What is the recommended lifelong multidisciplinary surveillance and treatment plan for patients with neurofibromatosis (NF1, NF2, or schwannomatosis)?

Management of Neurofibromatosis

All patients with confirmed or suspected neurofibromatosis (NF1, NF2, or schwannomatosis) require lifelong care through a specialized NF clinic with multidisciplinary coordination, as this approach significantly reduces morbidity and mortality. 1, 2

Initial Diagnosis and Baseline Assessment

NF1 Diagnostic Confirmation

• Document ≥6 café-au-lait macules (≥5mm prepubertal or ≥15mm postpubertal), axillary/inguinal freckling (Crowe's sign), cutaneous/subcutaneous neurofibromas, and Lisch nodules on slit-lamp examination 3
• Refer any patient meeting ≥2 NIH diagnostic criteria to genetics for confirmation and counseling 3
• Genetic testing of the NF1 gene is indicated for diagnostic uncertainty, evaluation of parents when a child is newly diagnosed, prenatal diagnosis, and preimplantation genetic diagnosis 3

Baseline Imaging and Evaluation

• Ophthalmologic assessment: Visual acuity, visual fields, fundoscopy, and optical coherence tomography starting at 6-8 months of age to screen for optic pathway gliomas (20% cumulative risk) 4
• Brain/orbit MRI: Obtain once if visual examination is unreliable or inconsistent in patients ≥2 years old, though normal MRI does not eliminate need for continued visual surveillance 4
• Baseline MRI of plexiform neurofibromas: Consider for known or suspected non-superficial plexiform neurofibromas to establish tumor burden 3

Surveillance Protocol by Age

Childhood (Birth to 8 Years)

• Annual visual assessment (fundoscopy, visual acuity, visual fields) until age 8, then every other year until adulthood 4
• Comprehensive physical examination every 6-12 months focusing on new or changing neurofibromas, blood pressure measurement, neurologic examination, and developmental assessment 1, 3
• Scoliosis screening with Adam's forward bend test at each visit 5
• Developmental/educational support for learning disabilities, attention-deficit hyperactivity disorder, and cognitive impairments 3, 2

Adolescence and Young Adulthood

• Annual comprehensive evaluation including assessment for malignant peripheral nerve sheath tumor (MPNST) warning signs: progressive severe pain, rapid tumor volume change, new unexplained neurologic symptoms 1, 3
• Whole-body MRI once postpubertally/prior to transition to adulthood to evaluate asymptomatic tumors for ANNUBP (atypical neurofibromatous neoplasm of uncertain biological potential) and future MPNST risk 4
• Blood pressure monitoring at every visit to screen for pheochromocytoma (1-5% lifetime risk, median onset 40-50 years) and renovascular hypertension 4, 3

Adulthood

• Annual comprehensive physical examination throughout life assessing for new/rapidly growing neurofibromas, severe pain, blood pressure, and symptoms of pheochromocytoma (diaphoresis, palpitations, hypertensive episodes) 1, 3
• Breast cancer surveillance in women: Annual mammography starting at age 30 years, with consideration of breast MRI between ages 30-50 years due to increased breast density and early-onset breast cancer risk 4, 3
• Symptom-directed imaging with MRI preferred over CT to minimize ionizing radiation exposure 3

Treatment Interventions

Medical Therapy for Plexiform Neurofibromas

• Selumetinib (FDA-approved): First-line MEK inhibitor for children ≥2 years with symptomatic, inoperable plexiform neurofibromas, producing clinically meaningful tumor shrinkage (≥20% volume decrease) and functional improvement 1
• Early intervention: Consider selumetinib in children <8 years with small orbital-periorbital plexiform neurofibromas to prevent progression and facial disfigurement 1
• Trametinib: Alternative MEK inhibitor when selumetinib is unavailable 1
• Cabozantinib: Receptor tyrosine kinase inhibitor showing activity in patients ≥16 years with NF1 plexiform neurofibromas 1
• Important caveat: Unknown whether MEK inhibitors modify ANNUBP or MPNST transformation risk, mandating close clinical monitoring throughout treatment 1

Surgical Management

• Indications for plexiform neurofibroma surgery: Visual decline or risk to vision, progressive tumor growth, new/worsening functional deficits, progressive disfigurement 1
• MPNST treatment: Complete surgical resection with clear margins is the cornerstone of curative treatment, even for large abdominal tumors (84% overall survival with timely diagnosis and surgery) 4, 1
• Adjuvant therapy for MPNST: Consider chemotherapy (doxorubicin plus ifosfamide, ~21% response rate) and radiation for selected non-metastatic patients, though randomized studies are lacking 1
• ANNUBP management: Resection with narrow margin if achievable without significant morbidity; unresected lesions require close monitoring for malignant transformation 4

