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.

Asymptomatic parental mosaicism for osteogenesis imperfecta associated with a new splice site mutation in COL1A2

“…Osteoporosis develops in the majority of patients with complete OI, and analyses of bone histomorphometry have revealed increased bone formation and increased bone resorption with a net effect of a small progressive bone loss 4. Altered bone microstructure and bone geometry, evaluated by HR‐pQCT, has been reported in patients with OI types I, III, and IV 28, 29.…”

“…Laboratory testing for OI may include either biochemical testing of collagen or, increasingly, next‐generation sequencing (NGS) of genes associated with OI. At present, 17 genes associated with OI and closely related disorders have been identified 4. In 90% of cases, heterozygous mutations in the COL1A1 or COL1A2 genes, encoding the alpha 1 and alpha 2 chains of collagen type I, respectively, are responsible for the phenotype 5.…”

“…COL1A1‐ and COL1A2 ‐related OI are inherited in an autosomal dominant manner. For OI types II‐IV, the intertwining of mutated and normal collagen type I chains results in production of abnormal collagen type I protein, which is rapidly degraded, explaining the dominant negative effect of the mutations 4. A number of genes, including but not restricted to cartilage‐associated protein (CRTAP) and prolyl‐3‐hydroxylase‐1 (P3H1, encoded by the LEPRE1 gene), have recently been identified to be involved in autosomal recessive OI.…”

“…The condition may be detected by an abnormal ultrasound scan around 20 weeks of gestation. The fetus presents with growth retardation, shortening, and bowing of long bones which are severely under‐modeled and crumbled 4. Multiple fractures of the ribs leads to a beaded appearance of the ribs (Sillence type IIA) or ribs can be thin (Sillence type IIB) 4.…”

“…The fetus presents with growth retardation, shortening, and bowing of long bones which are severely under‐modeled and crumbled 4. Multiple fractures of the ribs leads to a beaded appearance of the ribs (Sillence type IIA) or ribs can be thin (Sillence type IIB) 4. The postnatal presentation includes multiple fractures, small thorax, decreased ossification of the skull, and respiratory distress 7.…”