Osteogenesis imperfecta(OI)is a group of diseases caused by defects in type I collagen processing which result in skeletal fragility.While these disorders have been regarded as defects in osteoblast function,the role ...Osteogenesis imperfecta(OI)is a group of diseases caused by defects in type I collagen processing which result in skeletal fragility.While these disorders have been regarded as defects in osteoblast function,the role of matrix-embedded osteocytes in OI pathogenesis remains largely unknown.Homozygous human SP7(c.946 C>T,R316C)mutation results in a recessive form of OI characterized by fragility fractures,low bone mineral density and osteocyte dendrite defects.To better understand how the OI-causing R316C mutation affects the function of SP7,we generated Sp7^(R342C)knock-in mice.Consistent with patient phenotypes,Sp7^(R342C/R342C)mice demonstrate increased cortical porosity and reduced cortical bone mineral density.Sp7^(R342C/R342C)mice show osteocyte dendrite defects,increased osteocyte apoptosis,and intracortical bone remodeling with ectopic intracortical osteoclasts and elevated osteocyte Tnfsf11 expression.展开更多
Osteogenesis imperfecta（OI,also known as brittle bone disease）is caused mostly by mutations in two type I collagen genes,COL1A1 and COLIA2 encoding the pro-α1（I）and pro-α2（I）chains of type I collagen,respectiv...Osteogenesis imperfecta（OI,also known as brittle bone disease）is caused mostly by mutations in two type I collagen genes,COL1A1 and COLIA2 encoding the pro-α1（I）and pro-α2（I）chains of type I collagen,respectively.Two Chinese families with autosomal dominant OI were identified and characterized.Linkage analysis revealed linkage of both families to COL1A2 on chromosome 7q21.3-q22.1.Mutational analysis was carried out using direct DNA sequence analysis.Two novel missense mutations,c.3350AG and c.3305GC,were identified in exon 49 of COL1A2 in the two families,respectively.The c.3305GC mutation resulted in substitution of a glycine residue（G）by an alanine residue（A）at codon 1102（p.G1102A）,which was found to be mutated into serine（S）,argine（R）,aspartic acid（D）,or valine（V）in other families.The c.3350AG variant may be a de novo mutation resulting in p.Y1117C.Both mutations co-segregated with OI in respective families,and were not found in 100 normal controls.The G1102 and Y1117 residues were evolutionarily highly conserved from zebrafish to humans.Mutational analysis did not identify any mutation in the COX-2 gene（a modifier gene of OI）.This study identifies two novel mutations p.G1102A and p.Y1117C that cause OI,significantly expands the spectrum of COL1A2 mutations causing OI,and has a significant implication in prenatal diagnosis of OI.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
Tooth development is a complex process that involves precise and time-dependent orchestration of multiple genetic, molecular,and cellular interactions. Ameloblastin(AMBN, also named "amelin" or "sheathl...Tooth development is a complex process that involves precise and time-dependent orchestration of multiple genetic, molecular,and cellular interactions. Ameloblastin(AMBN, also named "amelin" or "sheathlin") is the second most abundant enamel matrix protein known to have a key role in amelogenesis. Amelogenesis imperfecta(AI [MIM: 104500]) refers to a genetically and phenotypically heterogeneous group of conditions characterized by inherited developmental enamel defects. The hereditary dentin disorders comprise a variety of autosomal-dominant genetic symptoms characterized by abnormal dentin structure affecting either the primary or both the primary and secondary teeth. The vital role of Ambn in amelogenesis has been confirmed experimentally using mouse models. Only two cases have been reported of mutations of AMBN associated with non-syndromic human AI. However, no AMBN missense mutations have been reported to be associated with both human AI and dentin disorders.We recruited one kindred with autosomal-dominant amelogenesis imperfecta(ADAI) and dentinogenesis imperfecta/dysplasia characterized by generalized severe enamel and dentin defects. Whole exome sequencing of the proband identified a novel heterozygous C-T point mutation at nucleotide position 1069 of the AMBN gene, causing a Pro to Ser mutation at the conserved amino acid position 357 of the protein. Exfoliated third molar teeth from the affected family members were found to have enamel and dentin of lower mineral density than control teeth, with thinner and easily fractured enamel, short and thick roots, and pulp obliteration. This study demonstrates, for the first time, that an AMBN missense mutation causes non-syndromic human AI and dentin disorders.展开更多
Osteogenesis imperfecta（OI） comprises a group of heritable connective tissue disorders generally defined by recurrent fractures, low bone mass, short stature and skeletal fragility. Beyond the skeletal complications...Osteogenesis imperfecta（OI） comprises a group of heritable connective tissue disorders generally defined by recurrent fractures, low bone mass, short stature and skeletal fragility. Beyond the skeletal complications of OI,many patients also report intolerance to physical activity, fatigue and muscle weakness. Indeed, recent studies have demonstrated that skeletal muscle is also negatively affected by OI, both directly and indirectly. Given the well-established interdependence of bone and skeletal muscle in both physiology and pathophysiology and the observations of skeletal muscle pathology in patients with OI, we investigated the therapeutic potential of simultaneous anabolic targeting of both bone and skeletal muscle using a soluble activin receptor 2B（ACVR2B） in a mouse model of type Ⅲ OI（oim）. Treatment of 12-week-old oim mice with ACVR2 B for 4 weeks resulted in significant increases in both bone and muscle that were similar to those observed in healthy,wild-type littermates. This proof of concept study provides encouraging evidence for a holistic approach to treating the deleterious consequences of OI in the musculoskeletal system.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(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
