Systemic immune dysregulation in neurofibromatosis type 1: Translational validation of atopic multimorbidity

Neurofibromin deficiency drives a proinflammatory tumor microenvironment through neuroimmune crosstalk. However, whether this local dysregulation translates into a clinically relevant systemic inflammatory phenotype remains unclear. Using the TriNetX global network, we identified 23,218 individuals with neurofibromatosis type 1 and propensity score-matched them 1:1 with controls. The primary outcomes were new diagnoses of atopic multimorbidity, including atopic dermatitis, asthma, allergic rhinitis, urticaria, and atopic keratoconjunctivitis. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHRs). Our analysis revealed that patients with neurofibromatosis type 1 exhibited profoundly elevated risks of atopic dermatitis (aHR = 7.45; 95% confidence interval [CI] = 4.18-13.28); asthma (aHR = 4.68; 95% CI = 3.72-5.90); allergic rhinitis (aHR = 7.15; 95% CI = 5.52-9.25); urticaria (aHR = 3.54; 95% CI = 2.28-5.48); and, notably, atopic keratoconjunctivitis (aHR = 17.35; 95% CI = 6.92-43.50) (all P < .0001). Subgroup analyses indicated that these associations were generally more pronounced in adults, females, and other racial groups. These findings provide epidemiological validation that the neuroinflammatory drive in neurofibromatosis type 1 is not confined to tumorigenesis but manifests as a pervasive systemic neuroimmune dysregulation. This implies that targeting shared pathways could offer dual benefits for tumor control and systemic inflammation.