What are the clinical features, surveillance recommendations, and treatment options for neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2)?

Neurofibromatosis: Clinical Features, Surveillance, and Treatment

Neurofibromatosis Type 1 (NF1)

Clinical Features and Diagnosis

NF1 diagnosis requires at least two of the following: six or more café-au-lait macules, axillary/inguinal freckling, two or more neurofibromas, optic glioma, two or more Lisch nodules, distinctive osseous lesions, or a first-degree relative with NF1. 1 Alternatively, a pathogenic heterozygous NF1 gene variant identified through molecular testing is sufficient for diagnosis. 1

• NF1 affects 1 in 2,000-3,000 live births, making it one of the most common cancer predisposition syndromes. 2, 1
• Approximately 50% of cases arise de novo, with autosomal dominant inheritance and variable expressivity. 2, 1
• The NF1 gene encodes neurofibromin, a negative regulator of the RAS-MAPK pathway. 2, 1

Key clinical manifestations include:

• Cutaneous features: café-au-lait macules, axillary/inguinal freckling, cutaneous and plexiform neurofibromas. 3
• Neurologic tumors: optic pathway gliomas (20% of patients, median age 4-5 years), low-grade gliomas, and malignant peripheral nerve sheath tumors (MPNST). 4, 3
• Skeletal abnormalities: scoliosis, sphenoid dysplasia, and other bone dysplasias. 5, 3
• Other features: Lisch nodules (iris hamartomas), learning disabilities, epilepsy, and vascular dysplasia. 5, 3

Surveillance Recommendations for NF1

Pediatric Surveillance (Birth to 18 Years)

Comprehensive clinical evaluations every 6-12 months are essential, focusing on growth parameters, blood pressure, neurological examination, and skin assessment for new or changing neurofibromas. 4

• Annual ophthalmologic examination by a pediatric ophthalmologist or neuro-ophthalmologist is mandatory to screen for optic pathway gliomas, as 15-20% progress and require intervention. 4
• Perform Adam's forward bend test at each visit to screen for scoliosis and skeletal abnormalities. 4
• Brain MRI with orbits should be obtained only if visual examination raises concerns for optic pathway glioma—routine screening brain MRI in asymptomatic patients is not recommended. 4
• Targeted imaging for plexiform neurofibromas is indicated when clinical examination suggests rapid growth, pain, or compression symptoms, as these occur in approximately 50% of NF1 patients and grow faster in young children. 4
• Monitor for juvenile myelomonocytic leukemia, rhabdomyosarcoma, and neuroblastoma in early childhood, though these remain rare. 4
• Increase vigilance for MPNST in adolescence and young adulthood, as these represent the most significant malignant risk with 8-13% cumulative lifetime risk. 2, 4

Adult Surveillance (18+ Years)

• Obtain detailed history focusing on pain, neurological deficits, or rapid tumor growth, as these symptoms warrant immediate imaging evaluation for potential malignant transformation. 4
• Refer to specialized NF1 clinic for multidisciplinary management including medical genetics, neurology, and oncology as clinically indicated. 4

Critical Surveillance Pitfalls

Clinical symptoms should guide imaging decisions rather than routine screening protocols in asymptomatic patients. 4 This approach balances surveillance benefits against radiation exposure risks, particularly in pediatric patients requiring lifelong monitoring. 4

• Genotype-phenotype correlations do not support risk-stratified protocols based on specific NF1 variants or mosaicism—surveillance should not be modified based on genotype. 2, 4
• When NF1 is suspected but clinical criteria are not met and NF1 testing is negative, consider Legius syndrome (SPRED1), other RASopathies (KRAS), CDKN2A-related melanoma-astrocytoma syndrome, or constitutional mismatch repair deficiency. 2

Treatment Options for NF1

RAS-MAPK pathway inhibitors are now available for symptomatic, unresectable plexiform neurofibromas and gliomas, transforming NF1 management by reducing tumor burden and preventing morbidity. 2, 4

• Surgical resection remains the primary treatment for accessible tumors, particularly MPNST, where timely diagnosis enables curative treatment with 84% overall survival. 2
• Multidisciplinary team approach is essential for managing this complex disorder. 6

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Neurofibromatosis Type 2 (NF2)

Clinical Features and Diagnosis

The hallmark of NF2 is bilateral vestibular schwannomas on the vestibular nerves, though diagnosis can also result from unilateral vestibular schwannoma plus at least two other NF2-related tumors. 2

• NF2 affects 1 in 25,000-40,000 persons, comprising only 2% of neurofibromatosis cases. 2, 5, 7
• Autosomal dominant inheritance with mutations in the NF2 gene on chromosome 22, which encodes a tumor suppressor protein. 2, 5
• NF2 is associated with significant morbidity, decreased life span, and higher incidence of CNS tumors compared to NF1. 5

Key clinical manifestations include:

• Bilateral vestibular schwannomas (hallmark feature), often presenting with hearing loss in late teens. 2, 7, 3
• Other tumors: meningiomas, spinal cord schwannomas, ependymomas, and gliomas. 2, 5, 3
• Juvenile cataracts with paucity of cutaneous features compared to NF1. 5
• Vestibular schwannomas in NF2 grow faster than sporadic counterparts. 2

Surveillance Recommendations for NF2

While specific surveillance protocols for NF2 are less standardized than NF1, whole-body MRI has proven efficacy in detecting number, volume, and distribution of schwannomas and other NF2-related tumors. 2

• In a study of 247 subjects with NF2 who underwent unenhanced whole-body MRI, 1286 neurofibromas were detected, involving 59% of cases. 2
• Despite evidence supporting whole-body MRI, it is not yet included in current guidelines for NF2 assessment and surveillance. 2
• The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration (REiNS) has provided recommendations on image acquisition and analysis methods to enable whole-body MRI as an endpoint in NF2 clinical trials. 2

Treatment Options for NF2

Surgery is the primary clinical tool for NF2 management, though vestibular schwannoma surgery frequently leads to deafness, loss of facial nerve function, infections, and headaches. 2

• Microsurgery and radiotherapy offer initial treatment options for accessible tumors. 2, 5
• There is no known medical treatment broadly beneficial to NF2 patients—the mainstay of care is anticipatory guidance, early detection, and symptomatic treatment of disease complications. 5
• Vestibular schwannoma surgery is intricate because the vestibular nerve is close to the acoustic (cochlear) and facial nerves. 2
• No correlation exists between tumor size and hearing loss in NF2, complicating treatment decisions. 2