ABSTRACT 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. "
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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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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ABSTRACT: We present a case of hyperimmunoglobulin E (hyper-IgE) syndrome in a three year old boy. There are many pitfalls in diagnosing this disease in the very young population, mainly due to the ambiguity of some diagnostic criteria in this population. Recognizing this syndrome early in life can potentially be very beneficial to the patients involved and the medical system as a whole. Early diagnosis can lead to fewer diagnostic tests, fewer referrals, and more focused exams, thus potentially reducing medical cost while also reducing the number of serious infections later in life, including those which are potentially fatal. Additionally, a wellknown association between lymphoma and hyper-IgE syndrome has been established; while no recommendations are currently in place for screening, early diagnosis could help medical providers have a higher threshold for diagnosis of this disease.Infectious disease reports 01/2013; 5(1):e6. DOI:10.4081/idr.2013.e6