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Keywords = Osteogenesis Imperfecta

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18 pages, 1790 KiB  
Case Report
Genotype–Phenotype Correlation Insights in a Rare Case Presenting with Multiple Osteodysplastic Syndromes
by Christos Yapijakis, Iphigenia Gintoni, Myrsini Chamakioti, Eleni Koniari, Eleni Papanikolaou, Eva Kassi, Dimitrios Vlachakis and George P. Chrousos
Genes 2025, 16(8), 871; https://doi.org/10.3390/genes16080871 - 24 Jul 2025
Viewed by 252
Abstract
Background: Osteodysplastic syndromes comprise a very diverse group of clinically and genetically heterogeneous disorders characterized by defects in bone and connective tissue development, as well as in bone density. Here, we report the case of a 48-year-old female with a complex medical history [...] Read more.
Background: Osteodysplastic syndromes comprise a very diverse group of clinically and genetically heterogeneous disorders characterized by defects in bone and connective tissue development, as well as in bone density. Here, we report the case of a 48-year-old female with a complex medical history characterized by bone dysplasia, hyperostosis, and partial tooth agenesis. Methods: Genetic testing was performed using WES analysis and Sanger sequencing. Molecular modeling analysis and dynamics simulation explored the impact of detected pathogenic variants. Results: The genetic analysis detected multiple pathogenic variants in genes CREB3L1, SLCO2A1, SFRP4, LRP5, and LRP6, each of which has been associated with rare osteodysplastic syndromes. The patient was homozygous for the same rare alleles associated with three of the identified autosomal recessive disorders osteogenesis imperfecta type XVI, primary hypertrophic osteoarthropathy, and metaphyseal dysplasia Pyle type. She also had a variant linked to autosomal dominant endosteal hyperostosis and a variant previously associated with increased risk of osteoporosis and bone fractures. Two of the detected variants are predicted to cause abnormal splicing, while molecular modeling and dynamics simulations analysis suggest that the other three variants probably confer altered local secondary structure and flexibility that may have functionally devastating consequences. Conclusions: Our case highlights the rare coexistence of multiple osteodysplastic syndromes in a single patient that may complicate differential diagnosis. Furthermore, this case emphasizes the necessity for early genetic investigation of such complex cases with overlying phenotypic traits, followed by genetic counseling, facilitating orchestration of clinical interventions and allowing prevention and/or prompt management of manifestations. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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16 pages, 720 KiB  
Article
Demographic and Clinical Profile of Patients with Osteogenesis Imperfecta Hospitalized Due to Coronavirus Disease (COVID)-19: A Case Series of 13 Patients from Brazil
by Luana Lury Morikawa, Luiz Felipe Azevedo Marques, Adriele Evelyn Ferreira Silva, Patrícia Teixeira Costa, Lucas Silva Mello, Andrea de Melo Alexandre Fraga and Fernando Augusto Lima Marson
Healthcare 2025, 13(15), 1779; https://doi.org/10.3390/healthcare13151779 - 23 Jul 2025
Viewed by 257
Abstract
Background: Osteogenesis imperfecta (OI) is a rare genetic connective tissue disorder characterized by bone fragility, most often caused by pathogenic variants in type I collagen genes. In this context, we aimed to describe the clinical and epidemiological characteristics of patients with OI who [...] Read more.
