Integration of Clinical, Radiographic, Histologic, and Molecular Findings to Diagnose Craniofacial Fibrous Dysplasia

Fibrous dysplasia (FD) is a benign bone tumor consisting of fibrotic deposits interwoven with disorganized bone. Craniofacial FD is characterized by progressive expansile overgrowth resulting in facial disfigurement, vision loss, jaw disfunction, and pain. Diagnosis is often made by clinical presentation and suggestive radiographic findings, with histologic and genetic analyses recommended in questionable cases. However, genetic testing of the FD lesions can lead to false negatives, as lesions contain both normal and neoplastic cells. To explore the concordance between FD diagnostic tools, we evaluated clinical history, imaging, histology, and genetic testing of 6 cases. Six subjects presented with abnormal bony overgrowth and imaging suggestive of FD. Histologic examination of excised FD lesions revealed 4 cases with pathologic findings consistent with FD, 1 case diagnosed as juvenile psammomatoid ossifying fibroma (JPOF), and 1 with a vascular malformation. Given that somatic mosaicism underpins FD pathogenesis, targeted sequencing of the GNAS gene was performed from different tissue sources, including blood, bone lesion, and primary bone cell culture. GNAS pathogenic gene variants were detected in the lesion of all 6 cases, including the case demonstrating JPOF histologic features. The authors found the mutational burden of cells containing the pathogenic GNAS variant ranges from 35.8% to 46.8% in abnormal bone and 31.0% to 49.7% in cultured stromal cells. The variable correlation of the radiographic, histologic, and molecular diagnosis in this study highlights the clinical heterogeneity of FD and challenges in accurate diagnosis. By culturing primary stromal cells, the authors provide source material for somatic molecular diagnosis and future experiments.