PTHP-14. Two-hit inactivation of <i>NSD1</i> in a patient with Sotos syndrome and pineoblastoma

Abstract BACKGROUND Sotos syndrome, a congenital overgrowth disorder caused by monoallelic loss-of-function variants in NSD1, is associated with a 3-5% lifetime risk of pediatric malignancies. While NSD1 alterations are implicated in various cancers, their role in carcinogenesis for Sotos syndrome patients is not completely characterized. Pineoblastoma in the context of Sotos syndrome is extremely rare and albeit recently reported in the literature, we herein offer novel insights on the underlying molecular mechanisms. METHODS Case Report RESULTS Patient was prenatally found to have ventriculomegaly and observed with serial brain MRIs over her first 1.5 years of life. After being lost to follow-up, she presented to the emergency department at 3 years old with emesis, obstructive hydrocephalus and a new pineal mass. Endoscopic biopsy of the tumor was most consistent with localized pineoblastoma. DNA Methylation profiling of the tumor was most suggestive of CNS WHO Grade 4, MYC/FOXR2-activated pineoblastoma. Germline testing identified a de novo heterozygous frameshift variant in NSD1 c.3584dup (p.Val1196Cysfs*7), confirming Sotos syndrome. Subsequent exome sequencing revealed the known germline NSD1 variant at a 46% allele frequency and a second somatic frameshift variant in NSD1 c.4591dupA (p.Met1531Asnfs*4) at a 39% allele frequency, strongly suggestive of biallelic inactivation. CONCLUSION This case provides the first combined germline and tumor molecular analysis in a Sotos syndrome patient with pineoblastoma, demonstrating biallelic inactivation of NSD1 through a germline and a somatic frameshift variant. These findings underscore NSD1’s role as a tumor suppressor in this context. In addition, they highlight the importance of considering NSD1 in pediatric cancer susceptibility and suggest a potential mechanistic link between NSD1 dysfunction and pineoblastoma, particularly in the MYC/FOXR2-activated subgroup. Further research is warranted to explore this association in sporadic pineoblastoma and to potentially refine cancer surveillance strategies for Sotos syndrome patients.