Evaluation and Management of Isolated Multiple Café au Lait Spots in Infants

Initial Assessment and Surveillance

The American Academy of Pediatrics recommends documenting the number and size of café au lait spots, performing a thorough physical examination for associated features of neurofibromatosis type 1 (NF1) and other genetic syndromes, and establishing close clinical surveillance rather than routine imaging or genetic testing at this stage 1
The National Institutes of Health (NIH) diagnostic criterion for NF1 is met if there are ≥6 café au lait spots, and each spot should be measured to determine if they meet size criteria: ≥5mm in prepubertal children 1, 2

A thorough skin examination should be performed to look for axillary or inguinal freckling (Crowe's sign), which is highly specific for NF1 and often appears within the first 3 years of life 1, 2
Cutaneous or subcutaneous neurofibromas, although rare in infancy, should be examined for 1
Plexiform neurofibromas, which may be congenital but often subtle in infancy, should be assessed for 1
A slit-lamp examination for Lisch nodules (iris hamartomas) should be performed, as these are diagnostic for NF1 1, 2
Visual assessment should be done, as optic pathway gliomas occur in 15-20% of NF1 patients, typically in young children 1

Dysmorphic facial features, congenital heart defects, short stature, and cryptorchidism should be examined for, as these may suggest RASopathies (Noonan, Costello, CBL syndromes) 1, 2
Hypopigmented spots in addition to café au lait spots, pilomatrixomas (calcifying skin tumors), and family history of childhood cancers may suggest Constitutional Mismatch Repair Deficiency (CMMRD) 2

A detailed three-generation family history should be obtained to examine for café au lait spots, neurofibromatosis, childhood cancers, learning disabilities, or unexplained tumors 1, 2
Referral to genetics is recommended if ≥2 NIH diagnostic criteria for NF1 are met, or if there are developmental delays, hypotonia, dysmorphic features suggesting RASopathy, or family history of childhood cancers suggesting CMMRD 1, 2

Close clinical follow-up should be established, with examination every 3-6 months during the first 3 years of life, and annual visits after age 3-5 years if no additional features develop 1, 3, 4
Parents should be counseled to monitor for and report new skin freckling, skin lumps or bumps, vision changes, developmental concerns, and rapid growth, bleeding, or pain in any skin lesion 1, 2, 3, 4