Osteogenesis Imperfecta Patients Research Articles

Adapting to Adulthood: A Review of Transition Strategies for Osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI), known as "brittle bone disease," presents a rare genetic disorder characterized by bone fragility, often accompanied by skeletal deformities and extraskeletal complications. OI is primarily associated with collagen type I defects, responsible for the syndromic nature of the disease affecting a broad range of tissues. As such, its multisystemic complexity necessitates multidisciplinary care approaches in all patient life stages. OI treatment remains largely supportive, commonly including bisphosphonates and orthopedic surgeries, which show promise in children. Although rehabilitation programs for children exist, guidelines for adult care and especially the transition from pediatric to adult care, are lagging behind in OI care and research. The current systematic review summarizes the literature on OI patient pediatric to adult care transition experiences and compares OI transition approaches to other chronic diseases. The review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Systematic searches were conducted across multiple databases. Search terms encompassed synonyms and closely related phrases relevant to "OI" and "Transition to adult care". The initial screening involved the evaluation of article titles, followed by a thorough review of abstracts to assess relevance for the purpose of the current review. Programs aimed at easing the transition from pediatric to adult OI care necessitate a multifaceted approach. Collaborative efforts between different medical disciplines including pediatricians, endocrinologists, orthopedics, cardiology, pulmonology, ophthalmology, otolaryngologists, maxillofacial specialists, psychologists and medical genetics, are crucial for addressing the diverse needs of OI patients during this critical life phase. Comprehensive education, readiness assessments, personalized transition plans, and further follow-up are essential components of a structured transition framework. Further research is warranted to evaluate the feasibility and efficacy of sequential stepwise transition systems tailored to individuals with OI.

Cone Beam Computed Tomography Evaluation of Socket Healing After Third Molar Germ Extraction: A Case Series Study Including Adolescents with Osteogenesis Imperfecta Type I Treated with Bisphosphonates and Healthy Age-Matched Subjects

Bisphophonates (BPs) are widely used in Osteogenesis imperfecta (OI). Cone Beam Computed Tomography (CBCT) shows clinical usefulness in evaluating impacted teeth and adjacent structure relationships, extraction socket healing, bone mineral density (BMD) and BP-related jaw osteonecrosis (BRONJ). The aim of the study was to compare alveolar sockets and the adjacent bone area before and after third molar extraction in OI type I (OI-I) adolescents treated with BPs and age-matched healthy subjects (HSs) by CBCT. Methods: Five adolescents with genetically proven OI-I treated with BPs (three males and two females, mean age: 15.2 ± 1.78 years) and four age-matched healthy subjects (two males and two females, mean age: 15.5 ± 1.29 years) were included in this study. Eight Regions of Interest (ROIs) were evaluated: between 3.7 and 3.8 (ROI-1) and 4.7 and 4.8 (ROI-2); after 3.8 (ROI-3) and 4.8 (ROI-4); alveolar sockets 3.8 (ROI-5) and 4.8 (ROI-6); left (ROI-7) and right (ROI-8) cortical bone. Results: ROIs were evaluated on both sides of the mandible for all the subjects except one OI patient in which CBCTs were performed pre- and-post third molar extraction only on the right side. CBCT was performed 12.8 ± 4.60 and 11.5 ± 2.51 days before and 8.0 ± 1.41 and 7.7 ± 0.5 months after extraction in OI-I and HSs, respectively. BPs were discontinued 62.0 ± 36.5 months before extraction. None of the OI-I adolescents developed BRONJ. Statistically significant greater values were observed in OI-I for ROI-1 and -2 (p = 0.0464), ROI-3 and -4 (p = 0.0037) and ROI-7 and -8 (p = 0.0079) after extraction. Conclusions: This descriptive study confirms that, in OI-I adolescents treated with BPs, third molar extraction is safe, and socket healing occurs properly. In addition, it demonstrates that, if the same device and imaging conditions are used and comparisons to predetermined standard values are avoided, CBCT can be used to monitor BMD changes. The significant greater BMD observed for different ROIs in OI-I could reflect the increased secondary mineralization related to the BP-dependent reduction in bone turnover.

