Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment

Abstract

Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Keywords: classification; collagen type I; fractures; heterogeneity; osteogenesis imperfecta.

Figure 1

Overview of collagen type I biosynthesis. Collagen type I consists of two α1-chains and one α2-chain. After translation, pro-α1-chains and pro-α2 chains are processed in the rough Endoplasmic reticulum (rER). These chains have to align in order to start the folding process of (pro)collagen type I into a triple helix. The next step is alignment of the three chains in order to commence folding into a triple helical structure. During this folding process, post-translational modification by specific proteins takes place. The genes encoding proteins involved in post-translational modification and in which mutations have been reported to cause OI, are depicted in this figure. After transport of procollagen type I to the Golgi complex and following exocytosis into the extracellular matrix, cleavage of the C-and N-propeptides results in formation of collagen type I. Subsequently, cross-linking of collagen type I molecules leads to formation of fibrils. Multiple collagen type I fibrils form into collagen fibers, important constituents of bone.