Background: Osteogenesis imperfecta (OI) is a rare genetic connective tissue disorder characterized by bone fragility, most often caused by pathogenic variants in type I collagen genes. In this context, we aimed to describe the clinical and epidemiological characteristics of patients with OI who were hospitalized for coronavirus disease (COVID)-19 in Brazil between 2020 and 2024. Methods: We conducted a retrospective descriptive analysis using data from the Brazilian Unified Health System (SUS, which stands for the Portuguese Sistema Único de Saúde) through the Open-Data-SUS platform. Patients with a confirmed diagnosis of OI and hospitalization due to COVID-19 were included. Descriptive statistical analysis was performed to evaluate demographic, clinical, and outcome-related variables. We included all hospitalized COVID-19 cases with a confirmed diagnosis of OI between 2020 and 2024. Results: Thirteen hospitalized patients with OI and COVID-19 were identified. Most were adults (9; 69.2%), male (7; 53.8%), self-identified as White (9; 69.2%), and all were residents of urban areas (13; 100.0%). The most frequent symptoms were fever (10; 76.9%), cough (9; 69.2%), oxygen desaturation (9; 69.2%), dyspnea (8; 61.5%), and respiratory distress (7; 53.8%). Two patients had heart disease, one had chronic lung disease, and one was obese. As for vaccination status, five patients (38.5%) had been vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Four patients (30.8%) required admission to an intensive care unit (ICU), and six (46.2%) required noninvasive ventilatory support. Among those admitted to the ICU, only two required invasive mechanical ventilation. The clinical outcome was death in two cases (15.4%). Both patients were male, White, and had not been vaccinated against SARS-CoV-2. One was 47 years old, was not admitted to the ICU, but required noninvasive ventilation. Despite the underlying condition most patients had favorable outcomes, consistent with an international report. Conclusions: This is the first report to describe the clinical and epidemiological profile of patients with OI hospitalized for COVID-19 in Brazil, providing initial insights into how a rare bone disorder intersects with an acute respiratory infection. The generally favorable outcomes observed—despite the underlying skeletal fragility—suggest that individuals with OI are not necessarily at disproportionate risk of severe COVID-19, particularly when appropriately monitored. The occurrence of deaths only among unvaccinated patients underscores the critical role of SARS-CoV-2 vaccination in this population. Although pharmacological treatment data were unavailable, the potential protective effects of bisphosphonates and vitamin D merit further exploration. These findings support the need for early preventive strategies, systematic vaccination efforts, and dedicated clinical protocols for rare disease populations during infectious disease outbreaks. Full article
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10 pages, 265 KiB  
Article
Children and Adolescents with Mucopolysaccharidosis and Osteogenesis Imperfecta: The Dentistry on the Multiprofessional Team
by Mariana Laís Silva Celestino, Natália Cristina Ruy Carneiro, Heloisa Vieira Prado, Glória Maria Pimenta Cabral, Mauro Henrique Nogueira Guimarães Abreu and Ana Cristina Borges-Oliveira
J. Pers. Med. 2025, 15(7), 323; https://doi.org/10.3390/jpm15070323 - 18 Jul 2025
Viewed by 319
Abstract
Background/Objectives: To identify factors associated with the referral by a multiprofessional team to dental services for children and adolescents with rare genetic diseases. Methods: A cross-sectional study was developed with 87 children/adolescents with mucopolysaccharidosis (n = 26) and osteogenesis imperfecta (n [...] Read more.
Background/Objectives: To identify factors associated with the referral by a multiprofessional team to dental services for children and adolescents with rare genetic diseases. Methods: A cross-sectional study was developed with 87 children/adolescents with mucopolysaccharidosis (n = 26) and osteogenesis imperfecta (n = 61) and their caregivers. Recruitment took place at reference centers for rare genetic conditions in five Brazilian states. The caregivers answered a questionnaire on the children. They were examined for malocclusion, dental anomalies, caries experience, and gingivitis. Bivariate and multivariate analyses of the data were performed, considering a 95% confidence level. Results: The average age of children/adolescents was 10.4 years (±5.6) and 17.3% had never gone to a dentist. Among those with past dental experience, the reason for most appointments was oral prophylaxis/preventive maintenance (62.1%). With regard to referrals to a dentist by the multidisciplinary team, 29.9% had never received a referral. The likelihood of having been referred to a dentist by the multiprofessional team was 2.67 times greater for female patients (95% CI: 0.96–7.42) and 7.74 times greater for children/adolescents with a history of toothache (95% CI: 1.61–37.14). Conclusions: Female children/adolescents with mucopolysaccharidosis and osteogenesis imperfecta and those with a history of dental pain were more likely to have been advised by the multiprofessional team to seek dental treatment. Full article
(This article belongs to the Special Issue Advances in Oral Health: Innovative and Personalized Approaches)
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15 pages, 1629 KiB  
Article
Molecular and Clinical Aspects of Osteogenesis Imperfecta Type VI: A Case Series with Novel SERPINF1 Gene Variants
by Elena S. Merkuryeva, Tatyana S. Nagornova, Vladimir M. Kenis, Anna S. Deviataikina, Daria B. Akimova, Dmitry S. Buklaev, Ilya S. Dantsev, Aisluu O. Dulush, Ekaterina Y. Zakharova and Tatiana V. Markova
Int. J. Mol. Sci. 2025, 26(13), 6200; https://doi.org/10.3390/ijms26136200 - 27 Jun 2025
Viewed by 392
Abstract
Osteogenesis imperfecta type VI is a rare autosomal recessive disorder characterized by bone fragility and defective mineralization, caused by pathogenic variants in the SERPINF1 gene. This study aimed to expand the understanding of OI type VI by analyzing clinical, radiological, and molecular findings [...] Read more.
