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Osteogenesis imperfecta (OI) is a group of inherited disorders of connective tissue that cause significant deformities and fragility in bones. Most cases of OI are associated with pathogenic variants in collagen type I genes and are characterized by pronounced polymorphisms in clinical manifestations and the absence of clear phenotype-genotype correlation. The objective of this study was to conduct a comprehensive molecular-genetic and clinical analysis to verify the diagnosis of OI in six Russian patients with genetic variants in the COL1A1 and COL1A2 genes. Clinical and laboratory data were obtained from six OI patients who were observed at the Medical Genetics Center in Saint Petersburg from 2016 to 2023. Next-generation sequencing on MGISEQ G400 (MGI, China) was used for DNA analysis. The GATK bioinformatic software (version 4.5.0.0) was used for variant calling and hard filtering. Genetic variants were verified by the direct automatic sequencing of PCR products using the ABI 3500X sequencer. We identified six genetic variants, as follows pathogenic c.3505G>A (p. Gly1169Ser), c.769G>A (p.Gly257Arg), VUS c.4123G>A (p.Ala1375Thr), and c.4114A>T (p.Asn1372Tyr) in COL1A1; and likely pathogenic c.2035G>A (p.Gly679Ser) and c.739-2A>T in COL1A2. In addition, clinical cases are presented due to the presence of the c.4114A>T variant in the COL1A2 gene. Molecular genetics is essential for determining different OI types due to the high similarity across various types of the disease and the failure of unambiguous diagnosis based on clinical manifestations alone. Considering the variable approaches to OI classification, an integrated strategy is required for optimal patient management.
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BACKGROUND: The 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. METHODS: We 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). RESULTS: Significant 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 ß-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). CONCLUSIONS: Our 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.
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Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular , Osteogênese Imperfeita , Animais , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Osteogênese Imperfeita/metabolismo , Camundongos , Humanos , Feminino , Masculino , Densidade Óssea , Osteogênese , Células-Tronco Mesenquimais/metabolismoRESUMO
OBJECTIVE: To investigate the extent of extraskeletal manifestations along with inpatient outcomes and complications associated with osteogenesis imperfecta (OI). STUDY DESIGN: This cross-sectional study utilized the Kids' Inpatient Database as a part of the Healthcare Cost and Utilization Project to investigate inpatient hospital outcomes and management in patients with OI from 1997 through 2016. Data regarding hospital characteristics, cost of treatment, inpatient outcomes, and procedures were collected and analyzed. RESULTS: There were 7291 admissions that listed OI as a diagnosis in the Kids' Inpatient Database from 1997 through 2016. Unexpectedly, more than one-third of all admissions in these children with OI presented with an extraskeletal manifestation. The rate of major complications was 3.85%. The rate of minor complications was 19.4%, most commonly respiratory problems. The mortality rate was 18.2% in the neonatal period and 1.0% in all other admissions. Total charges of hospital stay increased over the years. CONCLUSIONS: We identified a striking prevalence of extraskeletal manifestations in OI along with inpatient outcomes and complications associated with OI, of which respiratory complications were predominant. We observed a significant financial burden for patients with OI and identified additional risks for financial crisis, in addition to disparities in care identified among socioeconomic groups. These data contribute to a more holistic understanding of OI from diagnosis to management.
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Osteogenesis imperfecta (OI) is a group of genetic disorders of bone formation characterized by soft and shorter brittle bones in affected individuals. OI is generally considered a collagenopathy resulting from abnormal expression of type I collagen. As assay system to detect the cellular level and quality of type I collagen would help in rapid and correct detection of OI from the diagnostic perspectives. Here, we report an immunofluorescence assay for detection of type I collagen in fibroblast models of OI and represented them into two broad categories based on the expression level and aggregation characteristics of pro-α1(I). Cell phenotypic assays of pro-α1(I) in OI-related gene knocked down fibroblasts revealed aggregates of pro-α1(I) in conditions with knockdown of SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, TMEM38B, MESD, and KDELR2, whereas pro-α1(I) expression was very low in fibroblasts which had knockdown of IFITM5, SP7, BMP1, WNT1, CREB3L1, MBTPS2, and CCDC134. The expression of pro-α1(I) showed abundant and non-aggregated distribution in the fibroblasts with knockdown of non-OI skeletal disorder-related genes (RAB33B and IFT52). The in vitro assay accurately detected abnormally expressed pro-α1(I) levels in cellular models of various types of OI. Thus, this procedure represents a promising point-of-detection assay for potential diagnosis and therapeutic decisions in OI.
