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PubMed2006

Genetic evaluation of suspected osteogenesis imperfecta (OI).

Osteogenesis imperfecta (OI) is probably the most common genetic form of fracture predisposition. The term OI encompasses a broad range of clinical presentations that may be first apparent from early in pregnancies to late in life, reflecting the extent of bone deformity and fracture predisposition at different stages of development or postnatal ages. Depending on the age of presentation, OI can be difficult to distinguish from some other genetic and nongenetic causes of fractures, including nonaccidental injury (abuse). The strategies for evaluation and the testing discussed here provide guidelines for evaluation that should help to distinguish among causes for fracture and bone deformity.

Child, Preschool↗

PubMed1994

Cranial reconstruction in osteogenesis imperfecta.

Although osteogenesis imperfecta (OI) is recognized as a cause of craniosynostosis, therapeutic endeavors have not been reported. We present an 8-month-old girl with type 3 OI, in whom bilateral occipital flattening, biparietal widening, and frontal narrowing were effectively managed with a combined surgical release and reconstruction and molding cap therapy. The quality of the calvarial bone in OI requires a modified approach to the conventional bone techniques commonly used in the correction of craniosynostosis deformities.

Craniosynostoses↗

PubMed2000

MRI-visible pericochlear lesions in osteogenesis imperfecta type I.

Osteogenesis imperfecta (OI) is an inherited generalized disorder of type-I collagen synthesis often associated with hearing loss. We present a case of OI type I in which hearing loss led to examination of the temporal bone with MRI. In the osseous otic capsule MRI demonstrated pericochlear lesions with soft tissue signal intensity and contrast enhancement. Changes similar to otosclerosis have been described in the temporal bone of OI patients when applying CT, but reports on MRI findings do not yet exist.

Cochlea↗

PubMed1984

Molecular heterogeneity in the mild autosomal dominant forms of osteogenesis imperfecta.

Mild osteogenesis imperfecta (OI type I and OI type IV) is characterized by postnatal onset of fractures, absence of skeletal deformity, presenile hearing loss with or without blue sclerae, and dentinogenesis imperfecta. Using one common DNA polymorphism associated with the pro alpha 2(I) human collagen gene, we found genetic heterogeneity in this disorder. In three families, the OI phenotype segregated independently of the DNA polymorphism, whereas in one family, the OI phenotype cosegregated with a DNA polymorphism in a manner suggesting linkage. Use of DNA polymorphisms associated with both type I procollagen genes should provide a tool to unravel the molecular heterogeneity of various heritable disorders of the connective tissue.

DNA Restriction Enzymes↗

PubMed1987

[Sliding centro-medullary nailing. Application to the treatment of severe forms of osteogenesis imperfecta].

In osteogenesis Imperfecta, the bowing of bones concures to increase their fragility. In order to avoid bowing of bones, Sofield, followed by Bailey have proposed centro medullary nailing. The pins used by Sofield do not expand and repeated changes are necessary. The expanding rods used by Bailey are to large and they can't be used in neonates. The author describe a new technique of bipolar centro medullary pinning. Two bowed K. Wires are introduced in the centromedullary canal, the first one through the proximal epiphysis, the second one through the distal epiphysis. During growth, each pin migrates distally and the osteosynthesis expand regularly. The technique can be used in the neonates and protects their bone from progressive bowing.

Fracture Fixation, Intramedullary↗

PubMed1989

Osteogenesis imperfecta. Perspectives.

Osteogenesis imperfecta is a heterogenous group of inherited conditions arising from a variety of biochemical and morphological collagen defects. The broad manifestations of abnormalities in bones, teeth, scleri, ligaments, and other collagen-containing tissues point to the heterogeneity of the condition. Diagnosis in the neonatal period is based on clinical characteristics, roentgenograms, and a detailed family history. Treatment is conservative when possible, and particular attention is paid to the social development of the growing child as well as to genetic counseling for parents. Modes and surgical treatment include osteoclasis and percutaneous pinning for long-bone deformities in the infant and, in the child older than two years of age, segmentation and the use of telescoping rods. Surgical treatment of spinal deformity is dependent on the age of the patient and the severity of the condition. Biochemical research is being conducted using direct tissue analyses and analyses of cultured fibroblasts and osteoblasts.