Symptomatic Management

• Pain management: Implement routine screening with pain-interference scales, with referral to pain clinics employing both pharmacologic and non-pharmacologic approaches 1
• Neurologic complications: Treat NF1-associated migraine, seizures, and sleep disorders with standard medications used in the non-NF1 population 1
• Nutritional support: Detailed history for oropharyngeal dysphagia symptoms and nutritional assessment, particularly in children with large plexiform neurofibromas causing compression 5

Malignancy Surveillance and Detection

MPNST Surveillance (8-13% Lifetime Risk)

• Clinical warning signs requiring urgent evaluation: Progressive severe pain in existing neurofibroma, rapid change in tumor volume, new unexplained neurologic symptoms, deep truncal plexiform neurofibromas 1, 3
• Advanced imaging when clinically indicated: 18F-FDG PET/MRI or PET/CT (sensitivity 0.89, specificity 0.95; SUVmax ≥3.5 should trigger biopsy), regional MRI with diffusion-weighted imaging 4, 1
• Important: No routine CT abdomen/pelvis screening recommended; use symptom-directed imaging with MRI preferred to minimize radiation exposure 3

Pheochromocytoma Surveillance

• No routine biochemical or imaging screening for asymptomatic patients 3
• Testing indicated for: Hypertensive patients, pregnant patients, paroxysmal hypertension, diaphoresis/palpitations (plasma free metanephrine testing) 4, 3

Other Malignancies

• Gastrointestinal stromal tumors: 200-fold increased risk, typically presenting around age 50 years, lacking KIT or PDGFRA alterations 4
• Melanoma: <1% incidence but higher association and inferior survival compared to sporadic cases 4
• No surveillance indicated for juvenile myelomonocytic leukemia (<1% risk) or rhabdomyosarcoma (<1% risk, enriched in males with genitourinary predilection), but provide clinical education 4

Pregnancy and Family Planning

Pregnancy Management

• Referral to high-risk obstetrician for all women with NF1 due to increased maternal morbidity (gestational hypertension, preeclampsia) 3
• Genetic counseling: Educate about 50% offspring recurrence risk for autosomal dominant inheritance 1, 3
• Prenatal diagnosis options: Amniocentesis or chorionic villus sampling for known familial mutations 3
• Preimplantation genetic diagnosis: Available option for families with NF1 history 1, 3

Contraception Considerations

• Safe options: Oral estrogen-progestogen or pure progestogen preparations (89% of women report no associated neurofibroma growth) 1
• Avoid: High-dose depot contraceptives containing synthetic progesterone (3% reported significant tumor growth) 1

Multidisciplinary Team Composition

Core team members required for comprehensive NF care: medical genetics, neurology, oncology, ophthalmology, orthopedics, dermatology 1

Additional specialists as needed: pain management, endocrinology, gastroenterology, high-risk obstetrics, developmental/educational support, psychology/psychiatry for psychosocial stress 1, 5, 2

NF2 and Schwannomatosis Considerations

NF2 Surveillance

• 90-95% of NF2 patients develop bilateral vestibular schwannomas 6
• Whole-body MRI has proven efficacy in detecting number, volume, and distribution of tumors in NF2 patients 4
• Off-label treatment with bevacizumab for vestibular schwannomas shows promise 6

Schwannomatosis Management

• Pain is the most prominent symptom; two-thirds develop spinal schwannomas 6
• Whole-body MRI detected 1286 neurofibromas in 59% of patients with NF1, NF2, and schwannomatosis in one study 4
• Despite evidence, whole-body MRI for assessment and surveillance is not yet included in current guidelines, though REiNS has provided recommendations for its use as an endpoint in clinical trials 4

Critical Pitfalls to Avoid

• Do not assume disease progression ceases after the second decade: NF1 patients experience continued tumor growth into late adulthood 1
• Do not use standard cytotoxic chemotherapy for plexiform neurofibromas: No demonstrated benefit and carries risk of treatment-induced secondary malignancies 1
• Do not confuse Legius syndrome with NF1: Legius patients have café-au-lait macules but lack tumor risks and require different surveillance 3
• Do not delay genetics referral in children with café-au-lait macules plus developmental delays, hypotonia, or leukemia, as these suggest syndromic diagnoses requiring specialized care 3
• Do not rely solely on imaging: Severity and prognosis are not closely correlated with radiological findings; neurologic deficits, malignant transformation, and psychosocial stress are of greater clinical importance 6