Neurofibromatosis Type 1

Overview

Epidemiology

• Neurofibromatosis type 1 (NF1) is the most common type of neurofibromatosis.
• Incidence: approximately 1 in 2,600–3,000 individuals, regardless of ethnicity and gender
• Inherited in about half of the cases
• Life expectancy:
  • The mean age at death is 54.4 years.
  • The median age at death is 59 years.

Etiology

• Autosomal dominant inheritance
• Less commonly, de novo mutations (primarily in paternally derived chromosomes)

Pathophysiology

• Mutations in the NF1 gene located on chromosome 17
• NF1 encodes neurofibromin, a cytoplasmic protein.
  • Predominantly expressed in neurons, Schwann cells, oligodendrocytes, leukocytes
  • Multidomain molecule regulating several important intracellular processes:
    • RAS-cyclic AMP pathway
    • Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade
    • Adenylyl cyclase
    • Cytoskeletal assembly
  • Also functions as a tumor suppressor
• Involvement of neurofibromin in various pathways explains the wide range of clinical manifestations.

Diagnosis

The diagnosis of NF1 is usually made clinically based on the typical clinical presentation and confirmed by genetic testing.

• Diagnostic criteria: At least 2 features must be present:
  • ≥ 6 CALMs:
    • > 5 mm in diameter in prepubertal individuals
    • > 15 mm in diameter in postpubertal individuals
    • The longest diameter is measured.
    • Ordinary room light is used.
  • ≥ 2 neurofibromas of any type or 1 plexiform neurofibroma
  • Freckling in the axillary or inguinal regions
  • Optic glioma
  • ≥ 2 Lisch nodules
  • A distinctive bony lesion (e.g., sphenoid dysplasia, thickening of the cortex of long bones with or without pseudoarthrosis)
  • A 1st-degree relative (parent, sibling, or offspring) with NF1 defined by the above criteria
• Genetic testing
• Screening of family members
• Prenatal testing
• Neuroimaging (MRI or CT), potential findings:
  • Focal bright spots on T2-weighted images (disappear with age)
  • Increased brain volume
  • Abnormal cerebral vasculature

Management

Tumors

• Cutaneous and subcutaneous neurofibromas
  • Removal by surgery, laser, or electrodesiccation
  • Indications for removal include:
    • Pain
    • Bleeding
    • Interference with function
    • Disfigurement
  • Gabapentin (for pruritus)
• Plexiform neurofibromas:
  • Selumetinib (for tumor regression)
  • Surgical resection (debulking)
  • Imatinib or pegylated interferon (shrinkage)
• Optic pathway gliomas and other low-grade gliomas:
  • Chemotherapy:
    • Carboplatin
    • Vincristine
    • Vinblastine
  • Radiation (avoided in pediatric individuals)
• High-grade gliomas:
  • Surgical resection
  • Conventional radiation + temozolomide
• Malignant peripheral nerve sheath tumors:
  • Surgical resection
  • Adjunctive radiation therapy
• Rhabdomyosarcoma:
  • Chemotherapy
  • Surgery, if feasible
  • Radiotherapy
• GI stromal tumors: poorly responsive to imatinib

Neurologic abnormalities

• Cognitive and learning deficits:
  • Learning disabilities: academic support
  • Speech deficits: speech therapy
  • Motor impairment: occupational therapy and PT
• Seizures: antiseizure drugs
• Peripheral neuropathy: Treat the underlying cause and alleviate symptoms.

Others

• Psychosocial issues: counseling
• Hypertension: antihypertensives
• Genetic counseling for affected individuals and their families

Differential Diagnosis

• Neurofibromatosis type 2: a neurocutaneous disorder that can arise from mutations in the NF2 gene. The main clinical features are bilateral vestibular schwannomas and intracranial/spinal meningiomas. Diagnosis is made clinically and confirmed based on genetic testing, MRI, and histopathology. Tumor surveillance, follow-up, and screening of at-risk family members are recommended. Management includes surgical intervention, radiation therapy, and/or monoclonal antibody therapy with bevacizumab.
• Noonan syndrome: a genetic disorder that occurs following a mutation in one of several genes involved in the RAS signaling pathway, especially protein-tyrosine phosphatase, nonreceptor type. Clinical features include short stature, webbed neck, hypertelorism, downward eye slant, low-set ears, pulmonic stenosis, and CALMs. Management involves the identification and timely monitoring of various clinical presentations.
• Tuberous sclerosis: an autosomal dominant disorder that mainly presents with neurocutaneous symptoms. Mutation in the TSC gene causes excessive tumor-like growth in the brain, eyes, heart, kidney, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash-leaf spots) or excessive growth (i.e., angiofibroma). The diagnosis is made clinically and confirmed by genetic testing. Management entails a multidisciplinary approach that targets the monitoring and treatment of various manifestations of the disorder.
• Constitutional mismatch repair-deficiency syndrome: a rare autosomal recessive disorder resulting from the inheritance of deleterious mutations in both copies of 1 of the 4 mismatch-repair genes. Constitutional mismatch repair-deficiency syndrome results in early-onset (< 18 years of age) hematologic, brain, or colon cancers and may present with skin pigmentations similar to those in NF1. Diagnosis is made clinically. Management is centered around early screening for tumors and genetic counseling for families of affected individuals.