The packet identifies NF1 (chromosome 17; ClinGen validity Definitive) as the associated gene and lists autosomal dominant inheritance. The packet states that the condition results from pathogenic variants in NF1, which encodes neurofibromin, a tumor suppressor that regulates the RAS signaling pathway, and that loss of neurofibromin leads to increased cell proliferation.

GeneReviews states that approximately 50% of individuals diagnosed with NF1 have an affected parent and approximately 50% have the disorder as the result of a de novo pathogenic variant, consistent with the packet's de novo rate of approximately 50%. GeneReviews notes that an apparently de novo case may alternatively reflect a variant inherited from a mosaic parent or, rarely, from a heterozygous parent with reduced penetrance, and that parental mosaicism may be present without clinical signs. It describes penetrance as nearly complete after childhood, with reduced penetrance documented in a small number of individuals, and reports a high NF1 mutation rate of about 1 in 8,000 whose cause is unknown.

GeneReviews describes NF1 as suspected in individuals with any of the following: six or more cafe-au-lait macules (5 mm or larger in prepubertal individuals, 15 mm or larger in postpubertal individuals); axillary or inguinal freckling; two or more neurofibromas of any type or one plexiform neurofibroma; optic pathway glioma; two or more Lisch nodules or choroidal abnormalities; a distinctive osseous lesion such as sphenoid dysplasia, anterolateral tibial bowing, or pseudarthrosis of a long bone; a parent who meets the criteria; or a germline NF1 pathogenic variant. The diagnosis is established in a proband with two or more of these features.

The packet's diagnostic methods field lists clinical diagnosis using NIH diagnostic criteria, NF1 sequencing with deletion/duplication analysis, MRI for internal tumor assessment, and ophthalmologic evaluation. GeneReviews states that splicing variants account for 22%-30% of pathogenic variants and that methods including cDNA sequencing have higher detection rates than methods analyzing genomic DNA alone.

The differential diagnosis in GeneReviews includes Legius syndrome, in which about half of individuals have pigmentary features meeting NF1 criteria but lack neurofibromas, optic pathway gliomas, Lisch nodules, or typical osseous lesions. The packet does not include newborn screening information for NF1.

GeneReviews states that there is currently no cure for NF1 and that specialist medical or surgical management exists for many NF1-associated morbidities, with targeted MEK inhibitor therapy available for inoperable plexiform neurofibromas. The packet lists two FDA records with market status ACTIVE, both new drug applications: Gomekli (mirdametinib, 2025-02-11) and Koselugo (selumetinib, 2025-09-10). The packet's orphan drug records list Gomekli and selumetinib as approved for treatment of neurofibromatosis type 1, and its foundational therapies field lists selumetinib (Koselugo) for inoperable plexiform neurofibromas. Other orphan entries for NF1 in the packet are DESIGNATED, and designation is not approval.

The packet's foundational therapies field also lists surgical removal of symptomatic neurofibromas and educational support for learning difficulties. GeneReviews describes surgical removal, laser, or electrocautery for disfiguring or uncomfortable cutaneous neurofibromas, notes that surgery for larger plexiform tumors is often unsatisfactory because of nerve involvement and regrowth, and states that complete surgical excision is the only treatment offering the possibility of cure for MPNST. For progressive optic pathway glioma it lists chemotherapy, with mixed results. GeneReviews states that radiotherapy is contraindicated or generally avoided in NF1 because of the risk of inducing MPNST or other tumors in the treated field, and that methylphenidate may be beneficial in children with ADHD.

The packet does not certify life expectancy or survival figures for NF1. GeneReviews describes NF1 as variable in progression and severity and notes that most gliomas exhibit a benign course. It describes MPNST as occurring at a younger age with a worse prognosis than in the general population, and states that the lower prevalence of NF1 in older cohorts in the Finnish study reflects increased mortality. Other outcome data are not certified in this packet.

The packet reports 75 active clinical trials for NF1 on ClinicalTrials.gov, with intervention types including drug therapy, procedural interventions, medical devices, and other interventions, and no gene therapy trials. Detailed records include NCT07850635, a Phase 1 study of mirdametinib in infants and toddlers with NF1-associated plexiform neurofibromas sponsored by SpringWorks Therapeutics (not yet recruiting; 2026-12-09 to 2032-10-21); NCT04750928, a Phase 1 study of abemaciclib for NF1-related atypical neurofibromas sponsored by the National Cancer Institute (recruiting; 2021-11-29 to 2029-12-31); NCT07888517, an observational study of selumetinib in adults with symptomatic, inoperable plexiform neurofibroma sponsored by AstraZeneca (recruiting; 2026-09-28 to 2030-12-31); NCT05581511, a natural history study of cutaneous neurofibromas at Johns Hopkins University (active, not recruiting); and NCT01885767, the NF Registry sponsored by the Children's Tumor Foundation (recruiting). Titles alone do not establish the intervention studied.

GeneReviews describes investigation of therapies for NF1-related MPNST and gliomas, gene therapy to correct NF1 variants in model systems, and clinical studies of treatments for scoliosis, leukemia, cutaneous neurofibromas, pain, constipation, hypertension, and cognitive, learning, behavioral, and motor impairments. The packet's research directions field lists MEK inhibitor therapies, novel targeted therapies for different tumor types, and natural history studies, and its research landscape digest classifies 856 publications, with case reports and case series the dominant type.