When the signs are missed: A pediatric case of late-diagnosed neurofibromatosis type I with complex comorbidities

Abstract

Neurofibromatosis type I (NF1) is an autosomal dominant neurocutaneous disorder characterized by a mutation in the NF1 gene, leading to loss of neurofibromin function and subsequent hyperactivation of the Ras-MAPK signaling pathway. Early diagnosis is critical to initiate appropriate surveillance and therapeutic interventions, yet clinical recognition can be challenging due to phenotypic variability and frequent de novo mutations. This case highlights a 17-year-old male with a delayed NF1 diagnosis due to initially inconclusive clinical features and limited family history. The diagnosis was confirmed only after the development of multiple hallmark findings, including café-au-lait macules, axillary freckling, Lisch nodules, and a symptomatic plexiform neurofibroma. The delay in diagnosis resulted in missed opportunities for early intervention and surveillance. The patient was eventually started on selumetinib, a mitogen-activated protein kinase inhibitor approved for inoperable plexiform neurofibromas. This case underscores the importance of early clinical suspicion, timely genetic confirmation, and multidisciplinary management to improve outcomes in NF1.

Keywords

Neurofibromatosis type I / Von Recklinghausen’s disease / Plexiform neurofibroma / Café au lait macules / Lisch nodules / Neurocutaneous syndrome

References

[1] García B, Catasus N, Ros A, et al.Neurofibromatosis type1 families with first-degree relatives harbouring distinct NF1 pathogenic variants. Genetic counselling and familial diagnosis: What should be offered? J Med Genet. 2022; 59(10):1017-1023. doi: 10.1136/jmedgenet-2021-108301

[2] Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: Estimates from a UK family genetic register service. Am J Med Genet A. 2010; 152A(2):327-332. doi: 10.1002/ajmg.a.33139

[3] Ly KI, Blakeley JO.The diagnosis and management of neurofibromatosis type 1. Med Clin North Am. 2019; 103(6):1035-1054. doi: 10.1016/j.mcna.2019.07.004

[4] Huson SM, Harper PS, Compston DA. Von Recklinghausen neurofibromatosis. A clinical and population study in South-East Wales. Brain. 1988; 111(Pt 6):1355-1381. doi: 10.1093/brain/111.6.1355

[5] Hirbe AC, Gutmann DH. Neurofibromatosis type 1: A multidisciplinary approach to care. Lancet Neurol. 2014; 13(8):834-843. doi: 10.1016/S1474-4422(14)70063-8

[6] Chong S. Lifelong management of neurofibromatosis 1 patients. J Korean Neurosurg Soc. 2025; 68(3):261-271. doi: 10.3340/jkns.2025.0057

[7] Wang W, Wei CJ, Cui XW, et al.Impacts of NF1 gene mutations and genetic modifiers in neurofibromatosis type 1. Front Neurol. 2021;12:704639. doi: 10.3389/fneur.2021.704639

[8] Mitchell DK, Brewster K, Makri SC, et al. DLK1 distinguishes subsets of NF1-associated malignant peripheral nerve sheath tumors with divergent molecular signatures. Clin Cancer Res. 2025; 31(10):1988-2009. doi: 10.1158/1078-0432.CCR-24-3029

[9] Hirbe AC, Dehner CA, Dombi E, et al. Contemporary approach to neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Am Soc Clin Oncol Educ Book. 2024; 44(3):e432242. doi: 10.1200/edbk_432242

[10] Na B, Shah SR, Vasudevan HN. Correction to: Past, present, and future therapeutic strategies for NF-1-associated tumors. Curr Oncol Rep. 2024;26:1223. doi: 10.1007/s11912-024-01581-y

[11] Pizzimenti C, Fiorentino V, Germanò A, Martini M, Ieni A, Tuccari G. Pilocytic astrocytoma: The paradigmatic entity in low-grade gliomas (review). Oncol Lett. 2024; 27(4):146. doi: 10.3892/ol.2024.14279

[12] Buccarelli M, Castellani G, Fiorentino V, et al. Biological implications and functional significance of transglutaminase type 2 in nervous system tumors. Cells. 2024; 13(8):667. doi: 10.3390/cells13080667

