What is the recommended management and treatment for neurofibromatosis (NF)?

Management and Treatment of Neurofibromatosis (NF)

The recommended management of neurofibromatosis requires a specialized multidisciplinary approach coordinated through an NF clinic, with regular monitoring for complications and early intervention for symptomatic manifestations to reduce morbidity and mortality. 1

Types and Diagnosis

• Neurofibromatosis type 1 (NF1) is the most common hereditary tumor predisposition syndrome with an incidence of 1 in 3,000-4,000 individuals 2
• NF1 is an autosomal dominant disorder with 50% of cases being sporadic mutations and 50% being inherited 1, 2
• Clinical hallmarks include café-au-lait spots and neurofibromas, but NF1 should not be underestimated as a "mere cosmetic problem" 2

Recommended Monitoring and Surveillance

General Monitoring

• Regular evaluation by a specialized NF1 clinic is strongly recommended for all patients 1
• Annual physical examination to detect new or changing lesions 1, 3
• Age and gender-specific health screening (e.g., cholesterol, colonoscopy, cervical cancer screening) should be followed regardless of NF1 diagnosis 1, 3

Specific Monitoring

• Ophthalmologic evaluation for orbital-periorbital plexiform neurofibromas (OPPNs), with highest risk of growth before age 8 1
• Monitor for signs of malignant transformation: progressive severe pain, changes in tumor volume, new unexplained neurologic symptoms 1
• Screening for pheochromocytoma symptoms: diaphoresis, palpitations, hypertension 1
• Gastrointestinal surveillance: patients have 200-fold increased risk of GISTs, typically presenting around age 50 3

Treatment Approaches

Plexiform Neurofibromas

• Indications for intervention include:

  • Visual decline or risk to vision
  • Progressive tumor growth that may invade critical structures
  • New or worsening functional deficits
  • Progressive disfigurement 1

• Surgical considerations:

  • Timing is critical - optimal timing remains uncertain as tumor growth is unpredictable 1
  • Multiple procedures are often required for long-term management 1
  • For adults, a more definitive surgical approach might be considered as OPPNs are less likely to continue growing 1

• Medical therapy:

  • MEK inhibitor selumetinib has shown promising results with tumor volume decreases ≥20% in clinical trials 1
  • Other agents under investigation include cabozantinib and PD-0325901 1
  • Early intervention with targeted agents may prevent progression of established but small OPPNs 1

Malignant Complications

• Monitor for malignant peripheral nerve sheath tumors (MPNST), which should be suspected if tumor growth exceeds typical rates 1
• Radiation therapy to the orbital region should be avoided as it's a risk factor for malignant transformation 1
• Evaluate for optic pathway gliomas, especially in children 1
• Screen for gastrointestinal stromal tumors (GISTs) when symptomatic 3

Pregnancy and Family Planning

• Pregnancy requires referral to a high-risk obstetrician 1
• Preanesthesia neuraxial imaging to evaluate for spinal or paraspinal neurofibromas is generally not needed 1
• Educate patients about 50% offspring recurrence risk 1
• Preimplantation genetic diagnosis (PGD) and prenatal diagnosis are available options 1
• Patients with de novo mutations, somatic mosaicism, and large genomic rearrangements may have technical limitations for PGD 1

Multidisciplinary Care Model

• Core team should include: medical genetics, neurology, oncology, ophthalmology, orthopedics, and dermatology 4
• For OPPNs: oculofacial plastics, pediatric ophthalmology, neuro-ophthalmology, medical genetics, and neuro-oncology 1
• For GI manifestations: gastroenterologists should be involved 3
• Primary care physician coordination is essential, even when an NF clinic serves as medical home 1

Common Pitfalls and Caveats

• Not all symptoms are NF-related - common explanations remain common (e.g., most hypertension is essential, not pheochromocytoma-related) 1
• Malignant transformation should be suspected with rapid growth or new neurological symptoms, but is more common in adults than children 1
• Avoid radiation therapy when possible due to increased risk of malignant transformation 1
• Regular patient education about worrisome symptoms is crucial for early detection of complications 1
• Failure to coordinate care through a specialized NF clinic may result in missed opportunities for early intervention and clinical trials 1, 4