Osteogenesis imperfecta(OI)is a genetically heterogeneous monogenic disease characterized by decreased bone mass,bone fragility,and recurrent fractures.The phenotypic spectrum varies considerably ranging from prenatal...Osteogenesis imperfecta(OI)is a genetically heterogeneous monogenic disease characterized by decreased bone mass,bone fragility,and recurrent fractures.The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature.The basic mechanism is a collagen-related defect,not only in synthesis but also in folding,processing,bone mineralization,or osteoblast function.In recent years,great progress has been made in identifying new genes and molecular mechanisms underlying OI.In this context,the classification of OI has been revised several times and different types are used.The Sillence classification,based on clinical and radiological characteristics,is currently used as a grading of clinical severity.Based on the metabolic pathway,the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches.Genetic classification has the advantage of identifying the inheritance pattern,an essential element for genetic counseling and prophylaxis.Although genotype-phenotype correlations may sometimes be challenging,genetic diagnosis allows a personalized management strategy,accurate family planning,and pregnancy management decisions including options for mode of delivery,or early antenatal OI treatment.Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches.This narrative review summarizes our current understanding of genes,molecular mechanisms involved in OI,classifications,and their utility in prophylaxis.展开更多
Being such a rare condition in paediatrics, osteogenesis imperfecta (OI) is not a diagnosis which is made often. It is however, a diagnosis necessitating early diagnosis and timeous and effective management to improve...Being such a rare condition in paediatrics, osteogenesis imperfecta (OI) is not a diagnosis which is made often. It is however, a diagnosis necessitating early diagnosis and timeous and effective management to improve morbidity and increase the quality of life for our patients. We report two cases of osteogenesis imperfecta in this case report to highlight the different phenotypic presentations. Both of these patients are unique in their presentations and each case highlights the importance of a high clinical index of suspicion by the practitioner in making the diagnosis of osteogenesis imperfecta. The first case is a patient who was diagnosed with osteogenesis imperfecta on day one of life. She had disproportionate short stature, blue sclera, a small chest and bowing of her lower limbs with swellings and tenderness over both of her femurs. A babygram radiograph revealed multiple fractures, with the presence of callus formation at some fracture sites suggesting intrauterine fractures. The second case is a patient who had normal anthropometry and was well at birth. She was subsequently diagnosed at two weeks of age when she presented to the Chris Hani Baragwanath Academic Hospital with an E. coli meningitis and she was suspected to have a right clavicular fracture and possibly rib fractures as she had pain on palpation over these areas. She was noted to have no blue sclera. Subsequent X-rays confirmed a right clavicular fracture as well as left and right rib fractures at different stages of healing. A lateral skull radiograph revealed Wormian bones. With no available genetic testing in South Africa, both diagnoses were made clinically. Both of our patients were started on zoledronic acid at three months of age and were followed up by the Metabolic Unit at the Chis Hani Baragwanath Academic Hospital. This case report of two patients highlights the characteristics important in diagnosing and treating this uncommon condition with varying phenotypical presentations, thus ensuring that the diagnosis is not missed or misdiagnosed: one disorder, two different faces.展开更多
The allogenic bone marrow derived mesenchymal stem cells transplantation was given to the newborn girl diagnosed with osteogenesis imperfecta type III, with multiple bone fractures, extreme shortness and limbs deformi...The allogenic bone marrow derived mesenchymal stem cells transplantation was given to the newborn girl diagnosed with osteogenesis imperfecta type III, with multiple bone fractures, extreme shortness and limbs deformities. The treatment was performed at the age of 4 and 6 weeks. The clinical diagnosis was supported by biochemical analysis of collagen type I recovered from culture medium of cultivated patient’s skin fibroblast, which revealed its triple helix instability at temperature about 2?C lower than normal. Sequencing of both genes encoding procollagen type I revealed heterozygous substitution G23569Ain COL1A2 gene causing change of glycine at position 517 to aspartate. The donor of mesenchymal stem cells was the girl’s father. She received two intravenous infusions of suspended cultured mesenchymal cells in 16 days apart without any side effects. An analysis of procollagen type I secreted to the culture medium by bone marrow-derived mesenchymal stem cells obtained from the patient, 3 months following transplantation revealed its normal triple helix stability. During the subsequent two years of follow up two new bone fractures were noted. Currently a two-year-old girl’s presents extreme growth and weight deficiency. The motoric development is also retarded, but the patient constantly improves and makes progresses.展开更多
