Novel mutation in the carboxyl-terminal propeptide of the procollagen α1(I) chain in a girl with prenatal cortical hyperostosis and multiple fractures

Mutations in the gene encoding the procollagen a1(I) chain (COL1A1) usually cause the autosomal-dominant bone dysplasia osteogenesis imperfecta (OI), which is characterized by the occurrence of fractures without adequate trauma. In addition, some mutations are known to result in Ehlers–Danlos-Syndrome (EDS), and one mutation is associated with infantile cortical hyperostosis (Caffey-disease).

We report on a girl of non-consanguineous parents, who exhibited cortical hyperostosis as well as multiple fractures at birth. Sequence analysis revealed a novel and probably de novo missense mutation in exon 50 of the COL1A1-gene, which encodes a part of the carboxyl-terminal propeptide of the procollagen a1(I) chain. Mutations in this location are very rare and can cause a wide range of severities in OI, but no case of cortical hyperostosis has been reported to date. In addition, we performed biochemical analyses of serum and urine samples, allele-ancestry analysis, as well as an in silico protein prediction, which showed significant structural changes around the propeptide site involved in protein chain association.

Interestingly, the healthy father of our patient also showed hyperostosis, mainly at the mandible, although the mutation could not be detected in his peripheral blood cells. Two possible explanations for these observations are discussed; firstly, that the presence of fractures and hyperostosis are coincidental with the mutation associated only with the fractures and, secondly, that the father is carrier of a somatic mosaic (including the gonads) of the mutation which we were unable to detect.