What are the differential diagnoses for a large café‑au‑lait macule present since birth?

Differential Diagnosis of Large Café-au-Lait Patch Present Since Birth

A large café-au-lait macule present since birth requires systematic evaluation for neurofibromatosis type 1 (NF1), McCune-Albright syndrome, congenital melanocytic nevus, and other genetic syndromes, with the specific morphology, distribution pattern, and associated features guiding the differential diagnosis.

Primary Differential Diagnoses

Neurofibromatosis Type 1 (NF1)

• Most common syndrome associated with café-au-lait macules in children, affecting 1 in 2,000-3,000 individuals 1, 2
• Café-au-lait spots in NF1 are typically well-circumscribed, evenly pigmented, round to oval macules 3
• Diagnosis requires ≥2 NIH criteria: ≥6 café-au-lait spots (≥5mm prepubertal), axillary/inguinal freckling (Crowe's sign), neurofibromas, Lisch nodules, optic glioma, distinctive bone lesions, or first-degree relative with NF1 1, 2
• Critical examination points: Look for axillary or inguinal freckling (highly specific, appears within first 3 years), palpate for cutaneous/subcutaneous neurofibromas, perform slit-lamp examination for Lisch nodules 1, 2
• NF1 carries an 8-15 year reduction in life expectancy due to malignant peripheral nerve sheath tumors and cardiovascular disease 2

McCune-Albright Syndrome

• Pathognomonic feature: Café-au-lait macules with irregular, jagged "coast of Maine" borders arranged in a Blaschko-linear pattern in broad bands 4, 5
• This linear arrangement reflects the genetic mosaicism characteristic of the disease 4
• Classic triad: café-au-lait spots, fibrous dysplasia of bone, and endocrine disorders (especially precocious puberty) 4
• Key distinction: The irregular borders and segmental distribution are diagnostic even before bone or endocrine manifestations appear 4
• Diagnosis can be confirmed by genetic testing showing arginine substitution at position 201 of Gs alpha protein 4

Congenital Melanocytic Nevus (CMN)

• Large CMN can present as raised, hypertrichotic, verrucous, cerebriform, or papillated lesions present at birth 6
• Size classification matters: Small (<1.5cm), medium (1.5-20cm), large (>20cm), or giant (>40cm or >5% body surface area) 6
• Patients with large, giant, or multiple CMN should establish care with pediatric dermatology in the neonatal period 6
• Critical surveillance: Monitor for proliferative nodules (benign but can mimic melanoma) and true melanoma risk, which can occur in skin or CNS 6
• MRI screening for neurocutaneous melanosis is recommended for giant CMN, multiple medium CMN, or ≥10 satellite lesions 6

Mastocytoma

• Solitary mastocytomas can be several centimeters in diameter, resembling large pigmented patches 6
• Typically present at birth or develop within one week of life 6
• Diagnostic feature: Positive Darier's sign (urtication and flare upon rubbing the lesion) 6
• Can vesiculate and blister, particularly in infancy 6
• Most cases resolve by puberty, though persistent lesions occur in adults 6

Secondary Differential Diagnoses

RASopathies (Noonan, Costello, CBL Syndromes)

• Present with café-au-lait macules plus dysmorphic facial features, congenital heart defects, short stature, and cryptorchidism 1, 2
• Lack the tumor risks associated with NF1 2

Legius Syndrome (SPRED1 mutations)

• Mimics NF1 with café-au-lait macules and axillary/inguinal freckling 2, 7
• Critical distinction: Lacks neurofibromas, optic gliomas, and tumor risks 2, 7
• Normal life expectancy, unlike NF1 2
• Genetic testing (SPRED1 vs. NF1 gene) definitively distinguishes these conditions 2

Constitutional Mismatch Repair Deficiency (CMMRD)

• Can mimic NF1 with café-au-lait macules, freckling, and even neurofibromas in one-third of patients 2
• Red flags: Hypopigmented spots in addition to café-au-lait spots, pilomatrixomas (calcifying skin tumors), family history of childhood cancers 1, 2
• Extremely high cancer risk (childhood leukemia, brain tumors, GI malignancies) 2

Nijmegen Breakage Syndrome (NBS)

• Café-au-lait macules occur alongside microcephaly, dysmorphic facial features, growth deficiency, and immunodeficiency 6
• Approximately 50% show borderline to mild intellectual disability 6
• High risk of lymphomas and leukemias 6

Algorithmic Approach to Evaluation

Step 1: Document Lesion Characteristics

• Measure and count all café-au-lait spots precisely (≥6 spots ≥5mm meets one NIH criterion for NF1) 1, 2
• Assess borders: Smooth/regular (NF1, Legius) vs. irregular/jagged (McCune-Albright) 4, 5
• Evaluate distribution: Random/scattered vs. Blaschko-linear/segmental (McCune-Albright) 4, 5
• Examine texture: Flat/smooth vs. raised/verrucous/hairy (CMN) 6
• Test Darier's sign: Rub lesion to check for urtication (mastocytoma) 6

Step 2: Comprehensive Physical Examination

• Skin: Examine entire body for axillary/inguinal freckling, neurofibromas, hypopigmented spots, pilomatrixomas 1, 2
• Eyes: Slit-lamp examination for Lisch nodules (NF1) 1, 2
• Dysmorphic features: Facial features, body proportions, cardiac examination (RASopathies) 1, 2
• Neurologic: Developmental assessment, head circumference (NBS) 6
• Endocrine: Signs of precocious puberty (McCune-Albright) 4

Step 3: Family History Assessment

• Obtain three-generation family history examining for café-au-lait spots, neurofibromatosis, childhood cancers, learning disabilities 1
• Family history of childhood cancers suggests CMMRD 1, 2

Step 4: Determine Referral Needs

• Immediate genetics referral if: ≥2 NIH criteria for NF1, developmental delays/hypotonia, dysmorphic features suggesting RASopathy, family history of childhood cancers, or café-au-lait spots plus childhood leukemia/brain tumors 1, 2
• Pediatric dermatology referral for large/giant CMN in neonatal period 6
• Specialized NF1 clinic for confirmed or suspected NF1 2

Step 5: Surveillance Protocol

• For isolated large café-au-lait spot without other features: Close clinical follow-up every 3-6 months during first 3 years of life, then annually after age 3-5 years 1
• For suspected NF1: Annual comprehensive examination, blood pressure monitoring, neurologic assessment 2
• For large/giant CMN: Serial photographs, palpation for nodules, MRI screening if indicated 6

Critical Pitfalls to Avoid

• Do not dismiss a single large café-au-lait spot as benign without thorough evaluation—McCune-Albright can present with a single segmental lesion before other manifestations appear 4
• Do not confuse Legius syndrome with NF1—Legius patients lack tumor risks and require different surveillance 2, 7
• Do not delay referral in children with café-au-lait spots plus developmental delays, hypotonia, or leukemia—these suggest high-risk syndromic diagnoses requiring specialized care 1, 2
• Do not overlook palpation of café-au-lait spots and surrounding skin—deep nodules in CMN can indicate melanoma without surface color change 6
• Do not assume all large pigmented patches are café-au-lait spots—mastocytomas can mimic them but have positive Darier's sign 6

Parent Education Priorities

Counsel parents to monitor for and report: 1, 2

• New skin freckling in armpits or groin
• Skin lumps or bumps
• Vision changes
• Developmental concerns
• Rapid growth, bleeding, or pain in the lesion