Neurofibromatosis type 1 (NF1)

NF1 is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the germline pathogenic variant. Approximately half of all cases arise from a de novo NF1 pathogenic variant. Penetrance is close to 100%, but expressivity may be highly variable within and between families carrying the same germline pathogenic variant. Prenatal molecular testing is technically possible once the pathogenic variant in a family has been identified.

Diagnosis is based on the revised international consensus criteria for NF1 and Legius syndrome. NF1 should be suspected in individuals with defined clinical features. The diagnosis of NF1 is established in a proband with two or more diagnostic criteria if the individual does not have a parent diagnosed with NF1, or with one or more diagnostic criteria if a parent is diagnosed with NF1. A heterozygous pathogenic NF1 variant is being evaluated as one criterion. Supporting investigations include slit-lamp examination for Lisch nodules, optical coherence tomography or near-infrared reflectance imaging for choroidal abnormalities, MRI for plexiform neurofibromas, optic pathway gliomas, brain lesions and other internal tumours, and chest CT for diffuse lung disease.

Main differential diagnoses include:

• : multiple café au lait macules and intertriginous freckling without neurofibromas, Lisch nodules, optic pathway gliomas, or other CNS or peripheral nerve tumors; additional lipomas, macrocephaly, learning disabilities; SPRED1
• : short stature, congenital heart defect (often pulmonary valve stenosis), neck webbing, and characteristic facies (low-set, posteriorly rotated ears, vivid blue or blue-green irides, hypertelorism, downslanted palpebral fissures, epicanthal folds, ptosis); PTPN11 and others
• Constitutional mismatch repair deficiency: rare childhood cancer predisposition syndrome with a NF1-like cutaneous phenotype, colorectal cancer or cancer of the small intestine prior to 2nd decade of life, autosomal recessive with parents often consanguineous without clinical findings consistent with NF1; MLH1, MSH2, MSH6, PMS2

• Establishing the diagnosis: a germline NF1 pathogenic variant identified by genetic testing serves as one criterion for diagnosis. Negative NF1 molecular testing does not rule out a diagnosis of NF1.
• Surveillance and clinical management: molecular diagnosis is supportive to confirm a diagnosis of NF1 and can enable specific and individualised surveillance and clinical management.
• Family member testing: predictive and carrier testing of at-risk relatives can be offered once the pathogenic variant in a family has been identified.

• Friedman JM. Neurofibromatosis 1. 1998 Oct 2 [updated 2025 Apr 3]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:20301288.
• Kallionpää RA, Uusitalo E, Leppävirta J, Pöyhönen M, Peltonen S, Peltonen J. Prevalence of neurofibromatosis type 1 in the Finnish population. Genet Med. 2018;20(9):1082-6. doi:10.1038/gim.2017.215. PMID:.
• Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23(8):1506-13. doi:10.1038/s41436-021-01170-5. PMID:; PMCID: PMC8354850