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Colágeno Tipo I , Osteogênese Imperfeita , Humanos , Colágeno Tipo I/genética , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Genes Recessivos , Fibroblastos/metabolismo , Mutação , Proteínas de Transporte Vesicular/genética , Proteínas de Membrana/genéticaRESUMO
The epidemiological data on osteogenesis imperfecta (OI) in Asia is limited. This study, representing the first comprehensive epidemiological investigation on OI in Taiwan, reveals high medical resource utilization and underscores the importance of early diagnosis to enhance care quality. INTRODUCTION: This study examines osteogenesis imperfecta, a hereditary connective tissue disorder causing pediatric fractures and limb deformities, using a nationwide database from Taiwan to analyze clinical features and medical burden. METHODS: The study identified validated OI patients from the Catastrophic Illness Registry in the National Health Insurance Research Database from 2008 to 2019. Demographic data and medical resource utilization were analyzed. A multivariate Cox model assessed the influence of sex, validation age, and comorbidities. RESULTS: 319 OI patients (M/F = 153/166) were identified, with 58% validated before age 20. Prevalence and incidence were 0.8-1.3/100,000 and 0.02-0.09/100,000, respectively, with higher rates in the pediatric demographic. In the study period, 69.6% of the patients had admission history, primarily to pediatric and orthopedic wards. The median admission number was 3, with a median length of stay of 12 days and a median inpatient cost of approximately 3,163 USD during the period. Lower limb fractures were the main reason for hospitalization. 57% of OI patients received bisphosphonate treatment. The leading causes of mortality were OI-related deaths, neurovascular disease, and cardiovascular disease. The median age of validation in the non-survival group was significantly higher compared to the survival group (33 vs. 14 years), and patients validated during childhood required more inpatient fracture surgeries than those validated during adulthood. CONCLUSION: This study provides comprehensive real-world evidence on the clinical characteristics and high medical resource utilization of OI patients in a low prevalence region like Taiwan. Early diagnosis is crucial for improving care quality and enhancing health outcomes.
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Bases de Dados Factuais , Osteogênese Imperfeita , Humanos , Osteogênese Imperfeita/epidemiologia , Osteogênese Imperfeita/complicações , Masculino , Feminino , Criança , Adolescente , Pré-Escolar , Taiwan/epidemiologia , Adulto Jovem , Lactente , Adulto , Prevalência , Incidência , Efeitos Psicossociais da Doença , Pessoa de Meia-Idade , Hospitalização/estatística & dados numéricos , Comorbidade , Distribuição por Idade , Sistema de Registros , Recém-Nascido , Distribuição por Sexo , Tempo de Internação/estatística & dados numéricosRESUMO
Osteogenesis imperfecta (OI) is a rare heritable connective tissue disorder of skeletal fragility with an incidence of roughly 1:15,000. Approximately 85% of the pathogenic variants responsible for OI are in the type I collagen genes, COL1A1 and COL1A2, with the remaining pathogenic OI variants spanning at least 20 additional genetic loci that often involve type I collagen post-translational modification, folding, and intracellular transport as well as matrix incorporation and mineralization. In addition to being the most abundant collagen in the body, type I collagen is an important structural and extracellular matrix signaling molecule in multiple organ systems and tissues. Thus, OI disease-causing variants result not only in skeletal fragility, decreased bone mineral density (BMD), kyphoscoliosis, and short stature, but can also result in hearing loss, dentinogenesis imperfecta, blue gray sclera, cardiopulmonary abnormalities, and muscle weakness. The extensive genetic and clinical heterogeneity in OI has necessitated the generation of multiple mouse models, the growing awareness of non-skeletal organ and tissue involvement, and OI being more broadly recognized as a type I collagenopathy.This has driven the investigation of mutation-specific skeletal and extra-skeletal manifestations and broadened the search of potential mechanistic therapeutic strategies. The purpose of this review is to outline several of the extra-skeletal manifestations that have recently been characterized through the use of genetically and phenotypically heterogeneous mouse models of osteogenesis imperfecta, demonstrating the significant potential impact of OI disease-causing variants as a collagenopathy (affecting multiple organ systems and tissues), and its implications to overall health.
