Severe Osteogenesis Imperfecta Research Articles

Galunisertib downregulates mutant type I collagen expression and promotes MSCs osteogenesis in pediatric osteogenesis imperfecta

Qualitative alterations in type I collagen due to pathogenic variants in the COL1A1 or COL1A2 genes, result in moderate and severe Osteogenesis Imperfecta (OI), a rare disease characterized by bone fragility. The TGF-β signaling pathway is overactive in OI patients and certain OI mouse models, and inhibition of TGF-β through anti-TGF-β monoclonal antibody therapy in phase I clinical trials in OI adults is rendering encouraging results. However, the impact of TGF-β inhibition on osteogenic differentiation of mesenchymal stem cells from OI patients (OI-MSCs) is unknown. The following study demonstrates that pediatric skeletal OI-MSCs have imbalanced osteogenesis favoring the osteogenic commitment. Galunisertib, a small molecule inhibitor (SMI) that targets the TGF-β receptor I (TβRI), favored the final osteogenic maturation of OI-MSCs. Mechanistically, galunisertib downregulated type I collagen expression in OI-MSCs, with greater impact on mutant type I collagen, and concomitantly, modulated the expression of unfolded protein response (UPR) and autophagy markers. In vivo, galunisertib improved trabecular bone parameters only in female oim/oim mice. These results further suggest that type I collagen is a tunable target within the bone ECM that deserves investigation and that the SMI, galunisertib, is a promising new candidate for the anti-TGF-β targeting for the treatment of OI.

Ventriculosubgaleal shunt placement for hydrocephalus in osteogenesis imperfecta with novel compound heterozygous CRTAP variants

Osteogenesis imperfecta is characterized by frequent fractures, bone deformities, and other systemic symptoms. Severe osteogenesis imperfecta may progress to hydrocephalus; however, treatment strategies for this complication remain unclear. Here, we describe severe osteogenesis imperfecta in an infant with symptomatic hydrocephalus treated with ventriculosubgaleal shunt placement. Targeted next-generation sequencing revealed novel compound heterozygous CRTAP variants, i.e., NM_006371.5, c.241 G > T, p.(Glu81*) and NM_006371.5, c.923-2_932del. We suggest that ventriculosubgaleal shunt placement is an effective and safe treatment for hydrocephalus in patients with severe osteogenesis imperfecta.

Low-Dose Spinal Anesthesia for Emergency Cesarean Delivery in a Case of Severe Osteogenesis Imperfecta

Low-Dose Spinal Anesthesia for Emergency Cesarean Delivery in a Case of Severe Osteogenesis Imperfecta

Automated measurement of lamellar thickness in human bone using polarized light microscopy

Lamellar bone formed in individuals with moderate and severe osteogenesis imperfecta (OI) is often composed of lamellae that are structurally abnormal. Measuring the thickness of these lamellae can be helpful in assessing the effect of specific collagen and collagen-related mutations on OI bone synthesis.Manual measurement of lamellar thicknesses in large quantities is very time consuming. The method for automated measurement described in this article utilizes an image processing script to identify the average thickness of multiple lamellae automatically from histologic images of bone. This allows for faster measurements that are less prone to human error and can account for variability in the thickness of a lamella along its length.•OI and control bone samples are prepared per the glycol methacrylate resin (JB-4 plastic) technique and viewed using polarized light microscopy.•Ideal bone regions for measurement are identified using specific qualitative criteria designed to ensure uniform and accurate thickness measurements.•The method was validated with dataset containing 211 lamellae from control bone and 212 lamellae from OI bone.

Whole-Body Metabolism and the Musculoskeletal Impacts of Targeting Activin A and Myostatin in Severe Osteogenesis Imperfecta.

