Osteosarcoma in the Setting of Genetically Confirmed IFITM5-Related Osteogenesis Imperfecta.

Abstract

Background: Osteogenesis imperfecta (OI) is a group of skeletal dysplasias characterized by recurrent fractures and fragile bones. Two pathogenic variants in the IFITM5 gene cause distinct forms of OI: The recurrent c.-14C>T variant causes OI type V (MIM #610967), characterized by hyperplastic callus formation and interosseous membrane ossification, while the rare c.119C>T (p.Ser40Leu) variant causes a phenotypically distinct, severe form of IFITM5-related OI without these hallmark features. Radiographically, OI-related skeletal lesions may resemble malignant bone tumors such as osteosarcoma, leading to diagnostic challenges. Although the co-occurrence of OI and osteosarcoma has been reported, with approximately nine documented cases, all involved other OI subtypes. No case of true osteosarcoma arising in a patient with genetically confirmed IFITM5-related OI has been previously described. We present this case to highlight the novelty of this association, improve recognition of the distinguishing features, and prevent future misdiagnosis.

Case presentation: A 23-year-old female with IFITM5-related OI, confirmed by molecular testing showing heterozygosity for a pathogenic IFITM5 mutation (c.119C>T, p.Ser40Leu; parental testing to determine inheritance was not performed) presented to our Comprehensive Cancer Center in May 2025 with localized groin pain, later diagnosed as a nondisplaced pelvic fracture. Although initial clinical and radiographic findings were consistent with the patient's underlying OI, further evaluation revealed features concerning for concomitant osteosarcoma. The patient was treated with the MISER chemotherapy protocol with subsequent surgical resection.

Conclusion: Distinguishing OI-related skeletal changes from malignant bone tumors requires integration of clinical history, genetic testing, and careful pathologic evaluation via a multidisciplinary approach. While prior reports of concomitant osteosarcoma and OI have involved other subtypes, this case represents the first documented true co-occurrence in a patient with IFITM5-related OI and underscores the importance of recognizing the overlapping and divergent features of these conditions when rendering a diagnosis and initiating treatment protocols.