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Osteogenesis imperfecta (OI) is a Mendelian connective tissue disorder associated with increased bone fragility and other clinical manifestations most commonly due to abnormalities in production, structure, or post-translational modification of type I collagen. Until recently, most research in OI has focused on the pediatric population and much less attention has been directed at the effects of OI in the adult population. This is a narrative review of the literature focusing on the skeletal as well as non-skeletal manifestations in adults with OI that may affect the aging individual. We found evidence to suggest that OI is a systemic disease which involves not only the skeleton, but also the cardiopulmonary and gastrointestinal system, soft tissues, tendons, muscle, and joints, hearing, eyesight, dental health, and women's health in OI and potentially adds negative affect to health-related quality of life. We aim to guide clinicians as well as draw attention to obvious knowledge gaps and the need for further research in adult OI.
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Pain is a challenge in persons with OI and causes much concern in the Osteogenesis Imperfecta (OI) population. We aim to evaluate the usability of the Nordic Musculoskeletal Questionnaire (NMQ) to identify painful sites in adults with OI and to describe the occurrence of musculoskeletal (MSK) pain and its impact on their work and daily activities. This cross-sectional pilot study uses the OI-NMQ to study MSK pain prevalence in nine separate anatomical regions (neck, upper back, lower back, shoulder, elbow, hand/wrist, hip, knee, and ankle/foot) and its impact on regular work and daily activities in adults with OI. The questionnaire was distributed among participants of the 2023 annual meeting of The Danish OI Society. The response rate was 68%, and all participants considered the OI-NMQ helpful in assessing the presence of pain and its consequences. The analysis included 27 adults with OI type I, III, or IV above 18 years. Among all 27 participants, MSK pain was present in 15-56% of the 9 sites within the last 7 days and 33-89% of the nine anatomical regions during the last 12 months. In 7-48% of all the participants, their regular work and daily activities had been affected by the presence of MSK pain. The OI-NMQ was feasible in assessing MSK pain among adults with OI and displayed a high prevalence of MSK pain with a moderate impact on their regular work and daily activities in this OI population. A larger and repeated measurement of MSK pain in adults with OI is needed to confirm these results.
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Osteogenesis Imperfecta is a rare, hereditary bone condition with an incidence of 1/15,000-20,000. Symptoms include bone fragility, long bone deformity, scoliosis, hypermobility, alongside secondary features such as short stature, basilar invagination, pulmonary and cardiac complications, hearing loss, dentinogenesis imperfecta and malocclusion. Osteogenesis Imperfecta can have a large impact on the child and their family; this impact starts immediately after diagnosis. Fractures, pain, immobility, hospital admissions and the need for equipment and adaptations all influence the health-related quality of life of the individual and their family. This narrative review article aims to examine the impact the diagnosis and management of osteogenesis imperfecta has on the health-related quality of life of a child. It will touch on the effect this may have on the quality of life of their wider family and friends and identify strategies to optimise health-related quality of life in this population. Optimising health-related quality of life in children with Osteogenesis Imperfecta is often a complicated, multifaceted journey that involves the child, their extended family, school, extracurricular staff and numerous health professionals.
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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.
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Osteogenesis imperfecta (OI) is a rare genetic disorder caused by abnormal collagen type I production. While OI is primarily characterized by bone fragility and deformities, patients also have extraskeletal manifestations, including an increased risk of cardiovascular disease. This review provides a comprehensive overview of the literature on cardiovascular diseases in OI patients in order to raise awareness of this understudied clinical aspect of OI and support clinical guidelines. In accordance with the PRISMA guidelines, a systematic literature search in PubMed, Embase, Web of Science and Scopus was conducted that included articles from the inception of these databases to April 2023. Valvular disease, heart failure, atrial fibrillation, and hypertension appear to be more prevalent in OI than in control individuals. Moreover, a larger aortic root was observed in OI compared to controls. Various cardiovascular diseases appear to be more prevalent in OI than in controls. These cardiovascular abnormalities are observed in all types of OI and at all ages, including young children. As there are insufficient longitudinal studies, it is unknown whether these abnormalities are progressive in nature in OI patients. Based on these findings, we would recommend referring individuals with OI to a cardiologist with a low-threshold.
