Osteogenesis Imperfecta Type Research Articles

SUN-440 Osteogenesis Imperfecta and Hypopituitarism: A Life-Long Consequences Case Report

Background: Osteogenesis imperfecta is a genetic disorder of the synthesis of collagen type 1 mainly due to mutations on the COL1A1 and COL1A2 genes. Symptoms involve predominantly bone fractures, blue sclera, teeth abnormalities and hearing loss. Hypopituitarism and osteogenesis imperfecta have not been yet genetically related. Case Report: Male patient born in January of 1988, came to pediatric consult 4 days after birth due to abnormalities in lower limb. X-ray showed fractures in left femur and non-ossified head of the same bone. Continuous investigation demonstrated numerous intra-uterus breakages, low bone mineral density and blue sclera, receiving the diagnosis of osteogenesis imperfecta type 1. Throughout childhood, the patient’s Z score growing rates were always below -2.5, which was thought to be caused by the collagen mutation. At the age of seven, while playing with his same age cousin, parents realized significant height difference, seeking an endocrinologist consult. MRI of sella turcica performed in November of 1994 revealed an empty sela. Subsequent clonidine GH stimulation test in January of 1995 indicated no value greater than 2,1 ng/mL (Normal: ≥ 5 ng/mL) leading to hypopituitarism suspicion. July of 1997 TSH levels of 0,145 mU/L (0,3-4,0 mU/L) and T4 of 4,9 (5,4-13,3 mg/dL) indicated thyroid dysfunction. At the age of 19, patient’s gonadal and pubic hair development was at stage 1 of the Tanner Scale, weighted 45 kg and measured 147 cm, total testosterone level was lower than 20 ng/dL (normal pre-pubertal: 20-270 ng/dL), FSH of 0,31 mUI/mL (normal pre-pubertal: < 5 mUI/mL), LH of 0,17 mUI/mL (normal pre-pubertal: < 4 mUI/mL), and 08:00 AM cortisol of 1,21 mcg/dL (normal: 5-25 mcg/dL). Management of the condition included testosterone cypionate 125mg every 28 days to induce puberty and growth support, somatropin 6UI/d to assist bone maturation, levothyroxine 100mcg/d to compensate the thyroid dysfunction, and prednisone 5mg/d for corticotropin insufficiency. Semen analysis performed in 2010 confirmed gonadal sterility. In the last consult in October of 2018, patient was 30 years old, 160 cm tall, weighting 58 kg, and requiring prednisone 5mg/d, testosterone undecanoate 250mg every 3 months, somatropin 1,33 UI/d, levothyroxine 125 mcg/d, and Calcium carbonate 1250mg + Vitamin D 400 UI twice a day for symptomatic control. Patient affirms that without those medications and dosages he becomes symptomatic and with poor daily life performance. Conclusion: The case consists in two uncommon and unrelated disorders in one individual, which implications started in childhood and remain until present time. Therefore, continuous investigation is required and genetic association is necessary to corroborate mutation.

Dentinogenesis imperfecta in Osteogenesis imperfecta type XI in South Africa: a genotype\u2013phenotype correlation

BackgroundThe maxillofacial and dental manifestations of Osteogenesis imperfecta (OI) have significant implications in terms of management. Although the occurrence of abnormal dentine in some forms of OI is well documented, there is scant information on the association of abnormal dentine in the Black African persons with phenotypic OI III and genotypic OI XI in South Africa.MethodsThis was a cross-sectional analytic study. A series of 64 Black South African individuals with a confirmed phenotypic diagnosis of OI III, ages ranging from 3 months to 29 years, were assessed clinically, radiographically, and at a molecular level.ResultsA total number of 64 saliva samples were analyzed and 3 DNA variations were identified in exon 5 of the FKBP10 gene. The homozygous mutation, c.[831dupC]; [831dupC], was identified in 23 affected persons who had no clinically obvious features of DI in their primary and secondary teeth. Radiologically, mild features of DI were evident in 10 persons in whom radiographic images were obtained and were given a Clinical–radiological score of 2. A compound heterozygous mutation, c. [831delC]; [831dupC], was identified in three siblings. An intraoral examination of these affected persons revealed no clinically apparent features of DI in their primary and secondary teeth. Due to the lack of radiological facilities, the presence or absence of DI could not be confirmed or negated. A second compound heterozygous mutation, c.[831dupC]; [1400-4C>G], was identified in a female of 29 years belonging to the Xhosa linguistic group. Her teeth appeared clinically normal but it was not possible to obtain radiographs. In 37 affected individuals, no disease-causing mutations were identified.ConclusionBlack African individuals in SA with the homozygous mutation in the FKBP10 gene have clinically unaffected teeth yet exhibited radiographic features of DI to varying degrees. This characterization is suggestive of a relationship between the genetic abnormality and the clinical manifestations of DI. The authors suggest that this diagnosis must include teeth that are clinically and/or radiologically aberrant, and should not exclude the presence of other, milder, dentinal aberrations associated with OI. There was no correlation between severity of OI and DI in this cohort of individuals.