Child↗

PubMed1990

Radiological "metamorphosis" in a patient with severe congenital osteogenesis imperfecta.

Congenital osteogenesis imperfecta (OI) was diagnosed by ultrasound in a 31-week-old fetus, and the diagnosis confirmed after delivery by caesarean section at week 36. The baby survived the neonatal period, but failed to thrive, had recurrent respiratory infections and ultimately died at 8 months. Cultured fibroblasts synthesized both normal type I collagen and unstable type I collagen harbouring a structural defect in the alpha 1 (I) cyanogen bromide-derived peptide number 8 (CB8) region of the molecule, indicating a heterozygous dominant mutation. At birth, the radiological picture was that of the "thin bone"-type of congenital OI (OI type IIB/III in the Sillence classification); at the age of 12 weeks ribs and long bones had undergone a marked expansion giving a very different picture, that of the "thick bone"-type congenital OI (OI type IIA). The mechanism responsible for this change in bone structure is not known, but fractures and callus formation are unlikely to be the only factors. Caution is needed in the interpretation of radiographs of newborns with OI for prognostic or genetic purposes.

Collagen↗

PubMed2000

Stapedotomy in osteogenesis imperfecta patients.

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by osseous fragility, blue sclerae and hearing loss. In order to assess the impact of stapedotomy on improving hearing on OI, a retrospective, one-group, pre-test-post-test design was used to compare the pre-operative and post-operative audiograms of nine OI patients, treated with stapedotomy for their mixed hearing loss. Operative findings included fixation or thickening of the stapes footplate with normal superstructure configuration and hypervascularization of the promontory mucosa. Immediate post-operative results showed a significant improvement (p < 0.05) from 250-4000 Hz in air conduction and from 250-2000 Hz in bone conduction. A significant closure of the air-bone gap between 250-2000 Hz was also achieved (p < 0.05). The long-term results remained satisfactory with a mean threshold shift of 8 dB HL and an almost unchanged air-bone gap. These satisfactory results and the lack of complications make stapedotomy an appealing method for the management of OI-associated hearing loss.

Adult↗

PubMed2001

Mortality in various types of osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a group of closely related inherited diseases characterized by abnormal bone fragility. The current clinical classification system delineates 6 types, one of which (type II) is so severe that mortality is 100%, either intrauterine or perinatal. The types are differentiated by clinical groups, by severity, and by the presence or absence of other features such as blue sclerae or dentinogenesis imperfecta. There are no known previous studies of mortality in OI. RESULTS: From a registry created in association with the Brittle Bone Society, 743 patients with OI in England and Wales were observed in the period 1980-1993. These were classified into 3 groups (type IA, type III, and types IB, IVA, and IVB combined). Average annual mortality rates were determined in each group by sex and attained age. These rates were compared with 1981 rates in the population of England and Wales, matched by sex and age. Results are given in terms of exposures, observed and expected deaths, and 2 indices of excess mortality: mortality ratios and excess death rates per 1000 person-years. CONCLUSION: In type IA, 51.5% of the OI cases overall, there was no significant excess mortality (mortality ratio 108%, based on 15 deaths). In type III, on the other hand, excess mortality was very high in children and still significantly high at ages 15-34 years. In the combined group of types IB, IVA, and IVB, the mortality ratio was 157% in patients aged 45 and up (not significant at the 95% confidence level), but higher ratios at younger ages were significant, even though based on a total of only 5 deaths.

Adult↗

PubMed1995

Absence of mutations in the promoter of the COL1A1 gene of type I collagen in patients with osteogenesis imperfecta type I.

Osteogenesis imperfecta type I results from decreased production of structurally normal type I collagen as a result of a COL1A1 "null" allele. Steady state amounts of COL1A1 mRNA are reduced in both the nucleus and cytoplasm of dermal fibroblasts from most affected subjects. Mutations involving key regulatory sequences in the COL1A1 promoter, such as the TATAAA and CCAAAT boxes, could alter steady state levels of mRNA, and therefore lead to this phenotype. To determine the frequency of such mutations in OI type I cell strains, we used PCR amplified genomic DNA in conjunction with denaturing gradient gel electrophoresis (DGGE) and SSCP, to screen the 5' untranslated domain, exon 1, and a small portion of intron 1 of the COL1A1 gene. In addition, direct sequence analysis was performed on an amplified genomic DNA fragment that included the TATAAA and CCAAAT boxes. Forty unrelated probands with OI type I, in whom no causative mutation was known, were included in the study. No mutations were included in the study. No mutations were identified in either the TATAAA or CCAAAT boxes in any of the affected people. In addition, there was little evidence of sequence diversity among any of the 40 subjects. These data suggest that mutations in the COL1A1 promoter do not play a significant role in the aetiology of OI type I.