Outcome of Locking Plate Fixation Adjunctive to Intramedullary Rodding in Osteogenesis Imperfecta Patients.

An intramedullary rodding is the preferred fixation method in limb stabilization of OI patients. However, the intramedullary rod may not provide adequate fixation and rotational stability, especially in adolescents and adults. The incorporation of adjunctive plate fixation alongside intramedullary rodding has been introduced to enhance this stability, although its complications remain insufficiently understood. The goal of this study was to explore the outcomes of adjunctive plating in conjunction with intramedullary rodding for limb stabilization in OI patients, emphasizing the complications related to the plates during the healing phase and following plate removal. This retrospective study examined 74 limb segments from 45 patients with OI who underwent intramedullary rodding and adjunctive plating from 2008 to 2022. Criteria for inclusion comprised surgical treatment followed by a minimum of 2 years of follow-up or complication before that time point. The need for adjunctive plating arose from inadequate fixation, rotational instability, and persistent cortical gaps with intramedullary rodding alone. Medical records and follow-up radiographs were reviewed to assess the healing of the target lesion and any complications. The study encompassed 30 males and 15 females, ranging in age from 4 to 38 years, with 51 femoral and 23 tibial segments receiving treatment. Union was successfully achieved in 63 cases (85.3%), with an average union time of 14.4 months. Plates were subsequently removed in 62 cases after an average duration of 18.0 months. Before union, 11 revision surgeries were performed in 4 peri-implant fractures, 1 screw pull-out, and 6 failure of union. One sustained peri-implant fracture after the union. Following the removal of plates, complications included 10 refractures at screw sites, 3 progressive angulations at the previously targeted lesions, and 1 osteomyelitis. Kaplan-Meier analysis revealed that half of the refractures occurred within 1.8 years postplate removal. The overall complication showed borderline significance (P=0.056) among age groups. All the plate-related complications occurred at the diaphyseal, unicortical screws. Plate fixation, when used as an adjunct to intramedullary rodding, effectively stabilizes limbs in OI patients when intramedullary rods alone are inadequate. Nevertheless, given the significant risks associated with plate-related complications, adjunctive plating should be employed selectively only in instances where the union is unlikely to be achieved with intramedullary rodding alone. Level IV-case series.

Correlative Raman spectroscopy and electron microscopy identifies glycogen rich deposits correlated with local structural defects in long bones of type IV osteogenesis imperfecta patients

Osteogenesis imperfecta (OI) is a genetic bone disease occurring in approximately 1 in 10,000 births, usually as a result of genetic mutation. OI patients suffer from increased fracture risk and - depending on the severity of the disease - deformation of the limbs, which can even lead to perinatal death.Despite extensive studies, the way in which the genetic mutation is translated into structural and compositional anomalies of the tissue is still an open question. Different observations have been reported, ranging from no structural (or chemical) differences to completely chaotic bone structure and composition.Here, we investigated bone samples from two adolescent OI-IV patients, focusing on the bone structure and chemistry in naturally occurring fractures. The exposed fracture plane allows the investigation of the structure and composition of the weakest bone plane. We do so by combining scanning electron microscopy (SEM) imaging with chemical information from Raman microscopy.The exposed fracture planes show different regions within the same tissue, displaying normal osteonal structures next to disorganized osteons and totally disordered structures, while the collagen mineralization in all cases is similar to that of a healthy bone.In addition, we also detected significant amounts of depositions of glycogen-rich, organic, globules of 250-1000nm in size. These depositions point to a role of cellular disfunction in the disorganization of the collagen in qualitative OI.Overall, our results unite multiple, sometimes contradicting views from the literature on qualitative OI.

Zebrafish Models for Skeletal and Extraskeletal Osteogenesis Imperfecta Features: Unveiling Pathophysiology and Paving the Way for Drug Discovery.