Osteogenesis imperfecta type VI is a rare autosomal recessive disorder characterized by bone fragility and defective mineralization, caused by pathogenic variants in the SERPINF1 gene. This study aimed to expand the understanding of OI type VI by analyzing clinical, radiological, and molecular findings in four patients from three unrelated families. Genotyping revealed two novel SERPINF1 variants, c.185G>T (p.Gly62Val) and c.992_993insCA (p.Glu331Asnfs), in a compound heterozygous state in one patient, and a known pathogenic variant, c.261_265dup (p.Leu89Argfs26), in a homozygous form in three patients. Clinical manifestations included early-onset fractures, severe skeletal deformities, impaired mobility, and growth failure. Radiological assessments revealed multilevel and multiplanar bone deformities and metaphyseal widening. RNA analysis demonstrated that the c.992_993insCA variant results in a truncated PEDF protein without triggering nonsense-mediated decay. Population screening identified a carrier frequency of 0.0044 for the c.261_265dup variant, suggesting a founder effect in the Tuvinian population. These findings expand the mutational spectrum of the SERPINF1 gene and provide new insights into the phenotypic variability of OI type VI. Our results highlight the importance of genetic screening in isolated populations and emphasize the need for further research to develop more effective therapeutic approaches for patients with limited response to bisphosphonate therapy. Full article
(This article belongs to the Special Issue Molecular Insight into Bone Diseases)
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12 pages, 844 KiB  
Communication
Impact of Somatic Development and Course of Osteogenesis Imperfecta on FGF23 Levels in Children
by Agnieszka Byrwa-Sztaba and Elżbieta Jakubowska-Pietkiewicz
Int. J. Mol. Sci. 2025, 26(13), 6007; https://doi.org/10.3390/ijms26136007 - 23 Jun 2025
Viewed by 352
Abstract
Osteogenesis imperfecta (OI) is a rare bone dysplasia that occurs with a frequency of 1/15,000–20,000 live births. It is characterized by increased susceptibility of bone fractures, skeletal deformities, low stature, and low bone mass. It results in impaired production of type I collagen. [...] Read more.
Osteogenesis imperfecta (OI) is a rare bone dysplasia that occurs with a frequency of 1/15,000–20,000 live births. It is characterized by increased susceptibility of bone fractures, skeletal deformities, low stature, and low bone mass. It results in impaired production of type I collagen. About 90% of people with OI have heterozygous mutations in the COL1A1 and COL1A2 genes. Fibroblast growth factor 23 (FGF23) is a protein involved in the regulation of phosphate and 1,25-dihydroxyvitamin D3 metabolism on a negative feedback basis. FGF23 is secreted by osteocytes in response to increased serum calcitriol and phosphorus. The purpose of this study was to evaluate the concentration of FGF23 among children with osteogenesis imperfecta and the differences in reference values in a healthy population of children and adolescents. Then, this study sought to evaluate how the course of osteogenesis imperfecta, including type of disease, number of bone fractures, and bone mineral density, are related to FGF23 concentration. The study included 47 children aged 3 to 17 years with a diagnosis of osteogenesis imperfecta, confirmed by genetic tests. The patients were hospitalized at the Department from August 2019 to September 2020 and were treated with intravenous infusions of sodium pamidronate. The course of the disease was analyzed, including the number of bone fractures, clinical symptoms, and anthropometric parameters, and bone densitometry was performed by dual X-ray absorptiometry (DXA) in Total Body Less Head (TBLH) and Spine options with Z-score evaluation. FGF23 concentration was determined by the ELISA method. The study was prospective in nature. Results: The mean level of FGF23 in the study group of patients was 645.09 pg/mL and was within the reference values for the developmental age population. There was no significant correlation between FGF23 concentration and anthropometric measurements: body weight (p = 0.267), height (p = 0.429), gender (p = 0.291), or pubertal stage (p = 0.223) in the study group of patients. FGF23 levels were not related to the number of fractures (p = 0.749), the number of sodium pamidronate cycles administered (p = 0.580), bone mineral density parameters (Z-score), the form of osteogenesis imperfecta (p = 0.156), or the genetic test result (p = 0.573). FGF23 levels decrease with age (r = −0.32, p = 0.030) and BMI (r = −0.34, p = 0.020). The level of FGF23 in patients with osteogenesis imperfecta is lower among older children and those having a higher BMI. This index cannot be a diagnostic tool in this group of patients, for no differences were found between the concentrations in patients with osteogenesis imperfecta and the developmental age population. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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16 pages, 1668 KiB  
Systematic Review
Use of COX Inhibitors in Plastic Surgery Fibroproliferative Disorders: A Systematic Review
by Yu Ting Tay, Elisha Purcell, Ishith Seth, Gianluca Marcaccini and Warren M. Rozen
J. Pers. Med. 2025, 15(6), 257; https://doi.org/10.3390/jpm15060257 - 17 Jun 2025
Viewed by 429
Abstract
Background/Objectives: Fibroproliferative disorders (FPDs), such as Dupuytren’s contracture, scleroderma, capsular contracture, rhinophyma, and keloid scars, are characterised by excessive fibroblast activity and collagen deposition. These conditions are frequently encountered in plastic and reconstructive surgery and remain therapeutically challenging. Cyclooxygenase (COX) inhibitors have emerged [...] Read more.