Surgical treatment of comminuted intraarticular distal femur fracture in patient with osteogenesis imperfecta type I

Aim. Osteogenesis imperfecta (OI) is characterized by bone fragility and long bones deformities. Most studies are dedicated to surgical treatment of diaphyseal fractures. To our knowledge, there are no reports giving recommendations about surgical treatment of distal femur intraarticular fractures.&#x0D; Clinical case. We describe the surgical treatment of a 14-year-old girl with OI who had intraarticular fracture of the left distal femur and fracture of a right femur diaphysis. Surgical treatment was complicated by migration of a titanium elastic nail and impaired consolidation, which had to be fixed with a plate and led to peri-implant fracture. Results were assessed before trauma and at 1 and 2 years after trauma with Gillette Functional Assessment Questionnaire (GFAQ) and Bleck score.&#x0D; Discussion. During surgical treatment of comminuted intraarticular distal femur fractures in patients with OI, we had to use big cancellous screw that made implantation in an intramedullary fixator more difficult. Internal fixation with a plate in patients with OI is associated with high risks of peri-implant fracture.&#x0D; Conclusion. For treatment of comminuted intraarticular fracture of the distal femur, it is necessary to have large variety of internal fixators, follow the principles of absolute and relative stability, and be familiar with minimally-invasive techniques.

Treatment of tibial deformities with the Fassier-Duval telescopic nail and minimally invasive percutaneous osteotomies in patients with osteogenesis imperfecta type III.

Osteogenesis imperfecta (OI) is a rare congenital osteodystrophy. Patients with OI present with osteoporosis, extreme bone fragility and severe deformities of the lower limbs, which predispose them to frequent fractures. The aim of our study is to describe the minimally invasive osteotomy technique to correct the tibial deformities in patients with OI type III, using the Fassier-Duval (FD) intramedullary nailing, which is considered the gold standard in this kind of surgery. We analyzed the results obtained from 14 patients with OI type III, treated for tibial deformities with the minimally invasive percutaneous osteotomy technique and osteosynthesis with the FD telescopic nail. The results were compared with that of a control group composed of 18 patients with OI type III, treated for tibial deformities with open technique osteotomies and osteosynthesis with FD telescopic nail. The follow-up was set at 18 months postoperatively. The data concerning the following were collected from the two groups: duration of surgery, number of osteotomies performed, postoperative pain, time required for functional recovery, and for the formation of bone callus. To analyze the variations in the quality of life, all the patients were given the Pediatric Outcomes Data Collection Instrument questionnaire, before surgery and at the end of the follow-up. In patients who underwent corrective surgery with the percutaneous technique, the average duration of surgery was inferior, the postoperative pain was significantly lower, the recovery of 90° range of motion of knee flexion was reached at an average of 37.8 days, and they ambulated bearing full weight on the leg without auxiliary aids on average 45 days after surgery. The Pediatric Outcomes Data Collection Instrument questionnaire values were satisfactory in both groups. The osteosynthesis with the FD telescopic nail, performed with the minimally invasive surgical technique, has improved the management of deformities in OI. The minimally invasive technique, however, requires the maturation of three distinct learning curves: surgery on patients with OI, open technique with the FD nail, and percutaneous technique with the FD nail.

