Different Types Of Osteogenesis Imperfecta Research Articles

Setrusumab for the treatment of osteogenesis imperfecta: 12-month results from the phase 2b asteroid study.

Osteogenesis imperfecta (OI) is a rare genetic disorder commonly caused by variants of the type I collagen genes COL1A1 and COL1A2. OI is associated with increased bone fragility, bone deformities, bone pain, and reduced growth. Setrusumab, a neutralizing antibody to sclerostin, increased areal bone mineral density (aBMD) in a 21-week phase 2a dose escalation study. The phase 2b Asteroid (NCT03118570) study evaluated the efficacy and safety of setrusumab in adults. Adults with a clinical diagnosis of OI type I, III, or IV, a pathogenic variant in COL1A1/A2, and a recent fragility fracture were randomized 1:1:1:1 to receive 2, 8, or 20mg/kg setrusumab doses or placebo by monthly intravenous infusion during a 12-mo treatment period. Participants initially randomized to the placebo group were subsequently reassigned to receive setrusumab 20mg/kg open label. Therefore, only results from the 2, 8, and 20mg/kg double-blind groups are presented herein. The primary endpoint of Asteroid was change in distal radial trabecular volumetric bone mineral density (vBMD) from baseline at month 12, supported by changes in high-resolution peripheral quantitative computed tomography micro-finite element (microFE)-derived bone strength. A total of 110 adults were enrolled with similar baseline characteristics across treatment groups. At 12mo, there was a significant increase in mean (SE) failure load in the 20mg/kg group (3.17% [1.26%]) and stiffness in the 8 (3.06% [1.70%]) and 20mg/kg (3.19% [1.29%]) groups from baseline. There were no changes in radial trabecula vBMD (p>05). Gains in failure load and stiffness were similar across OI types. There were no significant differences in annualized fracture rates between doses. Two adults in the 20mg/kg group experienced related serious adverse reactions. Asteroid demonstrated a beneficial effect of setrusumab on estimates of bone strength across the different types of OI and provides the basis for additional phase 3 evaluation.

Dental anomalies in individuals with osteogenesis imperfecta: a systematic review and meta-analysis of prevalence and comparative studies.

Osteogenesis imperfecta (OI) is a rare genetic disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. OI is also known as brittle bone disease. This study aims to describe the prevalence of dental anomalies (except dentinogenesis imperfecta) in individuals with OI, and compare the prevalence of dental anomalies between individuals with and without OI and between individuals with different types of OI. Searches in PubMed, Web of Science, Scopus, Ovid, and gray literature were performed in October 2022. Observational studies (with or without a comparison group) that evaluated the prevalence of dental anomalies in individuals with OI. Data collection and analysis: Data items were extracted by two authors. Quality assessment employing the Joanna Briggs Institute checklists and meta-analyses was conducted. Results were provided in prevalence values and odds ratio (OR) / 95% confidence interval (CI). Strength of evidence was determined. Eighteen studies were included. Most prevalent dental anomalies in individuals with OI included pulp obliteration (46.4%), dental impaction (33.5%), dental impaction of second molars (27%), and tooth agenesis (23.9%). Individuals with OI type III/IV had 20.16-fold greater chance of exhibiting tooth discoloration in comparison with individuals with OI type I (CI: 1.10-370.98). In comparison with the group without OI, the individuals with OI had 6.90-fold greater chance of exhibiting dental impaction (CI: 1.54-31.00). High methodological quality was found in 47% of the studies. Strength of evidence was low or very low. Pulp obliteration, dental impaction, and tooth agenesis were the most prevalent dental anomalies in the OI group. Individuals with OI were more likely to have dental impaction than individuals without OI. Individuals with OI type III/IV (severe-moderate) are more likely to have tooth discoloration than individuals with OI type I (mild).

