Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. X:X | DOI: 10.5507/bp.2025.011

Unveiling the complexity of neurofibromatosis type 1: Innovations in genetic understanding and clinical management. A narrative review

Aurora Jurca1, Simona Pop2, Claudia Maria Jurca3, Cosmin Mihai Vesa3, Alexandru Daniel Jurca3
1 Doctoral School of Biomedical Sciences, University of Oradea, Oradea, Romania
2 Department of Psycho-Neuroscience and Recovery Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
3 Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene. The most important signs are café-au-lait spots, intertriginous freckling, and neurofibromas. The disease has a progressive course, the penetrance is almost complete, and reduces life expectancy by approximately 15%. This review examines the current literature, including NIH (National Institute of Health) diagnostic criteria, genetic testing, genotype-phenotype correlations, and emerging therapies. Genetic testing has improved diagnostic accuracy, particularly for age-dependent clinical features. The genotype-phenotype correlation in NF1 underscores that specific genetic alterations, such as large deletions in the NF1 gene, are frequently linked to more severe clinical outcomes. These deletions often result in early onset of symptoms, a higher frequency of tumor development, and increased tumor burden, all of which contribute to a more complex clinical course. Consequently, individuals with these genetic changes require intensive and continuous monitoring to manage potential complications and prevent further health deterioration. Advances in therapies such as MEK inhibitors offer hope for inoperable plexiform neurofibromas, while surgery remains the primary option for localized tumors, despite the risk of recurrence. Multidisciplinary care and genetic advancements are crucial for improving the prognosis and quality of life of patients with NF1.

Keywords: neurofibromatosis type 1, NF1 gene, genotype-phenotype correlation, MEK inhibitors

Received: January 3, 2025; Revised: April 1, 2025; Accepted: April 1, 2025; Prepublished online: April 14, 2025 

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    References

    1. . Yoshida Y. Neurofibromatosis 1 (von Recklinghausen Disease). Keio J Med 2025;74(1):37-41. doi: 10.2302/kjm.2023-0013-IR Go to original source... Go to PubMed...
    2. . Adil A, Koritala T, Munakomi S, Singh AK. Neurofibromatosis Type 1; StatPearls Publishing, 2023.
    3. . Legius E. Genetics of neurocutaneous syndromes. In: Panteliadis CP, Benjamin R, Hagel C, eds. Neurocutaneous Disorders: A Clinical, Diagnostic and Therapeutic Approach Third Edition. Springer 2022: 3-16. Go to original source...
    4. . Jurca CM, Frățilă O, Iliaș T, Jurca A, Cătana A, Moisa C, Jurca AD. A New Frameshift Mutation of PTEN Gene Associated with Cowden Syndrome-Case Report and Brief Review of the Literature. Genes (Basel) 2023;14(10):1909. doi: 10.3390/genes14101909 Go to original source... Go to PubMed...
    5. . Farschtschi S, Mautner VF, McLean ACL, Schulz A, Friedrich RE, Rosahl SK. The Neurofibromatoses. Dtsch Arztebl Int 2020;117(20):354-60. doi: 10.3238/arztebl.2020.0354 Go to original source... Go to PubMed...
    6. . Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988;45(5):575-8. Go to original source...
    7. . DeBella K, Szudek J, Friedman JM. Use of the National Institutes of Health Criteria for Diagnosis of Neurofibromatosis 1 in Children. Pediatrics 2000;105(3):608-14. doi: 10.1542/peds.105.3.608 Go to original source... Go to PubMed...
