Neurofibromatosis encompasses conditions with hereditary etiologies, with specific genetic mechanisms differing by subtype. No causative genes are certified in this packet for the umbrella neurofibromatosis entity. For NF1 specifically, the disorder follows an autosomal dominant inheritance pattern. Approximately 50% of NF1 cases arise from de novo variants, meaning the causative change occurs for the first time in the affected individual rather than being inherited from a parent. The mutation rate for the underlying genetic cause of NF1 is among the highest known for any gene in humans. Parental somatic and germline mosaicism may be present even when standard molecular testing of leukocyte DNA does not detect a variant in either parent. The cause of the unusually high mutation rate in NF1 is currently unknown. The natural history of the condition is variable; disease progression and complications depend significantly on which subtype is present and on individual factors.

Diagnosis of NF1 is established when an individual meets two or more of the recognized diagnostic criteria: six or more café au lait macules of specified size (five mm or more in prepubertal individuals or fifteen mm or more in postpubertal individuals); freckling in the axillary or inguinal regions; two or more neurofibromas of any type or one plexiform neurofibroma; optic pathway glioma; two or more Lisch nodules identified by slit lamp examination, or two or more choroidal abnormalities; a distinctive osseous lesion such as sphenoid dysplasia, anterolateral tibial bowing, or pseudarthrosis of a long bone; a parent meeting the diagnostic criteria for NF1; or a confirmed germline pathogenic variant. Molecular genetic testing can be performed to confirm the diagnosis, including sequence analysis and gene-targeted deletion analysis. Many clinical features of NF1 increase in frequency with age, meaning some individuals who have unequivocal NF1 as adults may not meet diagnostic criteria in early childhood. Negative molecular testing does not rule out the clinical diagnosis. Differential diagnosis considerations include Legius syndrome, which shares pigmentary features but does not produce neurofibromas or optic pathway gliomas.

There is currently no cure for NF1. Management is directed at the specific manifestations present and includes both standard medical or surgical care and targeted therapies. Targeted therapy with MEK inhibitors is available for NF1-related inoperable plexiform neurofibromas. Cutaneous and subcutaneous neurofibromas that are disfiguring or cause discomfort may be addressed through surgical removal, laser treatment, or electrocautery. Malignant peripheral nerve sheath tumors are managed by surgical oncologists; complete surgical excision provides the primary opportunity for curative intent when feasible. Optic pathway gliomas are evaluated by brain MRI in collaboration with ophthalmology and oncology specialists; chemotherapy may be used for progressive optic pathway gliomas. Radiotherapy is generally contraindicated in individuals with NF1 due to the elevated risk of malignancy induction within the treated field, including malignant peripheral nerve sheath tumor development. Developmental concerns are addressed through specialist referrals in physical therapy, occupational therapy, and speech-language pathology. No approved therapies are certified in this packet for neurofibromatosis type 2 or schwannomatosis. The three designated orphan drugs in this packet (bevacizumab, bortezomib, and Trineumin) carry designations specifically for neurofibromatosis type 2 and are investigational, not approved.

The prognosis of neurofibromatosis varies substantially by subtype and by the specific complications that develop in an affected individual. For NF1, population data indicate increased mortality compared to the general population, with prevalence estimates lower in older cohorts. Women with NF1 face elevated breast cancer risk and increased complications during pregnancy. The development of malignant peripheral nerve sheath tumors represents the most serious life-threatening complication of NF1, occurring in 8–13% of individuals; these tumors carry a substantially worse prognosis than peripheral nerve sheath tumors arising in individuals without NF1. Learning difficulties and behavioral challenges affect a significant proportion of individuals and persist throughout life. Many individuals with NF1 have a relatively normal lifespan, particularly those with primarily dermatological manifestations; the variability of the condition means outcomes differ markedly between individuals. Prognosis data specific to neurofibromatosis type 2 or schwannomatosis are not certified in this packet.

Multiple active clinical trials are enrolled for individuals with neurofibromatosis. Among the packet-certified active trials: NCT00924196 (National Cancer Institute, active) is a natural history study of neurofibromatosis; NCT02544022 (NCI, recruiting) focuses on development and validation of patient-reported outcome measures; NCT01362803 (NCI, Phase 1, active not recruiting) evaluates a MEK inhibitor for nervous system tumors in children; NCT04750928 (NCI, Phase 1, recruiting) examines abemaciclib, a CDK4/6 inhibitor; NCT02407405 (NCI, Phase 2, active not recruiting) investigates selumetinib, a MEK1/2 inhibitor; NCT04374305 (Phase 2, recruiting) assesses targeted therapies; and NCT06222203 (NCI, recruiting) conducts surveillance for malignant transformation. Therapies under active investigation for NF1 include improved delivery of agents to the central nervous system, combinations of MEK inhibitors with other targeted therapies, and immunotherapy approaches. For NF1-associated malignant peripheral nerve sheath tumors, research is exploring MEK inhibitors, other targeted therapies, immunotherapies, and gene therapy approaches. The unusual molecular characteristics of the NF1 mutation landscape, including among the highest known de novo mutation rates for any human gene, continue to drive research into underlying mechanisms.