Bladder and bowel symptoms experienced by children with osteogenesis imperfecta

ObjectiveTo estimate the prevalence and presentation of bladder, bowel, and combined bladder and bowel symptoms experienced by children with osteogenesis imperfecta and to describe the socio-demographic and clinical profile of these children. MethodA descriptive study was conducted with a convenience sample of parent-child pairs of toilet-trained children aged from 3 to 18 years. Pairs were interviewed using three tools: (1) Socio-Demographic and Clinical Questionnaire; (2) Dysfunctional Voiding Scoring System; (3) Rome III Criteria along with the Bristol Stool Scale. Data were stratified by socio-demographic and clinical variables and analyzed using descriptive statistics. ResultsThirty-one parent-child pairs participated in the study; 38.7% (n=12) children reported bowel symptoms, 19.4% (n=6) reported a combination of bladder issues (such as holding maneuvers and urgency) and bowel symptoms (such as hard or painful bowel movements and large diameter stools). There were no reports of isolated bladder issues. Among the child participants, 16 (51.7%) identified as female and 20 (64.5%) were 5–14 years old. The most prevalent type of osteogenesis imperfecta was type III (n=12; 38.7%) and eight (25.8%) children reported using a wheelchair. ConclusionThis is the first study to examine the prevalence and presentation of bladder, bowel, and combined bladder and bowel symptoms in children with osteogenesis imperfecta, offering a preliminary socio-demographic and clinical profile of these children. This research is an important step toward effective screening, detection, and access to care and treatment, especially for clinicians working with this group of very fragile patients.

Elastic intramedullary nailing of the femur fracture in patients affected by osteogenesis imperfecta type 3: Indications, limits and pitfalls

IntroductionPatients with Osteogenesis Imperfecta (OI) Type 3 may exhibit both primitive deformities and secondary fracture malunions on a femoral level. The orthopaedic surgeon’s objective is to cure the deformities in order to prevent fractures and to treat the fractures in order to prevent deformities, by using telescopic nails as the gold standard method of fixation. However, the titanium elastic nail (TEN) is indicated as a possible alternative in certain selected cases. Materials and methodsThe Centre for Congenital Osteodystrophy of the Sapienza University of Rome follows 485 patients with osteogenesis imperfecta. For the purpose of this study, we selected 36 patients with OI type 3 (15 females and 21 males), aged between 2 and 10 years old, who were surgically treated for femur fractures with Titanium Elastic Nail (TEN) from January 2007 to December 2009. In 12 cases a single TEN was implanted, while 24 of the cases were treated by implanting 2 TENs with the Sliding Nail (SN) technique. A retrospective evaluation was carried out by analysing the data from the medical charts and dossiers related to pain symptoms, knee and hip Range of Motion (ROM), any possible complications that could cause implant revisions (infections, nail slide failure, nail migration, traumatic events following surgery, delayed consolidation, epiphysiodesis). ResultsAt the 60th post-surgical month, the revision rate was 75%, mostly due to migration, osteolysis, nail slide failure and nail fracture. The Kaplan-Meier's survival curve analysis showed a coefficient of 0.25–60 months (confidence interval −0.31 and 0.81). DiscussionThe percentage of complications and the high rate of revisions recorded in our sample confirm that telescopic nail is the gold standard in the treatment of femoral fractures in patients with OI type 3. ConclusionsIn patients under the age of 4, with narrow medullary canals, low life expectancy, few to nil rehabilitative prospectives or severe comorbidities, the use of TEN may be considered as a less invasive approach compared to telescopic nail surgery, however only temporarily, as it will still most probably require a surgical revision a few years down the line.

Caries prevalence and experience in individuals with osteogenesis imperfecta: A cross-sectional multicenter study.

Dentinogenesis Imperfecta (DI) forms a group of dental abnormalities frequently found associated with Osteogenesis Imperfecta (OI), a hereditary disease characterized by bone fragility. The objectives of this study were to quantify the dental caries prevalence and experience among different OI-types in the sample population and quantify how much these values change for the subset with DI. To determine which clinical characteristics were associated with increased Caries Prevalence and Experience (CPE) in patients with OI, the adjusted DFT scores were used to account for frequent hypodontia, impacted teeth and retained teeth in OI population. For each variable measured, frequency distributions, means, proportions and standard deviations were generated. Groups means were analyzed by the unpaired t-test or ANOVA as appropriate. For multivariate analysis, subjects with caries experience of zero were compared with those with caries experience greater than zero using logistic regression. The stepwise regression analysis while controlling for all other variables demonstrated the presence of DI (OR 2.43; CI 1.37-4.32; P=0.002) as the significant independent predictor of CPE in the final model. This study found no evidence that CPE of OI subjects differs between the types of OI. The presence of DI when controlled for other factors was found to be the significant predictor of CPE.

