PTHP-05. Pediatric low-grade diffusely infiltrative tumor with hemispheric and brainstem involvement driven by somatic SMARCB1 loss and copy-neutral LOH on chromosome 22

Abstract Low-grade diffusely infiltrative tumors (LGDITs), SMARCB1-mutant, are a newly recognized subset of rare pediatric brain tumors characterized by microscopic infiltrative growth, low proliferative index, and potential progression to atypical teratoid/rhabdoid tumors (ATRT)-MYC. Previous case reports described radiographic solitary tumors at diagnosis in all cases. We report the first case of LGDIT with extensive involvement of supratentorial and infratentorial structures, including the brainstem, associated with a novel somatic SMARCB1 loss-of-function (LoF) mutation and copy-neutral loss of heterozygosity (cnLOH) on chromosome 22. An 8-year-old boy presented with progressive cranial nerve III palsy, ataxia, and facial weakness. MRI revealed non-enhancing T2/FLAIR hyperintensity involving the hypothalamus, right thalamus, cerebral peduncle, deep gray nuclei, and frontal lobe. Biopsied tumor demonstrated a gliomatosis-like infiltrative neuroepithelial tumor with absent vascularity and necrosis, low proliferative index (Ki67 <5%), rare atypical cells, and loss of INI1 immunoreactivity. Molecular testing identified a SMARCB1 frameshift variant (NM_003073.5:c.351dup, p.Thr118fs) and cnLOH spanning chr22:16054712–51213826, where SMARCB1 is located. Germline testing for SMARCB1 was negative. Additional findings included chromosomal imbalances and variants of uncertain significance in NF1 and KIT. The diagnosis of LGDIT, SMARCB1-mutant, was made. The patient received radiation therapy, with initial improvement followed by recurrence and dissemination within six months of completing radiation. Patient is alive with slow progressive disease at 21 months after diagnosis. This case is notable for its unique clinical presentation with cranioneuropathy from tumor infiltration of brainstem, disseminated tumor consistent with gliomatosis, and a novel somatic SMARCB1 LoF mutation with cnLOH rather than large deletions commonly reported in prior cases. This report expands the known clinical and molecular spectrum of LGDITs and supports the hypothesis that the combination of SMARCB1 LoF and cnLOH may represent an alternative two-hit mechanism. It underscores the need to consider LGDIT in pediatric patients with brainstem or centrally-located infiltrative tumors and to pursue molecular characterization to confirm this rare diagnosis.