Amino Acid Sequence↗

PubMed1997

Stapes surgery in osteogenesis imperfecta patients.

Osteogenesis imperfecta (OI), or the Van der Hoeve-de Kleyn syndrome, is a heterogeneous group of connective tissue disorders. The key features in this disease are bone fragility with a tendency to spontaneous fractures and deformations. The classical traid of symptoms involves a conductive and/or sensorineural hearing impairment together with a tendency to spontaneous bone fractures and blue sclerae. Between January 1988 and December 1994, ear surgery was performed on eight ears of six OI patients who presented with mixed hearing loss preoperatively. Pathological changes observed in the middle ear were atrophy and/or fractures of the stapedial crura in combination with thickening and fixation of the stapes footplate. Partial stapedectomy was performed in seven cases and a neo-window was created in the promontory of one patient when an overhanging facial canal obscured visualization of the oval window niche. Pre- and postoperative bone conduction thresholds did not differ in any of the patients. Postoperatively, mean values of the air-bone gap in the main speech frequency range were below 10 dB. Functional results following stapes surgery in patients with otosclerosis during the same time interval (n = 857) did not differ significantly. These data indicate that stapes surgery in OI patients can be performed with the same functional predictability as in otosclerosis patients, even though the underlying etiology is considerably different.

Adult↗

PubMed2004

Genetic and biochemical analyses of Israeli osteogenesis imperfecta patients.

Osteogenesis imperfecta (OI) is clinically characterized by abnormal bone fragility, with most patients harboring heterozygote germline mutations in the COL1A1 or COL1A2 genes that encode the chains of type I procollagen, the major protein in bone. More than 250 mutations in both genes in OI patients have been reported, mostly missense mutations affecting glycine residues in the triple helical domains of the two chains. These mutations disrupt protein folding and structure, and their effects often can be detected by the analysis of proteins synthesized but cultured fibroblasts or, less often, osteoblasts. In this study, mutational analysis of all the COL1A1 and part of the COL1A2 was performed using exon-specific PCR amplification followed by denaturing gradient gel electrophoresis (DGGE) analysis and complemented by DNA sequencing in 57 Israeli OI patients from 55 unrelated families. Protein analysis was also performed using cultured fibroblasts obtained from a subset of these OI patients. Of 57 OI patients analyzed, 35 had OI type 1, 12 has OI type III, 8 had OI type IV, and 2 had OI type II. Fourteen different pathogenic mutations (10 novel) were identified in the COL1A1 gene: 3 missense, 5 nonsense, 3 insertion/deletion frameshift, 2 splice junction mutations, and 1 in frame deletion. We conclude that COL1A1 mutations underlie a subset of Israeli OI patients, that most commonly in OI type I, the mutations are contained within the COL1A1 gene, and that there are no predominant mutations in Jewish OI patients. Lastly, the use of protein analyses complements genetic analyses.

Adolescent↗

PubMed2006

Alendronate treatment in osteogenesis imperfecta.

AIMS: Osteogenesis imperfecta (OI) is a chronic, disabling condition characterized by bone fragility resulting from defective production of type I collagen. Pamidronate therapy is the most extensively studied treatment and has proved beneficial. Our objective was to evaluate the effect of alendronate, a more potent bisphosphonate than pamidronate, in OI. MATERIALS AND METHODS: Three patients (age, 3-7 years; mean, 5 years) (one case, type III; 2 cases, type IV) have been given alendronate (0.3-0.56 mg/kg per day orally) for 2 years. Number of fractures, ambulation, height growth, and bone mineral density by dual-energy x-ray absorptiometry (DXA) were followed up. RESULTS: Bone mineral density improved significantly after the 2-year alendronate treatment, which increased by 47.8% to 106.6% in the lumbar spine and by 24% to 51.4% in forearm bones. The z-score of lumbar spine DXA values increased from -5.26 +/- 0.84 to -3.1 +/- 0.59. The mean of fracture rates did not change significantly. Only one of the patients was highly limited in ambulation. She had curved legs and could not sit without support before the treatment. She improved to walk with help by the treatment. Serum parathormone and alkaline phosphatase concentrations did not change significantly. No side effect was detected in clinical and laboratory evaluations. CONCLUSION: The study suggests that alendronate is a safe and well-tolerated drug and that it could increase bone density in children with OI, all of which encourage further studies with the bisphosphonates that are more potent than pamidronate and can be used orally. In addition, this study is the first report using the forearm bone mineral density measurement in OI.