In the last decades, the easy genetic manipulation, the external fertilization, the high percentage of homology with human genes and the reduced husbandry costs compared to rodents, made zebrafish a valid model for studying human diseases and for developing new therapeutical strategies. Since zebrafish shares with mammals the same bone cells and ossification types, it became widely used to dissect mechanisms and possible new therapeutic approaches in the field of common and rare bone diseases, such as osteoporosis and osteogenesis imperfecta (OI), respectively. OI is a heritable skeletal disorder caused by defects in gene encoding collagen I or proteins/enzymes necessary for collagen I synthesis and secretion. Nevertheless, OI patients can be also characterized by extraskeletal manifestations such as dentinogenesis imperfecta, muscle weakness, cardiac valve and pulmonary abnormalities and skin laxity. In this review, we provide an overview of the available zebrafish models for both dominant and recessive forms of OI. An updated description of all the main similarities and differences between zebrafish and mammal skeleton, muscle, heart and skin, will be also discussed. Finally, a list of high- and low-throughput techniques available to exploit both larvae and adult OI zebrafish models as unique tools for the discovery of new therapeutic approaches will be presented.

A Single-Center Retrospective Cohort Study of Genotype–Phenotype Correlation of Osteogenesis Imperfecta in UAE

Abstract Background Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterized by skeletal fragility. Patients with OI suffer recurrent fractures, limb deformities, and kyphoscoliosis. Multiple extraskeletal manifestations might also be present. Autosomal dominant variants in the COL1A1 or COL1A2 genes account for approximately 90% of cases. Objective The aim of the study was to describe the variant spectrum and genotype–phenotype correlations in patients with OI seen in Tawam Hospital in the UAE. Methods The authors conducted a retrospective chart review for all patients with OI assessed by geneticists at Tawam Hospital from January 2010 to December 2021. They retrieved each patient's baseline characteristics, detailed history and physical examination, laboratory, imaging, and genetic results. Results A total of 40 patients with OI were found and included in this study. The majority (80%) were Emirati, and 57.5% were females. Consanguinity was documented in 24.3%. Thirty-seven patients (92.5%) had positive molecular testing; 28 patients (75.7%) had an autosomal dominant inheritance, and 9 patients (24.3%) had an autosomal recessive inheritance. The majority had missense variants. Four variants were novel. A high prevalence of pathogenic variants in the COL1A1 gene (57%) was found. Patients with variants in the LEPRE1 gene had early and severe phenotypes, while patients with variants in the TMEM38B gene had variable presentations. The majority of patients (85%) had skeletal phenotypes: fractures, bone deformity, scoliosis, and osteopenia. Extraskeletal phenotypes included blue sclera, dentinogenesis imperfecta, hearing loss, and dysmorphic features. Conclusion This study reports the genotype–phenotype correlation of OI patients from the UAE. A high prevalence of pathogenic variants in the COL1A1 gene with OI type IV phenotype was found. Further multicenter more extensive studies are recommended.

Voices of Parent-Carers Navigating the Care for Children With Osteogenesis Imperfecta.

Parent-carers of children with rare diseases, including osteogenesis imperfecta (OI), represent a vulnerable and largely invisible population. Despite existing research on familial OI caregiving, the unique experiences, perspectives, and feelings of parent-carers remain poorly understood, prompting this study to delve into these aspects through the subjective lens of voices. The aim of this study was to explore the voices of parent-carers in navigating the complexities of pediatric OI care. Employing a narrative design informed by social constructionism, 15 parent-carers of pediatric OI patients were purposively sampled from a tertiary hospital in Shandong Province, China, between May and August 2021. Individual face-to-face interviews were conducted, and data were analyzed using the voice-centered relational approach followed by thematic analysis. Parent-carers' narratives revealed two overarching themes. The first theme, "the all-encompassing caregiver role," highlighted the profound internal transformation parent-carers underwent, with three key aspects of experiences: "the centrality of care," "life on hold," and "guarded silence." The second theme, "navigating ambivalence," captured the complex psycho-emotional journey of parent-carers as they balanced denial and acceptance, experienced the burden and responsibility of caregiving, navigated uncertainty with hope, and sought to normalize the care recipients' experiences while acknowledging their unique needs. Our findings suggest the need for developing tailored support strategies that address not only practical challenges but also the psychosocial dimensions of caregiving, to effectively assist and empower this marginalized carer population.