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Osteogênese Imperfeita , Osteogênese Imperfeita/complicações , Humanos , Anormalidades Cardiovasculares/epidemiologia , Anormalidades Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologiaRESUMO
Osteogenesis imperfecta (OI) is a group of rare hereditary collagen disorders. Hearing loss (HL) is a known complication linked to changes in the bones of the middle ear seen in OI. We aimed to determine the prevalence, age at debut, incidence, and risk of HL, surgery on bones of the middle ear, and use of hearing aids. A Danish nationwide, register-based cohort study. Data were extracted from the Danish National Patient register. Anyone with an OI diagnosis between January 1st 1977 and December 31st 2018, matched 1:5 with a reference population (Ref.Pop) on birthyear and sex, were included. 864 persons (487 women) with OI were included in the study and 4276 (2330 women) in the Ref.Pop. The sub-hazard ratio (SHR) for any HL was 4.56 [95% CI 3.64-5.71], with a prevalence of 17.0% and 4.0% in the OI cohort and Ref.Pop. Median age at debut was 42 and 58 years, respectively. The risk of otosclerosis and/or surgery was higher in the OI cohort (SHR 22.51 [95% CI 12.62-40.14]), with a median age at debut of 43 and 32 years in the OI cohort and Ref.Pop, respectively. Hearing aid use was more frequent in the OI cohort (SHR 4.16 [95% CI 3.21-5.40]) than in the Ref.Pop. The median age at debut was 45 and 60 years in the OI cohort and Ref.Pop, respectively. Persons with OI have a higher risk and prevalence of HL, hearing aids, and surgery, debuting younger, and prevalence increases with age.
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Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal dysplasia characterized by bone fragility and deformity, growth deficiency, and other secondary connective tissue defects. OI is now understood as a collagen-related disorder caused by defects of genes whose protein products interact with collagen for folding, post-translational modification, processing and trafficking, affecting bone mineralization and osteoblast differentiation. This review provides the latest updates on genetics of OI, including new developments in both dominant and rare OI forms, as well as the signaling pathways involved in OI pathophysiology. There is a special emphasis on discoveries of recessive mutations in TENT5A, MESD, KDELR2 and CCDC134 whose causality of OI types XIX, XX, XXI and XXI, respectively, is now established and expends the complexity of mechanisms underlying OI to overlap LRP5/6 and MAPK/ERK pathways. We also review in detail new discoveries connecting the known OI types to each other, which may underlie an eventual understanding of a final common pathway in OI cellular and bone biology.
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Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis and clinical trials are ongoing to study their effectiveness in OI adults. Additionally, novel bone-protective agents are in preclinical studies and various phases of OI clinical trials. This review summarizes current knowledge on available pharmacologic agents and current drug trials involving OI participants. A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in August 2022. Articles screened were restricted to adults. A ClinicalTrials.gov database search of all studies involving "osteogenesis imperfecta" was performed in August 2023. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving bone mineral density. As of yet, no clinical trials are available that adequately evaluate the usefulness of current therapies in reducing fracture risk. Several therapeutics, including teriparatide, setrusumab, anti-TGF-ß antibodies, and allogeneic stem cells, are being studied in clinical trials. Preclinical studies involving Dickkopf-1 antagonists present promising data in non-OI bone disease, and could be useful in OI. Research is ongoing to improve therapeutic options for adults with OI and clinical trials involving gene-editing may be possible in the coming decade.
