Linking genetic variants to bone microstructure: Histological signatures of osteogenesis imperfecta subtypes.

Abstract

Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder characterized by bone fragility, skeletal deformities, and wide clinical variability. While clinical manifestations of OI are well recognized, the microstructural relationships of specific genetic subtypes remain less systematically addressed. Therefore, we aimed to examine and review mutations in genes involved in collagen type I biosynthesis and its processing and relate these genetic alterations to mineralization patterns and distinct histological bone signatures. Common features across OI types include irregular lamellae, excessive woven bone, and abnormal mineralization, whereas subtype-specific changes, such as hyperplastic callus in type V, osteomalacia in type VI, and collagen overmodification in CRTAP related OI, highlight unique pathogenic pathways. By integrating genetic, histological, and clinical perspectives, we underscore the value of genotype-phenotype relationships in refining diagnosis and informing therapeutic strategies. This synthesis emphasizes that understanding the relationship between mutation and histology is central to advancing personalized management in OI.