[13] Ferner RE, Gutmann DH. Neurofibromatosis type 1 (NF1): Diagnosis and management. Handb Clin Neurol. 2013;115:939-955. doi: 10.1016/B978-0-444-52902-2.00053-9

[14] Angelova-Toshkina D, Holzapfel J, Huber S, et al. Neurofibromatosis type 1: A comparison of the 1997 NIH and the 2021 revised diagnostic criteria in 75 children and adolescents. Genet Med. 2022; 24(9):1978-1985. doi: 10.1016/j.gim.2022.05.013

[15] Suerink M, Ripperger T, Messiaen L, et al. Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: Consensus guidelines for testing a child without malignancy. J Med Genet. 2019; 56(2):53-62. doi: 10.1136/jmedgenet-2018-105664

[16] Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: An international consensus recommendation. Genet Med. 2021; 23(8):1506-1513. doi: 10.1038/s41436-021-01170-5

[17] Abdelmaksoud-Dammak R, Ammous-Boukhris N, BenAyed-Guerfali D, et al. Strategies for diagnosis and management of CMMRD in low-resource countries: Report of a Tunisian family. Fam Cancer. 2024; 23(4):515-522. doi: 10.1007/s10689-024-00386-z

[18] Bin Naeem S, Ullah N, Jhatial MA, et al. Constitutional mismatch repair deficiency (CMMRD) syndrome: A case report of a patient with multiple metachronous malignancies. Cureus. 2023; 15(7):e41870. doi: 10.7759/cureus.41870

[19] Yohay K.Neurofibromatosis types 1 and 2. Neurologist. 2006; 12(2):86-93. doi: 10.1097/01.nrl.0000195830.22432.a5

[20] Solares I, Viñal D, Morales-Conejo M, Rodriguez- Salas N, Feliu J. Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: A comprehensive review. ESMO Open. 2021; 6(4):100223. doi: 10.1016/j.esmoop.2021.100223

[21] Yu Y, Wei C, Yue M, Zhang C, Wang Y, Wang Z. From benign neurofibromas to malignant peripheral nerve sheath tumors (MPNST): A gaming among multiple factors. Cell Oncol (Dordr). 2025; 48(4):841-857. doi: 10.1007/s13402-025-01054-9

[22] Esra S, Ceren G, Erdal S, Hatice B, Fatma E, Banu A. Is there a tendency for autoimmunity in neurofibromatosis type 1? Case reports. Indian J Pediatr. 2022; 89(5):510-512. doi: 10.1007/s12098-021-04010-1

[23] Nanda A.Autoimmune diseases associated with neurofibromatosis type 1. Pediatr Dermatol. 2008; 25(3): 392-393. doi: 10.1111/j.1525-1470.2008.00692.x

[24] Akyüz SG, Çaltik A, Bülbül M, Erdoğan Ö, Renda R, Demircin G. An unusual pediatric case with neurofibromatosis and systemic lupus erythematosus. Rheumatol Int. 2012; 32(8):2345-2347. doi: 10.1007/s00296-011-1966-z

[25] Das S. Neurofibromatosis type 1, sarcoidosis, and anterior uveitis: A simple coincidence or coexistence? An interesting case report. Kerala J Ophthalmol. 2025; 37(1):66-70. doi: 10.4103/kjo.kjo_35_23

[26] Srivastava P, Gupta S, Bamba C, et al. Neurofibromatosis type 1: Clinical characteristics and mutation spectrum in a North Indian cohort. Heliyon. 2023; 10(1):e23685. doi: 10.1016/j.heliyon.2023.e23685

[27] Gjorgjievska M, Bozhinovski G, Sukarova-Angelovska E, et al. Mutational spectrum and genotype-phenotype correlations in neurofibromatosis type 1 patients from North Macedonia: Identification of ten novel NF1 pathogenic variants. Balkan Med J. 2023; 40(4):252-261. doi: 10.4274/balkanmedj.galenos.2023.2022-12-28

[28] Gross AM, Glassberg B, Wolters PL, et al. Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity. Neuro Oncol. 2022; 24(11): 1978-1988. doi: 10.1093/neuonc/noac109

[29] Campagne O, Yeo KK, Fangusaro J, Stewart CF. Clinical pharmacokinetics and pharmacodynamics of selumetinib. Clin Pharmacokinet. 2021; 60(3):283-303. doi: 10.1007/s40262-020-00967-y