Background/Objectives: Fibroproliferative disorders (FPDs), such as Dupuytren’s contracture, scleroderma, capsular contracture, rhinophyma, and keloid scars, are characterised by excessive fibroblast activity and collagen deposition. These conditions are frequently encountered in plastic and reconstructive surgery and remain therapeutically challenging. Cyclooxygenase (COX) inhibitors have emerged as a potential adjunct therapy to modulate fibrotic pathways and improve clinical outcomes. This systematic review aims to evaluate the efficacy and safety profile of COX inhibitors in the management of plastic-surgery-related FPDs. In doing so, it explores how phenotype-guided and route-specific COX-inhibitor use may contribute to precision, patient-centred care. Methods: To identify eligible studies, a comprehensive search was conducted in MEDLINE, Embase, and the Cochrane Library. Data were synthesised using both tabular summaries and narrative analysis. The certainty of evidence was appraised according to the GRADE guidelines. Results: Thirteen studies from 1984 to 2024 met inclusion criteria, addressing FPDs such as hypertrophic scarring, Dupuytren’s contracture, and desmoid tumours, representing 491 patients. Of those, five studies were related to Dupuytren contracture, three studies were related to hypertrophic scar, and one study each was on topics related to scleroderma, keloid scar, osteogenesis imperfecta, actinic keloidalis nuchae/dissecting cellulitis of the scalp, and desmoid tumours. Nine studies reported clinical improvements (four demonstrating statistically significant outcomes), three showed no difference, and one did not assess outcomes. The thirteen studies show minor side effects from oral and topical COX inhibitors. The overall certainty of evidence was graded as “low.” Conclusions: COX inhibitors demonstrate promising efficacy with minimal adverse effects in the management of plastic-surgery-related FPDs. Their accessibility, safety, and potential to reduce fibrosis underscore the need for future high-quality, large-scale studies to establish definitive clinical recommendations. Full article
(This article belongs to the Special Issue Plastic Surgery: New Perspectives and Innovative Techniques)
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16 pages, 1176 KiB  
Review
Orthodontics in Pediatric Osteoporosis: A Narrative Literature Review
by Anastasia Panagiota Gravia, Heleni Vastardis, Apostolos I. Tsolakis and Artemis Doulgeraki
Children 2025, 12(6), 691; https://doi.org/10.3390/children12060691 - 28 May 2025
Viewed by 587
Abstract
Osteoporosis is the most common metabolic bone disorder, characterized by reduced bone mass and abnormal bone microarchitecture, resulting in increased bone fragility and a heightened risk of low-energy fractures. Pediatric osteoporosis may be either primary, due to genetic factors, or secondary, arising from [...] Read more.