    8. . Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, Blakeley J, Babovic-Vuksanovic D, Cunha KS, Ferner R, Fisher MJ, Friedman JM, Gutmann DH, Kehrer-Sawatzki H, Korf BR., Mautner VF, Peltonen S, Rauen KA, Riccardi V, Schorry E, Stemmer-Rachamimov A, Stevenson DA, Tadini G, Ullrich NJ, Viskochil D, Wimmer K, Yohay K, Gomes A, Jordan JT, Mautner V, Merker VL, Smith MJ, Stevenson D, Anten M, Aylsworth A, Baralle D, Barbarot S, Barker F II, Ben-Shachar S, Bergner A, Bessis D, Blanco I., Cassiman C, Ciavarelli P, Clementi M, Frébourg T, Giovannini M, Halliday D, Hammond C, Hanemann CO, Hanson H, Heiberg A, Joly P., Kalamarides M, Karajannis M, Kroshinsky D, Larralde M, Lázaro C, Le L, Link M, Listernick R, MacCollin M, Mallucci C, Moertel C, Mueller A, Ngeow J, Oostenbrink R, Packer R, Papi L, Parry A, Peltonen J, Pichard D, Poppe B, Rezende N, Rodrigues LO, Rosser T, Ruggieri M, Serra E, Steinke-Lange V, Stivaros SM, Taylor A, Toelen J, Tonsgard J, Trevisson E, Upadhyaya M, Varan A, Wilson M, Wu H, Zadeh G, Huson SM, Evans DG, Plotkin S R. 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 Go to original source... Go to PubMed...
    9. . Hirbe AC, Gutmann DH. Neurofibromatosis Type 1: A Multidisciplinary Approach to Care. Lancet Neurol 2014;13(8):834-43. doi: 10.1016/s1474-4422(14)70063-8 Go to original source... Go to PubMed...
    10. . Kehrer-Sawatzki H, Cooper DN. Challenges in the Diagnosis of Neurofibromatosis Type 1 (NF1) in Young Children Facilitated by Means of Revised Diagnostic Criteria Including Genetic Testing for Pathogenic NF1 Gene Variants. Hum Genet 2022;141(2):177-91. doi: 10.1007/s00439-021-02410-z Go to original source... Go to PubMed...
    11. . Rekha A, Sanoop AV, Das S, Chapla A, Srinageshwari B, Barney A, Arunachalam G. Mohan S, Danda S. Clinical and Molecular Profile of Neurofibromatosis Type 1 Patients Using Revised Diagnostic Criteria - A Retrospective Cohort Study. Neurol India 2024;72(6):1174-8. doi: 10.4103/ni.ni_744_22 Go to original source... Go to PubMed...
    12. . Friedman JM. Neurofibromatosis 1998;2(1)[Updated 2022 Apr 21] In: Adam MP, Feldman J. Eeditors. GeneReviews® _[Internet]. Seattle (WA)
    13. . Stenson PD, Mort M, Ball E, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: Towards a Comprehensive Repository of Inherited Mutation Data for Medical Research, Genetic Diagnosis and next-Generation Sequencing Studies. Hum Genet 2017;136(6):665-77. doi: 10.1007/s00439-017-1779-6 Go to original source... Go to PubMed...
    14. . Tadini G, Brems H, Legius E. (2020). Proposal of New Diagnostic Criteria. In: Tadini G, Legius E, Brems H. (eds) Multidisciplinary Approach to Neurofibromatosis Type 1. Springer, Cham. doi: 10.1007/978-3-319-92450-2_21 Go to original source...
    15. . Koczkowska M, Callens T, Chen Y, Gomes A, Hicks AD, Sharp A, Johns E, Uhas KA, Armstrong L, Bosanko KA, Babovic-Vuksanovic D, Baker L, Basel DG, Bengala M, Bennett JT, Chambers C, Clarkson LK, Clementi M, Cortés FM, Cunningham M, D'Agostino MD, Delatycki MB, Digilio MC, Dosa L, Esposito S, Fox S, Freckmann ML, Fauth, C, Giugliano T, Giustini S, Goetsch A, Goldberg Y, Greenwood RS, Griffis C, Gripp KW, Gupta P, Haan E, Hachen RK, Haygarth TL, Hernández-Chico C, Hodge K, Hopkin RJ, Hudgins L, Janssens S, Keller K, Kelly-Mancuso G, Kochhar A, Korf BR, Lewis AM, Liebelt J, Lichty A, Listernick RH, Lyons MJ, Maystadt I, Martinez Ojeda M, McDougall C, McGregor LK, Melis D, Mendelsohn N, Nowaczyk MJM, Ortenberg J, Panzer K, Pappas JG, Pierpont ME, Piluso G, Pinna V, Pivnick EK, Pond DA, Powell CM, Rogers C, Ruhrman Shahar N, Rutledge SL, Saletti V, Sandaradura SA, Santoro C, Schatz UA, Schreiber A, Scott DA, Sellars EA, Sheffer R, Siqveland E, Slopis JM, Smith R, Spalice A, Stockton DW, Streff H, Theos A, Tomlinson GE, Tran G, Trapane PL, Trevisson E, Ullrich NJ, Van den Ende J, Schrier Vergano SA, Wallace SE, Wangler MF, Weaver DD, Yohay KH, Zackai E, Zonana J, Zurcher V, Claes KBM, Eoli M, Martin Y, Wimmer K, De Luca A, Legius E, Messiaen LM. Clinical Spectrum of Individuals with Pathogenic N F1 Missense Variants Affecting p.Met1149, p.Arg1276, and p.Lys1423: Genotype-Phenotype Study in Neurofibromatosis Type 1. Hum Mutat 2020;41(1):299-315. doi: 10.1002/humu.23929 Go to original source... Go to PubMed...
