Long Bone Deformities Research Articles

Correction of rotational deformities in long bones using guided growth: a scoping review.

The objective of this scoping review was to describe the extent and type of evidence of using guided growth to correct rotational deformities of long bones in children. This scoping review was conducted in accordance with the JBI methodology for scoping reviews. All published and unpublished studies investigating surgical methods using guided growth to perform gradual rotation of long bones were included. Fourteen studies were included: one review, three clinical studies, and ten preclinical studies. In the three clinical studies, three different surgical methods were used on 21 children. Some degree of rotation was achieved in all but two children. Adverse effects reported included limb length discrepancy (LLD), knee stiffness and rebound of rotation after removal of tethers. Of the ten preclinical studies, two were ex vivo and eight were in vivo. Rotation was achieved in all preclinical studies. Adverse effects reported included implant extrusions, LLD, articular deformities, joint stiffness and rebound of rotation after removal of tethers. Two of the studies reported on histological changes. All studies conclude that guided growth is a potential treatment for rotational deformities of long bones. There is great variation in animal models and surgical methods used and in reported adverse effects. More research is needed to shed light on the best surgical guided growth method, its effectiveness as well as the involved risks and complications. Based on current evidence the procedure is still to be considered experimental. 4.

RECOVERY OF STABILIZING MUSCLES THAT PROVIDE A VERTICAL POSITION OF THE TRUNK IN PATIENTS WITH POST-TRAUMATIC DEFORMITIES OF THE LONG BONES OF THE LOWER LIMBS IN THE DISTANT PERIOD

Rehabilitation treatment in the case of posttraumatic deformities of long bones of lower extremities (PDLBLE) in the distant period after trauma is aimed at the restoration of support ability of lower extremity while walking and standing. Objective. To work out the set of the exercises targeted on the restoration of muscle-stabilizer function in patients with (PDLBLE) Methods. Research group — 40 patients who received closed injuries of the long bones of the lower limbs, initial trauma occured 6–12 months ago. Among them were 21 women. (52.5 % of persons; age 27–73 years) and 19 men (47.5 % of people, age 29–77 years). The comparison group included 40 healthy volunteers, among which there were 12 women (30 % of persons; age 24–50 years) and 28 men (70 % of people, age 31–49 years). The assessment was carried out before and after rehabilitation for 2 weeks. Parameters evaluated: pain scores on VAS, the results of restoring the support ability using the scale of Tyazhelov O. A. Results. The results of observations are given, where in addition to descriptive statistics (minimum, maximum, average meanings), parameters of support ability and VAS, in patients and volunteers before and after treatment, cumulative group indicators (CG) were calculated for each group at the beginning (CG0) and 2 weeks after rehabilitation (CG1); the «rehabilitation» coefficient as a ratio of group indicators before and after treatment was calculated as well. Cumulative group indicator after rehabilitation (CG1) increased to 2 995 points, which indicates an increase in support ability. Cumulative group VAS score after rehabilitation (CG1) decreased to 116 points from 200 points before rehabilitation — reduction of pain in patients. After rehabilitation, volunteers showed a slight increase in the cumulatory group indicator (CG1) to 3 917 points. Conclusions. The system of rehabilitation of patients with PDLBLE in the remote period after injuries proved its effectiveness in restoring muscle-stabilizers vertical position of the trunk, pelvis, lower limbs and pain reduction.