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
In this report, we describe the performance of a conservative and minimally invasive dental approach in four patients exhibiting Amelogenesis Imperfecta (AI), a structural anomaly of the enamel. In each patient, appro...In this report, we describe the performance of a conservative and minimally invasive dental approach in four patients exhibiting Amelogenesis Imperfecta (AI), a structural anomaly of the enamel. In each patient, approximately 0.5 mm of the most external, porous, and colored enamel layer was removed, and the teeth were restored using two different nanocomposites. Posterior restorations were completed with the same approach. As a result, this contemporary restorative system is a conservative and successful treatment option to restore the loss of oral esthetics and function due to AI. Rehabilitation with direct resin restorations is not only an inexpensive treatment choice, but also a more conservative technique that reduces the amount of preparation required for teeth that are already compromised.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
Osteogenesis imperfecta is a hereditary disease characterized by bone fragility due to a defect in type I collagen synthesis. The diagnosis is typically suspected based on suggestive ultrasound findings and confirmed ...Osteogenesis imperfecta is a hereditary disease characterized by bone fragility due to a defect in type I collagen synthesis. The diagnosis is typically suspected based on suggestive ultrasound findings and confirmed through genetic studies. We present a case of osteogenesis imperfecta suspected during obstetrical ultrasound at 19 weeks’ gestation, which was later confirmed radiographically through computed tomography. Due to the severity of the condition, therapeutic termination of pregnancy was indicated.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
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 COLIA2 at 7q22.1. T...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 COLIA2 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. Se- quence analysis of COLIA1 revealed a splicing mutation （IVSS-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
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
Background Osteogenesis imperfecta （OI） is a rare bone disease and its effective treatment is relatively deficient. We tried to assess the effects of new bisphosphonate, ibandronate on children with OI.Methods In th...Background Osteogenesis imperfecta （OI） is a rare bone disease and its effective treatment is relatively deficient. We tried to assess the effects of new bisphosphonate, ibandronate on children with OI.Methods In this open-label, prospective, controlled study, 30 children with OI were enrolled. They received either infusions of ibandronate （2 mg） in every three months or oral calcitriol 0.25 μg daily for 24 months. All patients took 500 mg calcium plus 200 U vitamin D daily together. The endpoints were the change of annual new fracture rate （observed by case history and X ray films of spine）, bone mineral density （BMD, measured by dual energy X-ray absortiometry）, serum concentration of carboxy-telopeptide cross-links of type Ⅰ collagen （CTX, bone resorption marker） and alkaline phosphatase （ALP, bone formation marker） during the follow-up.Results After the cyclic infusions of ibandronate, the annual new fracture rate was significantly decreased from 1.9 to 0.13 time, obviously lower than that of calcitriol group, which decreased from 1.8 to 1.0 time after the treatment （P 〈0.001）.The significant increase of BMD at the lumbar spine, femoral neck, trochanter, total hip was found in the group of ibandronate by 59.0%, 42.0%, 47.5% and 36.6% in time dependent manner （compared with the baseline, P 〈0.001）. The increase of BMD in ibandronate group was greater than that of calcitriol group （P 〈0.001）. The concentrations of ALP and CTX were obviously decreased in ibandronate group, and the reduction of CTX was more significant than that of ALP （P 〈0.001）. The tolerance of the children to ibandronate was quite well. Mild fever and muscle pain were found in 9 cases within 1-3 days after the first infusion of ibandronate, which could relieve after 1-2 days without special management.Conclusions The benefits of cyclic infusions of ibandronate to children with OI are significant because ibandronate could significantly reduce annual bone fracture rate, increase lumbar and hip BMD, preserve vertebral morphometry of patients through inhibition of bone resorption.展开更多
Osteogenesis imperfecta （01）, 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 fractur...Osteogenesis imperfecta （01）, 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. 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 detbrmity, with normal sclera; and type Ⅳ： Moderate severity with normal sclera.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 encodingα1 chain of type I collagen.This study aimed to investigate the COL1A1 mutation spectrum...Background:Osteogenesis imperfecta(OI),a heritable bone fragility disorder,is mainly caused by mutations in COL1A1 gene encodingα1 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 ofα1 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
基金support from the National Institute of Health(K99AR081897,R00AR081897)M.N.W.acknowledges funding support from the National Institute of Health(P01DK011794,R01DK116716)+1 种基金the Smith Family Foundation Odyssey Award,and the Chen Institute Massachusetts General Hospital Research Scholar(2024-2029)awardμCT and bone histomorphometry were performed by the Center for Skeletal Research at Massachusetts General Hospital,a NIH-funded program(P30AR066261 and AR075042)led by Mary Bouxsein and Marie Demay.