Osteoporosis is the most common metabolic bone disorder, characterized by reduced bone mass and abnormal bone microarchitecture, resulting in increased bone fragility and a heightened risk of low-energy fractures. Pediatric osteoporosis may be either primary, due to genetic factors, or secondary, arising from chronic diseases and/or their treatment. Oral health and proper occlusion are integral components of overall health, influencing functionality, nutrition, facial aesthetics, and psychosocial development during childhood. Severe malocclusion can adversely affect speech, mastication, appearance, psychological well-being, and social interactions. The aim of this narrative review is to examine the existing literature on orthodontic anomalies and management strategies in pediatric patients with osteoporosis while highlighting clinical challenges, treatment limitations, and areas necessitating further research. A comprehensive literature search was conducted in the PubMed database, focusing on studies involving human subjects aged 3 to 18 years, published in English between 2002 and 2024. The findings indicate that children with osteoporosis present with more severe dental and occlusal complications compared to their healthy peers, often facing increased orthodontic complexity due to skeletal fragility and systemic comorbidities. These challenges necessitate careful, individualized treatment planning and close multidisciplinary collaboration. Although research in this field remains limited due to the rarity of pediatric osteoporosis, recognizing and addressing the specific needs of this population is critical to improving clinical outcomes and guiding future therapeutic approaches. Full article
(This article belongs to the Special Issue Prevention and Orthodontic Treatment of Malocclusion in Children)
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10 pages, 237 KiB  
Case Report
Further Evidence of Early-Onset Osteoporosis and Bone Fractures as a New FGFR2-Related Phenotype
by Alice Moroni, Elena Pedrini, Morena Tremosini, Alessia Di Cecco, Dario Cocciadiferro, Antonio Novelli, Lucia Santoro, Rosanna Cordiali, Luca Sangiorgi and Maria Gnoli
Int. J. Mol. Sci. 2025, 26(9), 4204; https://doi.org/10.3390/ijms26094204 - 29 Apr 2025
Cited by 1 | Viewed by 860
Abstract
Primary osteoporosis in children and young adults often suggests a monogenic disease affecting bone microarchitecture and bone mineral density. While Osteogenesis Imperfecta (OI) is the most recognized genetic cause of recurrent fractures, many other genes involved in bone metabolism may contribute to osteoporosis. [...] Read more.
Primary osteoporosis in children and young adults often suggests a monogenic disease affecting bone microarchitecture and bone mineral density. While Osteogenesis Imperfecta (OI) is the most recognized genetic cause of recurrent fractures, many other genes involved in bone metabolism may contribute to osteoporosis. Among them, FGFR2 plays a critical role in bone growth and development by regulating osteoblast differentiation and proliferation, as well as chondrogenesis. Germline pathogenic FGFR2 variants are typically associated with syndromic craniosynostosis, conditions not characterized by bone fragility or osteoporosis. A report recently identified FGFR2 as a potential cause of dominant early-onset osteoporosis and bone fractures in a family. We report the case of a child affected by severe osteoporosis with multiple fractures. We performed clinical exome sequencing in trio to investigate potential genetic causes of the observed phenotype and identified a likely mosaic pathogenic FGFR2 variant, absent in both parental samples. Our findings provide further evidence that FGFR2 pathogenic variants can lead to a novel non-syndromic bone mineralization disorder, reinforcing the role of FGFR2 in the pathogenesis of early-onset osteoporosis. Full article
(This article belongs to the Special Issue Advances in Osteogenesis)
14 pages, 1031 KiB  
Case Report
Example of Intrafamilial Clinical Polymorphism in a Family with Osteogenesis Imperfecta
by Varvara A. Galkina, Tatyana A. Vasilyeva, Inna S. Tebieva, Zolina K. Getoeva, Andrey V. Marakhonov, Vitaly V. Kadyshev, Sergey I. Kutsev and Rena A. Zinchenko
Genes 2025, 16(5), 475; https://doi.org/10.3390/genes16050475 - 23 Apr 2025
Viewed by 514
Abstract
Background/Objectives: According to the International Classification of Hereditary Skeletal Diseases (2019), osteogenesis imperfecta (OI) is classified as a disorder resulting from impaired formation of the cortical layer density of diaphyses and metaphyseal modeling. OI comprises a heterogeneous group of genetic diseases, with [...] Read more.
Background/Objectives: According to the International Classification of Hereditary Skeletal Diseases (2019), osteogenesis imperfecta (OI) is classified as a disorder resulting from impaired formation of the cortical layer density of diaphyses and metaphyseal modeling. OI comprises a heterogeneous group of genetic diseases, with most cases inherited in an autosomal dominant manner, while others follow autosomal recessive or X-linked recessive inheritance patterns. Accurate DNA testing is essential for precise medical and genetic counseling, ensuring reliable prognostic assessments for patients’ descendants and siblings. As part of a medical genetic study of the population of the Republic of the North Ossetia Alania, specifically in the Mozdok district, specialists from the Laboratory of Genetic Epidemiology at the Research Centre for Medical Genetics (RCMG) examined a family with 13 affected individuals with OI across four generations. Methods: A comprehensive clinical assessment was performed, followed by molecular genetic analysis using whole-exome sequencing (WES). Segregation analysis within the family was conducted via Sanger sequencing. Results: Clinical evaluation suggested a diagnosis of OI, which was subsequently confirmed by genetic testing. The severity and spectrum of symptoms varied considerably among affected family members and were influenced by age and specific nuclear family lineage. Molecular analysis in the proband identified a heterozygous pathogenic variant in the COL1A1 gene variant (c.1243C>T, p.(Arg415*)), confirming a diagnosis of OI type IV. The variant was found to co-segregate with the disease within the family. Conclusions: Molecular diagnosis enabled precise risk assessment for affected offspring in family members with mild phenotypic manifestations. Additionally, pediatric patients were referred for standard bisphosphonate therapy to manage the condition effectively. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Genetic Diseases)
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13 pages, 273 KiB  
Article
Diagnostic Challenges in Bone Fragility: Osteogenesis Imperfecta Case Series
by Andrei Costache, Anca-Lelia Riza, Mihaela Popescu, Rebecca-Cristiana Șerban, Andreea-Mădălina Mituț-Velișcu and Ioana Streață
Biomedicines 2025, 13(4), 865; https://doi.org/10.3390/biomedicines13040865 - 3 Apr 2025
Viewed by 1301
Abstract
Osteogenesis imperfecta (OI) is a rare hereditary connective tissue disorder. Diagnosis is typically clinical; genetic testing can contribute. Objectives: We are presenting a case series of type I OI in Romanian patients, showcasing the difficulties in diagnostic and case management in pediatric [...] Read more.