Osteogenesis imperfecta is a rare hereditary bone disease which is commonly classified into types I-IV,each of varying severity.The clinical symptoms of the disease consist of increased bone brittleness and recurrent ...Osteogenesis imperfecta is a rare hereditary bone disease which is commonly classified into types I-IV,each of varying severity.The clinical symptoms of the disease consist of increased bone brittleness and recurrent fractures coupled with a variety of complications.The disease damages children’s body functions and restricts their daily activities,thus affects their psychological experience of living conditions and reduces their quality of life.The quality of life of children with osteogenesis imperfecta is primarily assessed through a universal scale and so far there is no osteogenesis imperfecta-specific quality of life scale,which is of great value to the assessment of quality of life.Pain symptoms,related complications,and limitations on physical exercise have been shown to be related to the assessment of quality of life and negatively affect the physical and psychological aspects of quality of life in children with osteogenesis imperfecta.This negative effect is found to be more serious in children diagnosed with severe types of osteogenesis imperfecta.Initial research into bisphosphonate therapy as a treatment for osteogenesis imperfecta has shown promising results in providing a better quality of life,but this treatment needs to be further studied and guided by the assessing results of quality of life.In the future,better methods of assessment and improvement of quality of life for children with osteogenesis imperfecta still rely on the efforts of all sectors of society.展开更多
Due to the incurable characteristics of osteogenesis imperfecta,health management plays a crucial role for children in healthy growth,independent life and integrating into society.This paper summarizes three dimension...Due to the incurable characteristics of osteogenesis imperfecta,health management plays a crucial role for children in healthy growth,independent life and integrating into society.This paper summarizes three dimensions of "biology-psychology-society",which summarize the research progress for health management in children with osteogenesis imperfecta.In the dimension of biology,the management on diet and complications about children is relatively definite,but more experiments are still needed in order to find out the appropriate values for the using doses of bisphosphonate and treatment time.Additionally,there is a lack of tools to assess the painful degree in children and sports management methods with different types of children with osteogenesis imperfecta nowadays.In the dimension of psychology,it is found that children with osteogenesis imperfecta,their families and carers are all expected to maintain a good state of mind.In the social dimension,we have known the need of children and their families,but their supporting systems are still expected to be improved through practice.展开更多
Osteogenesis imperfecta(OI) is a rare inherited connective tissue disorder caused by mutation of collagen which results in a wide spectrum of clinical manifestations including long bone fragility fractures and deformi...Osteogenesis imperfecta(OI) is a rare inherited connective tissue disorder caused by mutation of collagen which results in a wide spectrum of clinical manifestations including long bone fragility fractures and deformities. While the treatment for these fractures was recommended as using intramedullary fixation for minimizing stress concentration, the selection of the best implant in the adolescent OI patients for the surgical reconstruction of femur was still problematic, due to anatomy distortion and implant availability. We are reporting the surgical modification by using a humeral nail for femoral fixation in three adolescent OI patients with favorable outcomes.展开更多
The use of near-infrared spectroscopy (NIRS) as a means of assessing regional oxygen supply is a method that has gained recent support and interest. Given the potential of NIRS, this technology was utilized in an infa...The use of near-infrared spectroscopy (NIRS) as a means of assessing regional oxygen supply is a method that has gained recent support and interest. Given the potential of NIRS, this technology was utilized in an infant patient with a case of severe osteogenesis imperfecta that precluded conventional blood pressure monitoring. Using NIRS as a monitor and titrating the anesthetic accordingly produced a good outcome, with no post-operative evidence of detrimental intra-operative hypotension or ischemia.展开更多
Osteogenesis imperfecta (OI) belongs to a group of congenital osteoporosis which hallmark feature is “affecting skeleton, increasing bone fragility that fracture easily and decreasing bone density due to quantitative...Osteogenesis imperfecta (OI) belongs to a group of congenital osteoporosis which hallmark feature is “affecting skeleton, increasing bone fragility that fracture easily and decreasing bone density due to quantitative and/or qualita-tive abnormalities”. We report a female sibling’s involvement in 3 cases with probable recessive inheritance pattern. Only female aged between 5 and 13 years were affected with skeletal lesions in the lower limbs. The boy of this family had no skeletal or extra-skeletal lesions. Their parents had no affection and no bond of consanguinity. The observed malformations can be classified as type V or VI according to Sillence’s clinical classification. Lack of genetic test in our context has limited accuracy of the diagnosis as new data evoke a genetic classification into 12 types that leading an effective therapeutic management.展开更多
Osteogenesis Imperfecta is a rare genetic disorder of connective tissue that is caused by an error in collagen formation. The disease is characterized by abnormal bone fragility, osteopenia, blue discoloration of the ...Osteogenesis Imperfecta is a rare genetic disorder of connective tissue that is caused by an error in collagen formation. The disease is characterized by abnormal bone fragility, osteopenia, blue discoloration of the sclerae and hearing loss. Chronic non-suppurative otitis media is frequent in Osteogenesis Imperfecta patients and usually attributed to Eustachian tube dysfunction due to cranial molding and deformities. In some cases of severe Osteogenesis Imperfecta, the fragile bone of the petrous carotid canal can be broken down by the pulsations of the carotid artery, this may result in prolapse of the carotid artery into the protympanum with resultant Eustachian tube obstruction and tympanic membrane retraction with adhesion to prolapsed carotid artery, a condition called myringocarotidopexy.展开更多
