SUPERStudy: Neurofibromatosis

By usmlevideoss

Introduction

Neurofibromatosis (NF) refers to a group of genetic disorders characterized by the development of multiple benign tumors of the nervous system, skin, and other organs. The two main types are Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, and Neurofibromatosis type 2 (NF2).

Etiology

  • NF1: Caused by mutations in the NF1 gene on chromosome 17, which encodes the protein neurofibromin (a tumor suppressor).
  • NF2: Caused by mutations in the NF2 gene on chromosome 22, which encodes the protein merlin (schwannomin), also a tumor suppressor.
  • Both conditions are inherited in an autosomal dominant fashion, but new (sporadic) mutations occur in ~50% of cases.

Epidemiology

  • NF1: Occurs in ~1 in 3,000 live births, making it the most common neurocutaneous disorder.
  • NF2: Less common, affecting ~1 in 25,000 people.
  • No gender or ethnic predilection.

Pathophysiology

  • Loss of function of the tumor suppressor genes leads to uncontrolled cell proliferation and the formation of benign and malignant tumors.
  • In NF1, lack of neurofibromin results in increased RAS/MAPK pathway signaling, promoting tumor growth.
  • In NF2, lack of merlin impairs cell growth regulation, leading to the development of Schwann cell tumors, especially bilateral vestibular schwannomas.

Clinical Manifestations

NF1 (Neurofibromatosis type 1):

  • Café-au-lait spots: Hyperpigmented macules, often the first sign (≥6 spots >5 mm in children or >15 mm in adults).
  • Neurofibromas: Benign nerve sheath tumors, often seen as soft, fleshy nodules on the skin.
  • Lisch nodules: Pigmented hamartomas on the iris, visible with a slit lamp.
  • Axillary or inguinal freckling: Pathognomonic for NF1.
  • Skeletal abnormalities: Scoliosis, pseudoarthrosis, and bone dysplasia.
  • Learning disabilities and cognitive impairment: Seen in ~50% of cases.
  • Optic pathway gliomas: Tumors along the optic nerve, often affecting vision. The most common primary CNS tumors seen in NF1 are optic gliomas, and bilateral optic gliomas are considered to be virtually pathognomonic for NF1.
  • Endocrine: Pheochromocytoma, carcinoid tumors, and precocious puberty
  • Vascular: Stenoses of renal and intracranial arteries

NF2 (Neurofibromatosis type 2):

  • Bilateral vestibular schwannomas (acoustic neuromas): Present with hearing loss, tinnitus, and balance problems.
  • Cataracts: Common in NF2 (posterior subcapsular cataracts).
  • Meningiomas and ependymomas: Tumors affecting the CNS, leading to headaches, seizures, or neurological deficits.
  • Skin schwannomas: Less common than in NF1 but still present.

Diagnosis

NF1 (Diagnostic Criteria – ≥2 of the following):

  1. ≥6 café-au-lait spots
  2. ≥2 neurofibromas or 1 plexiform neurofibroma
  3. Axillary or inguinal freckling
  4. Optic pathway glioma
  5. ≥2 Lisch nodules
  6. Distinctive bone lesion (e.g., sphenoid dysplasia)
  7. A first-degree relative with NF1

NF2 (Diagnostic Criteria):

  • Bilateral vestibular schwannomas on MRI OR
  • A family history of NF2 and unilateral vestibular schwannoma or any 2 of the following: meningioma, schwannoma, glioma, posterior subcapsular cataract.

Treatment

  • NF1:

    • Symptomatic management: Surgery for disfiguring or compressive neurofibromas.
    • Optic gliomas: Managed with chemotherapy or observation depending on severity.
    • Regular screening: Vision exams, developmental assessments, and imaging for complications.
    • The MEK inhibitor selumetinib has activity against inoperable plexiform neurofibromas and is the only treatment that targets the dysregulated signaling pathway.
  • NF2:

    • Surgical resection or radiosurgery for vestibular schwannomas.
    • Bevacizumab (anti-VEGF therapy): Can reduce tumor growth in some cases.
    • Hearing aids or cochlear implants for hearing loss.

Prognosis

  • NF1: Life expectancy is mildly reduced due to complications like malignant peripheral nerve sheath tumors (MPNSTs). Early detection and management improve outcomes.
  • NF2: Worse prognosis due to CNS tumors and progressive hearing loss. Early treatment can improve quality of life but not fully restore hearing.

Memory Aid or Mnemonic:

“CAFÉ SPOT” for NF1 diagnostic criteria:

  • C: Café-au-lait spots
  • A: Axillary or inguinal freckling
  • F: Family history
  • E: Eye findings (Lisch nodules, optic glioma)
  • S: Skeletal abnormalities (scoliosis, bone dysplasia)
  • P: Plexiform neurofibroma
  • O: Optic pathway glioma
  • T: Tumor (neurofibromas)

SUPERPoint:

Neurofibromatosis type 1 is characterized by café-au-lait spots, neurofibromas, Lisch nodules, and optic gliomas, while type 2 primarily involves bilateral vestibular schwannomas. Both types result from mutations in tumor suppressor genes and require multidisciplinary management.

SUPERFormula:

Multiple brown macules + soft, dome-shaped, flesh-colored nodules + Small pigmented nodules in the iris + Sphenoid wing dysplasia + Lisch nodules + optic gliomas = Neurofibromatosis type 1 

 Bilateral vestibular schwannomas + spinal tumors + glioma +  hearing loss + cataracts + NF2 gene mutation = Neurofibromatosis Type 2