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We report on a female neonate with a clinico-radiological presentation in keeping with a lethal form of prenatal Caffey disease (PCH). She had antenatal and postnatal features of severely bowed long bones, small chest, diaphyseal hyperostosis and polyhydramnios and died shortly after birth. Initial testing excluded COL1A1-related PCH, as an OI gene panel, consisting of COL1A1, COL1A2, CRTAP, and P3H1 genes, was negative. Targeted sequencing using a gene panel was performed and a de novo heterozygous, likely pathogenic variant in IFITM5: c.119C > T(p.Ser40Leu) was identified, which was previously described to cause a severe form of progressively deforming osteogenesis imperfect (OI). To our knowledge, variants in IFITM5 have not been reported in infantile Caffey disease (ICH) or PCH. Given that the pathogenesis of PCH is largely unknown, we postulate that a subset of PCH may be associated with variants in IFITM5.
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Doenças Fetais , Hiperostose Cortical Congênita , Osteogênese Imperfeita , Recém-Nascido , Humanos , Feminino , Gravidez , Osteogênese Imperfeita/genética , Mutação , Proteínas de Membrana/genética , Colágeno Tipo I/genética , Osso e Ossos/patologiaRESUMO
BACKGROUND: Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone deformities, fractures and reduced bone mass. OI can be inherited as a dominant, recessive, or X-linked disorder. The mutational spectrum has shown that autosomal dominant mutations in the type I collagen-encoding genes are responsible for OI in 85% of the cases. Apart from collagen genes, mutations in more than 20 other genes, such as CRTAP, CREB3L1, MBTPS2, P4HB, SEC24D, SPARC, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1, TMEM38B, and IFITM5 have been reported in OI. METHODS AND RESULTS: To understand the genetic cause of OI in four cases, we conducted whole exome sequencing, followed by Sanger sequencing. In case #1, we identified a novel c.506delG homozygous mutation in the WNT1 gene, resulting in a frameshift and early truncation of the protein at the 197th amino acid. In cases #2, 3 and 4, we identified a heterozygous c.838G > A mutation in the COL1A2 gene, resulting in a p.Gly280Ser substitution. The clinvar frequency of this mutation is 0.000008 (GnomAD-exomes). This mutation has been identified by other studies as well and appears to be a mutational hot spot. These pathogenic mutations were found to be absent in 96 control samples analyzed for these sites. The presence of these mutations in the cases, their absence in controls, their absence or very low frequency in general population, and their evaluation using various in silico prediction tools suggested their pathogenic nature. CONCLUSIONS: Mutations in the WNT1 and COL1A2 genes explain these cases of osteogenesis imperfecta.
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Colágeno Tipo I , Osteogênese Imperfeita , Proteína Wnt1 , Humanos , Colágeno Tipo I/genética , Sequenciamento do Exoma , Mutação/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genéticaRESUMO
PURPOSE: To evaluate the genotypic and phenotypic relationship in a large cohort of OI patients and to compare the differences between eastern and western OI cohorts. METHODS: A total of 671 OI patients were included. Pathogenic mutations were identified, phenotypic information was collected, and relationships between genotypes and phenotypes were analyzed. Literature about western OI cohorts was searched, and differences were compared between eastern and western OI cohorts. RESULTS: A total of 560 OI patients were identified as carrying OI pathogenic mutations, and the positive detection rate of disease-causing gene mutations was 83.5%. Mutations in 15 OI candidate genes were identified, with COL1A1 (n = 308, 55%) and COL1A2 (n = 164, 29%) being the most common mutations, and SERPINF1 and WNT1 being the most common biallelic variants. Of the 414 probands, 48.8, 16.9, 29.2 and 5.1% had OI types I, III, IV and V, respectively. Peripheral fracture was the most common phenotype (96.6%), and femurs (34.7%) were most commonly affected. Vertebral compression fracture was observed in 43.5% of OI patients. Biallelic or COL1A2 mutation led to more bone deformities and poorer mobility than COL1A1 mutation (all P < 0.05). Glycine substitution of COL1A1 or COL1A2 or biallelic variants led to more severe phenotypes than haploinsufficiency of collagen type I α chains, which induced the mildest phenotypes. Although the gene mutation spectrum varied among countries, the fracture incidence was similar between eastern and western OI cohorts. CONCLUSION: The findings are valuable for accurate diagnosis and treatment of OI, mechanism exploration and prognosis judgment. Genetic profiles of OI may vary among races, but the mechanism needs to be explored.