Objective To detect the peculiar mutation in a Chinese family with osteogenesis imperfecta, COL1A1 and COL1A2 being analysed. Methods A genome screen was undertaken covering COL1A1 at 17q21-22 and COL1A2 at 7q22.1. Th...Objective To detect the peculiar mutation in a Chinese family with osteogenesis imperfecta, COL1A1 and COL1A2 being analysed. Methods A genome screen was undertaken covering COL1A1 at 17q21-22 and COL1A2 at 7q22.1. The Linkage (Version 5.1) was used for 2-point analysis. DNA sequencing was used to screen and identify the mutation. Results A linkage to the markers on chromosome 17q21-22 was observed. Sequence analysis of COL1A1 revealed a splicing mutation (IVS8-2A>G) that converted the 3’ end of intron 8 from AG to GG. Conclusion This mutation (IVS 8-2A>G) is novel, and has not yet been registered in the Human Type Ⅰ and Type Ⅲ Collagen Mutations Database.展开更多
Background:There are several clinical reports about the co-occurrence of autosomal dominant polycystic kidney disease(ADPKD)and connective tissue disorders.A simultaneous occurrence of osteogenesis imperfecta(OI)type ...Background:There are several clinical reports about the co-occurrence of autosomal dominant polycystic kidney disease(ADPKD)and connective tissue disorders.A simultaneous occurrence of osteogenesis imperfecta(OI)type I and ADPKD has not been observed so far.Methods:This report presents the first patient with OI type I and ADPKD.Results:Mutational analysis of PKD1 and COL1A1 in the index patient revealed a heterozygous mutation in each of the two genes.Mutational analysis of the parents indicated the mother as a carrier of the PKD1 mutation and the father as a carrier of the COL1A1 mutation.The simultaneous occurrence of both disorders has an estimated frequency of 3.5:100000000.Conclusion:In singular cases,ADPKD can occur in combination with other rare disorders,e.g.connective tissue disorders.展开更多
Background:To present a female child patient with osteogenesis imperfecta who had bilateral papilledema.Case presentation:A twelve-year-old girl with osteogenesis imperfecta was referred to our clinic.Bilateral best c...Background:To present a female child patient with osteogenesis imperfecta who had bilateral papilledema.Case presentation:A twelve-year-old girl with osteogenesis imperfecta was referred to our clinic.Bilateral best corrected visual acuity of the patient was 5/10(corrected with+3.50 for right eye,+5.00 for left eye)with a standard Snellen scale at a distance of a 6 m.Anterior chamber,iris and lens examination of both of her eyes were unremarkable.In her fundus examination,bilateral stage 2 papilledema and the wrinkles in papillomacular area were noticed.Optical coherence tomography images revealed the macular pucker and thickening in the retinal nerve fibre layers of both eyes.Computed tomography images revealed that there were ossifications in the optic chiasma and occlusion in all periorbital sinus areas.Conclusion:Osteogenesis imperfecta is a rare,autosomal dominant connective tissue disorder characterised by bone fractures,deafness and blue sclera.We would like to draw attention to the clinical course of our patient with computed tomography,optical coherence tomography and visual field findings.展开更多
Congenital osteogenesis imperfecta is a rare autosomal dominant genetic disease.Pregnant women with the disease pose a treatment challenge to doctors who cannot predict the pregnancy outcome and recommend an appropria...Congenital osteogenesis imperfecta is a rare autosomal dominant genetic disease.Pregnant women with the disease pose a treatment challenge to doctors who cannot predict the pregnancy outcome and recommend an appropriate abortive approach.We present the case report of a 26-year-old female who showed typical symptom of congenital osteogenesis imperfecta.Considering the heredity of the disease,the patient and her family decided to prematurely terminate the gestation.The patient presented with a treatment dilemma was difficult to identify a route of uterine entry because it was impossible to prop the patient in a lithotomy position.After consulting with the patient,the pregnancy was terminated by cesarean delivery.The surgery was successful;in our opinion,however,the cesarean delivery was not the best abortive approach to use in this case because of the severity of the procedure and the complications that could have arisen from it.Further studies are needed to identify a better abortive approach for similar cases.展开更多
INTRODUCTION Osteogenesis imperfecta (OI), also known as brittle bone disease or Lobstein syndrome, is characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurr...INTRODUCTION Osteogenesis imperfecta (OI), also known as brittle bone disease or Lobstein syndrome, is characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractures.Based on clinical, genetic, and radiological features, Sillence et al.[1] classified the OI into four subtypes including type Ⅰ: Mild,common, with blue sclera;type Ⅱ: Perinatal lethal form;type Ⅲ: Severe and age-related progressive deformity, with normal sclera;and type Ⅳ: Moderate severity with normal sclera.Based on mutated genes and inheritance patterns, the four subtypes are further classified into 15 types of OI in Online Mendelian Inheritance in Man.More than 90％ of the patients with OI have mutations in collagen type Ⅰ alpha (COL1A) 1 and COL1A2.[2]展开更多
Osteogenesis imperfecta(OI)is mainly characterized by bone fragility and Ehlers-Danlos syndrome(EDS)by connective tissue defects.Mutations in COL1A1 or COL1A2 can lead to both syndromes.OI/EDS overlap syndrome is most...Osteogenesis imperfecta(OI)is mainly characterized by bone fragility and Ehlers-Danlos syndrome(EDS)by connective tissue defects.Mutations in COL1A1 or COL1A2 can lead to both syndromes.OI/EDS overlap syndrome is mostly caused by helical mutations near the amino-proteinase cleavage site of type Ⅰ procollagen.In this study,we identified a Thai patient having OI type Ⅲ,EDS,brachydactyly,and dentinogenesis imperfecta.His dentition showed delayed eruption,early exfoliation,and severe malocclusion.For the first time,ultrastructural analysis of the tooth affected with OI/EDS showed that the tooth had enamel inversion,bonelike dentin,loss of dentinal tubules,and reduction in hardness and elasticity,suggesting severe developmental disturbance.These severe dental defects have never been reported in OI or EDS.Exome sequencing identified a novel de novo heterozygous glycine substitution,c.3296G>A,p.Gly1099Glu,in exon 49 of COL1A2.Three patients with mutations in the exon 49 of COL1A2 were previously reported to have OI with brachydactyly and intracranial hemorrhage.Notably,two of these three patients did not show hyperextensible joints and hypermobile skin,while our patient at the age of 5 years had not developed intracranial hemorrhage.Here,we demonstrate that the novel glycine substitution in the carboxyl region of alpha2(Ⅰ)collagen triple helix leads to OI/EDS with brachydactyly and severe tooth defects,expanding the genotypic and phenotypic spectra of OI/EDS overlap syndrome.展开更多
