Headache in neurofibromatosis type 1: a systematic review

Abstract

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by mutations in the NF1 gene on chromosome 17. This gene encodes neurofibromin, a key protein in the regulation of cell proliferation. With an estimated incidence of 1 in 3,000 live births, NF1 presents a heterogeneous clinical course involving cutaneous, systemic and neurological manifestations. Among these, headache is a frequent complaint that significantly impacts patient quality of life. Furthermore, the potential relationship between headaches and structural alterations in the central nervous system—such as Chiari malformation and plexiform neurofibromas—must be considered, making headache a critical clinical component in the evaluation and management of NF1. Objective: To estimate the prevalence, phenotype and associated factors of headache in patients diagnosed with NF1. Methods: A systematic review was conducted on PubMed and Embase. Two independent authors screened 920 records, 901 of which were excluded after title and abstract review. Inclusion criteria targeted observational cross-sectional, case-control, and cohort studies. Case reports and studies that did not report headache prevalence were excluded. Nineteen full-text articles were assessed, of which 10 met the final inclusion criteria. Data extraction included study characteristics, headache incidence, clinical phenotypes, and brain imaging findings. Results: The included articles encompassed both pediatric and adult NF1 populations. The reported incidence of headache varied widely, ranging from 7.8% to 78%. Across a total of 1,770 patients with NF1, 491 (27.7%) were identified with headache complaints. Only one study utilized a control group, demonstrating a significantly higher prevalence of headache in NF1 patients compared to controls (62% vs. 14%). Migraine was identified as the primary etiology, with prevalence rates ranging between 6.5% and 83%. Most studies did not systematically investigate secondary causes. However, studies that utilized clinical criteria to prompt magnetic resonance imaging identified previously known NF1-related brain anomalies, including sporadic cases of Chiari malformations, cerebral gliomas, and optic pathway gliomas. Conclusion: Headache in patients with NF1 encompasses a broad clinical spectrum, ranging from primary headache disorders to complications directly related to the underlying condition. While the current literature does not definitively confirm a higher prevalence of secondary causes, the potential for disease-related neurological findings suggests that a lower threshold for neuroimaging may be clinically warranted in this population. However, significant gaps remain due to the heterogeneity of existing studies, the scarcity of control groups, and the lack of clear differentiation between primary and secondary presentations. Consequently, further robust research is essential to better characterize the headache profile in NF1 and to establish standardized management protocols.