Neurofibromatosis

🧠 Standard of Care & Symptoms

Neurofibromatosis consists of a group of autosomal dominant neurocutaneous disorders characterized by a predisposition to develop benign and malignant tumors of the central and peripheral nervous systems.

• Neurofibromatosis Type 1 (NF1): The most common form, characterized by:
  • **Café-au-lait macules:** Flat, light brown spots on the skin.
  • **Neurofibromas:** Benign nerve sheath tumors that can arise cutaneously or plexiformly (deep under the skin, potentially compromising local organs).
  • **Lisch Nodules:** Tiny pigment clumps in the iris.
  • **Axillary/Inguinal Freckling:** Freckling in the armpits or groin (Crowe's sign).
  • **Optic Pathway Gliomas:** Tumors affecting the optic nerve.
• Neurofibromatosis Type 2 (NF2): Much rarer, characterized by:
  • **Bilateral Vestibular Schwannomas:** Tumors on the vestibular nerves, causing hearing loss, tinnitus, and balance problems.
  • Other CNS tumors (meningiomas, ependymomas), cataracts, and minimal skin spots.
• Pathophysiology:
  • NF1: Loss-of-function mutation in the **NF1 gene** on chromosome 17, which encodes **neurofibromin**, a tumor suppressor that acts as a GTPase-activating protein to negatively regulate Ras pathway activity.
  • NF2: Mutation in the **NF2 gene** on chromosome 22, encoding **merlin (schwannomin)**, which stabilizes cell-to-cell adhesion to suppress mitogenic signaling.

🧬 Diagnostic Criteria (NF1, NF2 & Schwannomatosis)

Diagnosis is based on classic clinical criteria established by the NIH, supplemented by molecular genetic testing.

NIH Diagnostic Criteria for NF1

Requires **two or more** of the following features:

1. Six or more café-au-lait spots (≥ 5mm in children; ≥ 15mm in adults).
2. Two or more neurofibromas of any type, or one plexiform neurofibroma.
3. Freckling in the axillary or inguinal regions (Crowe's sign).
4. Optic glioma.
5. Two or more Lisch nodules (on slit-lamp examination) or two or more choroidal abnormalities.
6. A distinctive bony lesion (e.g. sphenoid dysplasia or thinning of long bone cortex).
7. A first-degree relative (parent, sibling, or child) diagnosed with NF1.

NIH Diagnostic Criteria for NF2

Requires **one** of the following features:

• Bilateral vestibular schwannomas (acoustic neuromas) confirmed on MRI.
• A first-degree relative diagnosed with NF2 and either unilateral vestibular schwannoma or any two of: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity (cataract).

Schwannomatosis Differentiation

Schwannomatosis is a third major neurocutaneous syndrome, genetically distinct from NF1 and NF2. It is characterized by multiple non-vestibular schwannomas throughout the body without the development of bilateral vestibular schwannomas or other NF-related tumors. Schwannomatosis is driven by mutations in the **LZTR1** or **SMARCB1** genes on chromosome 22.

💊 MEK Inhibitors & Medical Management

Management focuses on tumor surveillance and targeted medical therapy for inoperable lesions.

• MEK Inhibitors (Selumetinib / Koselugo): The first targeted therapy approved for pediatric patients (age 2 and older) with NF1 who have symptomatic, inoperable **plexiform neurofibromas**. Selumetinib selectively inhibits MEK1 and MEK2, downstream effectors of the hyperactive Ras pathway, leading to tumor shrinkage and pain reduction.
• Surgical Intervention: Indicated for rapidly growing cutanous neurofibromas, spinal tumors causing spinal cord compression, or vestibular schwannomas in NF2 to preserve hearing.
• Ophthalmologic Monitoring: Annual examinations in NF1 pediatric patients to monitor for asymptomatic optic pathway gliomas.

🔬 Active Clinical Trials

Clinical trials are currently evaluating next-generation selective MEK inhibitors, combo therapies combining MEK inhibitors with mTOR inhibitors, and gene repair strategies.

🗺️ Next Steps After Diagnosis

If you or your child has recently been diagnosed with Neurofibromatosis, implement these care pathways:

1. Schedule a Slit-Lamp Eye Examination: An ophthalmologist must perform a slit-lamp exam to evaluate for Lisch nodules or search for signs of optic pathway gliomas (visual field defects, decreased visual acuity).
2. Obtain a Baseline Brain/Spine MRI: Helpful to evaluate for subclinical optic pathway gliomas, plexiform neurofibromas, or cranial meningiomas.
3. Conduct Genetic Counseling: NF is autosomal dominant; half of all cases are de novo (spontaneous) mutations, but a diagnosed individual has a 50% chance of transmitting it to their children.
4. Perform Annual Growth/Scoliosis checks: Children with NF1 must be checked annually for sphenoid dysplasia, scoliosis, and rapid changes in head circumference.

❓ Patient FAQ

Q: Are all neurofibromas cancerous?
A: No. The vast majority of cutaneous and plexiform neurofibromas are entirely benign. However, patients with NF1 have an increased risk (approximately 8% to 12% lifetime risk) of developing a malignant peripheral nerve sheath tumor (MPNST), a rare cancer of the nerve sheath cells, marked by sudden, persistent pain or rapid growth of a pre-existing tumor.

Q: What is the difference between NF1 and NF2?
A: Despite similar names, NF1 and NF2 are entirely distinct genetic conditions located on different chromosomes. NF1 primarily causes skin spots (café-au-lait), freckling, and soft skin bumps. NF2 primarily causes tumors on the nerves of the inner ears (vestibular schwannomas), leading to hearing loss and balance impairment, with very few skin spots.