2025 Poster Presentations
P475: SPECTRUM OF BURDEN OF DISEASE IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2 UNDER THE UPDATED DIAGNOSTIC CRITERIA
Maya Harary; Alexandra White, MD; P. Leia Nghiemphu, MD; Richard Everson; UCLA
Introduction: Neurofibromatosis type 2 (NF2) is a genetic tumor predisposition syndrome that is classically associated with bilateral vestibular schwannomas (VS), but can also cause a myriad of tumor types. Genetically, it is defined as de novo or inherited loss of the NF2 tumor suppressor gene on chromosome 22q, followed by a somatic loss of heterogeneity (LOH) of the second NF2 copy. In 2022, a panel of experts released the updated consensus criteria for the diagnosis of NF2 and schwannomatosis (SWN), which updated both the clinical and molecular criteria to distinguish these syndromes given their overlapping phenoptypes.1 We sought to assess the spectrum of disease burden specifically in NF2 patients identified under these more precise diagnostic criteria.
Methods: Under IRB approval, medical records for patients seen at our institution’s NF2 clinic were reviewed, and clinical information was collected. All statistical analysis was done in R. Numerical variables were scaled for the purpose of clustering analysis.
Results: 71 patients who meet the updated 2022 diagnostic criteria were identified. Average age at diagnosis was 23-years (SD:15, range 1-65), time since diagnosis was 11.8years (IQR 5.2-19.1), 57.7% were female. Family history or genetic analysis was available in 67 patients: 18 had familial NF2, six had de novo mosaicism and 43 had de novo mutation (no information regarding germline vs. mosaic). All patients had at least one VS, and 63 patients (88.7%) had bilateral VS, 43 (60.6%) had intracranial meningiomas, five (7%) had schwanommas of other cranial nerves. 53 (6.8%) and 29 (41.4%) had at least one spinal intradural extramedullary (IDEM) or intradural intramedullary lesion (IDIM). Number of intracranial and spinal tumors were positively correlated (Pearson R=0.05, p<0.001, Fig1).
Eight patients (11.3%), all with bilateral VS, had normal hearing on audiometry. 53 (75.7%) had at least one surgery (median 1, IQR 1-2, range 1-14) to address an intracranial or spinal lesion. During their disease course, 25 (35.7%) patients received radiation therapy to one or more lesions. Medical treatments used included bevacizumab (27), tyrosine kinase inhibitor (6) and everolimus (6), sometimes in combination or in series. Though not statistically significant, patients with known mosaicism tended to have a lesser disease burden than those with inherited mutations, who in turn have generally less severe disease than those with de novo mutations (Fig2). This is likely associated with the higher prevalence of highly pathogenic truncating mutations in de novo disease compared to inherited NF2.2
Conclusions Despite the complete penetrance of germline NF2 mutation, and even with the new diagnostic criteria for NF2-related schwannomatosis, patients experience a wide range of disease severity and phenotypic manifestations. As emphasized in the updated diagnostic criteria, the identification of the implicated pathogenic variant(s) and determination of germline vs. mosaic status, remains central to patient counselling on disease severity.
References:
1. Plotkin et al.Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genetics in Medicine. 2022
2. Halliday D et al. Genetic Severity Score predicts clinical phenotype in NF2. J Med Genet. 2017