Osteogenesis imperfecta (OI) is a rare hereditary connective tissue disorder. Diagnosis is typically clinical; genetic testing can contribute. Objectives: We are presenting a case series of type I OI in Romanian patients, showcasing the difficulties in diagnostic and case management in pediatric and adult cases. Methods: Nine patients were referred to the Regional Centre for Medical Genetics (CRGM), Dolj, Craiova, between 2021 and 2024. Genetic testing was conducted using the commercially available kit Illumina® TruSight™ One. Results: Most of the patients showed blue sclerae, significant fracture history, and reduced stature. In our case series, the genetic variants for seven of the cases identified are primarily in the COL1A1 and COL1A2 genes. Our study reveals significant clinical variability among patients, even among those with identical genetic variants. This emphasizes the importance of tailored surgical and rehabilitation programs to improve the quality of life for these patients. Conclusions: Our study contributes to the genetic landscape of OI. Future research should aim to include larger, more diverse cohorts and incorporate advanced genetic analysis techniques to identify additional genetic variants and mechanisms involved in OI. Full article
19 pages, 2855 KiB  
Article
The Spectra of Pathogenic Variants and Phenotypes in a Chinese Cohort of 298 Families with Osteogenesis Imperfecta
by Siji Zhou, Xiuzhi Ren, Yixuan Cao, Huan Mi, Mingchen Han, Lulu Li, Chendan Jiang, Yuqian Ye, Chaoqun Zheng, Binshan Zhao, Tao Yang, Nan Wu, Zhen Li, Lingqian Wu and Xiuli Zhao
Genes 2025, 16(4), 416; https://doi.org/10.3390/genes16040416 - 31 Mar 2025
Viewed by 928
Abstract
Background: Osteogenesis imperfecta (OI) is marked by clinical and genetic heterogeneity, and the genotype–phenotype correlation remains not very clear. We conducted a clinical and genetic study in a Chinese OI cohort to determine the spectra of phenotypes and pathogenic variants. Methods: In this [...] Read more.
Background: Osteogenesis imperfecta (OI) is marked by clinical and genetic heterogeneity, and the genotype–phenotype correlation remains not very clear. We conducted a clinical and genetic study in a Chinese OI cohort to determine the spectra of phenotypes and pathogenic variants. Methods: In this study, 298 Chinese families were recruited from 2019 to 2024. Clinical phenotypes including fractures, short stature, skeletal deformities, blue sclera, dentinogenesis imperfecta, and hearing loss were recorded and analyzed. Next-generation sequencing combined with PCR-based techniques was used to detect candidate pathogenic variants. Variant pathogenicity was evaluated via conservation analysis, bioinformatics analysis, and functional studies at the cellular level. In this OI cohort, the spectra of pathogenic variants, clinical phenotypes, and genotype–phenotype correlations were analyzed. Results: Our OI cohort included 71 type I (23.83%), 122 type III (40.94%), 90 type IV (30.20%), and 15 type V (5.03%) probands. The cohort consisted of 196 children (65.77%) and 102 adults (34.23%). For the first time, phenotypic differences between different age groups were confirmed. In total, we identified 231 variants, including 47 novel pathogenic variants. Notable variants include two atypical splicing variants, one small deletion, two small duplications, one gross deletion, and one gross duplication. New genotype–phenotype correlations were observed: patients with SERPINF1 variants had the highest fracture frequency, followed by those with WNT1 variants, compared to patients with other gene variants. Conclusions: We performed the clinical and genetic analysis in a large Chinese OI cohort. The expanded spectra of genetic variants and clinical phenotypes were constructed by identifying 47 novel pathogenic variants and summarizing the skeletal and extra-skeletal manifestations. The current paper will provide important evidence for the precise diagnosis of the disease. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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24 pages, 5880 KiB  
Article
CRTAP-Null Osteoblasts Have Increased Proliferation, Protein Secretion, and Skeletal Morphogenesis Gene Expression with Downregulation of Cellular Adhesion
by Aileen M. Barnes, Apratim Mitra, Marianne M. Knue, Alberta Derkyi, An Dang Do, Ryan K. Dale and Joan C. Marini
Cells 2025, 14(7), 518; https://doi.org/10.3390/cells14070518 - 31 Mar 2025
Viewed by 518
Abstract
Type VII osteogenesis imperfecta (OI), caused by recessive CRTAP mutations, is predominantly lethal in the first year of life. Due to its early lethality, little is known about bone dysplasia mechanism. RNA-seq analysis of differentiated osteoblasts of siblings with a non-lethal homozygous CRTAP [...] Read more.
