Correlation of clinical and molecular biological abnormalities in osteogenesis imperfecta

Substitution of a glycine residue in the triple helix of the alpha 1(I) chain by either arginine, valine or alanine was associated with the type II lethal perinatal osteogenesis imperfecta phenotype. This phenotype was also produced by a frameshift mutation that resulted in an abnormal amino acid sequence of the carboxy-terminal propeptide of the pro-alpha 1(I) chain. The latter baby, however, showed some clinical and radiographic differences from the other babies with type II OI. The severity of the clinical and radiographic phenotypes are likely to be determined by both the type and site of the mutation as well as by the intra-uterine environment.     

常染色体隐性遗传性成骨不全症的分子遗传学研究进展

成骨不全症(osteogenesis imperfecta,OI)又称脆骨症,由于遗传缺陷而引起Ⅰ型胶原结构或功能异常,表现为全身骨骼等结缔组织异常.临床特点是多发性骨折,同时可伴有巨头畸形、蓝巩膜、耳聋、牙齿改变和脊柱后侧凸等.成骨不全症不仪临床表型变异度大,而且遗传异质性高,以常染色体显件或隐性遗传方式传递,本文就常染色体隐性遗传性成骨不全症的分子遗传学研究进展加以综述.     

常染色体隐性遗传性成骨不全症的分子遗传学研究进展

成骨不全症(osteogenesis imperfecta,OI)又称脆骨症,由于遗传缺陷而引起Ⅰ型胶原结构或功能异常,表现为全身骨骼等结缔组织异常.临床特点是多发性骨折,同时可伴有巨头畸形、蓝巩膜、耳聋、牙齿改变和脊柱后侧凸等.成骨不全症不仪临床表型变异度大,而且遗传异质性高,以常染色体显件或隐性遗传方式传递,本文就常染色体隐性遗传性成骨不全症的分子遗传学研究进展加以综述.     

常染色体隐性遗传性成骨不全症的分子遗传学研究进展

成骨不全症(osteogenesis imperfecta,OI)又称脆骨症,由于遗传缺陷而引起Ⅰ型胶原结构或功能异常,表现为全身骨骼等结缔组织异常.临床特点是多发性骨折,同时可伴有巨头畸形、蓝巩膜、耳聋、牙齿改变和脊柱后侧凸等.成骨不全症不仪临床表型变异度大,而且遗传异质性高,以常染色体显件或隐性遗传方式传递,本文就常染色体隐性遗传性成骨不全症的分子遗传学研究进展加以综述.     

Surgery in osteogenesis imperfecta

An analysis of 266 operations on 63 patients with osteogenesis imperfecta, mostly type III and IV, showed that about half had corrections of skeletal deformities and internal splinting with intramedullary stainless steel rods. The remaining operations were for other orthopaedic procedures as well as non-orthopaedic procedures such as hernia repairs. There were no major anaesthetic or post-operative complications. Mild pyrexia was common but without the features of malignant hyperpyrexia. Correction of long deformities and internal splintage of the bones with non-expanding rods effectively reduced the fracture rate but deformities and fractures recurred as the epiphyses grew off the ends of the rods. Expanding rods provided continuing splintage during growth but could not be used in children with very narrow or very fragile bones.     

Frontiers in rehabilitation medicine: osteogenesis imperfecta

This Frontiers in Osteogenesis Imperfecta conference has been organized to foster communication between clinical and laboratory scientists as well as future collaborations. In fact, one of the goals we have had as organizers of this meeting is that new areas of investigation would be fostered. I will attempt to present some of the as yet unanswered clinical questions that I believe are important for this population.     

Osteosarcoma occurring in osteogenesis imperfecta

We describe a case history of a 24-year-old male with osteogenesis imperfecta (OI) who developed osteosarcoma of the left thigh. High-dose ifosfamide therapy caused marked tumor regression of multiple lung metastases. Immunohistochemically, the tumor cells were diffusely positive for the p53 protein. Mutation of the p53 gene was not detected by direct genomic sequencing of exons 4–8. The radiographic characteristics, including irregularly distributed osteolytic lesions and cortical discontinuity, should not be confused with hyperplastic callus formation, a benign process. A biopsy is critical to establish the differential diagnosis between osteosarcoma and common hyperplastic callus formation in OI; however, it must be applied with great care.     

