ID #644 Pediatric high-grade glioma with germline PALB2 variant - a case report of a novel homologous recombination-deficient tumor with gliomatosis-like growth

Background

PALB2 is a core component of the homologous recombination (HR) DNA repair machinery through its interaction with BRCA2. Germline pathogenic variants in PALB2 confer cancer susceptibility and are implicated in Fanconi anaemia; however, their role in CNS tumorigenesis remains uncertain. We describe the clinicopathological and molecular features of an exceptionally rare pediatric high-grade glioma associated with a germline PALB2 variant—only the second case reported to date.

Case report

A 5-year-old boy presented with new-onset seizures. Brain MRI demonstrated partly contiguous, infiltrative, non-enhancing lesions involving the left insula/basal ganglia and the right middle cerebellar peduncle and white matter, without spinal dissemination. Supratentorial biopsy revealed a cellular astrocytic glioma composed of pleomorphic cells within a fibrillary–microcystic matrix, interspersed with frequent bizarre multinucleated forms showing nuclear pseudoinclusions. Mitotic figures were uncommon, and necrosis was absent. Immunohistochemistry demonstrated diffuse GFAP, Olig2, and nestin positivity, with strong p53 overexpression. DNA methylation profiling (Heidelberg Epignostix, Brain tumor classifier v12.8) did not assign a diagnostic class. Copy number analysis demonstrated multiple high-risk alterations, including EGFR amplification, gains of MET and MYC, and homozygous NF1 loss. Targeted DNA/RNA panel and whole-genome sequencing identified a pathogenic heterozygous PALB2 variant confirmed as germline, alongside a somatic TP53 mutation. Whole-genome ploidy gain (2.8) and chromoanagenesis events were present. Tumor mutational burden was 1.85 mut/Mb, with mutational signatures consistent with HR deficiency. Fanconi anaemia was excluded by chromosomal breakage studies. CSF sample was clear. The patient commenced radiotherapy (54 Gy in 30 fractions) with concomitant temozolomide.

Conclusion

This case highlights a novel HR-deficient pHGG with a germline PALB2 variant, exhibiting a gliomatosis cerebri–like growth pattern, consistent with a prior report[1]. The tumor’s location precludes complete resection and this case underscores the challenges of managing such HR-deficient pediatric gliomas and the potential role for targeted therapies.

1. Zhong Y, Schubert J, Wu J, Xu F, Lin F, Cao K, Zelley K, Luo M, Foster JB, Cole KA, MacFarland SP. A germline PALB2 pathogenic variant identified in a pediatric high-grade glioma. Molecular Case Studies. 2020 Aug 1;6(4):a005397.