Disseminated DIG–DIA With a Rare FMR1–RAF1 Fusion With Good Response to Targeted Therapy

Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are rare tumors that usually present at a young age [1]. Multifocal presentations and/or dissemination are even more rare [2]. Under the recent World Health Organization (WHO) classification of central nervous system (CNS) tumors, DIG and DIA are classified as glioneuronal and neuronal tumor subtypes of gliomas, glioneuronal tumors, and neuronal tumors [3]. Here we report an infant with an aggressive presentation of multifocal DIG/DIA in the setting of atypical activation of the mitogen-activated protein kinase (MAPK) pathway (RAF1 Fusion). An 8-month-old girl presented to the emergency room with progressive left-sided hemiparesis of the upper limb and lethargy. Head and spine magnetic resonance imaging (MRI) showed a large right frontotemporal mass with both cystic and solid components, measuring 8.2 × 6.1 × 7.2 cm3, along with diffuse intracerebral and spinal leptomeningeal spread, vasogenic edema, and hydrocephalus with transependymal resorption. The patient underwent a gross total resection of the predominant mass, which was attached to the dura, firm, moderately vascular, and contained multiple cystic areas. A ventriculoperitoneal shunt was not needed, as cerebrospinal fluid circulation was restored post-resection. The patient's hemiparesis almost completely resolved following surgery. Histopathology initially suggested a high-grade glioma with retained INI1 staining, ATRX wildtype, and p53 overexpression. Within 3 weeks post-surgery, while awaiting complete pathology results, the patient's condition worsened, with signs of increased irritability. A repeat MRI showed notable worsening of leptomeningeal spread. In response to the rapid progression and preliminary pathology findings, the patient began chemotherapy per the COG ACNS 0334 protocol (NCT00336024). MRI reassessment after the first chemotherapy cycle showed a slight regression of leptomeningeal dissemination and reduction of a primary spinal nodule at D5–D6. Molecular analysis was conducted at The Hospital for Sick Children (Toronto, ON, Canada). A methylation array classified the tumor as a DIG/DIA with a DKFZ v12.5 confidence of 0.999. Further RNA sequencing identified an FMR1::RAF1 fusion and a PTEN p.F341V single-nucleotide variant (Figure 1). On the basis of these findings, a diagnosis of disseminated DIG/DIA with MAPK pathway hyperactivation was confirmed. As a result, the initial high-grade glioma chemotherapy was modified to a combination of vinblastine (standard treatment for low-grade glioma in Canada) and an MEK inhibitor, low-dose trametinib (0.03 mg/kg per dose), to indirectly target the rare FMR1–RAF1 fusion. The treatment was well tolerated with no significant side effects. The patient completed 70 weeks of vinblastine in March 2024 and, now 2 years post-diagnosis, maintains clinically and radiologically stable disease while continuing trametinib (Figure 2). DIG and DIA are a subtype of glioneuronal and neuronal tumors [3] primarily affecting infants aged 1–24 months, with a male-to-female ratio of 1.7:1 [4]. Typically, these tumors are large, hemispheric, and located supratentorially with cystic components and a contrast-enhancing nodule attached to the dura [5, 6]. Molecular studies have identified common genetic alterations in DIG/DIA, such as the BRAF V600E mutation and non-canonical BRAF mutations, including BRAFV600D [7], which are considered key drivers in tumor pathogenesis and potential therapeutic targets [1]. Given the complexity of pediatric glial and glioneuronal tumors, the WHO CNS tumor classification (5th edition) [8] emphasizes the importance of methylome profiling in diagnosis. For our patient, methylation analysis was crucial for diagnostic confirmation. RAF1 fusions in pediatric tumors are exceptionally rare, documented with partners like QKI, FYCO, TRIM33, SRGAP3, NF1A, and ATG7 [9-14]. Recently, three cases of brain tumors with TRAK1–-RAF1 fusion were reported, involving female patients aged 8 years, 15 months, and 10 months, two of whom had DIG/DIA-compatible methylation profiles. Unlike our patient, however, all these children had localized tumors and were treated with surgery alone. To our knowledge, FMR1–RAF1 fusion gliomas have not been reported in the literature. Zhang et al. described an FMR1–RAF1 fusion in a pediatric sarcoma patient, who did not receive MEK inhibition [15]. The treatment of disseminated DIG/DIA is challenging due to its multifocal nature and the potential long-term effects of aggressive therapies in young patients. Although options include surgical resection, chemotherapy, and radiation, the latter is often avoided in young children to prevent neurocognitive and other sequelae. Treatment should be individualized, balancing disease control with a minimization of toxic effects. In this case, methylation profiling confirmed the diagnosis, and the identification of the RAF1 fusion enabled a targeted approach with less intensive chemotherapy while maintaining disease control. Ongoing trametinib therapy duration will depend on clinical and radiological responses, side effects, and future recommendations. DIG/DIA are rare and complex pediatric brain tumors requiring individualized, molecularly driven treatment strategies. Advances in molecular genetics provide valuable insights into DIG/DIA pathogenesis, guiding potential therapies. Comprehensive molecular analysis remains essential for accurate diagnosis and effective treatment of these rare tumors. The authors declare no conflicts of interest.

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