A Successful Laparoscopic Appendectomy for an Adult Male Patient with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetic connective tissue disease defined by the loss of bone mass and density, which makes the bones more brittle and more likely to fracture over time. Bone deformity and articular instability are the subsequent symptoms. This 25-year-old man had malformed lower limbs and trouble walking due to OI and dwarfism. He arrived complaining of fever, nausea, vomiting and diffuse peri-umbilical pain. During ultrasonography a blinded, oedematous lobe formation containing an appendicolith was discovered. Acute suppurative appendicitis was diagnosed, necessitating a laparoscopic appendectomy. Because the patient had previously undergone general anaesthesia, anaesthesia was thought to be attainable. Pneumoperitoneum and a 10 mm optical port inserted into the umbilicus were used in the surgical procedure. A diagnostic laparoscopy revealed faecolith obstruction and an acute suppurative appendicitis. After an hour, a laparoscopic appendectomy was performed effectively with little blood loss. Without experiencing any difficulties because of the surgery position, the patient was discharged. We present a case of an OI dwarf patient with acute suppurative appendicitis. It highlights the possibility of performing laparoscopic surgery in general and a laparoscopic appendectomy in particular on OI patients. In rare instances involving OI, laparoscopic surgery in general and laparoscopic appendectomy in particular are practical and efficient options.

Analyses of Osteogenesis Imperfecta in South Korea Using the Nationwide Health Insurance Service Claim Data: A Propensity Score-Matched Study.

Osteogenesis imperfecta (OI) is the most common inherited form of bone fragility and includes a heterogeneous group of genetic disorders that most commonly result from defects associated with type I collagen. Although genetic analyses have been developed, nationwide research on the incidence and associated fractures in OI is lacking. This study aimed to investigate the patterns of OI prevalence, incidence, fracture rate, etc. in South Korea using National Health Insurance Service (NHIS) claims data. We found 1596 patients newly diagnosed with OI between March 2002 and February 2020. We evaluated the incidence, prevalence, and history of fractures, fracture site, prescription of anti-osteoporosis drugs, etc. To compare medical costs, fracture rates, and scoliosis rates, we created a control group comprising patients without OI using 1:1 propensity score matching. The prevalence of OI increased slightly each year, with an annual incidence of 20.20 per 100,000 live births. Mean fracture frequency in OI patients was 17 (2-32) times per patient and the most frequent fracture site was the lower leg. A total of 21.4% patients were prescribed anti-osteoporosis drugs, and the most popular drug was pamidronate. After 1:1 propensity score matching, in terms of scoliosis, OI patients had a 3.91 times higher prevalence of scoliosis than in healthy patients which was statistically significant. The sum of medical care expenses for patients with OI was 3.5 times higher than that for patients without OI. We identified nationwide trends in OI occurrence, fractures, and medication use. This study also highlighted the real-world data of scoliosis and medical costs compared to the control group.

The vitamin D status in a Chinese osteogenesis imperfecta population and its correlation with bone metabolic markers and bone density.

Studies on the baseline vitamin D levels in osteogenesis imperfecta (OI) patients before medication are scarce. This study assessed the vitamin D status of a population with OI at both the overall level and within different age groups. It correlated baseline 25-hydroxyvitamin D (25(OH)D) levels with other bone-related factors, biochemical markers, and bone density. We collected 25(OH)D levels from 95 OI patients in East China (59 under 18 years old and 36 over 18 years old). Postmenopausal women and men over 50 years old are excluded. Measurements included body indicators, biochemical markers, and bone mineral density (BMD) assessed by Dual-energy X-ray absorptiometry (DXA). Data analysis was performed using SPSS 26.0. In the overall population, among those under 18 years old, and among those over 18 years old, 87.4, 83.1, and 94.4%, respectively, were vitamin D deficient (<30 ng/mL), while 47.4, 40.7, and 58.3% had vitamin D deficiency (<20 ng/mL), respectively. In the overall population and among those under 18 years old, serum 25(OH)D levels were negatively correlated with age and parathyroid hormone (PTH) levels, and 25(OH)D levels (<10 ng/mL, 10-20 ng/mL, 20-30 ng/mL, >30 ng/mL) showed a negative correlation with BMI. In OI patients under 18 years old, serum 25(OH)D was negatively correlated with serum β-CTX levels. In adult male OI population, 25(OH)D levels were negatively correlated with OI severity (Type I, IV, III). No statistically significant correlation was found between 25(OH)D levels and BMD Z-scores. This study on OI in East China reveals significant vitamin D insufficiency and deficiency in baseline levels among pediatric, adolescent and adult OI patients. It assesses the correlation of 25(OH)D levels with various influencing factors, providing crucial insights into understanding the impact of OI on vitamin D status across different age groups and aiding in better clinical management of OI patients.