SCOPING REVIEW OF ROTATIONAL GUIDED GROWTH IN THE GROWING BONE

The aim of this scoping review is to understand the extent and type of evidence in relation to the use of guided growth for correcting rotational deformities of long bones. Guided growth is routinely used to correct angular deformities in long bones in children. It has also been proven to be a viable method to correct rotational deformities, but the concept is not yet fully examined. Databases searched include Medline, Embase, Cochrane Library, Web of Science and Google Scholar.All identified citations were uploaded into Rayyan.ai and screened by at least two reviewers. The search resulted in 3569 hits. 14 studies were included: 1 review, 3 clinical trials and 10 pre-clinical trials. Clinical trials: a total of 21 children (32 femurs and 5 tibiae) were included. Surgical methods were 2 canulated screws connected by cable, PediPlates obliquely oriented, and separated Hinge Plates connected by FiberTape. Rotation was achieved in all but 1 child. Adverse effects reported include limb length discrepancy (LLD), knee stiffness and rebound of rotation after removal of tethers. 2 pre-clinical studies were ex-vivo studies, 1 using 8-plates on Sawbones and 1 using a novel z-shaped plates on human cadaver femurs. There were 5 lapine studies (2 using femoral plates, 2 using tibial plates and 1 using an external device on tibia), 1 ovine (external device on tibia), 1 bovine (screws and cable on metacarp) and a case-report on a dog that had an external device spanning from femur to tibia. Rotation was achieved in all studies. Adverse effects reported include implant extrusions, LLD, articular deformities, joint stiffness and rebound. All included studies conclude that guided growth is a viable treatment for rotational deformities of long bones, but there is great variation in models and surgical methods used, and in reported adverse effects.

Correction of Multiapical Deformities of Long Bones of the Lower Extremities: A Review

Background. Multiapical deformities of the long bones of the lower extremities represent a complex and widely prevalent orthopedic pathology. A numerous of publications address its individual aspects: diagnosis, planning, and correction. However, no single study was found that offers a comprehensive assessment of contemporary views on treating patients with multiapical deformities of long bones.
 Aim of the review — to define current concepts and unresolved issues in the analysis, planning, and correction of multiapical deformities of the long bones of the lower limbs based on the scientific literature.
 Methods. Electronic databases were utilized for literature search: PubMed/MEDLINE, SAGE Publishing Journals, Embase, eLIBRARY, Google Scholar. Particular attention was paid to studies that provide information on diagnosis, planning, and correction methods for multiapical deformities. A total of 46 publications were included in the review.
 Results. In the literature, the terms “multiapical deformity” and “multilevel deformity” are used synonymously. At the same time, the term “multilevel deformity” is used to denote uniapical deformities of different limb segments. The main diagnostic feature of a multiapical deformity is the location of the apex outside the bone. Unlike uniapical deformities, the correction planning of multiapical deformities uses the axis of the intermediate fragment(s). Most authors define it as the mid-diaphyseal line. The correction of multiapical deformities is performed either acute or gradually. Acute correction with internal fixation is undoubtedly more comfortable for the patient. If there are contraindications to it, the deformity correction is performed gradually using Ilizarov hinges or orthopedic hexapods.
 Conclusion. The term “multiapical deformity” inherently indicates that the deformed bone has more than one apex, so it should take precedence over the term “multilevel deformity”. The diagnostic feature of the multiapical deformity “localization of the AOD outside the bone” is not absolute and requires clarification. There are challenges in planning the correction using mechanical axes, as well as in determining the axis of the nonlinear (bowing) intermediate fragment(s). The “spring technique” has significant advantages over other variants of using orthopedic hexapods in correcting a multiapical deformity. However, a rationale for the optimal characteristics of springs, their fixation points to supports, and clarification of the computer program’s use method is required. Addressing these issues will enhance the treatment efficiency for patients with multiapical deformities.

Clinical and radiological characteristics of two patients with osteoporosis–pseudoglioma syndrome caused by a pathogenic homozygotic variant in the <i> LRP5 </i> gene

BACKGROUND: Osteoporosis–pseudoglioma syndrome (OMIM #259770) is an ultrarare autosomal recessive disease characterized by congenital or infant blindness, severe osteoporosis, and spontaneous bone fractures. The syndrome is caused by pathogenic variants in the LRP5 gene, which encodes a protein involved in the transmission of signals in the Wnt/β-catenin signaling pathway. To date, 77 pathogenic variants associated with osteoporosis–pseudoglioma syndrome have been registered in LRP5, mainly localized in the second and third beta-propeller domains of the protein, which have a high affinity for the Wnt ligand.
 CLINICAL CASES: Two siblings presented with clinical manifestations of osteoporosis–pseudoglioma syndrome caused by a pathogenic homozygous missense variant c.1481GA (p.Arg494Gln) in LRP5. The phenotype of the patients was characterized by a combination of blindness, low bone-mineral density, short stature, and fractures and deformities of long tubular bones and the spine.
 DISCUSSION: The rarity of the osteoporosis–pseudoglioma syndrome and the similarity of the clinical manifestations of various skeletal disorders and their genetic heterogeneity lead to a late diagnosis and treatment.
 CONCLUSIONS: We are the first to present the clinical, radiological, and genetic characteristics of two siblings with clinical manifestations of osteoporosis–pseudoglioma syndrome. Its rarity necessitates detailed description of the clinical and genetic characteristics of this syndrome. Molecular genetic testing is an important part of a comprehensive diagnosis.

