What is the difference between Neurofibromatosis 1 (NF1) and Neurofibromatosis 2 (NF2)?

Differences Between Neurofibromatosis Type 1 (NF1) and Neurofibromatosis Type 2 (NF2)

Neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are distinct genetic disorders with different genetic mutations, clinical manifestations, and management approaches, despite sharing a common name.1

Genetic Basis

• NF1 is caused by mutations in the NF1 gene located on chromosome 17, which encodes neurofibromin, a key negative regulator in the RAS-MAPK pathway 1
• NF2 is caused by mutations in the NF2 gene located on chromosome 22, which encodes merlin (also called schwannomin) 1, 2
• Both conditions are autosomal dominant disorders but affect approximately 1:25,000 persons for NF2 compared to 1:2,000-3,000 for NF1 1

Hallmark Clinical Features

NF1 Hallmarks:

• Café-au-lait macules and axillary/inguinal freckling on the skin 3
• Multiple cutaneous and subcutaneous neurofibromas 3
• Plexiform neurofibromas (often congenital but grow during the first two decades) 1
• Optic pathway gliomas (presenting early in childhood) 1, 3
• Lisch nodules (iris hamartomas) 3
• Distinctive osseous lesions such as sphenoid dysplasia 3

NF2 Hallmarks:

• Bilateral vestibular schwannomas (VS) on the eighth cranial nerves - the defining feature 1
• Multiple meningiomas 1
• Ependymomas and other central nervous system tumors 1
• Few if any cutaneous manifestations compared to NF1 3, 4

Diagnostic Criteria

• NF1 is diagnosed based on clinical features including café-au-lait spots, neurofibromas, and Lisch nodules 1, 3
• NF2 is primarily diagnosed by the presence of bilateral vestibular schwannomas, or can be diagnosed with a unilateral vestibular schwannoma plus at least two other NF2-related tumors 1

Primary Morbidity and Mortality Concerns

NF1:

• Malignant peripheral nerve sheath tumors (leading cause of mortality) 3
• Optic pathway gliomas affecting vision 1
• Plexiform neurofibromas causing disfigurement and functional impairment 1
• Juvenile myelomonocytic leukemia, rhabdomyosarcoma, and neuroblastoma (rare but occur at higher frequencies than general population) 1

NF2:

• Vestibular schwannomas causing hearing loss, tinnitus, and balance problems 1
• Significant morbidity from surgical treatment of vestibular schwannomas, including deafness and facial nerve dysfunction 1
• Meningiomas causing neurological deficits depending on location 1
• Early mortality primarily related to complications of tumor burden 1

Management Approaches

NF1:

• Surveillance for optic pathway gliomas and other tumors 1
• Management of plexiform neurofibromas, including emerging targeted therapies inhibiting the RAS-MAPK pathway 1, 2
• Monitoring for malignant transformation of neurofibromas 3

NF2:

• Surgery is the primary clinical tool for management of vestibular schwannomas 1
• Early interventional surgery may help preserve hearing in some cases 1
• Cochlear implants or auditory brainstem implants for hearing loss 1
• Regular monitoring of tumor growth with imaging 3

Clinical Pitfalls and Caveats

• Despite sharing a name, NF1 and NF2 should be approached as completely different disorders with distinct management protocols 4, 5
• In NF2, there is no correlation between vestibular schwannoma size and hearing loss, making clinical monitoring complex 1
• Vestibular schwannomas in NF2 grow faster than their sporadic counterparts 1
• Both conditions require lifelong multidisciplinary management due to their complex and progressive nature 3, 6
• Mosaic forms of both conditions exist and may present with milder or segmental manifestations 5