Type VII osteogenesis imperfecta (OI), caused by recessive CRTAP mutations, is predominantly lethal in the first year of life. Due to its early lethality, little is known about bone dysplasia mechanism. RNA-seq analysis of differentiated osteoblasts of siblings with a non-lethal homozygous CRTAP-null variant showed an enrichment of gene ontology terms involved in DNA replication and cell cycle compared to control. BrdU incorporation confirmed a ≈2-fold increase in proliferation in non-lethal proband osteoblasts in comparison to control cells. In addition, the expression of cyclin dependent kinase inhibitor 2A (CDKN2A), encoding a protein involved in cell cycle inhibition, was significantly reduced (>50%) in CRTAP-null osteoblasts, while cyclin B1 (CCNB1), encoding a promoter of the cell cycle, was enhanced. Ossification and bone and cartilage development gene ontology pathways were enriched among upregulated genes throughout osteoblast differentiation, as was protein secretion. Ingenuity pathway analysis indicated an upregulation of BMP2 signaling, supported by increase in both BMP2 and MSX2, an early BMP2-responsive gene, by qPCR. Throughout differentiation, CRTAP-null osteoblasts showed a decrease in transcripts related to cell adhesion and extracellular matrix organization pathways. We propose that increased proliferation and osteogenesis of type VII OI osteoblasts may be stimulated through upregulation of BMP2 signaling, altering bone homeostasis, and leading to weaker bones. Full article
(This article belongs to the Special Issue Molecular Mechanism of Bone Disease)
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13 pages, 1444 KiB  
Article
Bone Changes During Growth in Patients with Osteogenesis Imperfecta
by Laura Burgueño-Torres, Lara García-Boedo and Manuel Joaquín de Nova-García
J. Clin. Med. 2025, 14(5), 1764; https://doi.org/10.3390/jcm14051764 - 6 Mar 2025
Cited by 1 | Viewed by 1042
Abstract
Background/Objectives: Osteogenesis Imperfecta (OI) is a congenital disorder, in which the production of collagen, mainly type I, is altered, leading to a decrease in bone mineral density, increasing the risk of fracture with minimal trauma. Several studies have analyzed bone mineral density [...] Read more.