Mutations in the COL1A1 and COL1A2 genes, which encode type I collagen, are present in around 85%-90% of osteogenesis imperfecta (OI) patients. Because type I collagen is the principal protein composition of bones, any changes in its gene sequences or synthesis can severely affect bone structure. As a result, skeletal deformity and bone frailty are defining characteristics of OI. Homozygous oim/oim mice are utilized as models of severe progressive type III OI. Bone adapts to external forces by altering its mass and architecture. Previous attempts to leverage the relationship between muscle and bone involved using a soluble activin receptor type IIB-mFc (sActRIIB-mFc) fusion protein to lower circulating concentrations of activin A and myostatin. These two proteins are part of the TGF-β superfamily that regulate muscle and bone function. While this approach resulted in increased muscle masses and enhanced bone properties, adverse effects emerged due to ligand promiscuity, limiting clinical efficacy and obscuring the precise contributions of myostatin and activin A. In this study, we investigated the musculoskeletal and whole-body metabolism effect of treating 5-week-old wildtype (Wt) and oim/oim mice for 11 weeks with either control antibody (Ctrl-Ab) or monoclonal anti-activin A antibody (ActA-Ab), anti-myostatin antibody (Mstn-Ab), or a combination of ActA-Ab and Mstn-Ab (Combo). We demonstrated that ActA-Ab treatment minimally impacts muscle mass in oim/oim mice, whereas Mstn-Ab and Combo treatments substantially increased muscle mass and overall lean mass regardless of genotype and sex. Further, while no improvements in cortical bone microarchitecture were observed with all treatments, minimal improvements in trabecular bone microarchitecture were observed with the Combo treatment in oim/oim mice. Our findings suggest that individual or combinatorial inhibition of myostatin and activin A alone is insufficient to robustly improve femoral biomechanical and microarchitectural properties in severely affected OI mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The Fate of the Bent Rod in Children With Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by brittle bones and long bone deformity. Realignment and intramedullary rodding with telescopic rods are indicated for progressive deformity and can help prevent fractures. Rod bending is a reported complication of telescopic rods and a common indication for revision; however, the fate of bent lower extremity telescopic rods in the setting of OI has not been reported. Patients with OI at a single institution who underwent lower extremity telescopic rod placement with at least 1-year follow-up were identified. Bent rods were identified, and for these bone segments, we collected the location and angle of bend, subsequent telescoping, refracture, increasing angulation of bend, and date of revision. One hundred sixty-eight telescopic rods in 43 patients were identified. Forty-six rods (27.4%) bent during follow-up, with an average angulation of 7.3 (range: 1 to 24) degrees. In patients with severe OI, 15.7% of rods bent compared with 35.7% in nonsevere OI ( P =0.003). The proportion of bent rods was different between independent and nonindependent ambulators (34.1% and 20.5%; P =0.035). Twenty-seven bent rods (58.7%) were revised, with 12 rods (26.0%) revised early (within 90 d). The angulation of rods that were revised early was significantly higher than rods not (14.6 and 4.3 degrees, P <0.001). Of the 34 bent rods not revised early, the average time to revision or final follow-up was 29.1 months. Twenty-five rods (73.5%) continued to telescope, 14 (41.2%) increased in angulation (average 3.2 degrees), and 10 bones (29.4%) refractured. None of the refractures required immediate rod revision. Two bones had multiple refractures. Bending is a common complication of telescopic rods in the lower extremities of patients with OI. It is more common in independent ambulators and patients with nonsevere OI, possibly because of the increased demand placed on the rods. Rods with a small bend and maintained fixation can telescope and need not be an indication for immediate revision. Level III-Retrospective review.

