What questions should be asked in the medical history of a patient with cafe au lait (cafe au lait spots) spots?

History Questions for Café au Lait Spots

When evaluating a patient with café au lait macules (CALMs), your history must systematically rule out neurofibromatosis type 1 (NF1) and other genetic syndromes, as ≥6 CALMs meeting size criteria (≥5mm prepubertal or ≥15mm postpubertal) is associated with NF1, which reduces life expectancy by 8-15 years primarily due to malignant peripheral nerve sheath tumors. 1

Essential Questions About the Café au Lait Spots Themselves

• Exact number of spots: Document whether there are ≥6 CALMs, as this meets one NIH diagnostic criterion for NF1 1
• Size of each spot: Measure whether any are ≥5mm (prepubertal) or ≥15mm (postpubertal), as size thresholds are critical for NF1 diagnosis 1
• Age of onset: Ask when spots first appeared—CALMs present since birth or early infancy suggest genetic syndromes 2
• Changes over time: Inquire about increasing number or size of spots, as progression may indicate underlying syndrome 3

Questions to Identify Associated NF1 Features

• Skin freckling: Ask specifically about freckling in armpits or groin (Crowe's sign), which is highly specific for NF1 1
• Skin lumps or bumps: Question about any cutaneous or subcutaneous nodules that could represent neurofibromas 1
• Rapidly growing or painful lumps: This suggests malignant peripheral nerve sheath tumor transformation, which has 8.5% risk by age 30 in NF1 1, 4
• Vision problems: Optic pathway gliomas occur in 15-20% of NF1 patients, typically in young children 1
• Bone abnormalities: Ask about bowing of legs or fractures, as tibial pseudoarthrosis occurs in NF1 4

Questions to Identify Other Genetic Syndromes

RASopathies (Noonan, Costello, CBL syndromes)

• Facial features: Ask about unusual facial appearance, as dysmorphic facies distinguish RASopathies from isolated CALMs 1
• Heart problems: Congenital heart defects are characteristic of RASopathies 1
• Growth concerns: Short stature is a feature of RASopathies 1
• Undescended testicles: Cryptorchidism occurs in RASopathies 1

Constitutional Mismatch Repair Deficiency (CMMRD)

• Cancer history: Ask about any childhood cancers, particularly brain tumors, leukemia (especially T-cell lymphoma), or gastrointestinal malignancies, as CMMRD carries 90% cancer risk by age 18 4
• Developmental concerns: Inquire about developmental delays, hypotonia, or learning disabilities, as these suggest CMMRD or other syndromes 1, 4
• Hypopigmented spots: Ask about lighter skin patches, as hypopigmentation is more common in CMMRD than NF1 4
• Other skin lesions: Question about pilomatrixoma (calcifying skin tumors), which are more frequent in CMMRD 4

Carney Complex

• Spotty pigmentation: Ask about pigmented spots on lips, conjunctiva, or genital mucosa 4
• Heart symptoms: Inquire about palpitations or shortness of breath suggesting cardiac myxoma 4
• Hormonal issues: Question about signs of acromegaly or Cushing syndrome from endocrine tumors 4

Critical Family History Questions

• Parental CALMs: Examine both parents for CALMs, as NF1 has 50% offspring recurrence risk but parents may not yet have cancer manifestations 1
• Extended family CALMs: Ask about café au lait spots in grandparents, aunts, uncles, as familial multiple CALMs can occur without NF1 5, 6
• Family cancer history: Specifically ask about:
  • Childhood cancers in siblings or relatives (suggests CMMRD) 4
  • Lynch syndrome-associated cancers (colorectal, endometrial) in family (suggests CMMRD carrier parents) 4
  • Brain tumors, especially in young adults 4
  • Leukemia or lymphoma in children 4
• Consanguinity: Ask if parents are related by blood, as CMMRD is more frequent with consanguinity 4
• Neurofibromas in relatives: Question about skin lumps in family members suggesting familial NF1 1

Developmental and Neurologic History

• Developmental milestones: Ask about delays in walking, talking, or learning, as these occur in some genetic syndromes with CALMs 1, 4
• School performance: Inquire about learning disabilities or need for special education 4
• Seizures: Question about any seizure history, as brain tumors occur in CMMRD and NF1 4
• Headaches: Persistent or progressive headaches may indicate CNS tumors 4
• Muscle tone: Ask about "floppiness" in infancy (hypotonia), which suggests syndromic diagnosis 4, 1

Cardiovascular Symptoms

• Blood pressure: Ask about documented hypertension, as renovascular hypertension and pheochromocytoma occur in NF1 1
• Palpitations or sweating episodes: These suggest pheochromocytoma in NF1 patients 1

Red Flag Symptoms Requiring Urgent Evaluation

• Severe progressive pain: In existing skin lumps suggests malignant transformation 1
• Rapid tumor growth: Any quickly enlarging mass warrants immediate assessment 1
• New neurologic deficits: Weakness, numbness, or coordination problems suggest nerve sheath tumor or CNS involvement 1
• Unexplained weight loss or fatigue: May indicate malignancy in high-risk syndromes 4

Common Pitfalls to Avoid

• Do not assume isolated CALMs are benign: Even 1-2 CALMs with developmental delays, hypotonia, or childhood leukemia warrant immediate genetics referral 1, 4
• Do not wait for neurofibromas to diagnose NF1: CALMs and freckling alone may meet diagnostic criteria, and early surveillance prevents complications 1
• Do not miss Legius syndrome: Patients with CALMs and freckling but no neurofibromas or optic gliomas have different prognosis and do not need tumor surveillance 1, 5
• Do not overlook parental examination: Parents of children with NF1 are often young and asymptomatic despite carrying the mutation 4