Background:Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is mainly caused by mutations in COL1A1 gene encoding α1 chain of type I collagen.This study aimed to investigate the COL1A1 mutation spec...Background:Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is mainly caused by mutations in COL1A1 gene encoding α1 chain of type I collagen.This study aimed to investigate the COL1A1 mutation spectrum and quantitatively assess the genotype-phenotype relationship in a large cohort of Chinese patients with OI.Methods:A total of 161 patients who were diagnosed as OI in Department of Endocrinology of Peking Union Medical College Hospital from January 2010 to December 2017 were included in the study.The COL1A1 mutation spectrum was identified by next generation sequencing and confirmed by Sanger sequencing.A new clinical scoring system was developed to quantitatively assess the clinical severity of OI and the genotype-phenotype relationship was analyzed.The independent sample t-test, analysis of variance, Mann-Whitney U-test, Chi-squared test, Pearson correlation, and multiple linear regression were applied for statistical analyses.Results:Among 161 patients with OI, 32.9% missense mutations, 16.8% non-sense mutations, 24.2% splice-site mutations, 24.8% frameshift mutations, and 1.2% whole-gene deletions were identified, of which 38 variations were novel.These mutations led to 53 patients carrying qualitative defects and 67 patients carrying quantitative defects in type I collagen.Compared to patients with quantitative mutations, patients with qualitative mutations had lower alkaline phosphatase level (296 [132, 346] U/L vs.218 [136, 284] U/L, P=0.009) and higher clinical score (12.2 ± 5.3 vs.7.4 ± 2.4, P<0.001), denoting more severe phenotypes including shorter stature, lower bone mineral density, higher fracture frequency, more bone deformity, vertebral compressive fractures, limited movement, and dentinogenesis imperfecta (DI).Patients would not present with DI if the glycine substitutions happened before the 79th amino acid in triple helix of α1 chains .Conclusions:This presented distinctive COL1A1 mutation spectrum in a large cohort of Chinese patients with OI.This new quantitative analysis of genotype-phenotype correlation would be helpful to predict the prognosis of OI and genetic counseling.展开更多
As the major cell precursors in osteogenesis, mesenchymal stem cells(MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversia...As the major cell precursors in osteogenesis, mesenchymal stem cells(MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversial. Composed of multiple constituent enhancers, super enhancers(SEs) are powerful cis-regulatory elements that identify genes that ensure sequential differentiation. The present study demonstrated that SEs were indispensable for MSC osteogenesis and involved in osteoporosis development. Through integrated analysis, we identified the most common SE-targeted and osteoporosis-related osteogenic gene,ZBTB16. ZBTB16, positively regulated by SEs, promoted MSC osteogenesis but was expressed at lower levels in osteoporosis.Mechanistically, SEs recruited bromodomain containing 4(BRD4) at the site of ZBTB16, which then bound to RNA polymerase IIassociated protein 2(RPAP2) that transported RNA polymerase Ⅱ(POL Ⅱ) into the nucleus. The subsequent synergistic regulation of POL Ⅱ carboxyterminal domain(CTD) phosphorylation by BRD4 and RPAP2 initiated ZBTB16 transcriptional elongation, which facilitated MSC osteogenesis via the key osteogenic transcription factor SP7. Bone-targeting ZBTB16 overexpression had a therapeutic effect on the decreased bone density and remodeling capacity of Brd4^(fl/fl)Prx1-cre mice and osteoporosis(OP) models.Therefore, our study shows that SEs orchestrate the osteogenesis of MSCs by targeting ZBTB16 expression, which provides an attractive focus and therapeutic target for osteoporosis.展开更多
文摘Osteogenesis imperfecta(OI)is a genetically heterogeneous monogenic disease characterized by decreased bone mass,bone fragility,and recurrent fractures.The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature.The basic mechanism is a collagen-related defect,not only in synthesis but also in folding,processing,bone mineralization,or osteoblast function.In recent years,great progress has been made in identifying new genes and molecular mechanisms underlying OI.In this context,the classification of OI has been revised several times and different types are used.The Sillence classification,based on clinical and radiological characteristics,is currently used as a grading of clinical severity.Based on the metabolic pathway,the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches.Genetic classification has the advantage of identifying the inheritance pattern,an essential element for genetic counseling and prophylaxis.Although genotype-phenotype correlations may sometimes be challenging,genetic diagnosis allows a personalized management strategy,accurate family planning,and pregnancy management decisions including options for mode of delivery,or early antenatal OI treatment.Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches.This narrative review summarizes our current understanding of genes,molecular mechanisms involved in OI,classifications,and their utility in prophylaxis.