Does the c.-14C>T Mutation in the IFITM5 Gene Provide Identical Phenotypes for Osteogenesis Imperfecta Type V? Data from Russia and a Literature Review

Osteogenesis imperfecta (OI) is a large group of genetically heterogeneous diseases resulting from decreased bone density and an abnormal microarchitecture, which are clinically manifested by abnormal bone fractures. A distinctive clinical feature of this group of diseases is the presence of spontaneous fractures and skeletal deformities. However, the clinical manifestations of different types of OI are characterized by marked polymorphism with variable severity of skeletal and extra-skeletal features. Previous studies have shown that a mutation (c.-14C>T) in the IFITM5 gene is responsible for autosomal dominant OI type V. However, the mutation has a variable expression pattern and marked clinical heterogeneity. In this study, a clinical and genetic analysis of 12 cases with molecularly confirmed OI type V from 12 unrelated families was performed. Significant clinical heterogeneity of the disease with the same molecular defect was detected. In six subjects (50%), there were no classic signs of OI type V (formation of a hyperplastic bone callus, calcification of the interosseous membrane and dislocation of the radial head). In all cases, the mutation occurred de novo.

Quantitative gait analysis in children with osteogenesis imperfecta: relationship between gait deviations and clinical features.

Osteogenesis imperfecta is a rare congenital disease of connective tissue characterized by recurrent fractures and progressive skeletal deformities which may impact on gait. The aims of this prospective study were to identify gait deviations in children with osteogenesis imperfecta compared to age-matched controls and establish relationships with clinical features. We evaluated 22 patients with different types of osteogenesis imperfecta using three-dimensional gait analysis. The incidence and location of frac- tures, fracture at birth, age at first fracture, use of intramedullary rodding and number of surgical in- terventions in the lower extremities, bone mineral density, hypermobility and number of injections of bisphosphonates were recorded for each patient. Step length was lower in the osteogenesis imperfecta group compared with the control group. Kinematics showed that sagittal pelvic and transversal hip range of motion were higher in the osteogenesis imperfecta group, whereas sagittal knee range of motion during swing phase was reduced. Regarding kinetics, hip flexion moment and hip negative power peak were significantly decreased in the osteogenesis imperfecta group. Mechanical and energetic parameters were considered as normal. The principal component analysis revealed that the bone mineral density was increased in children who had received more in- jections of bisphosphonates and these had also less deficit in kinematic parameters. Main modifications in gait parameters were observed in spatiotemporal, kinematic and kinetic data. More studies are necessary to allow stratification of severity of the osteogenesis imperfecta disease, help improve its challenging multidisciplinary treatment and ob- jectively assess treatment outcomes.

Comparative characteristics of the morphological structure of teeth in children with I and III types of osteogenesis imperfecta (in vitro)

Relevance . Osteogenesis imperfecta is a rare hereditary disease of the connective tissue and the skeleton caused by incomplete mineralization of the bony tissue and hard dental tissue of the primary and permanent dentition. The most common oral manifestations of osteogenesis imperfecta are polymorphism, anodontia, impairment of amelogenesis and dentinogenesis. Function and esthetics are impaired in hereditary amelognenesis imperfecta and dentinogenesis imperfecta. Materials and methods . 36 children aged from 4 to 6 years with different types of osteogenesis imperfecta were examined in the clinic of the department of pediatric dentistry of the Clinical Center for Maxillofacial and Plastic Surgery and Dentistry. Morphological structure of the dental samples was studied for the first time ever using scanning electron microscopy. Results . Characteristic changes were detected by the clinical and X-ray examination. The article presents for the first time the comparison of deciduous hard dental tissue morphology in children with different types of osteogenesis imperfecta studied by the scanning electron microscopy (in vitro). Conclusions . The received data are of primary importance for prognosis and strategy of the dental treatment in children with different types of osteogenesis imperfecta.

Postural balance, handgrip strength and mobility in Brazilian children and adolescents with osteogenesis imperfecta