Orofacial Features, Oral Health-Related Quality of Life, and Exposure to Bullying in Osteogenesis Imperfecta: A Cross-Sectional Study.

Osteogenesis imperfecta (OI) is a rare genetic disease that is responsible for bone fragility, but also for dental malocclusions and dentinogenesis imperfecta (DI). The aim of this study was to assess whether the severity of dental malocclusion influenced the oral health-related quality of life (OHRQoL) and exposure to bullying in a paediatric OI population compared with a control group. Dental and occlusal characteristics were noted during oral and radiographic examination. The severity of malocclusion was assessed using the PAR index. P-CPQ, COHIP(34), and BCS-A questionnaires were used to evaluate, respectively, externally and self-perceived OHRQoL and bullying. We included 39 patients with a mean age of 11.3 (±4.8 SD) in the OI group, and 45 patients with a mean age of 12.3 (±3.2 SD) in the control group. There were no significant differences between the two groups in terms of occlusal vertical and transverse dimensions. Patients with severe OI, presenting with bone fractures, bones deformities, and short stature, had significantly more anterior (p < 0.05) and posterior openbites (p < 0.05) and more DI (p < 0.05) compared to patients who had moderate or mild OI. Self-perceived OHRQoL was negatively impacted by the disease (p = 0.01), particularly in the domains of oral health (p < 0.05) and self-image (p < 0.001), but not by its severity. Exposure to bullying did not differ significantly between the two groups, although more patients with OI reported being teased (21.4% face to face and 7.1% online vs. 14.6% and 2.4% in the control group). Interventions for dental malocclusion and oral health in OI patients would help to improve their quality of life and self-image.

Effectiveness of whole exome sequencing analyses in the molecular diagnosis of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. This study aimed to investigate the molecular genetic etiology and to determine the relationship between genotype and phenotype in OI patients with whole exome sequencing (WES). Multiplex-Ligation dependent Probe Amplification (MLPA) analysis of COL1A1 and COL1A2 and WES were performed on cases between the ages of 0 and 18 whose genetic etiology could not be determined before using a targeted next-generation sequencing panel, including 13 genes (COL1A1, COL1A2, IFITM5, SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, SP7, BMP1, MBTPS2, PLOD2) responsible for OI. Twelve patients (female/male: 4/8) from 10 different families were included in the study. In 6 (50 %) families, consanguineous marriage was noted. The clinical typing based on Sillence classification; 3 (25 %) patients were considered to be type I, 7 (58.3 %) type III, and 2 (16.7 %) type IV. Deletion/duplication wasn't detected in the COL1A1 and COL1A2 genes in the MLPA analysis of the patients. Twelve patients were molecularly analyzed by WES, and in 6 (50 %) of them, a disease-causing variant in three different genes (FKBP10, P3H1, and WNT1) was identified. Two (33.3 %) detected variants in all genes have not been previously reported in the literature and were considered deleterious based on prediction tools. In 6 cases, no variants were detected in disease-causing genes. This study demonstrates rare OI types' clinical and molecular features; genetic etiology was determined in 6 (50 %) 12 patients with the WES analysis. In addition, two variants in OI genes have been identified, contributing to the literature.