文摘Osteogenesis imperfecta(OI)is a group of diseases caused by defects in type I collagen processing which result in skeletal fragility.While these disorders have been regarded as defects in osteoblast function,the role of matrix-embedded osteocytes in OI pathogenesis remains largely unknown.Homozygous human SP7(c.946 C>T,R316C)mutation results in a recessive form of OI characterized by fragility fractures,low bone mineral density and osteocyte dendrite defects.To better understand how the OI-causing R316C mutation affects the function of SP7,we generated Sp7^(R342C)knock-in mice.Consistent with patient phenotypes,Sp7^(R342C/R342C)mice demonstrate increased cortical porosity and reduced cortical bone mineral density.Sp7^(R342C/R342C)mice show osteocyte dendrite defects,increased osteocyte apoptosis,and intracortical bone remodeling with ectopic intracortical osteoclasts and elevated osteocyte Tnfsf11 expression.
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Osteogenesis imperfecta（OI,also known as brittle bone disease）is caused mostly by mutations in two type I collagen genes,COL1A1 and COLIA2 encoding the pro-α1（I）and pro-α2（I）chains of type I collagen,respectively.Two Chinese families with autosomal dominant OI were identified and characterized.Linkage analysis revealed linkage of both families to COL1A2 on chromosome 7q21.3-q22.1.Mutational analysis was carried out using direct DNA sequence analysis.Two novel missense mutations,c.3350AG and c.3305GC,were identified in exon 49 of COL1A2 in the two families,respectively.The c.3305GC mutation resulted in substitution of a glycine residue（G）by an alanine residue（A）at codon 1102（p.G1102A）,which was found to be mutated into serine（S）,argine（R）,aspartic acid（D）,or valine（V）in other families.The c.3350AG variant may be a de novo mutation resulting in p.Y1117C.Both mutations co-segregated with OI in respective families,and were not found in 100 normal controls.The G1102 and Y1117 residues were evolutionarily highly conserved from zebrafish to humans.Mutational analysis did not identify any mutation in the COX-2 gene（a modifier gene of OI）.This study identifies two novel mutations p.G1102A and p.Y1117C that cause OI,significantly expands the spectrum of COL1A2 mutations causing OI,and has a significant implication in prenatal diagnosis of OI.
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.
基金partially supported by a grant from the National Natural Science Foundation of China 31371279 (to Fu Xiong)the National Natural Science Foundation of China 81371137 (to Bu-Ling Wu)the Science and Technology Program of Guangzhou 201707010301 (to Fu Xiong)
文摘Tooth development is a complex process that involves precise and time-dependent orchestration of multiple genetic, molecular,and cellular interactions. Ameloblastin(AMBN, also named "amelin" or "sheathlin") is the second most abundant enamel matrix protein known to have a key role in amelogenesis. Amelogenesis imperfecta(AI [MIM: 104500]) refers to a genetically and phenotypically heterogeneous group of conditions characterized by inherited developmental enamel defects. The hereditary dentin disorders comprise a variety of autosomal-dominant genetic symptoms characterized by abnormal dentin structure affecting either the primary or both the primary and secondary teeth. The vital role of Ambn in amelogenesis has been confirmed experimentally using mouse models. Only two cases have been reported of mutations of AMBN associated with non-syndromic human AI. However, no AMBN missense mutations have been reported to be associated with both human AI and dentin disorders.We recruited one kindred with autosomal-dominant amelogenesis imperfecta(ADAI) and dentinogenesis imperfecta/dysplasia characterized by generalized severe enamel and dentin defects. Whole exome sequencing of the proband identified a novel heterozygous C-T point mutation at nucleotide position 1069 of the AMBN gene, causing a Pro to Ser mutation at the conserved amino acid position 357 of the protein. Exfoliated third molar teeth from the affected family members were found to have enamel and dentin of lower mineral density than control teeth, with thinner and easily fractured enamel, short and thick roots, and pulp obliteration. This study demonstrates, for the first time, that an AMBN missense mutation causes non-syndromic human AI and dentin disorders.