    16. . Albaghdadi M, Thibodeau ML, Lara-Corrales I. Updated approach to patients with multiple café au lait macules. Dermatol Clin 2022;40:9-23. doi: 10.1016/j.det.2021.08.002 Go to original source... Go to PubMed...
    17. . Ozarslan B, Russo T, Argenziano G, Santoro C, Piccolo V. Cutaneous findings in neurofibromatosis type 1. Cancers 2021;13:463. doi: 10.3390/cancers13030463 Go to original source... Go to PubMed...
    18. . Jurca MC, Iuhas OA, Puiu M, Chiriţă-Emandi A, Andreescu NI; Petcheşi CD, Jurca AD, Magyar I, Jurca SI, Kozma K, Severin EM, Bembea M. Cardiofaciocutaneous Syndrome - a Longitudinal Study of a Case over 33 Years: Case Report and Review of the Literature. Rom J Morphol Embryol 2021;62(2):563-8. doi: 10.47162/RJME.62.2 Go to original source...
    19. . Vagge A, Nelson LB, Capris P, Traverso C, Sburlati, C, Panarello S, Calevo MG, Traverso CE, Capris P. Freckling in Pediatric Patients Affected by Neurofibromatosis Type 1. J Pediatr Ophthalmol Strabismus 2016;53(5):271-4. doi: 10.3928/01913913-20160719-05 Go to original source... Go to PubMed...
    20. . Moramarco A, Mallone F, Sacchetti M, Lucchino L, Miraglia E, Roberti V, Lambiase A, Giustini S. Hyperpigmented Spots at Fundus Examination: A New Ocular Sign in Neurofibromatosis Type I. Orphanet J Rare Dis 2021;16(1):14. doi: 10.1186/s13023-021-01773-w Go to original source... Go to PubMed...
    21. . Touzé R, Manassera A, Bremond-Gignac D, Robert MP. Long-Term Follow-up of Choroidal Abnormalities in Children with Neurofibromatosis Type 1. Clin Experiment Ophthalmol 2021;49(5):516-19. doi: 10.1111/ceo.13936 Go to original source... Go to PubMed...
    22. . Di Nicola M, Viola F. Ocular manifestations of neurofibromatosis type 1. In: Tadini G, Legius E, Brems H, eds. Multidisciplinary Approach to Neurofibromatosis Type 1. Cham Switzerland: Springer 2020;71-84. doi: 10.1007/978-3-319-92450-2_6 Go to original source...
    23. . Shofty B, Ben Sira L, Constantini, S. Neurofibromatosis 1-Associated Optic Pathway Gliomas. Childs Nerv Syst 2020;36(10):2351-61 doi: 10.1007/s00381-020-04697-1 Go to original source... Go to PubMed...
    24. . Sellmer L, Marangoni M, Farschtschi S, Heran MK, Birch P, Wenzel R, Mautner VF, Friedman JM. Serial MRIs provide novel insight into natural history of optic pathway gliomas in patients with neurofibromatosis 1. Orphanet J Rare Dis 2018;13:62. doi: 10.1186/s13023-018-0811-9 Go to original source... Go to PubMed...
    25. . Kinori M, Armarnik S, Listernick R, Charrow J, Zeid JL. Neurofibromatosis Type 1-Associated Optic Pathway Glioma in Children: A Follow-up of 10 Years or More. Am J Ophthalmol 2021;221:91-6. doi: 10.1016/j.ajo.2020.03.053 Go to original source... Go to PubMed...
