Metaphyseal dysplasia is a phenotype often observed in various clinically skeletal dysplasia characterized by the shortening of the long tubular bones with viable severity. Many pathological mechanisms cause metaphyseal dysplasia. In this study, we recruited a series of skeletal dysplasia patients. The clinical diagnosis ranged from mild Patterson-Lowry rhizomelic dysplasia to Sedaghatian type spondylo-metaphyseal dysplasia which is lethal in uterus. By performing whole-exome sequencing analyses, we identified bi-allelic loss-of-function mutations of glutathione peroxidase 4 (GPX4) in eight patients from six pedigrees with multiple ethnic backgrounds.GPX4 is the only enzyme that can repair lipid peroxidation. It has been previously reported that insufficient GPX4 activity is the direct and major cause of ferroptosis, a type of programmed cell death characterized by the accumulation of lipid peroxides. Up-to-date, ferroptosis has only been only reported in organs with high oxygen-level and in common diseases. In this study, we proved that the pathogenic mechanism of the GPX4-related metaphyseal dysplasia was ferroptosis. We showed that ferroptosis could also take place in ultra-hypoxic organs such as the growth plate cartilage and could also be the cause of Mendelian diseases. Furthermore, we generated the cartilage-specific GPX4 conditional knockout mouse model. Our animal experiment showed efficient rescue effects by feeding the KO mice with Vitamin E, a natural antagonist of ferroptosis, indicating future treatment for the patients with GPX4 loss-of-function mutations.