Effect of sclerostin inactivation in a mouse model of severe dominant osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a rare bone disease that is associated with fractures and low bone mass. Sclerostin inhibition is being evaluated as a potential approach to increase bone mass in OI. We had previously found that in Col1a1Jrt/+ mice, a model of severe OI, treatment with an anti-sclerostin antibody had a minor effect on the skeletal phenotype. In the present study, we assessed the effect of genetic sclerostin inactivation in the Col1a1Jrt/+ mouse. We crossed Col1a1Jrt/+ mice with Sost knockout mice to generate Sost-deficient Col1a1Jrt/+ mice and assessed differences between Col1a1Jrt/+ mice with homozygous Sost deficiency and Col1a1Jrt/+ mice with heterozygous Sost deficiency. We found that Col1a1Jrt/+ mice with homozygous Sost deficiency had higher body mass, femur length, trabecular bone volume, cortical thickness and periosteal diameter as well as increased biomechanical parameters of bone strength. Differences between genotypes were larger at the age of 14 weeks than at 8 weeks of age. Transcriptome analysis of RNA extracted from the tibial diaphysis revealed only 5 differentially regulated genes. Thus, genetic inactivation of Sost increased bone mass and strength in the Col1a1Jrt/+ mouse. It appears from these observations that the degree of Sost suppression that is required for eliciting a beneficial response can vary with the genetic cause of OI.

Successful helmet therapy in an infant with positional brachycephaly associated with perinatal severe osteogenesis imperfecta.

Pediatrics InternationalAccepted Articles e15512 CLINICAL NOTE Successful helmet therapy in an infant with positional brachycephaly associated with perinatal severe osteogenesis imperfecta Kiri Hirata, Kiri Hirata Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan These authors contributed equallySearch for more papers by this authorRyoji Aoki, Ryoji Aoki orcid.org/0000-0002-9513-3863 Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan Department of Radiology, Nihon University School of Medicine, Tokyo, Japan These authors contributed equallySearch for more papers by this authorNobuhiko Nagano, Corresponding Author Nobuhiko Nagano [email protected] orcid.org/0000-0002-0890-1626 Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan Correspondence Nobuhiko Nagano, Department of Pediatrics and Child Health, Nihon University School of Medicine, 30-1, Oyaguchi, Kami-cho, Itabashi-ku, Tokyo 173-8610, Japan, Phone: +81-3-3972-8111, Fax: +81-3-3958-5744. Email: [email protected]Search for more papers by this authorRisa Kato, Risa Kato Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, JapanSearch for more papers by this authorMasako Aoki, Masako Aoki orcid.org/0000-0001-6471-4617 Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, JapanSearch for more papers by this authorOsamu Miyazaki, Osamu Miyazaki orcid.org/0000-0002-1793-4892 Division of Radiology, National Center for Child Health and Development, Tokyo, JapanSearch for more papers by this authorIchiro Morioka, Ichiro Morioka orcid.org/0000-0002-5685-2670 Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, JapanSearch for more papers by this author Kiri Hirata, Kiri Hirata Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan These authors contributed equallySearch for more papers by this authorRyoji Aoki, Ryoji Aoki orcid.org/0000-0002-9513-3863 Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan Department of Radiology, Nihon University School of Medicine, Tokyo, Japan These authors contributed equallySearch for more papers by this authorNobuhiko Nagano, Corresponding Author Nobuhiko Nagano [email protected] orcid.org/0000-0002-0890-1626 Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan Correspondence Nobuhiko Nagano, Department of Pediatrics and Child Health, Nihon University School of Medicine, 30-1, Oyaguchi, Kami-cho, Itabashi-ku, Tokyo 173-8610, Japan, Phone: +81-3-3972-8111, Fax: +81-3-3958-5744. Email: [email protected]Search for more papers by this authorRisa Kato, Risa Kato Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, JapanSearch for more papers by this authorMasako Aoki, Masako Aoki orcid.org/0000-0001-6471-4617 Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, JapanSearch for more papers by this authorOsamu Miyazaki, Osamu Miyazaki orcid.org/0000-0002-1793-4892 Division of Radiology, National Center for Child Health and Development, Tokyo, JapanSearch for more papers by this authorIchiro Morioka, Ichiro Morioka orcid.org/0000-0002-5685-2670 Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, JapanSearch for more papers by this author First published: 19 February 2023 https://doi.org/10.1111/ped.15512 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/ped.15512. AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Accepted ArticlesAccepted, unedited articles published online and citable. The final edited and typeset version of record will appear in the future.e15512 RelatedInformation