The Osteocyte Transcriptome Is Extensively Dysregulated in Mouse Models of Osteogenesis Imperfecta.

Osteocytes are long‐lived, highly interconnected, terminally differentiated osteoblasts that reside within mineralized bone matrix. They constitute about 95% of adult bone cells and play important functions including in the regulation of bone remodeling, phosphate homeostasis, and mechanical stimuli sensing and response. However, the role of osteocytes in the pathogenesis of congenital diseases of abnormal bone matrix is poorly understood. This study characterized in vivo transcriptional changes in osteocytes from CrtapKO and oim/oim mouse models of osteogenesis imperfecta (OI) compared with wild‐type (WT) control mice. To do this, RNA was extracted from osteocyte‐enriched cortical femurs and tibias, sequenced and subsequently analyzed to identify differentially expressed transcripts. These models were chosen because they mimic two types of OI with different genetic mutations that result in distinct type I collagen defects. A large number of transcripts were dysregulated in either model of OI, but 281 of them were similarly up‐ or downregulated in both compared with WT controls. Conversely, very few transcripts were differentially expressed between the CrtapKO and oim/oim mice, indicating that distinct alterations in type I collagen can lead to shared pathogenic processes and similar phenotypic outcomes. Bioinformatics analyses identified several critical hubs of dysregulation that were enriched in annotation terms such as development and differentiation, ECM and collagen fibril organization, cell adhesion, signaling, regulatory processes, pattern binding, chemotaxis, and cell projections. The data further indicated alterations in important signaling pathways such as WNT and TGF‐β but also highlighted new candidate genes to pursue in future studies. Overall, our study suggested that the osteocyte transcriptome is broadly dysregulated in OI with potential long‐term consequences at the cellular level, which deserve further investigations. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Cone-Beam Computed Tomography of Osteogenesis Imperfecta Types III and IV: Three-Dimensional Evaluation of Craniofacial Features and Upper Airways.

ABSTRACTThis cross‐sectional study investigated the natural history of craniofacial deformities in osteogenesis imperfecta (OI) and determined the impact of three‐dimensional (3D) analysis on diagnosis and treatment planning in orthodontics and orthognathic surgery in comparison to conventional two‐dimensional (2D) cephalometric examination. 3D images of the craniofacial complex were acquired during 1 calendar year using cone‐beam computed tomography (CBCT) from a cohort of 41 individuals (aged 11 to 35 years; 28 females) with OI type III (n = 13) or IV (n = 28). 3D evaluation of the craniocervical junction and upper airways was conducted using InVivoTM. 2D lateral cephalogram was constructed, traced, and examined using the University of Western Ontario analysis (DolphinTM). Quantitative and qualitative parameters were compared between OI type III and type IV groups (unpaired t test) and the unaffected population (Z‐score). 3D evaluation revealed a high prevalence of craniocervical abnormalities, craniofacial asymmetries, and nasal septum deviation in both OI groups. Mean airway dimensions were comparable to the non‐affected population norms, except for 5 individuals who had insufficient airway dimensions. In 2D, the maxilla was retrognathic and hypoplastic, and the mandibular position was convergent with respect to the face, resulting in mandibular prognathism and face height reduction. The 2D trends were more pronounced in OI type III, whereas the 3D craniocervical and airway abnormalities were common in both types. This study illustrates the prevalence of craniofacial and airway anomalies in OI that occur along with facial deformities are not associated with postcranial phenotype and OI type, are apparent only in 3D evaluation, and are likely to influence treatment strategy. For OI patients, a team effort involving a dentist, orthodontist, neurologist, and ear‐nose‐throat (ENT) practitioner is recommended for successful management of craniofacial deformities. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Suitability of growth standards for growth monitoring in children with genetic diseases.

