What is the appropriate workup for a patient with suspected Neurofibromatosis type 1 (NF1)?

Workup for Neurofibromatosis Type 1

The workup for suspected NF1 requires a structured clinical evaluation focusing on diagnostic criteria, followed by targeted screening for life-threatening complications including malignant peripheral nerve sheath tumors, pheochromocytoma, and breast cancer in women. 1, 2

Initial Clinical Assessment

History Taking

• Document presence of café-au-lait macules (≥6 spots measuring ≥5mm prepubertal or ≥15mm postpubertal) 3
• Screen for warning signs of malignant transformation: progressive severe pain, rapid tumor growth, new unexplained neurologic symptoms, changes in existing tumor volume 1, 4
• Assess for pheochromocytoma symptoms: paroxysmal hypertension, headache, palpitations, diaphoresis (particularly in patients >30 years, pregnant, or with hypertension) 1
• Evaluate for neuropathy, depression, chronic pain, pruritus, and fingertip pain 1
• Obtain family history to assess for autosomal dominant inheritance pattern (50% offspring recurrence risk) 1

Physical Examination

• Measure blood pressure to screen for hypertension (may indicate pheochromocytoma or NF1 vasculopathy) 1
• Perform Adam's forward bend test to evaluate for scoliosis with referral if abnormalities detected 1
• Document cutaneous neurofibromas and assess for symptomatic or bothersome lesions 1
• Examine for axillary or inguinal freckling 3
• Assess for Lisch nodules on ophthalmologic examination 5

Laboratory Investigation

Biochemical Testing

• Consider serum vitamin D concentrations in context of clinical presentation and age, as NF1 patients have increased risk of osteoporosis 1
• Measure plasma free metanephrines if pheochromocytoma is clinically suspected (most sensitive and specific single test) 1
• Perform 24-hour urine collection for catecholamines and metanephrines if plasma testing is equivocal (less than fourfold elevation) 1

Important caveat: Routine biochemical or imaging screening for pheochromocytoma in asymptomatic NF1 patients is NOT recommended 1

Imaging Studies

Baseline Imaging

• Obtain baseline MRI of known or suspected non-superficial plexiform neurofibromas to establish size and characteristics for future comparison 1, 2
• MRI is preferred over CT to assess full extent of neurofibromas and avoid ionizing radiation exposure 3
• Consider 18F-FDG PET/CT if malignant transformation is suspected (sensitivity 0.89, specificity 0.95 for detecting MPNST) 4

Age and Gender-Specific Imaging

For women with NF1:

• Begin annual mammography at age 30 years (earlier than general population) 1, 2
• Consider breast MRI with contrast between ages 30-50 years 1, 2

The evidence base for these breast cancer screening guidelines in NF1 is minimal and developed by analogy to other intermediate-risk breast cancer susceptibility syndromes, so caution is warranted 1

Bone Density Assessment

• Consider dual energy X-ray absorptiometry (DEXA) in context of clinical presentation and age to screen for osteoporosis 1

Genetic Testing and Counseling

• Refer to specialized NF1 clinic for evaluation and care coordination, as this multidisciplinary approach significantly reduces morbidity and mortality 2
• Provide genetic counseling regarding 50% offspring recurrence risk for each pregnancy 1
• Discuss availability of preimplantation genetic diagnosis (PGD) and prenatal diagnosis for family planning 1, 2

Note that individuals with de novo mutations, somatic mosaicism, and large genomic rearrangements are much less likely to have successful PGD due to technical limitations 1

Specialized Pathologic Evaluation (If Biopsy Indicated)

When biopsy is performed for suspicious lesions:

• Obtain minimum of 6 core biopsies (4-8mm each) if safe and feasible 1
• Ensure evaluation by subspecialized pathologist for assessment of cytologic atypia, loss of neurofibromatous architecture, hypercellularity, mitotic count per 10 HPF, and necrosis 1
• Screen all non-cutaneous neurofibromas undergoing biopsy for molecular features of atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) or MPNST 1

Critical Prognostic Information

Life expectancy in NF1 is reduced by 8-15 years compared to the general population, primarily due to malignant neoplasms and cardiovascular causes 2. The risk of MPNST increases with age: 8.5% by age 30,12.3% by age 50, and 15.8% by age 85 2, 4. High-grade MPNSTs are usually fatal and represent the main cause of death in NF1 patients under 40 years 5, 6.

Common Pitfalls to Avoid

• Do not assume all hypertension is pheochromocytoma-related (most is essential hypertension), but maintain high index of suspicion in appropriate clinical context 1
• Do not assume all back pain is MPNST (common explanations remain common), but investigate progressive severe pain 1
• Do not perform routine pheochromocytoma screening in asymptomatic patients 1
• Do not delay referral to specialized NF1 clinic, as coordinated multidisciplinary care improves outcomes 2