What is the management approach for a patient with familial benign café au lait (café au lait macules) macules?

Management of Familial Benign Café au Lait Macules

For patients with familial multiple café au lait macules (CALMs) without neurofibromas or other features of neurofibromatosis type 1 (NF1), clinical surveillance with annual skin examinations is sufficient, and these patients do not require the intensive monitoring protocols used for NF1. 1

Distinguishing Familial CALMs from NF1

Familial multiple café au lait spots represent a rare autosomal dominant pigmentary disorder that mimics the cutaneous features of NF1 but critically differs by the complete absence of neurofibromas and other neural crest tumors 1. This distinction is essential because:

• Between 19.5% to 57.1% of patients presenting with isolated CALMs do not ultimately develop NF1 after follow-up or genetic testing 2
• Familial CALMs can occur with or without axillary/inguinal freckling and even Lisch nodules, yet still not represent true NF1 1
• The clinical presentation remains consistent within affected families across multiple generations 1

Essential Clinical Evaluation

Document the complete phenotype to avoid misdiagnosis:

• Count and measure all CALMs precisely (≥6 spots with ≥5mm prepubertal or ≥15mm postpubertal meets one NIH criterion for NF1) 3
• Perform thorough skin examination for cutaneous or subcutaneous neurofibromas—their absence is the key distinguishing feature 1
• Check for axillary and inguinal freckling (Crowe's sign), which can occur in familial CALMs but does not automatically indicate NF1 3, 1
• Conduct slit-lamp examination for Lisch nodules, noting that their presence alone without neurofibromas does not confirm NF1 1
• Assess for plexiform neurofibromas, optic pathway gliomas, bone dysplasias, and other NF1-associated features 3

Genetic Testing Considerations

Genetic testing can definitively distinguish familial CALMs from NF1 and guide appropriate counseling:

• Testing is particularly valuable when clinical findings are ambiguous or when families need definitive reassurance 2, 4
• NF1 gene testing can confirm or exclude NF1, though the specific gene mutation(s) for familial multiple CALMs remain under investigation 1
• Consider testing for Legius syndrome (SPRED1 mutations), which also presents with CALMs and freckling but lacks neurofibromas and tumor risks 3

Surveillance Protocol for Confirmed Familial CALMs

Once neurofibromas and other NF1 features are definitively excluded:

• Annual dermatologic examination to monitor for any new skin lesions, particularly neurofibromas 1
• No routine imaging (MRI, CT) or specialized NF1 clinic referral is required 3
• No screening for pheochromocytoma, MPNST, or other NF1-associated malignancies 3
• No enhanced breast cancer screening protocols (unlike NF1 patients who require mammography starting at age 30) 3

Critical Counseling Points

Avoid erroneous NF1 diagnosis and its associated anxiety:

• Emphasize that familial CALMs do not carry the 8-15 year reduction in life expectancy associated with NF1 5, 1
• Explain the 50% autosomal dominant inheritance risk for offspring, but clarify they will inherit only the benign pigmentary condition 1
• Reassure families that without neurofibromas, the risks of MPNST (8.5% by age 30 in true NF1) do not apply 5, 3
• Document clearly in the medical record that this is not NF1 to prevent future providers from initiating unnecessary surveillance 1

Red Flags Requiring Re-evaluation

Any new findings warrant immediate reassessment for possible NF1:

• Development of any cutaneous or subcutaneous neurofibromas 3, 1
• New neurologic symptoms suggesting optic pathway glioma or other CNS involvement 3
• Bone abnormalities such as tibial bowing or pseudoarthrosis 6
• Vision changes in children (optic gliomas occur in 15-20% of NF1 patients) 3

Common Pitfalls to Avoid

• Do not automatically diagnose NF1 based solely on multiple CALMs with freckling or even Lisch nodules—the absence of neurofibromas over time distinguishes familial CALMs 1
• Do not subject these patients to intensive NF1 surveillance protocols including specialized clinic referrals, annual blood pressure monitoring for pheochromocytoma, or routine neuroimaging 3
• Do not confuse with Legius syndrome, which also lacks neurofibromas but may have additional features; genetic testing (SPRED1 vs. NF1 gene) can distinguish these conditions 3