PTPN11-Related Noonan Syndrome Predisposes to Multifocal Low-Grade CNS Tumors Harboring FGFR1 Variants

Purpose: To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Methods: 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. Results: 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 (89%) patients with NS developed CNS cancers, including low-grade glioma, (LGG; pure pilocytic/pilomyxoid astrocytoma; n =9) and mixed 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). All LGGs in patients with NS and germline PTPN11 variants except one (14/15; 93%) 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.182A>G (p.Asp61Gly) and c.417G>T (p.Glu139Asp). Ten patients with LGGs, including 7 (41%) with NS, required chemotherapy. After median follow-up of 7.5 years, one patient died of CNS cancer. Conclusion: PTPN11 -related NS predisposes to multifocal pure and mixed LGGs confirmed by radiological, histological, and molecular characteristics. Targeting FGFR1-related pathways may provide new treatment approaches for patients with NS and LGGs.