SGMS2 in primary osteoporosis with facial nerve palsy.

Pathogenic heterozygous variants in SGMS2 cause a rare monogenic form of osteoporosis known as calvarial doughnut lesions with bone fragility (CDL). The clinical presentations of SGMS2-related bone pathology range from childhood-onset osteoporosis with low bone mineral density and sclerotic doughnut-shaped lesions in the skull to a severe spondylometaphyseal dysplasia with neonatal fractures, long-bone deformities, and short stature. In addition, neurological manifestations occur in some patients. SGMS2 encodes sphingomyelin synthase 2 (SMS2), an enzyme involved in the production of sphingomyelin (SM). This review describes the biochemical structure of SM, SM metabolism, and their molecular actions in skeletal and neural tissue. We postulate how disrupted SM gradient can influence bone formation and how animal models may facilitate a better understanding of SGMS2-related osteoporosis.

Analysis of COL1A1 and COL1A2 gene variants in two fetuses with osteogenesis imperfecta

To explore the genetic basis of two fetuses with an osteogenesis imperfecta (OI) phenotype. Two fetuses diagnosed at the Affiliated Hospital of Weifang Medical College respectively on June 11, 2021 and October 16, 2021 were selected as the study subjects. Clinical data of the fetuses were collected. Amniotic fluid samples of the fetuses and peripheral blood samples of their pedigree members were collected for the extraction of genomic DNA. Whole exome sequencing (WES) and Sanger sequencing were carried out to identify the candidate variants. Minigene splicing reporter analysis was used to validate the variant which may affect the pre-mRNA splicing. For fetus 1, ultrasonography at 17+6 weeks of gestation had revealed shortening of bilateral humerus and femurs by more than two weeks, in addition with multiple fractures and angular deformities of long bones. WES revealed that fetus 1 had harbored a heterozygous c.3949_3950insGGCATGT (p.N1317Rfs*114) variant in exon 49 of the COL1A1 gene (NM_000088.4). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was classified as a pathogenic variant (PVS1+PS2+PM2_Supporting) for disrupting the downstream open reading frame resulting in premature translational termination, being de novo in origin, and lacking records in the population and disease databases.For fetus 2, ultrasonography at 23 weeks of gestation also revealed shortening of bilateral humerus and femurs by one and four weeks, respectively, in addition with bending of bilateral femurs, tibias and fibulas. Fetus 2 had harbored a heterozygous c.1557+3A>G variant in intron 26 of the COL1A2 gene (NM_000089.4). Minigene experiment showed that it has induced skipping of exon 26 from the COL1A2 mRNA transcript, resulting in an in-frame deletion (c.1504_1557del) of the COL1A2 mRNA transcript. The variant was inherited from its father and had been previously reported in a family with OI type 4. It was therefore classified as a pathogenic variant (PS3+PM1+PM2_Supporting+PP3+PP5). The c.3949_3950insGGCATGT (p.N1317Rfs*114) variant in the COL1A1 gene and c.1557+3A>G variant in the COL1A2 gene probably underlay the disease in the two fetuses. Above findings not only have enriched the mutational spectrum of OI, but also shed light on the correlation between its genotype and phenotype and provided a basis for genetic counseling and prenatal diagnosis for the affected pedigrees.