    26. . Brena M, Besagni F, Hernandez-Martin A. Multidisciplinary Approach to Neurofibromatosis Type 1. In Multidisciplinary Approach to Neurofibromatosis Type1. Springer 2020;1:46-70. doi: 10.1007/978-3-319-92450-2_5 Go to original source...
    27. . Serra E, Gel B, Fernández-Rodríguez J, Lázaro C. Genomics of Peripheral Nerve Sheath Tumors Associated with Neurofibromatosis Type 1. In Multidisciplinary Approach to Neurofibromatosis Type 1; Springer International Publishing 2020;1:117-47. Go to original source...
    28. . Messersmith L, Krauland K. Neurofibroma; StatPearls Publishing 2025; BK539707
    29. . Ehara Y, Yamamoto O, Kosaki, YoshidaY. Natural Course and Characteristics of Cutaneous Neurofibromas in Neurofibromatosis 1. J Dermatol 2018;45(1):53-7. doi: 10.1111/1346-8138.14025 Go to original source... Go to PubMed...
    30. . Well L, Jaeger A, Kehrer-Sawatzki H, Farschtschi S, Avanesov M, Sauer M, de Sousa MT, Bannas P, Derlin T, Adam G, Mautner VF, Salamon JM. The effect of pregnancy on growth-dynamics of neurofibromas in Neurofibromatosis type 1. PLoS One 2020;15:e0232031. doi: 10.1371/journal.pone.0232031 Go to original source... Go to PubMed...
    31. . Ristow I, Apostolova I, Kaul MG, Stark M, Zapf A, Schmalhofer ML, Mautner VF, Farschtschi S, Adam G, Bannas P. Discrimination of Benign, Atypical, and Malignant Peripheral Nerve Sheath Tumours in Neurofibromatosis Type 1 - Intraindividual Comparison of Positron Emission Computed Tomography and Diffusion-Weighted Magnetic Resonance Imaging. EJNMMI Res 2024;14(1):127. doi: 10.1186/s13550-024-01189-0 Go to original source... Go to PubMed...
    32. . Martin E, Coert JH, Flucke UE, Slooff WBM, van de Sande MAJ, van Noesel MM, Grünhagen DJ, Wijnen MHWA, Verhoef C. Neurofibromatosis-associated malignant peripheral nerve sheath tumors in children have a worse prognosis: a nationwide cohort study. Pediatr Blood Cancer 2020;67:e28138 doi: 10.1002/pbc.28138 Go to original source... Go to PubMed...
    33. . Sharma MR, Puj KS, Salunke AA, Pandya SJ, Gandhi JS, Parikh AR. Malignant peripheral nerve sheath tumor with analysis of various prognostic factors: a single-institutional experience. J Cancer Res Ther 202;17:106-13. doi: 10.4103/jcrt.JCRT_854_19 Go to original source... Go to PubMed...
    34. . Glombova M, Petrak B, Lisy J, Zamecnik J, Sumerauer D, Liby P. Brain gliomas, hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1. Brain Dev 2019;41:678-90. doi: 10.1016/j.braindev.2019.04.003 Go to original source... Go to PubMed...
    35. . Pardej SK, Glad DM, Casnar CL, Janke KM, Klein-Tasman BP. Longitudinal investigation of early motor development in neurofibromatosis type 1. J Pediatr Psychol 2022;47:180-8. doi: 10.1093/jpepsy/jsab090 Go to original source... Go to PubMed...
    36. . Evans DG, Kallionpää RA, Clementi M, Trevisson E, Mautner VF, Howell SJ, Lewis L, Zehou O, Peltonen S, Brunello A. Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five country cohort study. Genet Med 2020;22:398-406. doi: 10.1038/s41436-019-0651-6 Go to original source... Go to PubMed...
    37. . Vogel AC, Gutmann DH, Morris SM. Neurodevelopmental disorders in children with neurofibromatosis type 1. Dev Med Child Neurol 2017;59:1112-16. doi: 10.1111/dmcn.13526 Go to original source... Go to PubMed...