Functional Mobility Scale and Scoliosis Degree before and after Zoledronate Therapy in Children with Osteogenesis Imperfecta

Abstract Background Intravenous zoledronate, has been indicated for the treatment of Osteogenesis imperfecta (OI). It is a heritable disorder that causes bone fragility. The purpose of this study was to evaluate its effect on functional mobility scale and scoliosis degree on children with OI. Methods and Results This observational study was conducted on 28 OI patients (12 boys &amp; 16 girls) aged 1.3-7.15years. All parameters were evaluated at Pediatric Endocrinology clinic, Children’s Hospital, Ain Shams University. Treatment was started with zoledronate dose 0.05 mg/kg every 6 months. Children less than 3 years of age received intravenous Zoledronate at a dose of 0.025 mg/kg per dose every 6 months with a maximum dose of 2 mg, while children above 3 years old received 0.05 mg/kg/dose every 6 months with a maximum dose of 4 mg. FMS and scoliosis degree using cobb anglewere evaluated before and after zoledronate therapy. Patients showed highly significant improvement in FMS. Patients with mild and moderate degree of scoliosis showed a non significant improvement in the degree of scoliosis while patients with severe scoliosis didn’t show any statistically significant difference. Conclusion Our study showed that intravenous zoledronate treatment, given once every 6 months, is an effective mode of treatment in OI children. It was associated with improvement in FMS. Longer follow-up is necessary to monitor the effect of treatment on degree of scoliosis by cobb angle.

Surgical treatment of scoliosis in patients with osteogenesis imperfecta: a single institution case series.

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by skeletal deformities, bone fragility, and spinal complications. Various studies' insights underscored the impact of scoliosis on pulmonary function, positive outcomes with spinal fusion, and improved functional abilities post-surgery. However, partial loss of correction remains inevitable. This study examines six surgically treated OI patients with scoliosis. Surgical intervention using a posterior approach with pedicle screws and hooks aimed to correct spinal deformities. Preoperative, postoperative, and follow-up radiological assessments were conducted, revealing significant reductions in scoliotic angles post-surgery. Complications included infections and proximal junctional kyphosis requiring revision surgeries. Despite the challenges posed by poor bone quality and implant stability, no implant failures occurred in this series. Ponte osteotomies at the apex of deformity aided in corrective maneuvers. Surgical treatment of scoliosis in patients affected by OI is challenging and may be associated with perioperative and postoperative complications. Ponte osteotomy may improve the correction and reduce necessary force at the time of correction.

Changes in serum bone turnover markers and bone mineral density Z-score in children with osteogenesis imperfecta after zoledronic acid treatment.

The study aimed to investigate the changes in the levels of serum bone turnover markers (BTMs) and bone mineral density (BMD) Z-score in pediatric patients with osteogenesis imperfecta (OI) after intravenous bisphosphonate therapy and their association with age and estimated glomerular filtration rate (eGFR). This retrospective study analyzed data from 10 pediatric OI patients treated with intravenous zoledronic acid for over 1 year. Patients' clinical data were collected. The levels of BTMs and BMD Z-score before and after zoledronic acid treatment were analyzed. Significant improvement in BMD Z-score was observed after 6 and 12 months of treatment compared to baseline (all p < 0.05). The N-terminal propeptide of type I procollagen (PINP) levels decreased over time (all p < 0.05), indicating that zoledronic acid treatment decreased bone turnover. The levels of beta-C-terminal telopeptide of type I collagen remained stable after treatment. No correlation was found between PINP level and age, eGFR, or BMD (all p > 0.05). Bisphosphonate treatment can improve BMD and decrease bone turnover (indicated by decreased levels of PINP) in pediatric OI patients. PINP may serve as an independent indicator for monitoring the efficacy of bisphosphonate treatment in pediatric OI patients, particularly in those under the age of 6, where standardized BMD Z-score criteria are lacking.

Prevalence, number of fractures, and hospital characteristics among the pediatric population with osteogenesis imperfecta: results from the nationwide registry of Türkiye.