Growth references are used worldwide. The objective of monitoring growth of apparently healthy children is to identify treatable diseases early. Children with compromised growth, e.g. due to genetic disease, are assessed and compared to common growth references based on healthy children. But children with genetic diseases often fulfil the most referral criteria for further evaluation already due to their underlying disease. So, only the height deflection criteria (excessive decrease in height Z-score over time) seem reasonable in these children. But it is unclear whether one should expect these children to follow the standard growth references. The aim of the study was to develop a tool for evaluating the applicability of common growth standards for growth monitoring of children with specific genetic disease. We introduced the percentile parallelism test (PPT). This novel test assesses whether a height deflection is to be expected due to the underlying specific genetic disease, or if it is a sign of an additional disease. For illustration, the PPT was applied to a cohort of boys (n = 28, age 2-16 years) with osteogenesis imperfecta type IV. Boys with osteogenesis imperfecta showed a significant (p = 0.001) higher variability of their age specific height distribution than their healthy peers. Therefore, the commonly proposed cutoffs for the height deflection criteria had to be adjusted by the factor of 1.342 (95%CI 1.337-1.347). The PPT might improve the growth monitoring of children with genetic diseases, preventing them from unnecessary diagnostics.

Pigment epithelium-derived factor (PEDF) reduced expression and synthesis of SOST/sclerostin in bone explant cultures: implication of PEDF-osteocyte gene regulation in vivo

Mutations in Serpinf1 gene which encodes pigment epithelium-derived factor (PEDF) lead to osteogenesis imperfecta type VI whose hallmark is defective matrix mineralization. We reported previously that PEDF reduced expression and synthesis of Sost/Sclerostin as well as other osteocytes genes encoding proteins that regulate matrix mineralization [1]. To determine whether PEDF had an effect on osteocyte gene expression in bone, we used bone explant cultures. First, osteocytes were isolated from surgical waste of bone fragments obtained from patients undergoing elective foot surgeries under approved IRB protocol by Penn State College of Medicine IRB committee. Primary osteocytes treated with PEDF reduced expression and synthesis of Sost/Sclerostin and matrix phosphoglycoprotein (MEPE) as well as dentin matrix protein (DMP-1). On the whole, PEDF reduced osteocyte protein synthesis by 50% and by 75% on mRNA levels. For bone explants, following collagenase digestion, bone fragments were incubated in alpha-MEM supplemented with 250ng/ml of PEDF or BSA. After 7days of incubation in a medium supplemented with PEDF, analysis of mRNA by PCR and protein by western blotting of encoded osteocyte proteins showed reduced Sclerostin synthesis by 39% and MEPE by 27% when compared to fragments incubated in medium supplemented with BSA. mRNA expression levels of osteocytes in bone fragments treated with PEDF were reduced by 50% for both SOST and MEPE when compared to BSA-treated bone fragments. Taken together, the data indicate that PEDF has an effect on osteocyte gene expression in bone and encourage further studies to examine effect of PEDF on bone formation indices in animal models and its effect on osteocyte gene expression in vivo following PEDF administration.

Oro-dental and cranio-facial characteristics of osteogenesis imperfecta type V

Osteogenesis imperfecta (OI) type V is an ultrarare heritable bone disorder caused by the heterozygous c.-14C > T mutation in IFITM5. The oro-dental and craniofacial phenotype has not been described in detail, which we therefore undertook to evaluate in a multicenter study (Brittle Bone Disease Consortium). Fourteen individuals with OI type V (age 3–50 years; 10 females, 4 males) underwent dental and craniofacial assessment. None of the individuals had dentinogenesis imperfecta. Six of the 9 study participants (66%) for whom panoramic radiographs were obtained had at least one missing tooth (range 1–9). Class II molar occlusion was present in 8 (57%) of the 14 study participants. The facial profile was retrusive and lower face height was decreased in 8 (57%) individuals. Cephalometry, performed in three study participants, revealed a severely retrusive maxilla and mandible, and moderately to severly retroclined incisors in a 14-year old girl, a protrusive maxilla and a retrusive mandible in a 14-year old boy. Cone beam computed tomograpy scans were obtained from two study participants and demonstrated intervertebral disc calcification at the C2-C3 level in one individual. Our study observed that OI type V is associated with missing permanent teeth, especially permanent premolar, but not with dentinogenesis imperfecta. The pattern of craniofacial abnormalities in OI type V thus differs from that in other severe OI types, such as OI type III and IV, and could be described as a bimaxillary retrusive malocclusion with reduced lower face height and multiple missing teeth.