ObjectiveTo describe postural balance, handgrip strength and mobility in children and adolescents with different types of osteogenesis imperfecta. MethodsCross-sectional study. Fifty selected subjects diagnosed with types I (n=11), III (n=21), and IV (n=18), followed up at Brazilian reference center for osteogenesis imperfecta in the Midwest region, aged 2–21 years (9.2±5.0), were enrolled in this study. Children and adolescents were evaluated for postural balance in the upright position with eyes-open and eyes-closed conditions, handgrip strength and the mobility domain (Pediatric Dysfunction Assessment Inventory). Data normality and difference between groups was verified. ResultsHandgrip strength was significantly lower in people with type III of osteogenesis imperfecta when compared to the osteogenesis imperfecta types I and IV, and to the age-specific reference data. Center of pressure length and mean velocity in the condition with eyes closed were worse compared to the open-eyes condition for children and adolescents with type I of osteogenesis imperfecta. There were worse results in the mobility domain for the participants classified with the most severe type of osteogenesis imperfecta. ConclusionsIt was observed that the severity of the osteogenesis imperfecta disease affected handgrip strength and locomotor function assessed by the mobility domain. Comparing osteogenesis imperfecta types, the higher the severity of osteogenesis imperfecta, the lower the handgrip strength. These results can contribute to new strategies of treatment focused on improving functional capacity and quality of life in people with osteogenesis imperfecta.

Animal models of osteogenesis imperfecta: applications in clinical research.

Osteogenesis imperfecta (OI), commonly known as brittle bone disease, is a genetic disease characterized by extreme bone fragility and consequent skeletal deformities. This connective tissue disorder is caused by mutations in the quality and quantity of the collagen that in turn affect the overall mechanical integrity of the bone, increasing its vulnerability to fracture. Animal models of the disease have played a critical role in the understanding of the pathology and causes of OI and in the investigation of a broad range of clinical therapies for the disease. Currently, at least 20 animal models have been officially recognized to represent the phenotype and biochemistry of the 17 different types of OI in humans. These include mice, dogs, and fish. Here, we describe each of the animal models and the type of OI they represent, and present their application in clinical research for treatments of OI, such as drug therapies (ie, bisphosphonates and sclerostin) and mechanical (ie, vibrational) loading. In the future, different dosages and lengths of treatment need to be further investigated on different animal models of OI using potentially promising treatments, such as cellular and chaperone therapies. A combination of therapies may also offer a viable treatment regime to improve bone quality and reduce fragility in animals before being introduced into clinical trials for OI patients.

Cross-sectional and longitudinal growth patterns in osteogenesis imperfecta: implications for clinical care.

There is strikingly limited information on linear growth and weight in the different types of osteogenesis imperfecta (OI). Here, we define growth patterns further with the intent of implementing appropriate adaptations proactively. We report cross-sectional anthropometric data for 343 subjects with different OI types (144 children, 199 adults). Longitudinal height data for 36 children (18 girls, 18 boys) with OI type I and 10 children (8 girls, 2 boys) with OI type III were obtained. In all cases, the height Z-scores were negatively impacted, and final height Z-scores were impacted the most. In type I, the growth velocities taper near puberty, and there is a blunted pubertal growth spurt. The growth velocities of children with type III decelerate before age 5 y; poor growth continues without an obvious pubertal growth spurt. Obesity is a concern for all patients with OI, with type III patients being the most affected. The linear growth patterns, in addition to the marked increase in weight over time, indicate a need for lifestyle modifications early in childhood, especially a need for weight control. Further definition of the anthropometric measures in OI enables patients to begin modifications as early as possible.

BISPHOSPHONATE THERAPY IN PEDIATRIC PATIENTS WITH OSTEOGENESIS IMPERFECTA

Osteogenesis imperfecta (OI) is a group of rare inherited disorders of connective tissue with the common feature of excessive fragility of bones caused by mutations in collagen. We present the case of 2 patients diagnosed with different types of OI, both males, one admitted in the neonatal period and one in infancy. The aim of the study was to compare the efficiency of bisphosphonate therapy, following up the quality of life after receiving it, or in the absence of this treatment.

Bone structure assessed by HR-pQCT, TBS and DXL in adult patients with different types of osteogenesis imperfecta.

Bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) was assessed in adult patients with mild, moderate, and severe osteogenesis imperfecta (OI). The trabecular bone score (TBS), bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), and dual X-ray and laser (DXL) at the calcaneus were likewise assessed in patients with OI. Trabecular microstructure and BMD in particular were severely altered in patients with OI. OI is characterized by high fracture risk but not necessarily by low BMD. The main purpose of this study was to assess bone microarchitecture and BMD at different skeletal sites in different types of OI. HR-pQCT was performed in 30 patients with OI (mild OI-I, n = 18 (41.8 [34.7, 55.7] years) and moderate to severe OI-III-IV, n = 12 (47.6 [35.3, 58.4] years)) and 30 healthy age-matched controls. TBS, BMD by DXA at the lumbar spine and hip, as well as BMD by DXL at the calcaneus were likewise assessed in patients with OI only. At the radius, significantly lower trabecular parameters including BV/TV (p = 0.01 and p < 0.0001, respectively) and trabecular number (p < 0.0001 and p < 0.0001, respectively) as well as an increased inhomogeneity of the trabecular network (p < 0.0001 and p < 0.0001, respectively) were observed in OI-I and OI-III-IV in comparison to the control group. Similar results for trabecular parameters were found at the tibia. Microstructural parameters were worse in OI-III-IV than in OI-I. No significant differences were found in cortical thickness and cortical porosity between the three subgroups at the radius. The cortical thickness of the tibia was thinner in OI-I (p < 0.001), but not OI-III-IV, when compared to controls. Trabecular BMD and trabecular bone microstructure in particular are severely altered in patients with clinical OI-I and OI-III-IV. Low TBS and DXL and their significant associations to HR-pQCT parameters of trabecular bone support this conclusion.

Pamidronate Affects the Mandibular Cortex of Children with Osteogenesis Imperfecta

We hypothesized that mandibular cortical width (MCW) is smaller in children with osteogenesis imperfecta (OI) than in healthy children and that pamidronate can improve the cortical mandibular thickness. The aim of this study was to assess changes in the MCW on dental panoramic radiographs (DPRs) of children with normal bone mineral density (BMD) and with OI. We also compared the MCW of children with different types of OI regarding the number of pamidronate cycles and age at the beginning of treatment. MCW measurements were retrospectively obtained from 197 DPRs of 66 children with OI types I, III, and IV who were in treatment with a comparable dosage of cyclical intravenous pamidronate between 2007 and 2013. The control group had 92 DPRs from normal BMD children. Factorial analysis of variance was used to compare MCW measurements among different age groups and between sexes and also to compare MCW measurements of children with different types of OI among different pamidronate cycles and age at the beginning of treatment. No significant differences in results were found between male and female subjects in both OI and healthy children, so they were evaluated altogether (P > 0.05). There was an increase of MCW values related to aging in all normal BMD and OI children but on a smaller scale in children with OI types I and III. Children with OI presented lower mean MCW values than did children with normal BMD at the beginning of treatment (P < 0.05). A linear model estimated the number of pamidronate cycles necessary to achieve mean MCW values equivalent to those of healthy children. The thinning of the mandibular cortex depended on the number of pamidronate cycles, the type of OI, and the age at the beginning of treatment. DPRs could thus provide a way to identify cyclic pamidronate treatment outcomes in patients with OI.

Anthropometry, Nutritional Status, and Dietary Intake in Pediatric Patients with Osteogenesis Imperfecta

Objective: The aim of the present study was to assess anthropometric measurements, nutritional status, dietary intake, and body fat percentage of pediatric patients with osteogenesis imperfecta (OI). Method: A cross-sectional study evaluated 63 OI patients from 0 to 19 years of age. We analyzed anthropometric measurements, mobility, bisphosphonate treatment, body fat percentage (by dual-energy x-ray absorptiometry [DEXA] and sum of skinfold thickness), nutritional status, and dietary intake (using World Health Organization [WHO] and dietary reference intake recommendations for macronutrients and calcium intake, respectively). Participants’ energy requirements were calculated using both kilocalorie per centimeter measurements and WHO methods. Results: Patients with different types of OI had different anthropometric measurements (p < 0.05), where OI type III had severely limited stature and poor mobility. Nutritional status was correlated with measurements of arm circumference and body fat. We also found a strong correlation between the 2 methods used to calculate percentage of body fat (r = 0.803). OI type III had a higher percentage of energy intake. We observed that 75% of subjects had a calcium intake below 95% of recommended daily value and there was an inverse correlation between age and calcium intake. Conclusions: This study showed that stature was compromised mainly in OI type III. Skinfold thickness and arm circumference correlated to nutritional status and also to body fat calculated by DEXA. Daily calcium intake was below the recommended levels in pediatric patients with OI. These findings are important for the management of OI subjects.

