Osteogenesis Imperfecta

In book: GeneReviews™, Publisher: University of Washington, Seattle, Editors: Roberta A Pagon, Thomas D Bird, Cynthia R Dolan, Karen Stephens, Margaret P Adam
Source: PubMed


Osteogenesis imperfecta (OI) is a group of disorders characterized by fractures with minimal or absent trauma, dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal stature, and normal lifespan. Fractures can occur in any bone, but are most common in the extremities. DI is characterized by grey or brown teeth that may appear translucent and wear down and break easily. Before the molecular basis of OI was understood, OI was classified into four types on the basis of mode of inheritance, clinical presentation, and radiographic findings. With detailed radiographic and bone morphologic studies and molecular genetic analyses, the classification has expanded to seven types and it is likely that more will emerge. This classification into types of OI is helpful in providing information about prognosis and management, but it should be remembered that many of the types of OI represent an artificial construct on a broad clinical entity.
The clinical diagnosis of OI is based on family history, a history of fractures, characteristic physical findings including scleral hue, and radiographic findings. Radiographic findings include fractures of varying ages and stages of healing, wormian bones, "codfish" vertebrae, and osteopenia. Analysis of bone biopsies is an adjunct to the diagnosis of OI type V and OI type VI. Biochemical testing (i.e., analysis of the structure and quantity of type I collagen synthesized in vitro by cultured dermal fibroblasts) detects abnormalities in 98% of individuals with OI type II, about 90% with OI type I, about 84% with OI type IV, and about 84% with OI type III. About 90% of individuals with OI types I, II, III, and IV (but none with OI types V, VI and VII) have an identifiable mutation in either COL1A1 or COL1A2. Such testing is clinically available.
Osteogenesis imperfecta types I-V are inherited in an autosomal dominant manner. OI type VII is inherited in an autosomal recessive manner, and the mode of inheritance of OI type VI is not yet certain. For types I-IV, the proportion of cases caused by a de novo mutation in either COL1A1 or COL1A2 varies by the severity of disease. Approximately 60% of individuals with mild OI have de novo mutations; virtually 100% of individuals with lethal (type II) OI or with severe (type III) OI have a de novo mutation. Each child of an individual with a dominantly inherited form of OI has a 50% chance of inheriting the mutation and of developing some manifestations of OI. Prenatal testing in at-risk pregnancies can be performed by analysis of collagen synthesized by fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation if an abnormality of collagen has been identified in cultured cells from the proband. Biochemical analysis of collagen from amniocytes is not useful because amniocytes do not produce type I collagen. Prenatal testing in high-risk pregnancies can be performed by molecular genetic testing of COL1A1 and COL1A2 if the mutation has been identified in an affected relative. Prenatal ultrasound examination performed in a center with experience in diagnosing OI, and done at the appropriate gestational age, can be valuable in the prenatal diagnosis of the lethal form and most severe forms of OI prior to 20 weeks' gestation; fetuses affected with milder forms may be detected later in pregnancy when fractures or deformities occur.

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    • "It was proposed that in the pathogenesis of OI type 1, the hearing impairment, easy bruising and possibly the marked joint hypermobility would be best explained by secondary dysregulation of connective tissue composition. There is further evidence that the high prevalence of premature termination/nonsense/splicing mutations which cause the OI type 1 phenotype are associated with alterations in matrix composition [Byers and Cole, 2002]. Dentinogenesis imperfecta. "
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    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.
    American Journal of Medical Genetics Part A 06/2014; 164(6). DOI:10.1002/ajmg.a.36545 · 2.16 Impact Factor
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    • "In so doing, this study also illuminates two fundamental but debated aspects of nuclear structure, concerning the relationship of SC-35 domains to pre-mRNA metabolism, and the existence of posttranscriptional RNA tracks. OI is caused by mutations in the collagen type I genes that result in a wide range of phenotypes (Byers and Steiner, 1992). Mutant RNA studied here from a patient with OI type I (patient 054) was found to carry a G-A transition in the splice site of intron 26, identical to a mutation reported earlier from another OI Type I patient (053) (Stover et al., 1993). "
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    ABSTRACT: This study illuminates the intra-nuclear fate of COL1A1 RNA in osteogenesis imperfecta (OI) Type I. Patient fibroblasts were shown to carry a heterozygous defect in splicing of intron 26, blocking mRNA export. Both the normal and mutant allele associated with a nuclear RNA track, a localized accumulation of posttranscriptional RNA emanating to one side of the gene. Both tracks had slightly elongated or globular morphology, but mutant tracks were cytologically distinct in that they lacked the normal polar distribution of intron 26. Normal COL1A1 RNA tracks distribute throughout an SC-35 domain, from the gene at the periphery. Normally, almost all 50 COL1A1 introns are spliced at or adjacent to the gene, before mRNA transits thru the domain. Normal COL1A1 transcripts may undergo maturation needed for export within the domain such as removal of a slow-splicing intron (shown for intron 24), after which they may disperse. Splice-defective transcripts still distribute thru the SC-35 domain, moving ∼1–3 μm from the gene. However, microfluorimetric analyses demonstrate mutant transcripts accumulate to abnormal levels within the track and domain. Hence, mutant transcripts initiate transport from the gene, but are impeded in exit from the SC-35 domain. This identifies a previously undefined step in mRNA export, involving movement through an SC-35 domain. A model is presented in which maturation and release for export of COL1A1 mRNA is linked to rapid cycling of metabolic complexes within the splicing factor domain, adjacent to the gene. This paradigm may apply to SC-35 domains more generally, which we suggest may be nucleated at sites of high demand and comprise factors being actively used to facilitate expression of associated loci.
    The Journal of Cell Biology 08/2000; 150(3):417-432. · 9.83 Impact Factor
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    ABSTRACT: The aim of our study was to compare the surgical and conservative treatment of patients affected by fragility fractures and deformities of long bones in osteogenesis imperfecta (OI).Our series consisted of 29 consecutive OI patients treated at our Institute. The series comprised 14 females and 15 males of different ages. The mean age at the time of the first treatment was 8 years (median 6 years; SD ± 15; range 1 to 75). The mean follow-up was 88 months. The Sillence classification was used to classify OI. Fifteen patients were classified as Type I; five as Type III and nine as Type IV.A total number of 245 procedures were recorded. Of these, 147 were surgical (pinning; intramedullary nailing and plating) while 98 were conservative (cast, braces and bandages). Bisphosphonate use was a major variable in the study. Clinical charts and radiographic films were analyzed for complications (delayed union, nonunion, malunion, hardware loosening). We recorded 58 complications: 13 in Type I; 28 in Type III and 17 in Type IV OI. The rate of each complication was: 15/245 nonunions (6.1%), 14/245 delayed unions (5.7%), 14/245 malunions (5.7%) and 15/245 hardware loosenings (6.1%).We found no statistically significant differences between surgical and conservative treatments. Type III OI, which is a very crippling form of the disease, was associated with radiographically poorer results than the other types. In our analysis, the two groups were unbalanced and only five patients were treated with bisphosphonates. Nevertheless, bisphosphonate use can be considered a good adjuvant to both the conservative and surgical treatment of OI in order to reduce the rate of complications.
    Clinical Cases in Mineral and Bone Metabolism 09/2012; 9(3):191-4.
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