Health-related quality of life in children with osteogenesis imperfecta: a large-sample study.

Osteogenesis imperfecta (OI) is a hereditary disease characterized by multiple fragility fractures and progressive skeletal deformities. No detailed investigations about the quality of life (QoL) have been carried out in a large sample of patients with OI. We evaluated the QoL and its influencing factors in a large and well-characterized OI cohort. We used a validated questionnaire of PedsQL 4.0 to evaluate the health-related quality of life (HRQoL) of children and adolescents with OI. We compared HRQoL among patients with OI types I, III, and IV. The relationship between HRQoL and pathogenic mutations in candidate OI genes was investigated. We also evaluated the influencing factors of HRQoL in OI patients. A total of 138 children with OI and 138 healthy controls were enrolled in this study. The HRQoL scores of OI patients were 64.4 ± 30.0, 71.9 ± 22.2, 75.7 ± 24.8, 63.7 ± 24.5, and 68.9 ± 22.0 in physical, emotional, social, school functioning, and total score, respectively, which were significantly lower than those of healthy children (86.5 ± 12.7, 83.3 ± 16.0, 92.1 ± 11.8, 87.5 ± 11.8, and 87.3 ± 10.7, all p < 0.01). Moderate and severe OI (type III/IV) patients had poorer HRQoL scores than patients with mild OI (type I). Gene mutations inducing qualitative defects in type I collagen led to worse HRQoL scores than those with quantitative defects in type I collagen, except in emotional functioning. The total HRQoL score was positively correlated with family income, lumbar, and femoral bone mineral density (BMD) Z-scores and negatively correlated with disease severity and fracture frequency. HRQoL was significantly impaired in OI patients, and patients with more severe OI had poorer HRQoL scores. For the first time, we found that children with qualitative defects in type I collagen had poorer HRQoL scores than those with quantitative defects in type I collagen.

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The article presents a literature review on intrauterine bone fractures in fetuses suffering from osteogenesis imperfecta. Prenatal ultrasound investigation of the condition is made to identify pathologically changed bone tissue including shortened and deformed limb segments and ribs, bone fractures and callus formation and widened intracranial sutures. Comprehensive clinical, paraclinical and radiological evaluations are produced after the birth to determine treatment strategy. Skeletal fractures in newborns are treated conservatively. With diagnosis of osteogenesis imperfect established medical treatment with bisphosphonates is administered to inhibit osteoclast-mediated bone resorption, facilitate bone mineralization and lower fracture incidence. The case report describes fractures of both femurs and left tibia in a female newborn suffering from osteogenesis imperfecta type III diagnosed in utero with ultrasonographic screening. The case presented highlights infant’s trauma-focused status, radiological findings and the treatment performed.

Implant therapy for a patient with osteogenesis imperfecta type I: review of literature with a case report

Bone fragility and skeletal irregularities are the characteristic features of osteogenesis imperfecta (OI). Many patients with OI have weakened maxillary and mandibular bone, leading to poor oral hygiene and subsequent loss of teeth. Improvements in implant therapy have allowed for OI patients to achieve dental restoration. However, there is limited available literature on implant therapy for patients with OI. The greatest challenge in the restoration process for OI patients in an outpatient setting is ensuring primary stability and osseointegration. Improvements in synthetic grafts improve successful implant placement and prevent predisposing patients to unnecessary procedures. This report details the successful restoration process of an OI type I patient’s maxillary arch in addition to a review of the currently available literature.