Lamellar thickness measurements in control and osteogenesis imperfecta human bone, with development of a method of automated thickness averaging to simplify quantitation

Lamellar bone that forms in moderate and severe osteogenesis imperfecta (OI) is composed of structurally irregular lamellae compared to those in control bone. OI and control cortical bone fragments were prepared for light microscopy in standardized fashion: decalcified, embedded in plastic, sectioned and stained with toluidine blue. Polarization light microscopy (PLM) was used to demonstrate and quantify bright and dark lamellar thicknesses in cortical bone fragments from 5 patients with moderate to severe OI in whom type I collagen structural/molecular defects were detected and in control bone from 5 patients. Rigid selection criteria identified lamellar regions for quantification. Thicknesses of bright and dark lamellae were measured manually at 20X magnification using a histomorphometric image analysis system. A method of automated thickness averaging was developed to determine lamellar thicknesses from PLM images to make measurement faster. Our study demonstrates, for the first time, that in OI bone from patients with type I collagen structural/molecular defects mean lamellar thickness measurements (along with the bright and dark lamellar thicknesses) were less than those in control bone by statistically highly significant differences. The mean value for bright lamellae was less than that for dark lamellae in both control and OI bone. The ratio of mean values for bright/dark lamellar thicknesses was the same in control and OI bone. The automated method obtained similar results to the manual method. Lamellar bone in moderate and severe OI with type I collagen defects is composed of thinner and less structurally regular lamellae than those in control bone. This finding indicates that lamellar thickness measurements can be helpful in assessing the effect of specific collagen and collagen-related mutations on OI bone synthesis and warrant inclusion in research and clinical histomorphometric assessments.

Tendon properties in a mouse model of severe osteogenesis imperfecta

ABSTRACT Purpose/Aim of the study Osteogenesis imperfecta is a heritable bone disorder that is usually caused by mutations in collagen type I encoding genes. The impact of such mutations on tendons, a structure with high collagen type I content, remains largely unexplored. We hypothesized that tendon properties are abnormal in the context of a mutation affecting collagen type I. The main purpose of the study was to assess the anatomical, mechanical, and material tendon properties of Col1a1 Jrt/+ mice, a model of severe dominant OI. Materials and Methods The Flexor Digitorum Longus (FDL) tendon of Col1a1 Jrt/+ mice and wild-type littermates (WT) was assessed with in vitro mechanical testing. Results The results showed that width and thickness of FDL tendons were about 40% larger in WT (p < 0.01) than in Col1a1 Jrt/+ mice, whereas the cross-sectional area was 138% larger (p < 0.001). The stiffness, peak- and yield-force were between 160% and 194% higher in WT vs. Col1a1 Jrt/+ mice. The material properties did not show significant differences between mouse strains with differences <15% between WT and Col1a1 Jrt/+ (p > 0.05). Analysis of the Achilles tendon collagen showed no difference between mice strains for the content but collagen solubility in acetic acid was 66% higher in WT than in Col1a1 Jrt/+ (p < 0.001). Conclusions This study shows that the FDL tendon of Col1a1 Jrt/+ mice has reduced mechanical properties but apparently normal material properties. It remains unclear whether the tendon phenotype of Col1a1 Jrt/+ mice is secondary to muscle weakness or a direct effect of the Col1a1 mutation or a combination of both.

