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. The online version contains supplementary material available at 10.1007/s11060-026-05478-7. 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. The online version contains supplementary material available at 10.1007/s11060-026-05478-7. 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. The online version contains supplementary material available at 10.1007/s11060-026-05478-7.

Follow-up imaging is crucial in managing primary brain tumors, with changes in contrast enhancement often used as a marker of tumor activity. However, fluctuations of enhancement independent of tumor progression have been described in low grade tumors in the paediatric population. This study aims to characterize the phenomenon of spontaneous contrast enhancement fluctuations in pilocytic astrocytoma and other low-grade primary brain tumors in the adult population. A retrospective review of our MRI database (2011-2021) identified cases of pilocytic astrocytomas, pilomyxoid astrocytoma and rosette-forming glioneuronal tumors with stable tumor size with enhancement changes in clinically stable adult patients off medical treatment. After excluding those without serial MRIs, we reviewed the MRIs and clinical records of 238 patients. Number of cases with enhancement fluctuations, mean duration of increasing enhancement prior to stability or decline and number of fluctuation cycles were recorded. The cohort included 9 adult patients, 6 pilocytic astrocytomas, 1 pilomyxoid astrocytoma and 2 rosette-forming glioneuronal tumors. Four of these were unresected (44%), while five were residual or recurrent tumors (56%). Despite stable tumor size and clinical status, a variety of enhancement patterns over time were observed: 44% of cases (4/9) demonstrated new or increasing enhancement on follow-up, with subsequent regression of enhancement over a 1-4 year follow-up period. An additional 44% of cases (4/9) displayed cyclical increasing and decreasing enhancement over a longer 7-15 year follow-up period. Mean duration of increasing enhancement prior to stability or decline was 12.3 months (SD 7.1). One case exhibited complete spontaneous resolution of enhancement. Fluctuation in morphology of enhancement was also observed in 44% of cases (4/9). This is the first study to describe spontaneous fluctuation of enhancement in pilocytic astrocytoma and other circumscribed low-grade brain tumors in an adult population. Awareness of this phenomenon is crucial to prevent misinterpretation of enhancement changes as evidence of tumor progression or regression in clinically stable patients, circumventing unnecessary treatment changes and interventions.

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 (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. 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.

This case report highlights a case of suprasellar pilomyxoid astrocytoma (PMA) presenting with the diencephalic syndrome (DS) that was initially diagnosed as pilocytic astrocytoma (PA) but had subsequent histopathological re-classification as PMA. A 14-year-old male treated with four subtotal resections for PMA and post-operative radiation therapy presented with bilateral visual loss. The patient was initially diagnosed with PA until the fourth craniotomy was performed and the histopathology was revised from PA to PMA. The patient's ocular examination was remarkable for right cranial nerve III and VI nerve palsy and bilateral optic atrophy. This unique case demonstrated the behavior of a rare and aggressive variant of PA. Awareness of this glioma may help ophthalmologists distinguish PMA from PA. Due to the many histopathological similarities, previously diagnosed cases of PA may be the more aggressive variant, PMA. As PMA progresses, it affects the patient's vision; therefore, an ophthalmological evaluation should be included to monitor disease progression and vision loss.