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Studies were carried out to test the hypothesis that a disturbance in proline or hydroxyproline metabolism, or both, is associated with defective collagen formation in osteogenesis imperfecta, a generalized disorder of connective tissue. Oral tolerance for proline in affected patients was lower than in comparable controls.
BACKGROUND: Osteogenesis imperfecta (OI) is a clinical and genetic disorder characterised by bone fragility, growth deficiency and skeletal deformity. Ninety per cent of OI cases are attributable to autosomal dominant variants in the COL1A1 and COL1A2 genes. METHODS: Candidate variants were identified and verified through trio whole-exome sequencing (trio-WES), copy number variation sequencing (CNV-seq) and Sanger sequencing. Minigene splicing assays were performed in HeLa and HEK293T cells with pcDNA3.1 and pcMINI-C vectors to investigate the function of the candidate variants. A systematic review of COL1A1 splicing variants and the corresponding genotype-phenotype spectrum was performed. RESULTS: Trio-WES revealed a novel heterozygous variant in the C-terminal region of the COL1A1 gene: NM_000088.4:c.3423+5G>A. Sanger sequencing confirmed the variant in both the proband (II-2) and her foetus (III-1) who were clinically suspected of having OI. The c.3423+5G>A variant causes complete skipping of Exon 46, as demonstrated by a minigene splicing assay. We retrieved 419 COL1A1 splicing variants from PubMed, excluded 15 without phenotypic data and 2 linked to Ehlers-Danlos syndrome and stratified the remaining 402 variants into three types on the basis of splice site location: (1) Variants at canonical splicing sites (77.8%, 313/402) mostly cause mild phenotypes, whereas a minority may be severe. (2) Intron variants in other locations, such as splice region variants (17.9%, 72/402), usually cause mild clinical phenotypes, and deep intronic splice variants (0.4%, 2/402) that may result in severe phenotypes. (3) Other variants (3.7%, 15/402), such as exon variants or fragment loss, are extremely rare. We also preliminarily discuss the mechanisms underlying phenotypic variability and the characteristics of C-terminal variants. CONCLUSIONS: This intron variant in COL1A1 was classified as likely pathogenic and was confirmed to disrupt COL1A1 expression. The summary analysis results also revealed a correlation among splicing variants, C-terminal region variants and disease, suggesting that variant location provides a useful framework for prognosis prediction.
Iliac crest bone biopsies from nine children (6-15 yrs old) with osteogenesis imperfecta tarda (OI) 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 OI 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 OI seems, therefore, to be in the 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 OI with age. Our study therefore suggests that the osteopenia observed in OI 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.
A speculative suggestion for a curative approach to osteogenesis imperfecta is based on the experimental observation that a pluripotent stem cell for mesenchymatous tissues can be isolated from marrow or periosteum. This cell, referred to as a Mesenchymal Stem Cell (MSC) could provide a vehicle for gene therapy based on that fact that many mesenchymal tissues have reasonably high cellular turnover rates. If autologous MSCs with the "proper" gene construct can be transplanted into affected patients, it may be that the progeny of the gene-corrected MSC can replace the defective mature phenotypes and bring about curative events associated with normal cell turnover.
OBJECTIVE: The aim of this study was to explore ultrastructural characters of the newly formed bone in the correction of cleft palate (CP) bone defect by distraction osteogenesis (DO). METHODS: The CP experimental animal models (12 cats) were established surgically, and were divided randomly into the experimental group (10 cats), in which the hard palate bone defects were corrected with DO procedure at the rate of 0.4 mm x 2/day. The specimen retrieval with euthanasia was carried out at 2, 4, 6, 8, 12 weeks after completion of distraction. Ultrastructural study was then performed; the experimental control group (2 cats) was kept for 6 weeks before euthanasia without any correction, the other extra 2 cats were used as the negative control. RESULTS: New bone formation appeared in early 2 weeks. Exclusively intramembranous bone formation was observed in all specimens. The remodeling activities were keep observed throughout the period of study, and the bone structure matured gradually till 12 weeks after the completion of DO. No repair was observed in experimental control group. CONCLUSION: The reconstruction of CP bone defect by means of DO could get active intramembranous bone formation and remodeling, which adapted to normal functional activities.
The objective of this study was the investigation of morho-functional peculiarities of repair osteogenesis during the surgical extremity elongation using transosseous distraction osteosynthesis. In experiment performed in dogs it was found that the extremity elongation using Ilizarov apparatus the distraction changed the spatial organization of osseous regenerates which acquired the characteristic zonal structure. Spheroidal bony trabeculae were transformed in the distraction regenerates into cylindrical primary osteons, which were formed along vertically oriented vascular loops. The osteogenic cells demonstrate intracellular markers--mitochondrial crystalline mineral inclusions.