Serum Sclerostin Levels Are Decreased in Adult Patients With Different Types of Osteogenesis Imperfecta

There are no specific biochemical bone markers available for osteogenesis imperfecta (OI), and the role of sclerostin as a key regulator of bone formation in OI is unknown. We aimed to evaluate the role of sclerostin and its association with bone turnover markers as well as body composition parameters in adult patients with different types of OI. This was a case-control study in 27 adult patients and 50 healthy age- and gender-matched controls. Serum sclerostin levels and bone turnover markers including serum osteocalcin, amino terminal propeptide of type I procollagen, and CrossLaps as well as body composition parameters were determined in mild OI stage I (OI-I) and moderate-severe OI stages III-IV (OI-III-IV), according to Sillence classification. Data were compared with healthy controls. Sclerostin levels were significantly lower in OI-I (19.9 ± 10.9 pmol/L; P < .001) and OI-III-IV (13.3 ± 10.0 pmol/L; P < .001) compared with healthy adults (45.3 ± 14.9 pmol/L), even after adjustment for age, sex, bone mineral content, and body mass index. CrossLaps and PTH were significantly lower in OI-I (0.197 ± 0.15 ng/L; P = .007 and 33.7 ± 19.1 pg/L; P = .033, respectively) and OI-III-IV (0.221 ± 0.18 ng/L; P = .039, and 27.9 ± 14.7 pg/L; P = .001, respectively) than in healthy controls (0.322 ± 0.15 ng/L and 45.0 ± 16.6 pg/L). Amino-terminal propeptide of type I procollagen was below the reference range for OI-I and OI-III-IV. Patients with OI were shorter and lighter and had a decreased bone mineral content (P < .001) but similar fat distribution and lean body mass, compared with controls. Serum sclerostin levels were not related to any bone marker except osteocalcin, the number of prevalent fractures, or body composition readings. Decreased sclerostin levels in OI might reflect a down-regulation or negative feedback mechanism to prevent further bone loss.

The Severity of Osteogenesis Imperfecta and Type I Collagen Pattern in Human Skin as Determined by Nonlinear Microscopy: Proof of Principle of a Diagnostic Method

BackgroundThe confirmatory diagnosis of Osteogenesis Imperfecta (OI) requires invasive, commonly bone biopsy, time consuming and destructive methods. This paper proposes an alternative method using a combination of two-photon excitation fluorescence (TPEF) and second-harmonic generation (SHG) microscopies from easily obtained human skin biopsies. We show that this method can distinguish subtypes of human OI.Methodology/Principal FindingsDifferent aspects of collagen microstructure of skin fresh biopsies and standard H&E-stained sections of normal and OI patients (mild and severe forms) were distinguished by TPEF and SHG images. Moreover, important differences between subtypes of OI were identified using different methods of quantification such as collagen density, ratio between collagen and elastic tissue, and gray-level co-occurrence matrix (GLCM) image-pattern analysis. Collagen density was lower in OI dermis, while the SHG/autofluorescence index of the dermis was significantly higher in OI as compared to that of the normal skin. We also showed that the energy value of GLCM texture analysis is useful to discriminate mild from severe OI and from normal skin.Conclusions/SignificanceThis work demonstrated that nonlinear microscopy techniques in combination with image-analysis approaches represent a powerful tool to investigate the collagen organization in skin dermis in patients with OI and has the potential to distinguish the different types of OI. The procedure outlined in this paper requires a skin biopsy, which is almost painless as compared to the bone biopsy commonly used in conventional methods. The data presented here complement existing clinical diagnostic techniques and can be used as a diagnostic procedure to confirm the disease, evaluate its severity and treatment efficacy.

