De novo start-loss mutation in PHYKPL associated with a novel sclerosing and fibro-osseous bone dysplasia

Objectives: This study aimed to identify the genetic cause of bone dysplasia in a patient with fibro-osseous bone dysplasia. Methods: We performed longitudinal clinical, radiographic, biochemical, and molecular characterization (whole-exome sequencing) of a 20-year-old male presenting with an atypical severe sclerosing and fibro-osseous bone phenotype. Results: Over a 15-year clinical window, the patient demonstrated diffuse, mixed lytic and sclerotic lesions across the axial and appendicular skeleton, accelerated skeletal maturation, structural bone fragility resulting in an early pathological fracture, and marked metabolic osseous remodeling, as evidenced by chronically elevated alkaline phosphatase. A novel, de novo start-loss mutation in the PHYKPL gene (NM_153373.4:c.2T>C (p.?) was identified in this patient. Conclusion: This study describes a novel candidate dominant phenotype associated with a de novo PHYKPL variant. These findings introduce a novel candidate gene-disease association that warrants future confirmatory studies to define its role in skeletal metabolic matrix health.