Heterozygous C-propeptide mutations in COL1A1: Osteogenesis imperfecta type IIC and dense bone variant

Osteogenesis imperfecta type IIC (OI IIC) is a rare variant of lethal OI that has been considered to be an autosomal recessive trait. Twisted, slender long bones with dense metaphyseal margins and normal vertebral bodies in OI IIC contrast with crumpled, thick long bones and multiple vertebral compression fractures in OI IIA. Here, we report on two sporadic patients with classical OI IIC and a pair of siblings, with features of OI IIC but less distortion of the tubular bones (OI dense bone variant). One case with OI IIC and the sibs had novel heterozygous mutations in the C-propeptide region of COL1A1, while the second patient with clear-cut OI IIC had no mutation in this region. Histological examination in the two sporadic cases showed a network of broad, interconnected cartilaginous trabeculae with thin osseous seams in the metaphyses. These changes differed from the narrow and short metaphyseal trabeculae found in other lethal or severe cases of OI. Our experience sheds light on the genetics and etiology of OI IIC and on its phenotypic spectrum.