Does the Skeletal Phenotype of Osteogenesis Imperfecta Differ for Patients With Non-COL1A1/2 Mutations? A Retrospective Study in 113 Patients.

Abstract

Osteogenesis imperfecta (OI) is a heritable disease characterized by bone fragility and other extra skeletal manifestations. Most patients with OI have mutations in the COL1A1 or COL1A2 genes. However, a significant minority of patients with clinical OI have non-COL1A1/2 mutations, which have become easier to detect with the use of genetic panels. Traditional understanding of OI pathogenesis was expanded because of these new mutations, and their phenotypic-genotypic relationship is largely unknown. We hypothesized that patients with non-COL1A1/2 mutations have different skeletal clinical presentations from those with OI caused by COL1A1/2 mutations. Patients were categorized into 4 groups according to our modified functional classification, namely, quantitative COL1A1/2 haploinsufficiency (group 1), qualitative COL1A1/2 dominant negative mutations (group 2), mutations indirectly affecting type I collagen synthesis, processing and posttranslational modification (group 3) and mutations altering osteoblast differentiation and function (group 4). Both group 3 and 4 were classified as non-COL1A1/2 mutation group. Of 113 OI patients included, 51 had COL1A1/2 quantitative haploinsufficiency mutations (group 1), 39 had COL1A1/2 qualitative dominant negative mutations (group 2), and 23 patients had OI caused by mutations in 1 of 9 other noncollagen genes (groups 3/4). Patients with non-COL1A1/2 mutations (groups 3 and 4) have severe skeletal presentations. Specifically, OI patients with non-COL1A1/2 mutations experienced more perinatal fractures, vertebral compression fractures and had more long bone deformities. Although the occurrence of scoliosis was similar, the cobb angle was larger in the non-COL1A1/2 mutation group. Radial head dislocations, ossification of interosseous membrane, extraskeletal ossification, cervical kyphosis, and champagne glass deformity of the pelvis were more frequent in this group. The clinical phenotype of OI in patients with non-COL1A1/2 is severe and has unique features. This information is useful for clinical diagnosis and prognosis. Level III.