Neurologic profile in osteogenesis imperfecta

The clinically important neurlogic complications in 76 patients with OI seen at the NIH included brainstem compression from basilar invagination, skull fracture, and seizure disorders. Neuroimaging studies demonstrated sulcal prominence and ventriculomegaly consistent with communicating hydrocephalus in 17 patients. Basilar invagination was found in 8 individuals, all with clinically severe OI, and caused brain-stem compression in 3 patients. Head circumference growth showed abnormal kinetics with percentile crossing after fontanelle closure in 13 patients and absolute macrocephaly was present in 11 patients. Neurologic evaluation should be part of a team approach in the management of patients with severe OI types. Continued study of the underlying pathophysiology of neurologic features in OI is warranted.     

Hyperplastic callus formation in osteogenesis imperfecta

A case of a child with the hyperplastic callus formation in association with osteogenesis imperfecta is presented. The soft tissue mass arising at the site of femoral fracture was clinically and radiologically suspected to be a hyperplastic callus, although a possibility of osteosarcoma could not be completely excluded. A drill biopsy of the soft tissue mass was performed which showed osteocartilaginous callus. The soft tissue mass disappeared following biopsy. This occurrence is also reported in previously described cases.     

Bone cell defects in osteogenesis imperfecta

Iliac crest bone biopsies from nine children (6-15 years old) with osteogenesis imperfecta tarda (O.I.) have been studied by bone histomorphometry after double fluorescent labeling with tetracycline and compared to five unlabeled biopsies from normal children in the same age group. The results indicate that children with O.I. have a low trabecular bone volume associated with an increased bone turnover rate. Bone formation is increased at the tissue level despite a decrease in the activity of individual osteoblasts. The original defects in O.I. seem to be due to the altered rate of matrix synthesis by osteoblasts. It is, however, compensated by an increase in the number of these cells. These results suggest that these children were not losing bone at the time of the biopsy, which fits with the clinical stability of O.I. with age. Our study therefore suggests that the osteopenia observed in O.I. is most likely due to an inability to accumulate bone during growth, as normal children do, rather than to a progressive net loss of bone.     

Odontoblast dysfunction in osteogenesis imperfecta: an LM,SEM, and ultrastructural study

The inherited dentin defect dentinogenesis imperfecta (DI), while clinically obvious in osteogenesis imperfecta (OI) Types IB and IC, II, III, and IVB, is now thought to be present in all children with OI, in a continuum from minimal to severe dentin pathology. This collaborative study further clarifies the structural and ultrastructural dentin changes in the teeth of OI children with clinically obvious DI, and attempts to explain these in terms of odontoblast dysfunction. Collaborative studies were carried out in Melbourne, Australia, and Strasbourg, France, using light and polarized-light microscopy, scanning and transmission electron microscopy (SEM, TEM), selected-area diffraction (SAD), and x-ray spectroscopy (EDX). These showed structurally normal enamel (but containing long and broad lamellae) and a normally scalloped dentino-enamel junction (DEJ), but severe pathologic changes in the dentin. An initial narrow band of normal-appearing dentin tubules (including the mantle layer) ceased abruptly and was replaced by a wavelike laminar zone parallel to the DEJ with occluded tubules. Multiple parallel channels of 5-10 microns diameter were present at right angles to the DEJ indenting this zone, some terminating in retro-curved "processes." The abnormal dentin containing these channels almost completely occluded the pulp chamber. The structural and ultrastructural changes seen can be explained on the basis of the collagen defect in OI resulting in odontoblast dysfunction, which produces a distinct phenotype and one that is different from that in bone.     

Genetic heterogeneity in osteogenesis imperfecta.