Novel mutations in BMP1 induce a rare type of osteogenesis imperfecta

BackgroundOsteogenesis imperfecta (OI) is a group of hereditary disorders characterized by low bone mass and recurrent fractures. OI patients of autosomal recessive inheritance are extremely rare, of which OI type XIII is attributable to mutation in BMP1 gene. Case reportHere, we detect the pathogenic mutations and analyze their relation to the phenotypes in a Chinese family with OI using next-generation sequencing (NGS) and Sanger sequencing. We also evaluate the efficacy of alendronate treatment in the patient with OI type XIII. The clinical phenotypes of the patient included recurrent fractures, muscle weakness, bone deformity, macrocephaly and elbow contractures, but no blue sclera or dentinogenesis imperfecta. High-resolution peripheral quantitative computed tomography revealed high bone mineral density and bone volume, but reduced trabecular numbers, increased porosity and comprised strength in this patient. Novel heterozygous mutations of c.1324G > T (p.Asp442Tyr) and c.148 + 1G > A in BMP1 gene were found in the proband, which would affect the CUB2 domain and the prodomain of mutant proteins. The parents were heterozygous carriers for the two mutations respectively, but with normal phenotype. ConclusionsWe report for the first time that the novel pathogenic mutations in BMP1 can lead to the extremely rare OI type XIII, which exhibit unique characters of high bone mass, but with impaired bone microstructure and comprised bone strength. Alendronate is beneficial in increasing bone mineral density and decreasing bone resorption biomarkers, but concerns still remain whether it can reduce fracture incidence in this rare type of OI.

The dental perspective on osteogenesis imperfecta in a Danish adult population

BackgroundTo report on dental characteristics and treatment load in Danish adult patients with osteogenesis imperfecta (OI).MethodsOral examination of 73 patients with OI was performed and OI type I, III, and IV were represented by 75.3%, 8.2%, and 16.4%, respectively. Patients were diagnosed as having dentinogenesis imperfecta (DI) if they had clinical and radiological signs of DI. In the data analysis, mild OI (type I) was compared to moderate-severe OI (type III and IV).ResultsDiscoloration of teeth was prevalent in patients with moderate-severe compared to mild OI (83.3% vs. 5.5%, p < 0.001). Cervical constriction and pulpal obliteration were frequent findings in patients with moderate-severe OI (61.1% and 88.9%, respectively), whereas pulp stones and taurodontism were diagnosed in patients with mild OI only (29.1% and 9.1%, respectively). DI was found in 24.7% of OI patients and considerably more frequent in patients with moderate-severe (94.4%) compared to mild OI (1.8%) (p < 0.001). The number of teeth with artificial crowns was significantly higher in patients with moderate-severe OI than in patients with mild OI (median 1.5, range 0–23 vs. median 0, range 0–14) (p < 0.001). The number of teeth with fillings in patients with mild OI was significantly higher than in patients with moderate-severe OI (mean 9.7, SD 5.1, median 9.0, range 1–21 vs. mean 5.0, SD 4.4, median 4.0, range 0–16) (p < 0.001).ConclusionsOne fourth of patients with OI had DI, and the vast majority of them had moderate-severe OI. Whereas discoloration of teeth, cervical constriction and pulp obliteration were frequent findings in patients with moderate-severe OI, pulp stones and taurodontism were found in patients with mild OI only. In patients with moderate-severe OI, the dental treatment load was dominated by prosthetic treatment, whereas restorative treatment with fillings was more prevalent in patients with mild OI.

Clinical, Genetics, and Bioinformatic Characterization of Mutations Affecting an Essential Region of PLS3 in Patients with BMND18.

Background Bone mineral density quantitative trait locus 18 (BMND18, OMIM #300910) is a type of early-onset osteogenesis imperfecta (OI) caused by loss-of-function mutations in the PLS3 gene, which encodes plastin-3, a key protein in the formation of actin bundles throughout the cytoskeleton. Here, we report a patient with PLS3 mutation caused BMND18 and evaluated all the reported disease-causing mutations by bioinformatic analysis. Methods Targeted gene sequencing was performed to find the disease-causing mutation in our patient. Bioinformatic analyses mainly including homology modelling and molecular dynamics stimulation were conducted to explore the impact of the previously reported mutations on plastin-3. Results Gene sequencing showed a novel nonsense mutation (c.745G > T, p.E249X), which locates at a highly conserved region containing residues p.240–266 (LOOP-1) in the PLS3 gene. Further bioinformatic analyses of the previously reported mutations revealed that LOOP-1 is predicted to physically connect the calponin-homology 1 (CH1) and CH2 domains of the ABD1 fragment and spatially locates within the interface of ABD1 and ABD2. It is crucial to the conformation transition and actin-binding function of plastin-3. Conclusions This report identified a novel mutation that truncates the PLS3 gene. Moreover, bioinformatic analyses of the previous reported mutations in PLS3 gene lead us to find a critical LOOP-1 region of plastin-3 mutations at which may be detrimental to the integral conformation of plastin-3 and thus affect its binding to actin filament.

