Glial brain tumors in pediatric patients with germline biallelic variation in the MBD4 gene: Expanding the spectrum of MBD4 -associated neoplasia syndrome (MANS)

Background Germline biallelic variations in the MBD4 gene have been identified as a cancer predisposition syndrome, MBD4-associated neoplasia syndrome (MANS). Tumors associated with MANS have a higher tumor mutation burden (TMB), corresponding almost exclusively to CpG>TpG mutations. It is associated with colorectal polyps, myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), uveal melanoma, and colorectal carcinoma. Methods We present the first report of a family with germline biallelic variations in the MBD4 gene and glial brain tumors with high TMB in multiple members. Results In the family of 5, both parents (non-consanguineous) have monoallelic variations in the MBD4 gene. All three children have biallelic variations in the MBD4 gene. Parents have no history of tumors; however, 2 of the 3 children developed glial-brain tumors by the age of 10 years with high SNV and indels. The eldest child (6 years) was diagnosed with glioblastoma, WHO grade 4, and died of disease progression in 15 months. The middle child (10 years) was diagnosed with multiple diffuse astrocytomas, IDH-mutated, WHO grade 2 with IDH1, P53, and PTEN mutations. Her tumors continued to grow slowly, requiring a second debulking surgery, and acquired additional mutations over time. She was started on an IDH inhibitor (vorasidenib) and has had stable disease for 24 months. The youngest child (18 years) has no evidence of disease currently. Conclusion Our series expands the spectrum of cancers associated with MANS to include glioma. It remains to be investigated if gliomas are frequent enough in MANS to warrant CNS-directed surveillance.