An epidemiological and genetical study of osteogenesis imperfecta (OI) in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI. The largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae. A large proportion of adults had presenile deafness or a family history of presenile conductive hearing loss. A second group, who comprised the majority of newborns with neonatal fractures, all died before or soon after birth. These had characteristic broad, crumpled femora and beaded ribs in skeletal x-rays. Autosomal recessive inheritance was likely for some, if not all, of these cases. A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine. The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age. All patients in this group were sporadic cases. The mode of inheritance was not resolved by the study, but it is likely that the group is heterogeneous with both dominant and recessive genotypes responsible for the syndrome. The fourth group of patients showed dominant inheritance of osteoporosis leading to fractures, with variable deformity of long bones, but normal sclerae.     

Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: a new target for osteogenesis imperfecta pharmacological therapy

The molecular basis underlying the clinical phenotype in bone diseases is customarily associated with abnormal extracellular matrix structure and/or properties. More recently, cellular malfunction has been identified as a concomitant causative factor and increased attention has focused on stem cells differentiation. Classic osteogenesis imperfecta (OI) is a prototype for heritable bone dysplasias: it has dominant genetic transmission and is caused by mutations in the genes coding for collagen I, the most abundant protein in bone. Using the Brtl mouse, a well-characterized knockin model for moderately severe dominant OI, we demonstrated an impairment in the differentiation of bone marrow progenitor cells toward osteoblasts. In mutant mesenchymal stem cells (MSCs), the expression of early (Runx2 and Sp7) and late (Col1a1 and Ibsp) osteoblastic markers was significantly reduced with respect to wild type (WT). Conversely, mutant MSCs generated more colony-forming unit-adipocytes compared to WT, with more adipocytes per colony, and increased number and size of triglyceride drops per cell. Autophagy upregulation was also demonstrated in mutant adult MSCs differentiating toward osteogenic lineage as consequence of endoplasmic reticulum stress due to mutant collagen retention. Treatment of the Brtl mice with the proteasome inhibitor Bortezomib ameliorated both osteoblast differentiation in vitro and bone properties in vivo as demonstrated by colony-forming unit-osteoblasts assay and peripheral quantitative computed tomography analysis on long bones, respectively. This is the first report of impaired MSC differentiation to osteoblasts in OI, and it identifies a new potential target for the pharmacological treatment of the disorder.     

Familial dentinogenesis imperfecta,blue sclerae,and wormian bones without fractures: another type of osteogenesis imperfecta?

A unique connective tissue disorder characterised by the triad of dentinogenesis imperfecta, blue sclerae, and multiple wormian bones has been identified in 20 members of three generations of a large kindred of mixed ancestry in South Africa. The skeletons of affected subjects were moderately osteoporotic but, apart from minimal bowing of the femora and some vertebral flattening in late adulthood, this abnormality produced no untoward sequelae. Bone fragility was present in one young male, while a mother and her daughter had deafness of uncertain relationship with the primary disorder. Dental discolouration and a liability to caries were the only important complications. The condition is best regarded as yet another variety of osteogenesis imperfecta. It is inherited as an autosomal dominant trait with relatively consistent phenotypic expression.     

Craniofacial features in osteogenesis imperfecta: a cephalometric study

Osteogenesis imperfecta (OI) is a heterogeneous group of connective tissue diseases that mainly manifest as bone fragility and skeletal deformity. In most families it segregates as a dominant trait and results from mutations in type I collagen genes. In this study we analyzed the size and form of the bony structures in heads of 59 consecutive patients with OI types I, III, or IV (Sillence classification), using lateral radiographs. Paired controls were matched for gender and age. The purpose was to obtain baseline information of craniofacial development in OI patients that have not received bisphosphonate treatment. In OI type I we found smaller than normal linear measurements, indicating a general growth deficiency, but no remarkable craniofacial deformity. In OI types III and IV, the growth impairment was pronounced, and the craniofacial form was altered as a result of differential growth deficiency and bending of the skeletal head structures. We found strong support both for an abnormally ventral position of the sella region due to bending of the cranial base, and for a closing mandibular growth rotation. Vertical underdevelopment of the dentoalveolar structures and the condylar process were identified as the main reasons for the relative mandibular prognathism in OI. Despite of the widespread intervention with bisphosphonates, the facial growth impairment will probably remain characteristic for many OI patients, and their orthodontic treatment should be further developed.