Anesthesia in children with osteogenesis imperfecta: Retrospective chart review of 83 patients and 205 anesthetics over 7years.

Osteogenesis imperfecta is the collective term for a heterogeneous group of connective tissue syndromes characterized by bone fragility with multisystem involvement and perioperative implications. Literature review of anesthetic management of patients with osteogenesis imperfecta revealed a paucity of data on the incidence of perioperative challenges. We sought to determine the rates of these challenges in our study cohort. Data were collected in a specialty orthopedic hospital from 2008 to 2015 for 83 osteogenesis imperfecta patients undergoing 205 surgeries: 203 orthopedic surgeries and 2 mid-face reconstructive surgeries. Airway management, intravenous access, surgical blood loss, use of peripheral nerve blockade and/or neuraxial techniques, presence of perioperative fracture, and peak intraoperative temperature were evaluated and analyzed. Difficult airway was encountered in 3/205 (1.5%) cases and perioperative fracture in 2/205 (1%) cases. Neuraxial anesthesia was attempted in 64/205 cases with an 87.5% success rate. All peripheral nerve block attempts (33/205 cases) were successful. Difficult intravenous catheter placement was noted in 8/205 (4%) cases. Estimated blood loss >10% of estimated blood volume was considered significant, and occurred in 35/205 (17%) cases. Significant blood loss occurred more often in severe osteogenesis imperfecta types: 18/76 (23.7%) in Type III and 11/65 (16.9%) in Type IV, whereas only 4/47 (8.5%) occurred in mild Type I. In our 205 case cohort, osteogenesis imperfecta Type III had 5.6 times the odds [(95% CI=1.8-17.2) P=0.003] of having an anesthetic complication as compared to osteogenesis imperfecta Type I. Patients with osteogenesis imperfecta undergo frequent anesthetic exposures, but anesthetic challenges in our series were uncommon. Odds of challenges are greater in severe osteogenesis imperfecta Type III, with significant blood loss and difficulty placing intravenous catheters more likely encountered in the more severe types.

Use of flexible intramedullary nailing in combination with an external fixator for a postoperative defect and pseudarthrosis of femur in a girl with osteogenesis imperfecta type VIII: a case report

Telescopic rodding has been developed in order to obtain long-lasting osteosynthesis in the growing long bones of children with osteogenesis imperfecta (OI). The major and still unsolved drawback of any telescopic rod or nail design is a lack of rotational stability and, currently, no telescopic system allows immediate weight-bearing. When these problems are associated with insufficient longitudinal bone stability and diminished healing capacity, the result can be unfavourable causing secondary bone fragment displacement, delayed or non-union. This article presents a case report of operative treatment in a 9-year-old girl affected with OI type VIII complicated with postoperative defect and pseudarthrosis of the femur causing functional impairment with loss of walking ability. A combination of intramedullary flexible nailing and minimal external fixation was applied for treatment of femoral defect-pseudarthrosis in a girl of 9 years with OI type VIII. Intramedullary and extramedullary nails with wrapping of titanium nickel mesh subperiosteally provided osteosynthesis and deformity correction of the tibia of a small intramedullary canal diameter. Upright standing and walking with progressive weight-bearing was started 4 days after surgery. There were no septic or vascular complications nor complications related to Ilizarov fixator. Radiographs demonstrated bone union in the femur 46 days after surgery. At the follow-up visit 9 months after fixator removal, clinical alignment remained excellent without any relapse of deformity. Bone remodelling with restitution of medullary canal was noted on lower limb radiographs. The patient was able to stand and walk without pain with an aide or walker. At the follow-up visit 17 months after fixator removal, there was no decrease in achieved functional abilities and the treatment outcome remained satisfactory. Use of an external fixator with intramedullary nailing for treatment of postoperative pseudarthrosis in patient with severe OI (recessive form of OI, type VIII) provides longitudinal, rotational and angular stability. Furthermore, this approach ensured early functional activity and walking with full weight-bearing, both favourable conditions for bone tissue regeneration. The external fixator was applied for a short period and only for additional stability and not for progressive deformity correction or other manipulation. In addition, the combination of intramedullary and extramedullary nailing and subperiosteal titanium nickel mesh seems to be promising for osteosynthesis in the deformity correction of bones with small diameter in children with OI.