The authors operated on 7 children (5 girls, 2 boys) suffering from osteogenesis imperfecta (oi) type I according to Sillence classification, with lower limbs discrepancy. We elongated 10 segments (7 femurs and 3 tibias). Mean age at operation time was 14.7 years (13-17 years). The mean leg length discrepancy was 9.3 cm (4-18 cm), and shortening of one bone was 6.5 cm (4-9 cm). We used Ilizarov technique twice in tibial lengthening. We used Wagner technique in one tibial elongation and in 7 femur elongation. Except for one tibia, in the remaining cases there was Rush rod inserted intramedullary in the bone being elongated. During tibial elongation we fixed lateral malleous by screw. The osteotomy was performed in proximal metaphysis of the 5 femurs and 3 tibias, and in distal femurs in two cases. The elongation was 1 mm for day, with frequency 4 x 1/4 mm. The mean bone lengthening achieved was 5.5 cm (2-9 cm); the mean lengthening of the limb was 7.9 cm (2-18 cm). The mean time of elongation was 2.8 months (2-5 months). Elongation index was 26 days for 1 cm of lengthening. The mean time of fixator removal was 9.2 months (4-13 months). Healing index was 58 day/1 cm (overall number of days for 1 cm lengthening). The complications occurred in all the patients. Although the risk of numerous complication is high, lower limbs lengthening in children with type I osteogeneis imperfecta is possible to perform and allows equalizing discrepant limbs or, at least reducing the difference.
The minimum effective strain (MES) constitutes a threshold that separates biomechanically acceptable from unacceptable strains on growing bone and fibrous tissues. Strains above that threshold affect modeling and remodeling activities in ways that change the size and configuration of growing bones, tendons, ligaments, and fascia to fit their new mechanical usage and return their strains to the threshold level. Were that threshold set too high from birth, the effects of normal function on remodeling and modeling should lead to thin fibrous tissue structures, to slender, osteopenic diaphyses and spongiosa, and to increased fragility. Those and other predictable set point effects fit so precisely many of the known hard and soft tissue abnormalities of osteogenesis imperfecta patients, that an elevated MES set point may be a heretofore unrecognized basic pathogenetic factor in that disease.
A study of the distraction callus in the femur of the growing rabbit was performed. Thirty animals separated into 10 groups were used. Distraction between both ends of a femoral osteotomy induced the formation of a connective callus which subsequently ossified. This callus disappeared between the fourth and the eighth week after the lengthening was completed. The osteogenesis model was of a mixed type, intramembranous and endochondral, with a predominance of the former. The bone healing and the initial signs of remodeling in the newly formed bony tissue were seen at the end of the first week of distraction. The original cortex was resorbed during the lengthening and was progressively substituted by a new cortex, whose formation and remodeling was not finished 24 weeks after the completion of the distraction. Experimental conditions could explain some of the findings.
BACKGROUND: Skin mechanics may be affected by several dermatological and systemic conditions. The skin can act as a marker of generalized disease. Osteogenesis imperfecta (OI) is a heritable disorder characterized by fragile bones caused by a generalized disorder of collagen. The dermis has a relative increase of argyrophil and elastic fibers and a deficiency of adult collagen. The collagen defect is well described, but functional changes in tissue mechanics have not been studied in the skin. The functional changes may reflect general changes and may give insight into the pathogenesis of clinical problems in these patients. OBJECTIVE: To examine skin mechanics (elasticity, distensibility, and hysteresis) in patients with OI. METHODS: Ten patients with OI (mean +/- SD age, 45.9 +/- 11.5 years) and 24 age-matched control subjects (mean +/- SD age, 43.3 +/- 13.8 years) were studied. The suction cup technique was used (Dermaflex; Cortex Technology, Hadsund, Denmark). RESULTS: Significant differences between the patients and controls were found in all measurements (P<.002). Skin elasticity was decreased in patients vs controls (55.5% [range, 50.9%-60.1%] vs 73.8% [range, 70.3%-77.2%]). Similarly, distensibility was decreased (2.10 mm [range, 1.85-2.35 mm] vs 2.50 mm [range, 2.37-2.63 mm]), as was hysteresis (0.19 mm [range, 0.15-0.23 mm] vs 0.28 mm [range, 0.27-0.30 mm]). CONCLUSIONS: The skin of patients with OI is more stiff and less elastic than normal skin. It is speculated that similar differences may be found in other tissues in patients with OI. The results potentially offer a quantitative standardized measure of OI, which may further our understanding of the underlying physical problems of these patients, provide better case definitions, and assist in predicting the prognosis of patients with OI.