Absorptiometry, Photon↗

PubMed2004

Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients.

Osteogenesis imperfecta (OI) is caused by mutations in COL1A1 and COL1A2 that code for the alpha1 and alpha2 chains of type I collagen. Phenotypes correlate with the mutation types in that COL1A1 null mutations lead to OI type I, and structural mutations in alpha1(I) or alpha2(I) lead to more severe OI types (II-IV). However, correlative analysis between mutation types and OI associated hearing loss has not been previously performed. A total of 54 Finnish OI patients with previously diagnosed hearing loss or age 35 or more years were analyzed here for mutations in COL1A1 or COL1A2. Altogether 49 mutations were identified, of which 41 were novel. The 49 mutations represented the molecular genetic background of 41.1% of the Finnish OI population. A total of 38 mutations were in COL1A1 and 11 were in COL1A2. Of these, 16 were glycine substitutions and 16 were splicing mutations in alpha1(I) or alpha2(I). In addition, 17 null allele mutations were detected in COL1A1. A total of 32 patients (65.3%) with a mutation had hearing loss. That is slightly more than in our previous population study on Finnish adults with OI (57.9%). The association between the mutation types and OI type was statistically evident. Patients with COL1A1 mutations more frequently had blue scleras than those with COL1A2 mutations. In addition, patients with COL1A2 mutations tended to be shorter than those with COL1A1 mutations. However, no correlation was found between the mutated gene or mutation type and hearing pattern. These results suggest that the basis of hearing loss in OI is complex, and it is a result of multifactorial, still unknown genetic effects.

Adolescent↗

PubMed1990

Frameshift mutation near the 3' end of the COL1A1 gene of type I collagen predicts an elongated Pro alpha 1(I) chain and results in osteogenesis imperfecta type I.

Osteogenesis imperfecta (OI) is a heterogeneous disorder of type I collagen of which OI type I, an autosomal dominant condition, is the mildest and most common form. Affected individuals have blue sclerae, normal stature, bone fragility without significant deformity and osteopenia. Fibroblasts from most affected individuals produce about half the expected amount of structurally normal type I collagen as a result of decreased synthesis of one of its constituent chains, pro alpha 1(I), but the nature of the mutations which result in OI type I are unknown. We describe a three generation family with OI type I in which all affected members have one normal COL1A1 allele and another from which the intragenic Eco RI restriction site near the 3' end of the gene is missing. Amplification by polymerase chain reaction and sequence determination of the normal allele and of the mutant allele in the domain that normally contains the Eco RI site demonstrated a 5-bp deletion from the mutant allele. The deletion changes the translational reading-frame beginning at the Eco RI site and predicts the synthesis of a pro alpha 1(I) chain that extends 84 amino acids beyond the normal termination. Although the mutant pro alpha 1(I) chain is synthesized in an in vitro translation system, we are unable to detect its presence in intact cells, suggesting that it is unstable and rapidly destroyed in one of the cell's degradative pathways. Our analysis of individuals with OI type I from 20 families indicates that this is a unique mutation and suggests that the phenotype can result from multiple mechanisms that decrease the synthesis of normal type I procollagen molecules, including those that alter protein stability.

Adult↗

PubMed1993

Molecular heterogeneity in osteogenesis imperfecta type I.