Radiographic features of osteogenesis imperfecta

BackgroundOsteogenesis imperfecta (OI), commonly called “brittle bone disease”, is a genetic disorder characterised by increased bone fragility and decreased bone density due to quantitative and/or qualitative abnormalities of type I collagen. Different types of OI exist, from mild to severe; they may lead to death, multiple bone fractures, skeletal deformity and short stature.MethodsSevere cases are usually diagnosed before birth and may incite the parents to choose therapeutic abortion, whereas milder cases are much more difficult to diagnose and may be sometimes confused with non-accidental injury (NAI) (“child abuse”) in young children. Whatever the degree of severity, conventional radiography still remains the mainstay in diagnosing OI.ResultsThe prognosis of this disorder has changed in the last few years thanks to biphosphonate therapy.ConclusionThe aim of this pictorial review is to illustrate the radiographic manifestations of OI, including in children receiving biphosphonates, and to outline specific patterns that help differentiate OI from NAI when necessary.Key Points• The main radiographic features of OI are osteopenia, bone fractures and bone deformities.• Some radiographic features depend on the type of OI or may be encountered with biphosphonates.

English

Introduction Osteogenesis imperfecta (OI) is a human genetic disorder of increased bone fragility and low bone mass. Severity varies widely, ranging from intrauterine fractures and perinatal lethality to very mild forms without fractures. There is variable association of typical extra skeletal manifestations with the disorder, including blue sclera, dentinogenesis imperfecta, hyperlaxity of ligaments and skin, hearing impairment and the presence of Wormian bones on skull radiography1. The most widely used classification of OI distinguished four clinical types2. The most relevant clinical characteristic of all OI t-ypes is bone fragility, the severity of which increases in the order type I < type IV < type III < type II. It is now w-idely recognized that there may be m-any more types of OI than those class-ified by Sillence et al. Some forms of congenital brittle bones have been considered OI and have been added as types V, VI and VII3–5. There is still no perfect consensus about the definition of OI. Plotkin recently proposed defining OI as syndromes resulting from mutations in either COL1A1 or COL1A2 genes, and to group all other syndromes with congenital brittle bones as ‘syndromes resembling OI (SROI)’, pending the identification of their causal mutations6. In the new Nosology and Classification of the Genetic Skeletal disorders7, OI is declined in several forms depending on the severity of the phenotype, whatever the mode of the transmission or the gene involved. We first review the genetic mutations implicated in the eight different types of OI, then, the craniofacial consequences of OI mutations are summarized. * Corresponding author Email: mgoldberg.goldberg004@gmail.com

Femoral geometric parameters and BMD measurements by DXA in adult patients with different types of osteogenesis imperfecta

Osteogenesis imperfecta (OI) is an inherited disorder characterized by increased bone fragility with recurrent fractures that leads to skeletal deformities in severe cases. Consequently, in most OI patients, the hip is the only reliable measuring site for estimating future fracture risk. The aim of the study was to assess the applicability of hip structure analysis (HSA) by DXA in adult patients with osteogenesis imperfecta. We evaluated bone mineral density (BMD) and hip structure analysis (HSA) by DXA, including cross-sectional area (CSA), cross-sectional moment of inertia (CSMI) and femoral strength index (FSI) in 30 adult patients with different types of OI and 30 age-matched healthy controls (CO). The OI total group (OI-tot) was divided into two subgroups: the mild OI I group (OI-I) and the more severe OI III and IV group (OI-III-IV). The mean neck BMD of OI-I and OI-III-IV were significantly lower compared to CO (-15.9 %, p < 0.005 and -37.5 %, p < 0.001 respectively). Similar results were observed at trochanter and total hip. CSA and the CSMI value were significantly lower for OI-I (-23.2 %, p < 0.001) and OI-III-IV (-45.9 %, p < 0.001) in comparison to CO. In addition, significant differences were found between the mild OI-I and the severe OI-III-IV group (-29.6 %, p < 0.05). FSI was significantly decreased in the OI-III-IV (25.7 %, p < 0.05) in comparison to the CO. Furthermore, significant correlations between BMD and HSA and between HSA and height and weight were found in osteogenesis imperfecta and controls. BMD measurement in osteogenesis imperfecta patients is very critical. The combination of BMD and geometric structural measurements at the hip in osteogenesis imperfecta patients may represent an additional helpful means in estimating bone strength and fracture risk.

