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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ABSTRACT: A rare disease alicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders afect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. hese rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. his systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: ibrous dysplasia, Gorham-Stout syndrome, ibrodysplasia ossiicans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. he disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. he use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of ibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. here are still no current efective treatments for these bone disorders; however, signiicant promising advances in therapeutic modalities were developed that will limit patient sufering and treat their skeletal disabilities.BioMed Research International 10/2014; 2014(670842). DOI:10.1155/2014/670842 · 2.71 Impact Factor
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ABSTRACT: In recent years, as knowledge regarding the etiopathogenetic mechanisms of bone involvement characterizing many diseases has increased and diagnostic techniques evaluating bone health have progressively improved, the problem of low bone mass/quality in children and adolescents has attracted more and more attention, and the body evidence that there are groups of children who may be at risk of osteoporosis has grown. This interest is linked to an increased understanding that a higher peak bone mass (PBM) may be one of the most important determinants affecting the age of onset of osteoporosis in adulthood. This review provides an updated picture of bone pathophysiology and characteristics in children and adolescents with paediatric osteoporosis, taking into account the major causes of primary osteoporosis (PO) and evaluating the major aspects of bone densitometry in these patients. Finally, some options for the treatment of PO will be briefly discussed.Italian Journal of Pediatrics 06/2014; 40(1):55. DOI:10.1186/1824-7288-40-55
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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 · 2.05 Impact Factor