文摘Being such a rare condition in paediatrics, osteogenesis imperfecta (OI) is not a diagnosis which is made often. It is however, a diagnosis necessitating early diagnosis and timeous and effective management to improve morbidity and increase the quality of life for our patients. We report two cases of osteogenesis imperfecta in this case report to highlight the different phenotypic presentations. Both of these patients are unique in their presentations and each case highlights the importance of a high clinical index of suspicion by the practitioner in making the diagnosis of osteogenesis imperfecta. The first case is a patient who was diagnosed with osteogenesis imperfecta on day one of life. She had disproportionate short stature, blue sclera, a small chest and bowing of her lower limbs with swellings and tenderness over both of her femurs. A babygram radiograph revealed multiple fractures, with the presence of callus formation at some fracture sites suggesting intrauterine fractures. The second case is a patient who had normal anthropometry and was well at birth. She was subsequently diagnosed at two weeks of age when she presented to the Chris Hani Baragwanath Academic Hospital with an E. coli meningitis and she was suspected to have a right clavicular fracture and possibly rib fractures as she had pain on palpation over these areas. She was noted to have no blue sclera. Subsequent X-rays confirmed a right clavicular fracture as well as left and right rib fractures at different stages of healing. A lateral skull radiograph revealed Wormian bones. With no available genetic testing in South Africa, both diagnoses were made clinically. Both of our patients were started on zoledronic acid at three months of age and were followed up by the Metabolic Unit at the Chis Hani Baragwanath Academic Hospital. This case report of two patients highlights the characteristics important in diagnosing and treating this uncommon condition with varying phenotypical presentations, thus ensuring that the diagnosis is not missed or misdiagnosed: one disorder, two different faces.
基金part financed from Institutional grant KNW-1-010/P/1/0 and KNW-1-007/P/2/0 awarded to ALSco-financed by the EU funds(European Re-gional Development Fund)within the Sectoral Operational Program“Increase of Economic Competitiveness”No.WKP1/1.4/3/2/2005/103/223/565/2007/USilesian Bio-Farma Center for Biotechnology,Bioengineering and Bioinformatics,Project no POIG.02.01.00-00-166/08,THE OPERATIONAL PROGRAMME INNOVATIVE ECONOMY FOR 2007-2013,Priority Axis 2.R&D Infrastructure.
文摘The allogenic bone marrow derived mesenchymal stem cells transplantation was given to the newborn girl diagnosed with osteogenesis imperfecta type III, with multiple bone fractures, extreme shortness and limbs deformities. The treatment was performed at the age of 4 and 6 weeks. The clinical diagnosis was supported by biochemical analysis of collagen type I recovered from culture medium of cultivated patient’s skin fibroblast, which revealed its triple helix instability at temperature about 2?C lower than normal. Sequencing of both genes encoding procollagen type I revealed heterozygous substitution G23569Ain COL1A2 gene causing change of glycine at position 517 to aspartate. The donor of mesenchymal stem cells was the girl’s father. She received two intravenous infusions of suspended cultured mesenchymal cells in 16 days apart without any side effects. An analysis of procollagen type I secreted to the culture medium by bone marrow-derived mesenchymal stem cells obtained from the patient, 3 months following transplantation revealed its normal triple helix stability. During the subsequent two years of follow up two new bone fractures were noted. Currently a two-year-old girl’s presents extreme growth and weight deficiency. The motoric development is also retarded, but the patient constantly improves and makes progresses.
文摘Osteogenesis imperfecta is a rare hereditary bone disease which is commonly classified into types I-IV,each of varying severity.The clinical symptoms of the disease consist of increased bone brittleness and recurrent fractures coupled with a variety of complications.The disease damages children’s body functions and restricts their daily activities,thus affects their psychological experience of living conditions and reduces their quality of life.The quality of life of children with osteogenesis imperfecta is primarily assessed through a universal scale and so far there is no osteogenesis imperfecta-specific quality of life scale,which is of great value to the assessment of quality of life.Pain symptoms,related complications,and limitations on physical exercise have been shown to be related to the assessment of quality of life and negatively affect the physical and psychological aspects of quality of life in children with osteogenesis imperfecta.This negative effect is found to be more serious in children diagnosed with severe types of osteogenesis imperfecta.Initial research into bisphosphonate therapy as a treatment for osteogenesis imperfecta has shown promising results in providing a better quality of life,but this treatment needs to be further studied and guided by the assessing results of quality of life.In the future,better methods of assessment and improvement of quality of life for children with osteogenesis imperfecta still rely on the efforts of all sectors of society.