    38. . Chisholm AK, Haebich KM, Pride NA, Walsh KS, Lami F, Ure A, Maloof T, Brignell A, Rouel M, Granader, Y, Maier, A, Barton B, Darke B, Dabscheck G, Andersen VA, Williams K, North KN, Payne JM: Delineating the autistic phenotype in children with neurofibromatosis type 1. Mol Autism 2022;13:3. doi: 10.1186/s13229-021-00481-3 Go to original source... Go to PubMed...
    39. . Domon-Archambault V, Gagnon L, Benoît A, Perreault S. Psychosocial features of neurofibromatosis type 1 in children and adolescents. J Child Neurol 2018;33:225-32. doi: 10.1177/0883073817749367 Go to original source... Go to PubMed...
    40. . Bernardo P, Cinalli G, Santoro C. Epilepsy in NF1: a systematic review of the literature. Childs Nerv Syst 2020;36:2333-50. doi: 10.1007/s00381-020-04710-7 Go to original source... Go to PubMed...
    41. . Pinna V, Daniele P, Calcagni G. Prevalence, Type, and Molecular Spectrum of NF1 Mutations in Patients with Neurofibromatosis Type 1 and Congenital Heart Disease. Genes (Basel) 2019;10(9):675. doi: 10.3390/genes10090675 Go to original source... Go to PubMed...
    42. . Júnior A, Zanetti G, de Melo A. Neurofibromatosis type 1: State-of-the-art review with emphasis on pulmonary involvement. Respir Med 2019;149:9-15. doi: 10.1016/j.rmed.2019.01.002 Go to original source... Go to PubMed...
    43. . Peduto C, Zanobio M, Nigro, V, Perrotta S, Piluso G, Santoro, C. Neurofibromatosis Type 1: Pediatric Aspects and Review of Genotype-Phenotype Correlations. Cancers (Basel) 2023;15(4):1217. doi: 10.3390/cancers15041217 Go to original source... Go to PubMed...
    44. . Elefteriou F, Kolanczyk M, Schindeler A, Viskochil DH, Hock JM, Schorry EK, Crawford, AH, Friedman JM, Little D, Peltonen J, Carey J, Feldman JC, Yu X, Armstrong L, Birch P, Kendler DL, Mundlos S, Yang, Agiostratidou G, Hunter Schaedle K, Stevenson DA. Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options. Am J Med Genet A 2009;149A:2327-38. doi: 10.1002/ajmg.a.33045 Go to original source... Go to PubMed...
    45. . Mladenov KV, Spiro AS, Krajewski KL, Stücker R, Kunkel P. Correction to: Management of Spinal Deformities and Tibial Pseudarthrosis in Children with Neurofibromatosis Type 1 (NF-1). Childs Nerv Syst 2021;37(10):3281. doi: 10.1007/s00381-020-04775-4 Go to original source... Go to PubMed...
    46. . Jurca A, Petchesi CD, Jurca MC, Atasie D, Bembea D, Jurca AD. The Surprises of Molecular Testing in Neurofibromatosis Type 1: Rare Association between Two Mutational Variants. Pharmaophore 2024;15(2):70-8. doi.org/10.51847/QG2iHRJqUL Go to original source...
    47. . Mukhopadhyay S, Maitra A, Choudhury, S. Selumetinib the first ever approved drug for Neurofibromatosis-1 Related Inoperable Plexiform Neurofibroma. Curr Med Res Opin 2021;37(5):789-94. doi: 10.1080/03007995.2021.1900089 Go to original source... Go to PubMed...
    48. . Tamura R. Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis. Int J Mol Sci 2021;22(11):5850. doi: 10.3390/ijms2211585 Go to original source...
    49. . Armstrong AE, Belzberg AJ, Crawford J Hirbe AC, Wang ZJ. Treatment Decisions and the Use of MEK Inhibitors for Children with Neurofibromatosis Type 1-Related Plexiform Neurofibromas. BMC Cancer 2023;23(1):553. doi: 10.1186/s12885-023-10996-y Go to original source... Go to PubMed...
    50. . Brosseau JP, Pichard DC, Lu-Q Le. Therapeutic strategies in neurofibromatosis 1-related tumors. Clinical Cancer Research 2020;22;123(2):178-86. doi:10.1038/s41416-020-0903-x Go to original source... Go to PubMed...

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