Genotype–phenotype correlations and pharmacogenetic studies in 140 Swedish families with osteogenesis imperfecta

Objective: Osteogenesis imperfecta (OI) is a rare heterogeneous disease of connective tissue leading to varying degrees of bone fragility. The worst form (type II) is peri-natally lethal whereas the mildest form (type I) is compatible with a normal life span. Over 1000 mutations causing OI have been described in the genes encoding collagen type I. As COL1A1 and COL1A2 are large genes, there are still many codon positions where no mutations have been reported and only a fraction of theoretically possible glycine substitutions have been described. In this study the spectrum of mutations causing OI in Sweden will be investigated and genotype–phenotype correlations as well as pharmacogenetics will be studied. Method: All patients with OI cared for at the Uppsala Osteoporosis Unit (Uppsala University Hospital) or Astrid Lindgren's Paediatric Hospital (Karolinska Institutet, Stockholm) were offered to enter the study. Patients from 140 unrelated families with OI accepted participation; 77 type I, 34 type IV, 20 type III, 5 without previous diagnosis and 4 with unclear OI type. Extensive clinical data is currently being collected on enrolled patients. Exons and flanking intron sequences of COL1A1 and COL1A2 are being sequenced in these families. Results: So far 133/140 families have been completely analyzed and in 27 no mutation was found. A total of 120 mutations have been detected, of which 104 are of a typical OI-type. In COL1A1 73 mutations were found and in COL1A2 31 mutations were noted. In 7 families 2 mutations were present, but only one of these was a typical OI-causing mutation. To date 16 amino acid changing mutations that were not of a typical OI-causing type have been noted and the majority of these have an unclear significance. Calculations of delta BMD Z-score response to bisphosphonate treatment did not show a difference in treatment response between groups with different types of OI or between patients with OI type I due to a qualitative vs. a quantitative collagen type I defect. Conclusion: The spectrum of mutations causing OI described in this Swedish cohort is of the expected type, with the exception of the amino acid changing mutations. It is notable that in seven families two separate mutations were identified. Calculations do not support a mutation dependent response to bisphosphonate treatment.

A scoring system for the assessment of clinical severity in osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and fractures. Patients with OI have clinical features that may range from mild symptoms to severe bone deformities and neonatal lethality. Numerous approaches for the classification of OI have been published. The Sillence classification is the most commonly used. In this study, we aimed at developing a more refined sub-classification by applying a proposed scoring system for the quantitative assessment of clinical severity in different types of OI. This study included 43 patients with OI. Clinical examination and radiological studies were conducted for all patients. Cases were classified according to the Sillence classification into types I-IV. The proposed scoring system included five major criteria of high clinical value: number of fractures per year, motor milestones, long bone deformities, length/height standard deviation score (SDS), and bone mineral density (BMD). Each criterion was assigned a score from 1 to 4, and each patient was marked on a scale from 1 to 20 according to these five criteria. Applying the proposed clinical scoring system showed that all 11 patients with Sillence type I (100%) had a score between 6 and 10, denoting mild affection. The only patient with Sillence type II had a score of 19, denoting severe affection. In Sillence type III, 7 patients (31.8%) were moderately affected and 15 patients (68.2%) were severely affected. Almost all patients with Sillence type IV (88.9%) were moderately affected. Applying the proposed scoring system can quantitatively reflect the degree of clinical severity in OI patients and can be used in complement with the Sillence classification and molecular studies.

Orthognathic bimaxillary surgery in two patients with osteogenesis imperfecta and a review of the literature

Orthognathic surgery in patients with osteogenesis imperfecta is rare. Most cases result in a successful outcome with stable and good occlusion. Two patients with, probably severe types III and IV, and malocclusion class III with retrognathic maxilla and prognathic mandible, were treated with orthodontic treatment and bimaxillary surgical correction. The surgical outcome and follow up are presented together with a review of published cases of orthognathic surgery in patients with different types of osteogenesis imperfecta. The authors conclude that it is possible to perform combined orthodontic and orthognathic surgery in patients with osteogenesis imperfecta despite the greater risk of complications. The treatments were successful with follow up times of 5-6 years.