基金supported by China Association for Science and Technology Graduate Science Communication Ability Promotion Project(Grant kxyjskpxm2019024 and kxyjskpxm2019055)Key Research Base of Philosophy and Social Sciences in Shaanxi Province,Shaanxi Health Culture Research Center Projects(Grand JKWH2019-Q19).
文摘Due to the incurable characteristics of osteogenesis imperfecta,health management plays a crucial role for children in healthy growth,independent life and integrating into society.This paper summarizes three dimensions of "biology-psychology-society",which summarize the research progress for health management in children with osteogenesis imperfecta.In the dimension of biology,the management on diet and complications about children is relatively definite,but more experiments are still needed in order to find out the appropriate values for the using doses of bisphosphonate and treatment time.Additionally,there is a lack of tools to assess the painful degree in children and sports management methods with different types of children with osteogenesis imperfecta nowadays.In the dimension of psychology,it is found that children with osteogenesis imperfecta,their families and carers are all expected to maintain a good state of mind.In the social dimension,we have known the need of children and their families,but their supporting systems are still expected to be improved through practice.
文摘Osteogenesis imperfecta(OI) is a rare inherited connective tissue disorder caused by mutation of collagen which results in a wide spectrum of clinical manifestations including long bone fragility fractures and deformities. While the treatment for these fractures was recommended as using intramedullary fixation for minimizing stress concentration, the selection of the best implant in the adolescent OI patients for the surgical reconstruction of femur was still problematic, due to anatomy distortion and implant availability. We are reporting the surgical modification by using a humeral nail for femoral fixation in three adolescent OI patients with favorable outcomes.
文摘The use of near-infrared spectroscopy (NIRS) as a means of assessing regional oxygen supply is a method that has gained recent support and interest. Given the potential of NIRS, this technology was utilized in an infant patient with a case of severe osteogenesis imperfecta that precluded conventional blood pressure monitoring. Using NIRS as a monitor and titrating the anesthetic accordingly produced a good outcome, with no post-operative evidence of detrimental intra-operative hypotension or ischemia.
文摘Osteogenesis imperfecta (OI) belongs to a group of congenital osteoporosis which hallmark feature is “affecting skeleton, increasing bone fragility that fracture easily and decreasing bone density due to quantitative and/or qualita-tive abnormalities”. We report a female sibling’s involvement in 3 cases with probable recessive inheritance pattern. Only female aged between 5 and 13 years were affected with skeletal lesions in the lower limbs. The boy of this family had no skeletal or extra-skeletal lesions. Their parents had no affection and no bond of consanguinity. The observed malformations can be classified as type V or VI according to Sillence’s clinical classification. Lack of genetic test in our context has limited accuracy of the diagnosis as new data evoke a genetic classification into 12 types that leading an effective therapeutic management.
文摘Osteogenesis Imperfecta is a rare genetic disorder of connective tissue that is caused by an error in collagen formation. The disease is characterized by abnormal bone fragility, osteopenia, blue discoloration of the sclerae and hearing loss. Chronic non-suppurative otitis media is frequent in Osteogenesis Imperfecta patients and usually attributed to Eustachian tube dysfunction due to cranial molding and deformities. In some cases of severe Osteogenesis Imperfecta, the fragile bone of the petrous carotid canal can be broken down by the pulsations of the carotid artery, this may result in prolapse of the carotid artery into the protympanum with resultant Eustachian tube obstruction and tympanic membrane retraction with adhesion to prolapsed carotid artery, a condition called myringocarotidopexy.
基金Supported by grants from National Nature Science Foundation of China (30470951) and National Science Foundation for Distinguished YoungScholars of China (39925023).
文摘Objective To detect the peculiar mutation in a Chinese family with osteogenesis imperfecta, COL1A1 and COL1A2 being analysed. Methods A genome screen was undertaken covering COL1A1 at 17q21-22 and COL1A2 at 7q22.1. The Linkage (Version 5.1) was used for 2-point analysis. DNA sequencing was used to screen and identify the mutation. Results A linkage to the markers on chromosome 17q21-22 was observed. Sequence analysis of COL1A1 revealed a splicing mutation (IVS8-2A>G) that converted the 3’ end of intron 8 from AG to GG. Conclusion This mutation (IVS 8-2A>G) is novel, and has not yet been registered in the Human Type Ⅰ and Type Ⅲ Collagen Mutations Database.
文摘Background:There are several clinical reports about the co-occurrence of autosomal dominant polycystic kidney disease(ADPKD)and connective tissue disorders.A simultaneous occurrence of osteogenesis imperfecta(OI)type I and ADPKD has not been observed so far.Methods:This report presents the first patient with OI type I and ADPKD.Results:Mutational analysis of PKD1 and COL1A1 in the index patient revealed a heterozygous mutation in each of the two genes.Mutational analysis of the parents indicated the mother as a carrier of the PKD1 mutation and the father as a carrier of the COL1A1 mutation.The simultaneous occurrence of both disorders has an estimated frequency of 3.5:100000000.Conclusion:In singular cases,ADPKD can occur in combination with other rare disorders,e.g.connective tissue disorders.
