PTPN11-related Noonan syndrome predisposes to multifocal low-grade CNS tumors harboring FGFR1 variants

To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed. Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline PTPN11 variant; Nineteen of 24 participants (79%) were male. Seventeen of 19 (89%) patients with NS developed CNS tumors, including low-grade glioma, (LGG; pilocytic/pilomyxoid astrocytoma; n = 9) and dysembryoplastic neuroepithelial tumor (DNET; n = 6). Five patients incidentally diagnosed did not undergo histological confirmation. Radiological review showed multifocal parenchymal tumors in 9 patients with NS, including histologically confirmed neoplasm (n = 2), radiologic progression (n = 6), or typical tumoral imaging (n = 1). Fourteen of 15 (93%) tumors collected from 13 patients with NS and germline PTPN11 variants harbored somatic FGFR1 abnormalities. RNA sequencing of 12 tumors detected FGFR1 internal tandem duplication in one patient. Comparison with published data showed a statistically significant association between brain tumor occurrence and PTPN11-related NS, driven by two genotypes: NM_002834.5(PTPN11):c.182 A > G (p.Asp61Gly) and c.417G > T (p.Glu139Asp). Ten patients with CNS tumors, including 7/17 (41%) with PTPN11 variants, required chemotherapy. After median follow-up of 7.5 years, one patient died of CNS tumor. PTPN11-related NS predisposes to multifocal low-grade glial and glioneuronal tumors confirmed by radiological, histological, and molecular characteristics. Targeting FGFR1-related pathways may provide new treatment approaches for patients with NS and low-grade CNS tumors. Multifocal low-grade glial and glioneuronal tumors are common in patients with Noonan syndrome, especially in males. Concurrent PTPN11 and FGFR1 variants exist in nearly all patients with Noonan syndrome and low-grade CNS tumors. Targeting FGFR1 may provide novel treatment options for patients with Noonan syndrome and low-grade CNS tumors. Noonan syndrome (NS) has been recognized as a genetic predisposition to CNS tumors. However, no long-term clinical, radiological, or molecular patient data have previously been reported in a large patient cohort. Herein, we show that individuals with NS and germline PTPN11 variants, particularly those with NM_002834.5(PTPN11):c.182 A > G (p.Asp61Gly) and NM_002834.5(PTPN11):c.417G > C (p.Glu139Asp), are predisposed to develop low-grade tumors, including low-grade gliomas (LGGs) and dysembryoplastic neuroepithelial tumors (DNETs), which may have multifocal distant brain involvement in up to 50% of patients. An overwhelming male predominance was confirmed, for which the biological underpinnings remain unknown. Somatic FGFR1 variants were detected in 93% of tumors in individuals with PTPN11-related NS. Therefore, concurrent variants in both genes seem to be required to drive tumorigenesis. Most tumors exhibited indolent behavior, even in the presence of residual disease, and the affected patients experienced long-term survival. However, aggressive monitoring and treatment may be necessary in a subset of patients.