Intracranial manifestations in neurofibromatosis 1

Introduction: Gliomas in the brain and the optic pathway affect up to 20% of all children with neurofibromatosis 1 (NF1); however, their frequency and natural history in adults is poorly described. Our objectives were to characterize the frequency and natural history of gliomas seen in NF1 patients by serial head magnetic resonance imaging (MRI) and to investigate associations between combined annotation-dependent depletion (CADD) scores and the presence of MRI features of NF1. Methods: 1775 head and whole-body MRI scans of 562 unselected NF1 patients were collected at the University Hospital Hamburg-Eppendorf in Hamburg, Germany. All scans were analyzed, and the frequency and natural history of gliomas was determined. In addition, the constitutional disease-causing variants of the NF1 gene in 283 patients were annotated with CADD scores, and genotype-phenotype correlations were performed. Results: Between 1 and 12 MRI scans were collected for each patient; the median length of follow-up was 3.7 years. We found the prevalence of non-optic gliomas to be 4.3%, with a median age at glioma diagnosis at 21.2 years. The prevalence of optic pathway gliomas (OPGs) was 9.3%, with a median age at diagnosis at 12.1 years. We determined the rates of appearance, progression and regression of both of these tumour types. We found that individual CADD scores were associated with the presence of plexiform neurofibromas (but not with the presence of UBOs or optic gliomas) in NF1 patients in whom the pathogenic mutation had been identified. Conclusion: The frequencies of gliomas in the brain and optic pathway is higher in adults with NF1 than previously reported. NF1 patients with constitutional mutations associated with high CADD scores appear to be at higher risk to develop plexiform neurofibromas than other NF1 patients.Medicine, Faculty ofMedical Genetics, Department ofGraduat