Osteogenesis imperfecta (OI) type I is characterized by bone fragility without significant deformity, osteopenia, normal stature, blue sclerae, and autosomal dominant inheritance. Dermal fibroblasts from most affected individuals produce about half the expected amount of type I collagen, suggesting that the OI type I phenotype results from a variety of mutations which alter the apparent expression of either COL1A1 or COL1A2, the genes encoding the chains of type I collagen. Short-pulse labeling of dermal fibroblasts with [3H]proline from affected individuals in 19 families indicates that most have alterations in the expected 2:1 synthetic ratio of pro alpha 1(I): pro alpha 2(I), with most having decreased production of pro alpha 1(I). Ratios of COL1A1:COL1A2 mRNA from these individuals, using slot-blot hybridization, indicate that they fall into different groups, but that most have decreased COL1A1 mRNA levels, compared with controls. These data suggest that most of our OI I families have COL1A1 mutations. Copy number and size of the COL1A1 gene by restriction endonuclease analysis of genomic DNA from affected individuals are normal in the families examined. We have identified one 3 generation family in which all affected members have one normal COL1A1 allele and another with a 5 base-pair deletion near the 3' end of the gene. The deletion creates a shift in the translational reading-frame and predicts the synthesis of an elongated pro alpha 1(I) chain. In a second family, a father and a son have a single exon deletion that results from a splicing mutation. Chemical cleavage analysis of amplified cDNA from affected individuals in different regions of the COL1A1 gene, including the promoter, suggests that several individuals have point mutations within the coding region of the gene, while one individual may have a small deletion within the alpha 1(I) carboxyl-terminal propeptide region. Our data provide evidence for significant molecular heterogeneity within the OI type I phenotype and indicate that a variety of mutations can result in decreased synthesis of type I collagen.

Cells, Cultured↗

PubMed1995

[Autosomal dominant keratoconus as the chief ocular symptom in Lobstein osteogenesis imperfecta tarda].

BACKGROUND: Osteogenesis imperfecta is an autosomal inherited generalized disease of the soft tissue which can be divided into a congenital form (Vrolik) and a late-onset form named Lobstein. As the typical ocular symptom we find blue sclera whereas corneal changes as keratoconus are rarely documented. We report a family of 6 patients, all 5 examined being affected by keratoconus. PATIENTS AND METHODS: After a 14-year-period of wearing hard contact lenses due to a keratoconus a 26-year-old female patient developed a painful therapy-resistant keratitis (Acanthamoeba) which afforded a keratoplasty. A history of osteogenesis imperfecta tarda was known since childhood. Five further members in three generations of the family were certainly affected by osteogenesis imperfecta. We examined five patients with a computer-assisted corneal topography analysis system. RESULTS: Referring to localization and configuration of the keratoconus all of the five patients had a similar degree of affection. Only our patient revealed blue sclera. There was no correlation between the corneal curvature and the degree of affection of the bone. Both the keratoconus and the bone affections had shown no more progression after adolescence. CONCLUSION: With the use of computer-assisted corneal topography analysis we were able to show a keratoconus associated with osteogenesis imperfecta. The typical blue sclera was not found that often in this family. The shape of the keratoconus was similar in localization and configuration. Contrary to the normal progression of keratoconus in this family there was no more progression of refractive changes after adolescence. Association of keratoconus with osteogenesis imperfecta should be considered. Likewise in osteogenesis imperfecta the ophthalmologist should consider keratoconus beside blue sclera.

Acanthamoeba Keratitis↗

PubMed1994

Hyperfibers and vesicles in dentin matrix in dentinogenesis imperfecta (DI) associated with osteogenesis imperfecta (OI).

Dentin matrix of deciduous teeth from two patients affected by dentinogenesis imperfecta (DI) associated with types IB and IVB osteogenesis imperfecta (OI) displayed previously undescribed structures in transmission electron microscopic examination. Vesicles were seen in dentin of both patients, and abnormally thick collagen fibers (hyperfibers) were found in dentin of the patient with the rare type IB OI. Both vesicles and hyperfibers were situated in abnormal, atubular areas of dentin. Matrix vesicles, which have normally been identified in mantle dentin only, were abundant in selected areas of the affected dentin, thereby supporting the concept that dentin matrix in OI is elaborated by successive cell generations. The hyperfibers, not previously described in either normal or abnormal human dentin, have possibly been formed by fusion of several collagen fibers. Further ultrastructural studies of dentin in DI with OI may help to clarify the marked clinical variation in teeth of patients affected by OI.

Child↗