P14.12.B CLINICAL AND MOLECULAR SPECTRUM OF NON NF2 RELATED SCHWANNOMATOSIS

Abstract BACKGROUND phenotypes, are characterized by the development of multiple intracranial, spinal and peripheral schwannomas. Following the recent introduction of molecular diagnosis criteria for the subclassified of those conditions according a to the germline causing gene, we decided to investigate clinical and molecular characteristics of patients with a tumor burden suggestive of non NF2 related SWN. MATERIAL AND METHODS We selected 81 patients harbouring multiple schwannomas with at least one tumor with histological proven schwannoma diagnosis and, after a brain and a spine MRIs not fulfilling diagnostic criteria for NF2 related SWM following the Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis”. All patients underwent NF2, SMARCB1 and LZTR1 mutational screening by NGS and MPLA analysis using blood DNA or the tissue of two different tumours when available (13 cases). The following clinical parameters were investigate age of first symptom, age at diagnosis, tumor burden Schwannoma location, presence of meningioma, presence of other neoplasms, presence of skin hyperpigmentation, presence of pain, hereditary. RESULTS Constitutive analysis showed LZTR1 gene germline pathogenic variants in 24 subjects (29.6%), SMARCB1 in 6 cases (7.4%), a LZTR1 VUS in 5 cases and no mutations in the known schwannomatosis driven genes in 45 (55.5%). Following targeting sequencing of multiple tumors in 13 subjects, 4 patients with mosaic NF2 related schwannomatosis and 1 with LZTR1 related SWN were identified. Familiar cases were more frequent in SMARCB1 related SWN cases who showed also a higher tumor burden. CONCLUSION The results suggest that causal genetic alterations remain unknown in ~ 20-30% of SWN patients and illustrate the underestimated frequency of mosaic NF2 related SWN in cases harboring nerve schwannomas. Furthermore, some clinical differences are emerging when SWN are subclassified according a to the causing gene.