Prognostic factors for mobility in children with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility. Although the disease severity is known to influence the ability to walk, little is known about how children with severe OI can achieve practical ambulation (PA). This study aimed to determine the early predictors of future mobility in children with OI. Thirty OI patients with an average age of 12.1 years were classified into the PA group (22 patients) and nonambulator group (NA group: 8 patients) on the basis of the Hoffer classification. Various clinical parameters related to mobility were compared between the PA and NA groups. Therapeutic interventions were also compared between the 2 groups. The mean age at diagnosis and initial fracture were significantly lower in the NA group than in the PA group. The height was significantly smaller in the NA group than in the PA group at all ages examined (at birth, 3 years, and 6 years). The number of patients with respiratory failure was significantly higher in the NA group than in the PA group. The age at initial corrective osteotomy of the lower extremities in the PA group was significantly lower than that in the NA group, although there was no significant difference in the disease severity in infancy between the groups. Height during infancy, age at initial fracture, and neonatal respiratory status could be prognostic factors for mobility in OI. Surgical interventions at an early age may influence walking ability in children with moderate OI.

Phenotypic Variation in Vietnamese Osteogenesis Imperfecta Patients Sharing a Recessive P3H1 Pathogenic Variant.

Osteogenesis imperfecta (OI) is a syndromic disorder of bone fragility with high variation in its clinical presentation. Equally variable is molecular aetiology; recessive forms are caused by approximately 20 different genes, many of which are directly implicated in collagen type I biosynthesis. Biallelic variants in prolyl 3-hydroxylase 1 (P3H1) are known to cause severe OI by affecting the competence of the prolyl 3-hydroxylation—cartilage associated protein—peptidyl-prolyl cis-trans isomerase B (P3H1-CRTAP-CyPB) complex, which acts on the Pro986 residue of collagen type I α 1 (COL1A1) and Pro707 collagen type I α 2 (COL1A2) chains. The investigation of an OI cohort of 146 patients in Vietnam identified 14 families with P3H1 variants. The c.1170+5G>C variant was found to be very prevalent (12/14) and accounted for 10.3% of the Vietnamese OI cohort. New P3H1 variants were also identified in this population. Interestingly, the c.1170+5G>C variants were found in families with the severe clinical Sillence types 2 and 3 but also the milder types 1 and 4. This is the first time that OI type 1 is reported in patients with P3H1 variants expanding the clinical spectrum. Patients with a homozygous c.1170+5G>C variant shared severe progressively deforming OI type 3: bowed long bones, deformities of ribcage, long phalanges and hands, bluish sclera, brachycephaly, and early intrauterine fractures. Although it remains unclear if the c.1170+5G>C variant constitutes a founder mutation in the Vietnamese population, its prevalence makes it valuable for the molecular diagnosis of OI in patients of the Kinh ethnicity. Our study provides insight into the clinical and genetic variation of P3H1-related OI in the Vietnamese population.

Severe osteogenesis imperfecta caused by CREB3L1 mutation in a cat.

We examined the clinical features and pathology, and identified the causative mutation, of osteogenesis imperfecta in a 2-mo-old kitten with growth retardation and abnormal gait. Blood and radiographic examinations were performed on presentation. Radiographs revealed decreased opacity of numerous bones. Fractures were observed in some long bones, including femur and tibia. Histologic examination of the tibia showed decreased osteoid and osteoblasts at the primary spongiosa extending from the growth plate. The periosteum was thickened, and cortical bone and osteoblasts were decreased. Consequently, osteogenesis imperfecta was diagnosed. Genomic DNA and total RNA were extracted from the skin and used for PCR. Whole-genome sequencing identified a 2-bp deletion (c.370_371delTG; p.C124fs), which resulted in a homozygous frameshift mutation on exon 3 of CREB3L1. This mutation introduced a premature stop codon, suggesting production of the truncated protein without a functional domain as a transcription factor for expression of COL1A1 mRNA. This error may have affected collagen fibril formation, leading to the development of osteogenesis imperfecta.