文摘Background:To present a female child patient with osteogenesis imperfecta who had bilateral papilledema.Case presentation:A twelve-year-old girl with osteogenesis imperfecta was referred to our clinic.Bilateral best corrected visual acuity of the patient was 5/10(corrected with+3.50 for right eye,+5.00 for left eye)with a standard Snellen scale at a distance of a 6 m.Anterior chamber,iris and lens examination of both of her eyes were unremarkable.In her fundus examination,bilateral stage 2 papilledema and the wrinkles in papillomacular area were noticed.Optical coherence tomography images revealed the macular pucker and thickening in the retinal nerve fibre layers of both eyes.Computed tomography images revealed that there were ossifications in the optic chiasma and occlusion in all periorbital sinus areas.Conclusion:Osteogenesis imperfecta is a rare,autosomal dominant connective tissue disorder characterised by bone fractures,deafness and blue sclera.We would like to draw attention to the clinical course of our patient with computed tomography,optical coherence tomography and visual field findings.
文摘Congenital osteogenesis imperfecta is a rare autosomal dominant genetic disease.Pregnant women with the disease pose a treatment challenge to doctors who cannot predict the pregnancy outcome and recommend an appropriate abortive approach.We present the case report of a 26-year-old female who showed typical symptom of congenital osteogenesis imperfecta.Considering the heredity of the disease,the patient and her family decided to prematurely terminate the gestation.The patient presented with a treatment dilemma was difficult to identify a route of uterine entry because it was impossible to prop the patient in a lithotomy position.After consulting with the patient,the pregnancy was terminated by cesarean delivery.The surgery was successful;in our opinion,however,the cesarean delivery was not the best abortive approach to use in this case because of the severity of the procedure and the complications that could have arisen from it.Further studies are needed to identify a better abortive approach for similar cases.
基金supported by the China Natural Science Foundation grants (Nos. 30670736 and 30972655)the National Basic Research Program of China (973 Program) (No. 2007CB512002).
文摘成骨 imperfecta (OI，也已知的同样易碎的骨头疾病) 主要被变化在二种类型引起我编码类型的 pro-1 (I) 和 pro-2 (I) 链的骨胶原基因， COL1A1 和 COL1A2 我骨胶原分别地。有正染色体的主导的 OI 的二个中国家庭被识别并且描绘。连接分析在染色体 7q21.3-q22.1 上揭示了两个家庭的连接到 COL1A2。Mutational 分析用直接 DNA 顺序分析被执行。二个新奇错误感觉变化， c.3350A > G 和 c.3305G > C，在 exon 被识别在二个家庭的 49 COL1A2 分别地。c.3305G > C 变化在 codon 由丙氨酸残余(A) 导致了 glycine 残余(G) 的替换 1102 (p.G1102A ) ，它被发现在另外的家庭被变异进丝氨酸(S) ， argine (R) ，丁氨二酸酸(D) ，或缬氨酸(V) 。c.3350A > G 变体可以是导致 p.Y1117C 的一个 de novo 变化。两个变化在各自的家庭与 OI 共同分离，并且没在 100 正常控制被发现。G1102 和 Y1117 残余高度 evolutionarily 从 zebrafish 被保存到人。Mutational 分析没在 COX-2 基因(OI 的修饰词基因) 识别任何变化。这研究识别引起 OI 的二新奇变化 p.G1102A 和 p.Y1117C，显著地扩展引起 OI 的 COL1A2 变化的光谱，并且有在 OI 的出生前的诊断的一个重要含意。
文摘INTRODUCTION Osteogenesis imperfecta (OI), also known as brittle bone disease or Lobstein syndrome, is characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractures.Based on clinical, genetic, and radiological features, Sillence et al.[1] classified the OI into four subtypes including type Ⅰ: Mild,common, with blue sclera;type Ⅱ: Perinatal lethal form;type Ⅲ: Severe and age-related progressive deformity, with normal sclera;and type Ⅳ: Moderate severity with normal sclera.Based on mutated genes and inheritance patterns, the four subtypes are further classified into 15 types of OI in Online Mendelian Inheritance in Man.More than 90％ of the patients with OI have mutations in collagen type Ⅰ alpha (COL1A) 1 and COL1A2.[2]
基金supported by the 90th Anniversary of Chulalongkorn University,Rachadapisek Sompote FundFaculty of Dentistry(DFR62003),Chulalongkorn University+3 种基金Chulalongkorn Academic Advancement Into Its 2nd Century ProjectNewton FundThailand Research Fund(RSA6280001,DPG6180001)supported by Ratchadapisek Somphot Fund for Postdoctoral Fellowship,Chulalongkorn University,Thailand。
文摘Osteogenesis imperfecta(OI)is mainly characterized by bone fragility and Ehlers-Danlos syndrome(EDS)by connective tissue defects.Mutations in COL1A1 or COL1A2 can lead to both syndromes.OI/EDS overlap syndrome is mostly caused by helical mutations near the amino-proteinase cleavage site of type Ⅰ procollagen.In this study,we identified a Thai patient having OI type Ⅲ,EDS,brachydactyly,and dentinogenesis imperfecta.His dentition showed delayed eruption,early exfoliation,and severe malocclusion.For the first time,ultrastructural analysis of the tooth affected with OI/EDS showed that the tooth had enamel inversion,bonelike dentin,loss of dentinal tubules,and reduction in hardness and elasticity,suggesting severe developmental disturbance.These severe dental defects have never been reported in OI or EDS.Exome sequencing identified a novel de novo heterozygous glycine substitution,c.3296G>A,p.Gly1099Glu,in exon 49 of COL1A2.Three patients with mutations in the exon 49 of COL1A2 were previously reported to have OI with brachydactyly and intracranial hemorrhage.Notably,two of these three patients did not show hyperextensible joints and hypermobile skin,while our patient at the age of 5 years had not developed intracranial hemorrhage.Here,we demonstrate that the novel glycine substitution in the carboxyl region of alpha2(Ⅰ)collagen triple helix leads to OI/EDS with brachydactyly and severe tooth defects,expanding the genotypic and phenotypic spectra of OI/EDS overlap syndrome.
