(P 377) GERMLINE RECQL4 VARIANT IN A PEDIATRIC PATIENT WITH EWING SARCOMA AND DESMOID FIBROMATOSIS

Objective: RecQ helicases, including RECQL4, maintain genome stability and alterations that result in loss of function may predispose to malignancy.¹ However, malignancy risk in germline RECQL4 heterozygotes is inconclusive.2-3

Ewing sarcoma (ES) is a primary bone cancer driven by an EWSR1::FLI1 fusion. Genetic predisposition has not been strongly linked to development of ES.4

Desmoid fibromatosis (DF) is a benign but locally aggressive neoplasm typically associated with alteration of the WNT pathway, including alterations of CTNNB1 (somatic) or APC (germline or somatic). Risk factors for DF include abdominal trauma, preceding abdominal surgery, and high estrogen exposure.5

Methods: Literature search and retrospective chart review performed. Genetic sequencing performed and analyzed at the Institute of Genomic Medicine at Nationwide Children’s Hospital.

Results: An 11-year-old male with biopsy-proven localized ES of the left distal femur was treated on AEWS1031 Regimen B. He underwent surgical resection with negative margins and achieved radiographic remission post-therapy sans radiation.

A non-tender palpable abdominal mass was noted 6.5 years off-therapy. A biopsy verified DF in the pelvic region, followed by complete surgical resection with negative margins.

Paired exome sequencing revealed a germline heterozygous frameshift variant in RECQL4. No additional somatic variants were found in the ES sample. A hotspot missense variant in CNNTB1 was observed in the DF sample, consistent with the histopathologic diagnosis.

Due to recurrence of DF 2 years post-resection, the gamma secretase inhibitor Nirogacestat was initiated with radiograph remission.

Conclusion: Biallelic pathogenic RECQL4 alterations are associated increased risk for malignancy. However, the relationship between heterozygous RECQL4 carriers and malignancy risk is understudied. Currently, there is no known association between RECQL4 and risk for ES or DF; however, this case underscores the value of comprehensive genetic testing for pediatric solid tumors in uncovering potential germline predisposition and enhancing patient care.