A 4-year-old boy presents with 8 fractures from minor trauma over 2 years. Clinical examination reveals blue sclerae, opalescent teeth, and short stature. Radiographs show multiple long-bone fractures at various stages of healing with abundant callus formation, generalized osteopenia, anterolateral bowing of the femur and tibia, and numerous wormian bones in the skull. The condition marked **A** in the diagram is suspected. Which of the following genetic mutations is most commonly responsible for this disorder?

Explanation

## Why autosomal dominant mutations in COL1A1 or COL1A2 genes is right Osteogenesis imperfecta (marked **A**) is caused in ~90% of cases by autosomal dominant mutations in COL1A1 or COL1A2 genes, which encode the pro-α1(I) and pro-α2(I) chains of type I collagen. Type I collagen is the primary structural protein of bone, sclera, dentin, and ligaments. Mutations cause either quantitative deficiency (haploinsufficiency, milder phenotype) or qualitative abnormality (dominant-negative effect, severe phenotype). This patient's clinical presentation—blue sclerae, dentinogenesis imperfecta, multiple fractures with callus formation, osteopenia, bowing, and wormian bones—is the classic tetrad of OI and directly reflects defective type I collagen. (Nelson Pediatrics 22e, Osteogenesis Imperfecta section) ## Why each distractor is wrong - **Autosomal recessive mutations in CRTAP**: CRTAP mutations cause rarer autosomal recessive forms of OI affecting collagen post-translational modification (prolyl 3-hydroxylation). These account for <10% of OI cases and are not the most common cause. - **X-linked recessive mutations in FGFR3**: FGFR3 mutations cause achondroplasia and hypochondroplasia, not osteogenesis imperfecta. These conditions present with short stature and skeletal dysplasia but lack the characteristic blue sclerae, dentinogenesis imperfecta, and wormian bones of OI. - **Autosomal dominant mutations in PHEX**: PHEX mutations cause X-linked hypophosphatemic rickets, which presents with rickets, phosphate wasting, and bowing but not the blue sclerae, dentinogenesis imperfecta, or wormian bones diagnostic of OI. **High-Yield:** ~90% of osteogenesis imperfecta is autosomal dominant COL1A1/COL1A2; blue sclerae + dentinogenesis imperfecta + wormian bones + multiple fractures = classic OI tetrad. [cite: Nelson Pediatrics 22e — Osteogenesis Imperfecta; Sillence Classification]