OBJECTIVE: To assess the utility of distraction osteogenesis (DO) when applied to closure of a hard palate cleft in dogs. METHODS: A midline hard palate cleft was created in 10 mature dogs. Two were controls and had no distraction; the other 8 dogs underwent osteotomies with installation of customized DO devices to the hard palate. After a 10-day latency, distraction commenced at 1 mm/d. After a 14-day consolidation period, the device was removed and the mucosa closed. Each dog was injected with fluorochrome labels and serially killed at 2-week intervals. Bone healing was analyzed further with traditional histologic analysis and fluorochrome labeling. RESULTS: No serious complications occurred. Bone resorption and cleft widening occurred in both control dogs. Complete bone closure of the hard palate cleft was achieved with DO in 5 of 8 experimental dogs. Three experimental dogs had bone resorption and incomplete palatal closure. CONCLUSIONS: The application of DO techniques in closure of a hard palate cleft in a canine model is safe and well tolerated. Furthermore, in some cases, it proved effective in achieving bony closure of the cleft. Further investigation is warranted into innovative use of DO in treating children born with cleft palate.
The neurologic status of ten patients with osteogenesis imperfecta (OI) was evaluated. Four patients with mild OI (type I) had normal neurologic findings and normal computed tomographic scans. Three of these four patients had macrocephaly. All six patients with severe OI (type III) had cortical atrophy on computed tomographic scan and three were also macrocephalic.
Audiologic evaluations and impedance audiometry were obtained on persons from 13 families with dominant osteogenesis imperfecta (OI). Hearing impairment appeared in the late second or early third decade, usually with a conductive loss. Older patients had mixed or sensorineural losses. There was an increasing risk for hearing loss with advancing age. Impedance tests suggested that ossicular fixation may be the primary cause of middle ear disorders in patients with mixed or conductive hearing losses. The cause of sensorineural hearing loss could not be determined. The long-term success of otologic surgery in OI is uncertain. Amplification may be a reasonable alterative to surgery.
This study is the first in a series of experiments undertaken to obtain basic information regarding the behavior of vascularized periosteum. Ten adult dogs were used and in each animal costal periosteum was alternatively placed in contact with normal (but previously detached) rib, and rib segments devitalized by autoclaving, decorticated, and isolated by means of a Silastic wrap. Specimens were harvested at 10, 20, 40, and 70 days and were evaluated grossly, histopathologically, and by tetracycline hydrochloride fluorescence studies. Periosteum in contact with intact bone became osteogenic within 20 days. Periosteum in contact with autoclaved and decorticated bone also became osteogenic but at a slower rate. Isolated periosteum failed to produce bone. These findings indicate that osteogenesis in transferred periosteum depends not only on maintenance of its vascular supply but also on its proximity to viable bone and its ability to interact with the recipient surface.
Preoperative and postoperative hearing results and long-term results of stapedectomy have been investigated in 58 ears (47 patients) with osteogenesis imperfecta. After 3 months, hearing gain had been achieved in 49 (85%) of 58 ears. Twenty-seven (68%) of 40 ears followed up for an average of 9.6 years (range, 2 to 24 years) had no deterioration of their immediate postoperative hearing gain. In the other ears, the decrease in hearing gain in the long term was due to progression of the sensorineural component of the hearing loss. Complete closure of the air-bone gap remained unchanged in 26 (70%) of 37 ears. In 5 (9%) of 58 ears the sensorineural component of the hearing loss increased as an immediate result of the operation. In 6 other ears (10%) progressive sensorineural hearing loss was seen only after more than 1 year. A natural course of the disease is assumed as the cause because progressive sensorineural hearing loss has also been seen in the nonoperated on contralateral ears of these patients.
Twelve families with 29 patients showing various patterns of osteogenesis imperfecta are described, along with the genetic, pathological, and clinical features. No abnormal blochemical features were found. It has been shown that the best treatment is prophylactic (such as intramedullary nailingy or supportive. There was no remarkable improvement from any form of medical treatment. These data are compared to those of other authors.
A patient had recurrent pyogenic infections, chronic mucocutaneous candidiasis, and repeated long-bone fractures. Her disorder was diagnosed as hyper-IgE syndrome on the basis of clinical data, elevated levels of serum IgE, increased levels of IgE specific for Staphylococcus aureus, and impaired T-lymphocyte function. Roentgenograms confirmed the diagnosis of osteogenesis imperfecta tarda. The estimated likelihood of both conditions occurring in the same person is approximately one in 10 billion. The coincident finding of bone dysplasia in a patient with impaired T-lymphocyte function suggests a common mechanism for birth defects.
A substitution of arginine for glycine at amino acid position 154 of the alpha 1(I) collagen chain was found in a father and his three children. The phenotype of the patients includes manifestations of types I and III/IV osteogenesis imperfecta, but appears to be milder than that of the previously described two unrelated patients that had the identical mutation in the alpha 1(I) collagen chain. The variability in the phenotype raises the possibility of epistatic loci or environmental effects on expression of the disorder.