Background/Objectives: Osteogenesis Imperfecta (OI) is a congenital disorder, in which the production of collagen, mainly type I, is altered, leading to a decrease in bone mineral density, increasing the risk of fracture with minimal trauma. Several studies have analyzed bone mineral density in osteoporotic patients based on linear measurements such as radiomorphometric indices measured with panoramic radiographs, although few studies have investigated bone trabeculation in children diagnosed with OI. Therefore, the aim of the present investigation was to analyze the dental panoramic indices in panoramic radiographs in the cortical and trabeculated bone of children with OI. Methods: Thus, 66 pediatric patients diagnosed with OI under antiresorptive treatment were compared with a sample of controls matched for sex and age. Using Image J software (version: 1.54d), three radiomorphometric indices were analyzed in orthopantomographies of the study and control groups, evaluating the influence of disease severity as well as the type of antiresorptive treatment administered. Results: Patients with OI had a higher presence of type C2 and C3 MCI (mandibular cortical index) than their matched controls (p < 0.05), although no differences were found for the visual estimation of cortical width (SVE) and mandibular cortical width (MCW). Treatment with zoledronic acid was associated with a higher number of cases of type C1 MCI, in terms of sample description, while patients treated with a combination of pamidronate and zoledronic acid had a higher rate of type C1 and C2 MCI, with no statistical differences. Conclusions: In the overall sample, most patients showed a thin SVE index (59.1%), a C2 or C1 type MCI (46.2% and 42.4%) and an MCW of 2.9 mm. Differences in bone mineral density were also observed throughout growth and the different antiresorptive treatments. Zoledronic acid has been associated with a higher percentage of C1 and C3 ICM, and pamidronate alone or in combination is associated with a C1 and C2 MCI index. Full article
(This article belongs to the Section Orthopedics)
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13 pages, 1405 KiB  
Article
Complex Analysis of Micronutrient Levels and Bone Mineral Density in Patients with Different Types of Osteogenesis Imperfecta
by Diana Valeeva, Karina Akhiiarova, Ildar Minniakhmetov, Natalia Mokrysheva, Rita Khusainova and Anton Tyurin
Diagnostics 2025, 15(3), 250; https://doi.org/10.3390/diagnostics15030250 - 22 Jan 2025
Viewed by 883
Abstract
Background: Osteogenesis imperfecta (OI) is a rare monogenic connective tissue disorder characterized by fragility of bones and recurrent fractures. In addition to the hereditary component, there are a number of factors that influence the course of the disease, the contribution of which is [...] Read more.
Background: Osteogenesis imperfecta (OI) is a rare monogenic connective tissue disorder characterized by fragility of bones and recurrent fractures. In addition to the hereditary component, there are a number of factors that influence the course of the disease, the contribution of which is poorly understood, in particular the levels of micronutrients. Methods: A cross-sectional study was conducted involving 45 with OI and 45 healthy individuals. The concentrations of micronutrients (calcium, copper, inorganic phosphorus, zinc, and magnesium) and bone mineral density (BMD) were evaluated in all the participants. Results: The concentrations of micronutrients in all the groups were within the reference values. In the OI overall, magnesium and copper were elevated, and phosphorus and zinc were lower. Type I exhibited higher concentrations of magnesium and copper and the lowest phosphorus; type III was associated with lower zinc, type IV with lower calcium and higher copper, and type V with the lowest phosphorus. OI overall was associated with lower BMD values. A correlational analysis in the OI group showed that the number of fractures correlated with BMD in absolute values but not with the Z-score. Conclusions: The obtained data emphasize the importance of the levels of micronutrients in the pathogenesis of connective tissue diseases, in particular OI. As in the results of previous studies, the levels of micronutrients were within the population norm, which probably requires the development of individual criteria for the content of substances in this category of patients. Full article
(This article belongs to the Special Issue Diagnosis and Management of Metabolic Bone Diseases: 2nd Edition)
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24 pages, 1175 KiB  
Review
Modeling Musculoskeletal Disorders in Zebrafish: Advancements in Muscle and Bone Research
by Luca Dalle Carbonare, Michele Braggio, Arianna Minoia, Mattia Cominacini, Maria Grazia Romanelli, João Pessoa, Natascia Tiso and Maria Teresa Valenti
Cells 2025, 14(1), 28; https://doi.org/10.3390/cells14010028 - 30 Dec 2024
Viewed by 3170
Abstract
Zebrafish (Danio rerio) have emerged as a valuable model organism for investigating musculoskeletal development and the pathophysiology of associated diseases. Key genes and biological processes in zebrafish that closely mirror those in humans, rapid development, and transparent embryos make zebrafish ideal [...] Read more.
Zebrafish (Danio rerio) have emerged as a valuable model organism for investigating musculoskeletal development and the pathophysiology of associated diseases. Key genes and biological processes in zebrafish that closely mirror those in humans, rapid development, and transparent embryos make zebrafish ideal for the in vivo studies of bone and muscle formation, as well as the molecular mechanisms underlying musculoskeletal disorders. This review focuses on the utility of zebrafish in modeling various musculoskeletal conditions, with an emphasis on bone diseases such as osteoporosis and osteogenesis imperfecta, as well as muscle disorders like Duchenne muscular dystrophy. These models have provided significant insights into the molecular pathways involved in these diseases, helping to identify the key genetic and biochemical factors that contribute to their progression. These findings have also advanced our understanding of disease mechanisms and facilitated the development of potential therapeutic strategies for musculoskeletal disorders. Full article
(This article belongs to the Special Issue Modeling Developmental Processes and Disorders in Zebrafish)
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