Classification of osteogenesis imperfecta:Importance for prophylaxis and genetic counseling

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.

Osteogenesis Imperfecta: One Disease, Two or More Faces: A Case Report

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.

Administration of soluble activin receptor 2B increases bone and muscle mass in a mouse model of osteogenesis imperfecta

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.

Cell therapy of a patient with type Ⅲ Osteogenesis imperfecta caused by mutation in COL1A2 gene and unstable collagen type I

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.

Assessment of quality of life in children with osteogenesis imperfecta: a review

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.

Health management in children with osteogenesis imperfecta

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.

Case Report and Clinical Management of a Case of Osteogenesis Imperfecta Detected in the Prenatal Period

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.

Benefit of infusions with ibandronate treatment in children with osteogenesis imperfecta

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.

Identification and molecular characterization of two novel mutations in COL1A2 in two Chinese families with osteogenesis imperfecta

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.

Collagen Type I Alpha 1 Mutation Causes Osteogenesis Imperfecta from Mild to Perinatal Death in a Chinese Family

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.

Rare co-occurrence of osteogenesis imperfecta type Ⅰ and autosomal dominant polycystic kidney disease

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.

Bilateral papilledema in a child with osteogenesis imperfecta

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.

A Case of Pregnancy Combined with Congenital Osteogenesis Imperfecta

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.