Osteogenesis imperfecta is a rare connective tissue disorder with an estimated number of 4-20 cases per 100 000 inhabitants. Although the prevalence differs among regions, there are only a few number of national registry studies published previously. The aim of this study was to determine the prevalence of osteogenesis imperfecta among the pediatric age group in Türkiye, together with the patient and hospital characteristics. Via the e-health database of the Turkish Ministry of Health, we collected and retrospectively evaluated the medical records of the patients who were under 18 years of age with the diagnosis of osteogenesis imperfecta between 2016 and 2022. Total number of fractures, treatment modalities, and the hospital characteristics were also recorded. Two thousand seven hundred forty patients were extracted with a mean age of 9.77 ± 4.81 years. The prevalence of osteogenesis imperfecta in Türkiye among the pediatric population was calculated as 11.6 per 100 000 individuals. The median annual incidence was 31.5 per 100 000 live births between 2016 and 2022. There were 17.4 hospital admissions per patient per year. The mean age at the time of in-hospital mortality was 4.08 ± 5.03 years. The fracture rate per patient per year was 0.56 and conservative treatment was the most commonly preferred modality for all ages. This is the first registry-based nationwide study of osteogenesis imperfecta patients in Türkiye, providing important characteristics of the disease. Together with the help of the ongoing development of national health database systems, precision in patient identification would yield substantial benefits in terms of management of osteogenesis imperfecta.

Unraveling the Link of Altered TGFβ Signaling with Scoliotic Vertebral Malformations in Osteogenesis Imperfecta: A Comprehensive Review.

Osteogenesis Imperfecta (OI) is a genetic disorder caused by mutations in genes responsible for collagen synthesis or polypeptides involved in the formation of collagen fibers. Its predominant skeletal complication is scoliosis, impacting 25 to 80% of OI patients. Vertebral deformities of the scoliotic curves in OI include a variety of malformations such as codfish, wedged-shaped vertebrae or platyspondyly, craniocervical junction abnormalities, and lumbosacral spondylolysis and spondylolisthesis. Although the precise pathophysiology of these spinal deformities remains unclear, anomalies in bone metabolism have been implicated in the progression of scoliotic curves. Bone Mineral Density (BMD) measurements have demonstrated a significant reduction in the Z-score, indicating osteoporosis and a correlation with the advancement of scoliosis. Factors such as increased mechanical strains, joint hypermobility, lower leg length discrepancy, pelvic obliquity, spinal ligament hypermobility, or vertebrae microfractures may also contribute to the severity of scoliosis. Histological vertebral analysis has confirmed that changes in trabecular microarchitecture, associated with inadequate bone turnover, indicate generalized bone metabolic defects in OI. At the molecular level, the upregulation of Transforming Growth factor-β (TGFβ) signaling in OI can lead to disturbed bone turnover and changes in muscle mass and strength. Understanding the relationship between spinal clinical features and molecular pathways could unveil TGFβ -related molecular targets, paving the way for novel therapeutic approaches in OI.

Molecular Genetic Diagnosis with Targeted Next Generation Sequencing in a Cohort of Turkish Osteogenesis Imperfecta Patients and Their Genotype-phenotype Correlation.

Osteogenesis imperfecta (OI) is a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. This study aimed to investigate the molecular genetic etiology and determine the relationship between genotype and phenotype in OI patients with targeted next-generation sequencing (NGS). In patients with OI, a targeted NGS analysis panel (Illumina TruSight One) containing genes involved in collagen/bone synthesis was performed on the Illumina Nextseq550 platform. Fifty-six patients (female/male: 25/31) from 46 different families were enrolled in the study. Consanguinity between parents was noted in 15 (32.6%) families. Clinically according to Sillence classification; 18(33.1%) patients were considered to type I, 1(1.7%) type II, 26(46.4%) type III and 11(19.6%) type IV. Median body weight was -1.1 (-6.8, - 2.5) SDS, and height was -2.3 (-7.6, - 1.2) SDS. Bone deformity was detected in 30 (53.5%) of the patients, while 31 (55.4%) were evaluated as mobile. Thirty-six (60.7%) patients had blue sclera, 13 (23.2%) had scoliosis, 12 (21.4%) had dentinogenesis imperfecta (DI), and 2 (3.6%) had hearing loss. Disease-causing variants in COL1A1 and COL1A2 genes were found in 24 (52.1%) and 6 (13%) families, respectively. In 8 (17.3%) of the remaining 16 (34.7%) families, the NGS panel revealed disease-causing variants in three different genes (FKBP10, SERPINF1, and P3H1). Nine (23.6%) of the variants detected in all investigated genes were not previously reported in the literature and were classified to be pathogenic according to ACMG guidelines pathogenity scores. In ten (21.7%) families, a disease-related variant was not found in a total of 13 OI genes included in the panel. Genetic etiology was found in 38 (82.6%) of 46 families by targeted NGS analysis. In addition, 9 new variants were assessed in known OI genes which is a significant contribution to the literature.

Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease

BackgroundThe current treatment of osteogenesis imperfecta (OI) is imperfect. Our study thus delves into the potential of using Dickkopf-1 antisense (DKK1-AS) to treat OI.MethodsWe analysed serum DKK1 levels and their correlation with lumbar spine and hip T-scores in OI patients. Comparative analyses were conducted involving bone marrow stromal cells (BMSCs) and bone tissues from wild-type mice, untreated OI mice, and OI mice treated with DKK1-ASor DKK1-sense (DKK1-S).ResultsSignificant inverse correlations were noted between serum DKK1 levels and lumbar spine (correlation coefficient = − 0.679, p = 0.043) as well as hip T-scores (correlation coefficient = − 0.689, p = 0.042) in OI patients. DKK1-AS improved bone mineral density (p = 0.002), trabecular bone volume/total volume fraction (p < 0.001), trabecular separation (p = 0.010), trabecular thickness (p = 0.001), trabecular number (p < 0.001), and cortical thickness (p < 0.001) in OI mice. DKK1-AS enhanced the transcription of collagen 1α1, osteocalcin, runx2, and osterix in BMSC from OI mice (all p < 0.001), resulting in a higher von Kossa-stained matrix area (p < 0.001) in ex vivo osteogenesis assays. DKK1-AS also reduced osteoclast numbers (p < 0.001), increased β-catenin and T-cell factor 4 immunostaining reactivity (both p < 0.001), enhanced mineral apposition rate and bone formation rate per bone surface (both p < 0.001), and decreased osteoclast area (p < 0.001) in OI mice. DKK1-AS upregulated osteoprotegerin and downregulated nuclear factor-kappa B ligand transcription (both p < 0.001). Bone tissues from OI mice treated with DKK1-AS exhibited significantly higher breaking force compared to untreated OI mice (p < 0.001).ConclusionsOur study elucidates that DKK1-AS has the capability to enhance bone mechanical properties, restore the transcription of osteogenic genes, promote osteogenesis, and inhibit osteoclastogenesis in OI mice.

Musculoskeletal System and Gait Characteristics in Patients with Osteogenesis imperfecta

Objectives The aim of the study was to assess the muscoloskeletal system and spatiotemporal gait parameters of patients in three types of osteogenesis imperfecta. Design study Retrospective observational study. Settings The Department of Rehabilitation, Children's Memorial Health Institute in Warsaw, Poland. Participants This study investigated individuals with various types of osteogenesis imperfecta: 33 with osteogenesis imperfecta I (aged 13.9), 16 with osteogenesis imperfecta III (aged 10.4), and 14 with osteogenesis imperfecta IV (aged, 15.8), as well as a reference group of 400 healthy individuals. Main measures The musculoskeletal assessment included: medical record review, clinical evaluation, functional tests, long bone deformity assessment via clinical and X-ray examination, and objective gait analysis with the Vicon Motion Systems (Ltd, Oxford, UK). Results The study revealed notable differences in clinical presentation, deformities within the musculoskeletal system, gait parameters across the various types of osteogenesis imperfecta (p < 0.001). The most affected gait parameters were: cadence, gait speed and step length. The greatest deformities of lower limbs and spine were presented in patients with osteogenesis imperfecta type III. Conclusions These findings are significant for understanding gait abnormalities in osteogenesis imperfecta patients and designing customized physiotherapy programs to help them participate fully in daily life. Improvement of muscle strength is one of the key for easier engagement in activities like walking or stair-climbing.