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Doenças Ósseas Metabólicas , Fraturas por Compressão , Osteogênese Imperfeita , Fraturas da Coluna Vertebral , Humanos , Osteogênese Imperfeita/genética , Cadeia alfa 1 do Colágeno Tipo I , Colágeno Tipo I/genética , Genótipo , Fenótipo , MutaçãoRESUMO
PURPOSE: Lipocalin 2 (LCN2) is a newly recognized bone-derived factor that is important in regulation of energy metabolism. We investigated the correlation of serum LCN2 levels and glycolipid metabolism, and body composition in a large cohort of patients with osteogenesis imperfecta (OI). METHODS: A total of 204 children with OI and 66 age- and gender-matched healthy children were included. Circulating levels of LCN2 and osteocalcin were measured by enzyme-linked immunosorbent assay. Serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), and low- and high-density lipoprotein cholesterol (LDL-C, HDL-C) were measured by automated chemical analyzers. The body composition was measured by dual-energy X-ray absorptiometry. Grip strength and timed-up-and-go (TUG) were tested to evaluate the muscle function. RESULTS: Serum LCN2 levels were 37.65 ± 23.48 ng/ml in OI children, which was significantly lower than those in healthy control (69.18 ± 35.43 ng/ml, P < 0.001). Body mass index (BMI) and serum FBG level were significantly higher and HDL-C levels were lower in OI children than healthy control (all P < 0.01). Grip strength was significantly lower (P < 0.05), and the TUG was significantly longer in OI patients than healthy control (P < 0.05). Serum LCN2 level was negatively correlated to BMI, FBG, HOMA-IR, HOMA-ß, total body, and trunk fat mass percentage, and positively correlated to total body and appendicular lean mass percentage (all P < 0.05). CONCLUSIONS: Insulin resistance, hyperglycemia, obesity, and muscle dysfunction are common in OI patients. As a novel osteogenic cytokine, LCN2 deficiency may be relevant to disorders of glucose and lipid metabolism, and dysfunction of muscle in OI patients.
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Resistência à Insulina , Osteogênese Imperfeita , Criança , Humanos , Lipocalina-2 , Composição Corporal , HDL-Colesterol , Metabolismo dos Lipídeos , GlicolipídeosRESUMO
Osteoporosis is a metabolic bone disorder which increases fragility fracture risk. Elderly individuals, especially postmenopausal women, are particularly susceptible to osteoporosis. Although rare, osteoporosis in children and young adults is becoming increasingly evident, highlighting the need for timely diagnosis, management and follow-up. Early-onset osteoporosis is defined as the presence of a low BMD (Z-score of ≤ -2.0 in individuals aged < 20 years; T-score of ≤ -2.5 in those aged between 20 to 50 years) accompanied by a clinically significant fracture history, or the presence of low-energy vertebral compression fractures even in the absence of osteoporosis. Affected children and young adults should undergo a thorough diagnostic workup, including collection of clinical history, radiography, biochemical investigation and possibly bone biopsy. Once secondary factors and comorbidities are excluded, genetic testing should be considered to determine the possibility of an underlying monogenic cause. Defects in genes related to type I collagen biosynthesis are the commonest contributors of primary osteoporosis, followed by loss-of-function variants in genes encoding key regulatory proteins of canonical WNT signalling (specifically LRP5 and WNT1), the actin-binding plastin-3 protein (encoded by PLS3) resulting in X-linked osteoporosis, and the more recent sphingomyelin synthase 2 (encoded by SGMS2) which is critical for signal transduction affecting sphingomyelin metabolism. Despite these discoveries, genetic causes and underlying mechanisms in early-onset osteoporosis remain largely unknown, and if no causal gene is identified, early-onset osteoporosis is deemed idiopathic. This calls for further research to unravel the molecular mechanisms driving early-onset osteoporosis that consequently will aid in patient management and individualised targeted therapy.
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Fraturas por Compressão , Osteoporose , Fraturas da Coluna Vertebral , Criança , Idoso , Humanos , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Densidade Óssea/genética , Osteoporose/etiologia , Osteoporose/genética , Via de Sinalização WntRESUMO
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.