基金supported by NIAMS,of the National Institutes of Health,under award numbers R01AR062074 (to DJD) and R01AR060636 (to S-JL)the Harry Headley Charitable and Research Foundation,Punta Gorda,FL(to ELG-L)
文摘Osteogenesis imperfecta（OI） comprises a group of heritable connective tissue disorders generally defined by recurrent fractures, low bone mass, short stature and skeletal fragility. Beyond the skeletal complications of OI,many patients also report intolerance to physical activity, fatigue and muscle weakness. Indeed, recent studies have demonstrated that skeletal muscle is also negatively affected by OI, both directly and indirectly. Given the well-established interdependence of bone and skeletal muscle in both physiology and pathophysiology and the observations of skeletal muscle pathology in patients with OI, we investigated the therapeutic potential of simultaneous anabolic targeting of both bone and skeletal muscle using a soluble activin receptor 2B（ACVR2B） in a mouse model of type Ⅲ OI（oim）. Treatment of 12-week-old oim mice with ACVR2 B for 4 weeks resulted in significant increases in both bone and muscle that were similar to those observed in healthy,wild-type littermates. This proof of concept study provides encouraging evidence for a holistic approach to treating the deleterious consequences of OI in the musculoskeletal system.
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(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In this report, we describe the performance of a conservative and minimally invasive dental approach in four patients exhibiting Amelogenesis Imperfecta (AI), a structural anomaly of the enamel. In each patient, approximately 0.5 mm of the most external, porous, and colored enamel layer was removed, and the teeth were restored using two different nanocomposites. Posterior restorations were completed with the same approach. As a result, this contemporary restorative system is a conservative and successful treatment option to restore the loss of oral esthetics and function due to AI. Rehabilitation with direct resin restorations is not only an inexpensive treatment choice, but also a more conservative technique that reduces the amount of preparation required for teeth that are already compromised.
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.
文摘Osteogenesis imperfecta is a hereditary disease characterized by bone fragility due to a defect in type I collagen synthesis. The diagnosis is typically suspected based on suggestive ultrasound findings and confirmed through genetic studies. We present a case of osteogenesis imperfecta suspected during obstetrical ultrasound at 19 weeks’ gestation, which was later confirmed radiographically through computed tomography. Due to the severity of the condition, therapeutic termination of pregnancy was indicated.
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.
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 COLIA2 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. Se- quence analysis of COLIA1 revealed a splicing mutation （IVSS-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.
文摘Background Osteogenesis imperfecta （OI） is a rare bone disease and its effective treatment is relatively deficient. We tried to assess the effects of new bisphosphonate, ibandronate on children with OI.Methods In this open-label, prospective, controlled study, 30 children with OI were enrolled. They received either infusions of ibandronate （2 mg） in every three months or oral calcitriol 0.25 μg daily for 24 months. All patients took 500 mg calcium plus 200 U vitamin D daily together. The endpoints were the change of annual new fracture rate （observed by case history and X ray films of spine）, bone mineral density （BMD, measured by dual energy X-ray absortiometry）, serum concentration of carboxy-telopeptide cross-links of type Ⅰ collagen （CTX, bone resorption marker） and alkaline phosphatase （ALP, bone formation marker） during the follow-up.Results After the cyclic infusions of ibandronate, the annual new fracture rate was significantly decreased from 1.9 to 0.13 time, obviously lower than that of calcitriol group, which decreased from 1.8 to 1.0 time after the treatment （P 〈0.001）.The significant increase of BMD at the lumbar spine, femoral neck, trochanter, total hip was found in the group of ibandronate by 59.0%, 42.0%, 47.5% and 36.6% in time dependent manner （compared with the baseline, P 〈0.001）. The increase of BMD in ibandronate group was greater than that of calcitriol group （P 〈0.001）. The concentrations of ALP and CTX were obviously decreased in ibandronate group, and the reduction of CTX was more significant than that of ALP （P 〈0.001）. The tolerance of the children to ibandronate was quite well. Mild fever and muscle pain were found in 9 cases within 1-3 days after the first infusion of ibandronate, which could relieve after 1-2 days without special management.Conclusions The benefits of cyclic infusions of ibandronate to children with OI are significant because ibandronate could significantly reduce annual bone fracture rate, increase lumbar and hip BMD, preserve vertebral morphometry of patients through inhibition of bone resorption.
文摘Osteogenesis imperfecta （01）, 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. 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 detbrmity, with normal sclera; and type Ⅳ： Moderate severity with normal sclera.
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 encodingα1 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 ofα1 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.