基金grants from the National Natural Science Foundation of China (No.81570802)Chinese Academy of Medical Sciences Innovative Fund for Medical Sciences (CIFMS+1 种基金No.2016-I2M-3-003)The National Key Research and Development Program of China (No.2016YFC0901501).
文摘Background:Osteogenesis imperfecta (OI), a heritable bone fragility disorder, is mainly caused by mutations in COL1A1 gene encoding α1 chain of type I collagen.This study aimed to investigate the COL1A1 mutation spectrum and quantitatively assess the genotype-phenotype relationship in a large cohort of Chinese patients with OI.Methods:A total of 161 patients who were diagnosed as OI in Department of Endocrinology of Peking Union Medical College Hospital from January 2010 to December 2017 were included in the study.The COL1A1 mutation spectrum was identified by next generation sequencing and confirmed by Sanger sequencing.A new clinical scoring system was developed to quantitatively assess the clinical severity of OI and the genotype-phenotype relationship was analyzed.The independent sample t-test, analysis of variance, Mann-Whitney U-test, Chi-squared test, Pearson correlation, and multiple linear regression were applied for statistical analyses.Results:Among 161 patients with OI, 32.9% missense mutations, 16.8% non-sense mutations, 24.2% splice-site mutations, 24.8% frameshift mutations, and 1.2% whole-gene deletions were identified, of which 38 variations were novel.These mutations led to 53 patients carrying qualitative defects and 67 patients carrying quantitative defects in type I collagen.Compared to patients with quantitative mutations, patients with qualitative mutations had lower alkaline phosphatase level (296 [132, 346] U/L vs.218 [136, 284] U/L, P=0.009) and higher clinical score (12.2 ± 5.3 vs.7.4 ± 2.4, P<0.001), denoting more severe phenotypes including shorter stature, lower bone mineral density, higher fracture frequency, more bone deformity, vertebral compressive fractures, limited movement, and dentinogenesis imperfecta (DI).Patients would not present with DI if the glycine substitutions happened before the 79th amino acid in triple helix of α1 chains .Conclusions:This presented distinctive COL1A1 mutation spectrum in a large cohort of Chinese patients with OI.This new quantitative analysis of genotype-phenotype correlation would be helpful to predict the prognosis of OI and genetic counseling.
基金supported by the National Natural Science Foundation of China [82172385 to H.S., 82172349 to Y.W.]the Key-Area Research and Development Program of Guangdong Province [2019B020236001 to H.S.]+3 种基金the Shenzhen Key Medical Discipline Construction Fund [ZDSYS20190902092851024 to H.S.]the Natural Science Foundation of Guangdong Province [2020A1515010097 to Z.X.]the Shenzhen Outstanding Science and Technology Innovation Talents-Outstanding Youth Fund project [RCYX20210706092106042 to Z.X.]Funding for open access charge:Shenzhen Key Medical Discipline Construction Fund。
文摘As the major cell precursors in osteogenesis, mesenchymal stem cells(MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversial. Composed of multiple constituent enhancers, super enhancers(SEs) are powerful cis-regulatory elements that identify genes that ensure sequential differentiation. The present study demonstrated that SEs were indispensable for MSC osteogenesis and involved in osteoporosis development. Through integrated analysis, we identified the most common SE-targeted and osteoporosis-related osteogenic gene,ZBTB16. ZBTB16, positively regulated by SEs, promoted MSC osteogenesis but was expressed at lower levels in osteoporosis.Mechanistically, SEs recruited bromodomain containing 4(BRD4) at the site of ZBTB16, which then bound to RNA polymerase IIassociated protein 2(RPAP2) that transported RNA polymerase Ⅱ(POL Ⅱ) into the nucleus. The subsequent synergistic regulation of POL Ⅱ carboxyterminal domain(CTD) phosphorylation by BRD4 and RPAP2 initiated ZBTB16 transcriptional elongation, which facilitated MSC osteogenesis via the key osteogenic transcription factor SP7. Bone-targeting ZBTB16 overexpression had a therapeutic effect on the decreased bone density and remodeling capacity of Brd4^(fl/fl)Prx1-cre mice and osteoporosis(OP) models.Therefore, our study shows that SEs orchestrate the osteogenesis of MSCs by targeting ZBTB16 expression, which provides an attractive focus and therapeutic target for osteoporosis.