Atypical Femur Fracture in the Setting of Long-Term Bisphosphonate use for Osteogenesis Imperfecta: A Case Report

Bisphosphonate (BP) therapy for moderate to severe osteogenesis imperfecta (OI) has become a mainstay of treatment in the last three decades. Given the significant improvements in bone mineral density and theoretical reductions in fracture risk, many patients are treated with bisphosphonates for prolonged periods of time. There currently lacks consensus in the optimal duration of BP therapy for patients with OI, and patients are often treated on a case-by-case basis. Long-term BP therapy has been associated with atypical femur fractures in adult patients treated for osteoporosis. The American Society for Bone and Mineral Research concluded that the median duration of BP therapy in patients with atypical femur fractures was 7 years. The role of long-term BP therapy in OI patients with atypical femur fractures remains unclear. Here, a case report is presented of an adolescent patient with type V OI that sustained a subtrochanteric femur fracture with features of an atypical pattern following treatment with intravenous pamidronate for 10.5 years. At the time of injury, the contralateral femur was also found to have atypical features suggestive of an impending fracture. The completed fracture was treated with closed reduction and cephalomedullary nail fixation. The impending fracture was prophylactically stabilized using the same technique. Prior to the injury, limb-length radiographs obtained to evaluate lower extremity alignment demonstrated features of an impending fracture but went unnoticed. Further studies are needed to clarify the role of long-term BP therapy in patients with OI suffering from atypical femur fractures.

Comprehensive pain management strategy for infants with moderate to severe osteogenesis imperfecta in the perinatal period.

Osteogenesis imperfecta (OI) is a rare genetic heterogeneous disorder that causes increased bone fragility and recurrent fractures. For infants with OI and diffuse fractures, pain management, which is nuanced and specific for this population, is of the utmost importance to their neonatal care. Through experience at our center, we have developed a standard approach that has been successful in optimizing survival for these infants during this tenuous period. In this paper, we outline our multidisciplinary approach to pain management for infants with moderate to severe OI during the neonatal period, with emphasis on promotion of fracture healing and adequate pain control.

Non-collagen pathogenic variants resulting in the osteogenesis imperfecta phenotype in children: a single-country observational cohort study

Background/ObjectivesIn England, children (0–18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a ‘Highly Specialised Service’ (HSS OI); affected...

Eat, breathe, sleep with Osteogenesis Imperfecta

BackgroundAlthough Osteogenesis Imperfecta (OI) affects the connective tissue causing extremely brittle bones with consequent skeletal deformities, it is important to go beyond bones. Indeed, the quality of life in OI does not only depend on bones status, as OI might affect also other important functions. We have therefore implemented a multidisciplinary study to assess lung function, breathing pattern, sleep quality and nutritional status in 27 adult OI type III and IV patients (median age: 34.6 years; 19 women; 14 type III).ResultsAccording to nocturnal oxygen desaturation, two groups were identified: 13 patients with (OI_OSA, incidence: 48.2%) and 14 without (no_OSA) obstructive sleep apnea. The former was characterized by higher spinal and ribcage deformity, by more restrictive lung function, by paradoxical thoracic breathing in supine position, by rapid and shallow breathing, by higher body mass index, by longer neck and waist circumferences; by higher abdominal volume and by greater percentage of body fat mass, particularly localized in the trunk.The best predictor of OI_OSA was the negative value of the supine ribcage contribution to tidal volume, followed by the ratio between the neck and the waist circumferences with body height and the supine thoraco-abdominal volumes phase shift angle.ConclusionsThe pathophysiology of OI ensued a dangerous vicious circle, in which breathing, sleep and nutritional status are tightly linked, and they might all end up in negatively affecting the quality of life. The vicious circle is fed by some intrinsic characteristics of the disease (thoracic, cranial and mandibular deformities) and some bad daily habits of the patients (i.e. physical inactivity and low dietary quality). The former impacts on restricting the respiratory function, the latter makes Olers more prone to experience overweight or obesity. The main consequence is a high incidence of obstructive sleep apnea, which remains an underdiagnosed disorder in individuals with severe OI who are obese, with a neck to height ratio over than 31.6%, and characterized by paradoxical breathing in supine position. A multidisciplinary approach, including evaluations of breathing, sleep and nutrition, is required to better manage the disease and fulfil the maximizing well-being of OI patients.

