What is the recommended workup for an infant under one year of age with isolated multiple cafe au lait spots and no other features or significant past medical history?

Workup for Isolated Multiple Café au Lait Spots in an Infant

For an infant with isolated multiple café au lait spots and no other features, the workup should focus on documenting the number and size of 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

Initial Clinical Documentation

Count and measure every café au lait spot precisely:

• Document whether there are ≥6 spots, as this meets one NIH diagnostic criterion for NF1 1, 2
• Measure each spot to determine if they meet size criteria: ≥5mm in prepubertal children 1, 2
• Note the distribution pattern (generalized vs. segmental), as segmental distribution may suggest segmental neurofibromatosis 3
• Describe border characteristics (smooth vs. feathery edges), as feathery borders in fair-skinned, red/blond-haired children may represent a benign variant 4

Comprehensive Physical Examination for NF1 Features

Examine for the following specific findings that would elevate concern:

Skin Examination

• Axillary or inguinal freckling (Crowe's sign) - highly specific for NF1 and often appears within the first 3 years of life 1, 2, 3
• Cutaneous or subcutaneous neurofibromas (though rare in infancy) 1
• Plexiform neurofibromas (may be congenital but often subtle in infancy) 1

Ophthalmologic Assessment

• Slit-lamp examination for Lisch nodules (iris hamartomas) - these typically appear later in childhood but are diagnostic for NF1 1, 2
• Visual assessment, as optic pathway gliomas occur in 15-20% of NF1 patients, typically in young children 1

Skeletal Examination

• Assess for tibial bowing or other bone abnormalities that may suggest NF1 2

Neurologic and Developmental Assessment

• Evaluate developmental milestones, as delays may suggest NF1 or other syndromes 2
• Assess muscle tone, as hypotonia suggests syndromic diagnosis requiring immediate genetics referral 1, 2

Screening for Alternative Genetic Syndromes

Look for features that distinguish other conditions from isolated café au lait spots:

RASopathies (Noonan, Costello, CBL syndromes)

• Dysmorphic facial features 1, 2
• Congenital heart defects 1, 2
• Short stature 2
• Cryptorchidism 2

Legius Syndrome

• CALMs and freckling similar to NF1 but lacks neurofibromas, optic gliomas, and tumor risks 1
• Cannot be distinguished clinically from NF1 in early childhood without genetic testing 1

Constitutional Mismatch Repair Deficiency (CMMRD)

• Hypopigmented spots in addition to CALMs 2
• Pilomatrixomas (calcifying skin tumors) 2
• Family history of childhood cancers (brain tumors, leukemia, GI malignancies) 2
• Consanguinity 2

Family History Assessment

Obtain detailed three-generation family history:

• Examine both parents for café au lait spots, as 50% of NF1 cases are inherited but parents may have subtle manifestations 1, 2
• Ask about family history of neurofibromatosis, childhood cancers, learning disabilities, or unexplained tumors 2
• Document consanguinity, which increases risk of CMMRD 2

Baseline Cardiovascular Assessment

• Measure blood pressure to screen for renovascular hypertension or pheochromocytoma (though rare in infancy) 1, 2

When Imaging is NOT Indicated

For isolated café au lait spots without other features:

• MRI screening is NOT recommended - solitary or multiple small café au lait spots without other NF1 features are low risk for neurocutaneous melanosis and do not warrant MRI 5
• CT abdomen/pelvis is NOT indicated for routine screening 1
• Imaging should only be pursued if clinical signs or symptoms develop 1

When Genetic Testing is NOT Immediately Indicated

For isolated café au lait spots in an infant:

• Genetic testing is premature if the child has <2 NIH diagnostic criteria for NF1 1
• Most children with multiple café au lait spots who will develop NF1 manifest additional features (especially freckling) within 3 years, usually before age 5 3

Referral Criteria

Refer to genetics if ANY of the following are present:

• ≥2 NIH diagnostic criteria for NF1 are met 1
• Developmental delays or hypotonia in addition to café au lait spots 1, 2
• Dysmorphic features suggesting RASopathy 1
• Family history of childhood cancers suggesting CMMRD 2
• Parental concern warrants genetic counseling even without definitive diagnosis 1

Dermatology referral:

• Can be delayed or deferred to primary care unless there are concerning features (color variation, nodules, symptoms, or problematic location) 5

Surveillance Protocol for Isolated Café au Lait Spots

Establish close clinical follow-up:

• Examine every 3-6 months during the first 3 years of life, as this is when additional NF1 features typically emerge 3
• At each visit, reassess for freckling, neurofibromas, Lisch nodules, developmental milestones, and blood pressure 1, 3
• After age 3-5 years, if no additional features develop, surveillance can be decreased to annual visits 5

Parent Education

Counsel parents to monitor for and report:

• New skin freckling in armpits or groin 1, 2
• New skin lumps or bumps 2
• Vision changes 2
• Developmental concerns 2
• Rapid growth, bleeding, or pain in any skin lesion 5

Important Clinical Caveats

Recognize benign variants to avoid overdiagnosis:

• Fair-skinned children with red or blond hair may have multiple feathery-bordered café au lait spots (5-15 spots) without developing NF1 4
• In one study, only 24 of 41 children (59%) with ≥6 café au lait spots eventually developed NF1, while 8 remained with isolated spots after years of follow-up 3
• However, do not assume benign variant - maintain surveillance as most NF1 cases declare themselves within 3 years 3

Do not delay evaluation if red flags are present:

• Hypotonia or developmental delays require immediate genetics referral, as these suggest CMMRD or other high-risk syndromes 1, 2
• History of leukemia in a child with café au lait spots warrants urgent genetics evaluation 1