Neurofibromatosis type 1 (NF1)

Introduction
Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a common autosomal dominant genetic disorder characterized by the development of multiple benign tumors of the nervous system, skin, and other tissues, along with various cutaneous, skeletal, and ocular manifestations. It is caused by mutations in the NF1 gene on chromosome 17, which encodes neurofibromin, a tumor suppressor protein. Loss of neurofibromin function results in dysregulated cell growth through overactivation of the RAS/MAPK signaling pathway.

NF1 is a multisystem disorder that can vary significantly in severity, even within the same family. While many patients have mild symptoms and normal life expectancy, others may develop disfiguring tumors, malignant transformation, or disabling complications.

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Epidemiology

• Incidence: approximately 1 in 3,000 live births.

• Equal prevalence among all ethnicities and sexes.

• About 50% of cases result from new (de novo) mutations.

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Genetics and Pathophysiology

• Inheritance: Autosomal dominant with 100% penetrance but variable expressivity.

• Gene involved: NF1 gene on chromosome 17q11.2.

• Protein function: Neurofibromin is a GTPase-activating protein (GAP) that inhibits RAS signaling; loss leads to increased cell proliferation and tumor formation.

• Mutation spectrum: Includes nonsense, missense, splice-site mutations, large deletions.

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Diagnostic Criteria (NIH Consensus, 1987)

A diagnosis of NF1 is made if two or more of the following are present:

1. Café-au-lait macules:

   • ≥6 spots >5 mm in diameter in prepubertal individuals or >15 mm in postpubertal individuals.

2. Neurofibromas:

   • ≥2 cutaneous or subcutaneous neurofibromas of any type, or 1 plexiform neurofibroma.

3. Freckling:

   • In axillary or inguinal regions.

4. Optic glioma.

5. Lisch nodules:

   • ≥2 iris hamartomas identified by slit-lamp examination.

6. Distinctive osseous lesion:

   • Sphenoid wing dysplasia or thinning of long bone cortex with or without pseudarthrosis.

7. First-degree relative with NF1 by the above criteria.

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Clinical Features

Cutaneous and Soft Tissue

• Café-au-lait macules: Present in nearly all patients, often appearing in early childhood.

• Neurofibromas:

  • Cutaneous: Soft, flesh-colored nodules.

  • Subcutaneous: Firm nodules along peripheral nerves, sometimes painful.

  • Plexiform: Larger, more diffuse tumors that can cause functional impairment, cosmetic disfigurement, or malignant transformation.

• Axillary/Inguinal freckling: Usually appears between ages 3–5.

Ocular

• Lisch nodules (benign iris hamartomas) – do not affect vision.

• Optic pathway gliomas (often asymptomatic, but may cause vision loss in children).

Skeletal

• Sphenoid dysplasia.

• Congenital tibial pseudarthrosis.

• Scoliosis.

Neurological

• Learning disabilities (30–60% of children).

• Attention deficit hyperactivity disorder (ADHD).

• Seizures (less common).

• Increased risk of brain and spinal tumors.

Cardiovascular

• Hypertension (due to renal artery stenosis or pheochromocytoma).

Oncologic Complications

• Malignant peripheral nerve sheath tumors (MPNST): Most serious complication, lifetime risk ~8–13%.

• Other associated malignancies: Pheochromocytoma, rhabdomyosarcoma, juvenile myelomonocytic leukemia.

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Investigations

Clinical diagnosis is primary; genetic testing confirms mutation if needed.

Additional assessments

• Ophthalmology: Annual eye exam in children to detect optic glioma.

• MRI brain/orbit: If optic glioma suspected or neurological symptoms present.

• Blood pressure monitoring: To detect hypertension.

• X-rays/MRI of bones: If skeletal abnormalities suspected.

• Genetic testing: For confirmation, prenatal diagnosis, or family planning.

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Management

There is no cure for NF1; management focuses on surveillance, symptomatic treatment, and early intervention for complications.

1. Surveillance

• Annual physical examination by a clinician experienced in NF1.

• Annual ophthalmologic exam in children; periodic in adults.

• Regular blood pressure checks.

• Neurological assessment if new symptoms arise.

2. Surgical Management

• Excision of symptomatic or disfiguring cutaneous neurofibromas.

• Debulking of plexiform neurofibromas if causing functional impairment (recurrence common).

• Orthopedic surgery for skeletal deformities.

3. Pharmacologic Therapy

• Selumetinib (a MEK inhibitor) – approved for children (≥2 years) with symptomatic, inoperable plexiform neurofibromas; oral dose 25 mg/m² twice daily.

• Pain management: NSAIDs (ibuprofen 400–600 mg every 6–8 hours as needed), or gabapentin/pregabalin for neuropathic pain.

• Antihypertensives: e.g., amlodipine 5–10 mg once daily or other agents depending on cause.

• Chemotherapy: For malignant peripheral nerve sheath tumors or optic pathway gliomas requiring intervention.

4. Educational and Psychological Support

• Neuropsychological assessment for children with learning difficulties.

• Speech and occupational therapy as required.

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Prognosis

• Life expectancy is slightly reduced (~8–15 years less than general population), mainly due to malignancies and vascular complications.

• Most individuals have a normal lifespan and functional life if major complications are absent.

• Regular monitoring significantly improves outcomes by enabling early intervention.