Long-term vascular access for infants with moderate to severe osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder that causes skeletal fragility. For the most fragile infants and young children with OI, intravenous (IV) bisphosphonate administration is essential, but IV access attempts often cause fractures. Port-a-caths help prevent these events, but some surgeons are hesitant to insert these devices in these infants due to lack of data on their safety. Retrospective study of pediatric patients with OI who underwent port-a-cath placement from 1999 to 2018; incidence of complications such as infection and thrombosis and need for reoperation or replacement are described. Port-a-caths were placed in 17 patients with OI (median age, 8 mos [5-23 mos]; median weight, 5.8kg [3.96-9.08kg]) and remained in place for a median of 53.5 mos (10-127 mos). One port-a-cath was replaced because of thrombosis. Two port-a-caths were removed because of malfunction, one for skin erosion, and one for infection. In these five cases, replacement was not needed because patients could safely tolerate IV access. Two patients have their port-a-cath in place and the remaining ten patients had theirs removed electively as it was no longer needed. Port-a-cath placement in pediatric patients with OI is safe and efficacious for durable central access, enabling reliable IV bisphosphonate delivery and reducing iatrogenic trauma.

Несовершенный остеогенез: роль и место ортопедической хирургии нижних конечностей

Introduction Surgical correction of orthopedic problems in children and adults with severe osteogenesis imperfecta is of interest to the medical community. The aim of this study was to review the current relevant literature on the role of orthopedic surgery in the treatment of children and adults with osteogenesis imperfecta and the integration of surgery into a multidisciplinary approach to the treatment of patients with osteogenesis imperfecta. The review is based on the material of the report presented at the first educational conference of the European Pediatric Orthopedic Society which was held in Russia at the Ilizarov Center in 2021. Material and methods To prepare the review, we searched for information sources at the scientific platforms such as PubMed, Scopus, ResearchGate, RSCI, as well as published products (Elsevier, Springer). Results and discussion The review includes a discussion of the classification, indications, features of the surgical technique and the early postoperative period, the role of early functional loading, the features of long-term treatment results of using telescopic transphyseal constructs in the correction of deformities of lower limb long bones as well as issues of the combination of orthopedic surgery and bisphosphonate therapy. Conclusion Orthopedic support of children and adults with severe and moderate types of osteogenesis imperfecta requires construction of a multifactorial strategy that takes into account the requirements of physical therapy and medication treatment, as well as the use of specialized implants, instrumentation and methods of surgical intervention, while an optimal solution has been still sought.

Mesenchymal Stem Cell Engraftment in Bone Following In Utero Transplantation in a Patient with Severe Osteogenesis Imperfecta.

The purpose of the present study was to evaluate the ability of allogeneic fetal mesenchymal stem cells (MSCs) to engraft and differentiate after in utero transplantation. A female fetus with multiple intrauterine fractures, diagnosed as severe osteogenesis imperfecta, was transplanted with HLA-mismatched male fetal MSCs in the 32nd week of gestation. At nine months of age, whole Y genome FISH staining of a bone marrow biopsy showed a median of 7.4% Y-positive cells (range 6.8–16.6%). In slides stained for osteocalcin or osteopontin, a centromeric XY-specific probe revealed 0.3% of XY-positive cells. Bone histology showed regularly arranged and configured bone trabeculae. Patient lymphocyte proliferation against donor MSCs was not observed in in vitro co-culture experiments performed after MSC injection. Complementary bisphosphonate treatment was begun at four months. During the first two years of life three fractures were noted. At two years of corrected age, psychomotor development was normal, and growth followed the same channel, −5SD. Our findings show that allogeneic fetal mesenchymal stem cells can engraft and differentiate into bone in a human fetus even when the recipient is immunocompetent and HLA-incompatible.