family history:

• Parental CALMs (50% offspring recurrence risk for autosomal dominant NF1) 2
• Childhood cancers in family members, particularly brain tumors or leukemia (suggests Constitutional Mismatch Repair Deficiency with 90% cancer risk by age 18) 2
• Consanguinity increases risk of biallelic conditions 2

Risk Stratification and Referral Algorithm

HIGH-RISK: Immediate Genetics Referral Required

Refer immediately if CALMs plus any of the following: 1, 2

• Developmental delays or hypotonia
• Childhood leukemia (especially if diagnosed <18 years)
• History of brain tumors or GI malignancies
• Multiple NIH criteria for NF1 (≥2 criteria)

INTERMEDIATE-RISK: Close Follow-up with Genetics Consideration

Multiple CALMs (≥6 meeting size criteria) without clear syndrome features: 1

• Schedule close follow-up every 6-12 months
• Consider genetics referral for diagnostic clarity
• Note that 19.5-57.1% of patients with isolated CALMs do not ultimately develop NF1 3

LOW-RISK: Routine Follow-up

1-2 isolated CALMs without other features can be followed routinely 1

Differential Diagnosis Beyond NF1

Legius Syndrome (SPRED1 mutations)

• Presents with CALMs and freckling but lacks neurofibromas, optic gliomas, and tumor risks 1
• Requires different surveillance protocol (no cancer screening needed) 1
• Genetic testing (SPRED1 vs NF1 gene) definitively distinguishes these conditions 1

RASopathies (Noonan, Costello, CBL syndromes)

• CALMs plus dysmorphic facies, congenital heart defects, short stature, cryptorchidism 1

Constitutional Mismatch Repair Deficiency (CMMRD)

• CALMs plus childhood cancers, hypopigmented spots, pilomatrixomas 1, 2
• Extremely high cancer risk requiring specialized surveillance 1

Genetic Testing Indications

Offer genetic testing in the following scenarios: 1

• Diagnostic uncertainty after clinical evaluation
• Parent evaluation when child newly diagnosed with NF1
• Prenatal diagnosis for known familial mutations
• NF1 variant of uncertain significance detected on cancer panel
• To distinguish Legius syndrome from NF1

Management for Confirmed or Suspected NF1

Mandatory Referral

All patients meeting ≥2 NIH diagnostic criteria for NF1 must be referred to a specialized NF1 clinic for coordinated care and surveillance. 4, 1 This significantly reduces morbidity and mortality given the 15.8% lifetime risk of malignant peripheral nerve sheath tumors by age 85. 1

Annual Surveillance Protocol

Complete physical examination focusing on: 1

• New or rapidly changing neurofibromas
• Blood pressure measurement (renovascular hypertension, pheochromocytoma screening)
• Neurologic examination for new deficits
• Assessment for diaphoresis/palpitations

Imaging is symptom-directed, not routine: 1

• MRI preferred over CT to minimize radiation exposure
• Targeted MRI of concerning plexiform neurofibromas when clinically indicated
• No routine CT abdomen/pelvis for cancer screening

Women with NF1: 1

• Annual mammography starting at age 30
• Consider breast MRI with contrast between ages 30-50

Pheochromocytoma screening: 1

• No routine biochemical screening in asymptomatic patients
• Test plasma free metanephrines if hypertensive, pregnant, or paroxysmal symptoms

Patient Education Priorities

Educate patients to seek urgent evaluation for: 1

• Progressive severe pain in existing neurofibroma
• Rapid change in tumor volume
• New unexplained neurologic symptoms
• Diaphoresis, palpitations, or hypertensive episodes

Common Pitfalls to Avoid

• Do not confuse Legius syndrome with NF1 - Legius patients lack tumor risks and require no cancer surveillance 1
• Do not delay referral in children with CALMs plus developmental concerns - these suggest syndromic diagnoses requiring specialized care 1
• Do not order routine CT scans for surveillance - clinical examination drives imaging decisions, and cumulative radiation increases malignancy risk 1
• Do not assume all patients with multiple CALMs will develop NF1 - up to 57% may have isolated CALMs without NF1 3