What are the differences between familial benign café au lait (café au lait) macules and Legius syndrome in a patient presenting with multiple café au lait macules?

Distinguishing Familial Benign Café au Lait Macules from Legius Syndrome

The critical distinction is that familial benign café au lait macules represent an isolated pigmentary finding with no tumor risk or systemic complications, while Legius syndrome is a RASopathy caused by SPRED1 mutations that carries additional features including freckling, learning disabilities, and macrocephaly—though importantly, both conditions lack the tumor risks associated with NF1. 1, 2

Key Clinical Differences

Genetic Basis

• Familial benign CALMs: Unknown genetic mutation(s), distinct from NF1 and SPRED1 genes 3
• Legius syndrome: Caused by germline loss-of-function mutations in the SPRED1 gene 1, 4, 5

Clinical Features

Pigmentary manifestations:

• Familial CALMs: Multiple café au lait macules (≥6 spots meeting size criteria), may or may not have axillary/inguinal freckling, may rarely have Lisch nodules 3
• Legius syndrome: Multiple café au lait macules with or without intertriginous freckling 1, 4

Associated features:

• Familial CALMs: Isolated pigmentary findings only, no systemic manifestations 3
• Legius syndrome: Commonly includes lipomas, macrocephaly, learning disabilities (ADHD, developmental delays) 5, 6

Tumor Risk Profile

This is the most clinically significant distinction:

• Familial CALMs: No increased tumor risk, no neurofibromas, no optic pathway gliomas, no malignancies 2, 3
• Legius syndrome: No increased tumor risk compared to general population—specifically absent are neurofibromas, optic pathway gliomas, and NF1-associated bone abnormalities 1, 4, 6

Both conditions lack the 8-15 year reduction in life expectancy seen with NF1. 2, 7

Surveillance Recommendations

Familial Benign CALMs

• Annual dermatologic examination to monitor for any new skin lesions, particularly to ensure neurofibromas do not develop 2
• No routine imaging (MRI, CT) required 2
• No specialized NF1 clinic referral needed 2
• No screening for pheochromocytoma, MPNST, or other NF1-associated malignancies 2

Legius Syndrome

• No cancer surveillance recommended 1
• Clinical follow-up focused on developmental and learning assessments 4, 5
• Skin examination at least annually if specific concerns arise 1

Diagnostic Approach in Clinical Practice

When encountering a patient with multiple café au lait macules:

1. Document precise phenotype: Count and measure all CALMs (≥6 spots with ≥5mm prepubertal or ≥15mm postpubertal meets one NIH criterion for NF1) 2, 7

2. Perform thorough examination for distinguishing features:

   • Absence of cutaneous/subcutaneous neurofibromas (key negative finding for both conditions) 2, 3
   • Presence of learning disabilities, macrocephaly, or lipomas suggests Legius syndrome over familial CALMs 4, 5
   • Family history pattern: autosomal dominant inheritance in both 3, 5

3. Genetic testing is definitive:

   • SPRED1 gene testing confirms or excludes Legius syndrome 4, 5, 6
   • NF1 gene testing can exclude NF1 2, 8
   • If both are negative with isolated CALMs, familial benign CALMs is the diagnosis 3

Critical Clinical Pitfalls

Do not confuse either condition with NF1, as this leads to unnecessary anxiety, inappropriate surveillance (including repeated imaging with radiation exposure), and incorrect prognostic counseling about life expectancy and tumor risks 2, 3, 8

The phenotypic overlap is substantial in young children: In sporadic cases with multiple CALMs and freckling but no other NF1 manifestations, clinical examination alone cannot differentiate Legius syndrome from early NF1—molecular analysis is usually required 6

19.5% to 57.1% of patients with isolated café au lait macules do not have NF1 after follow-up or genetic testing, emphasizing the importance of not prematurely diagnosing NF1 8

Genetic Counseling Implications

Both conditions follow autosomal dominant inheritance with 50% offspring recurrence risk 2, 3, 5

However, the counseling differs dramatically:

• Familial CALMs: Reassurance about absence of tumor risk and normal life expectancy 2, 3
• Legius syndrome: Counseling about potential learning disabilities and developmental delays, but reassurance about absence of tumor risk 4, 5
• Both: Emphasize the critical distinction from NF1's significant morbidity and mortality 1, 2

Red Flags Requiring Reassessment

For either condition, development of any of the following warrants immediate re-evaluation for possible NF1:

• Cutaneous or subcutaneous neurofibromas 2, 7
• New neurologic symptoms 7
• Bone abnormalities 7
• Vision changes in children 7