MODERN TREATMENT OF POST-TRAUMATIC EXTRA-ARTICULAR DEFORMITY OF THE FEMUR

The issue of adequate treatment of post-traumatic deformities of long bones has become more urgent due to the large number of injured as a result of combat trauma and the presence of residual displacement of fragments after primary care providing. Objective. On the basis of literature analysis and own clinical experience, present methods of treatment of post-traumatic extra-articular deformity of the distal part of the femur (DF). Methods. The available professional literature, publications in electronic systems Google Scholar, PubMed, ScienceDirect were analyzed. The results of treatment of 38 patients with post-traumatic extra-articular deformities of the DF, in which the fracture line was extended to the area of the joint at the time of the primary injury, were studied. To plan the surgical treatment, the author's 3D-printing technology was used in 12 patients with the most complex cases. A clinical exampleis given. Results. Key moments of patient examination, principles of correction and approaches to its planning in case of DF multiplanar deformities are defined. The results of 3D-visualization and 3D-printing of the damaged segment during the examination and planning of deformity correction were evaluated. All patients to whom the 3D-modeling technique was applied were operated оn, considering the individual characteristics of the deformity.After each stage of surgical treatment, a course of individual rehabilitation treatment was carried out. Positive dynamics of functional results were obtained within 12 months according to SF-36 and AOFAS scales. Conclusions. The use of 3D-modeling during the planning of corrective surgery allows the surgeon to increase the accuracy of the correction and significantly reduce the time of the operation. Well-known and improved methods with individually selected rehabilitation, used for the treatment of post-traumatic extra-articular deformities of the distal femur contribute to faster recovery, avoiding potential complications and achieving positive functional outcome in such patients.

Multislice computed tomography in the complex assessment of deformities of long tubular bones of the lower extremities: prospective cohort study

BACKGROUND: Progress in science is attributed to improvements in research methods. The rapid development in diagnostic radiology observed in the last two decades has opened fundamentally new opportunities for clinical medicine, making practically all organs, and tissue structures of the human body accessible for research. Computer technology in medicine makes it possible to assess in more detail deformities of the lower extremity and improve methods of surgical treatment that determine the individual correction of the shape of the deformed bone.
 AIM: To comprehensively assess deformities of the long bones of the lower extremities using modern methods of radiation diagnostics computed tomography.
 MATERIALS AND METHODS: Surgery, as the main treatment of patients with deformities of the long bones of the limbs, cannot be effectively implemented without knowing detailed appearance of the femur and tibia and all the elements of the deformity. Angular deformities of the long bones are usually assessed by plain radiographs in frontal and lateral projections, and rotational deformities of the long bones are assessed by multislice computed tomography.
 RESULTS: In the National Medical Research Center of Traumatology and Orthopedics named after N.N. Priorov and Clinic of Scientific Medicine, computed tomography studies of the long bones of the lower extremities and hip and lower limb deformities were performed from 2015 to 2022. The study involved 265 patients aged 65 years, who were divided according to the type of deformity.
 CONCLUSION: Complex X-ray diagnostics for deformities of the long bones of the lower extremities according to our method allows us to represent the deformity not only in planimetric, but also in stereometric terms. This helps eliminate projectionangular and volumetric rotational deformations.

Comparison of the use of intramedullary telescopic system and titanium elastic rods in children with osteogenesis imperfecta I and III types

Comparison of the use of intramedullary telescopic system and titanium elastic rods in children with osteogenesis imperfecta I and III types

Қазақтандағы жетілмеген остеогенезі бар балаларды хирургиялық емдеуде отандық интрамедуллярлық телескопиялық жүйенің күтілетін үлесі

Osteogenesis imperfecta (OI) is a group of inherited connective tissue disorders in collagen structure, processing or cross-linking, new bone formation and osteoblast differentiation, which result in fragility of the bones, recurrent fractures and deformities.The article presents scientific data on the types and features of metal structures used in intramedullary osteotomy performed for the surgical treatment of fractures and deformities of long tubular bones with osteogenesis imperfecta in children and outlines the benefits of the developed domestic intramedullary telescopic system "DOSSANOV" in providing surgical treatment to children with osteogenesis imperfecta. For the "crystal children", whose number is growing in Kazakhstan, the expected advantages of using this system are analyzed.Key words: Osteogenesis imperfecta, children, intramedullary osteosynthesis, osteotomy, intramedullary rods, intramedullary telescopic system.

Влияние телескопического интрамедуллярного остеосинтеза большеберцовой кости на рост сегмента: пилотное экспериментальное исследование

Introduction Telescopic intramedullary osteosynthesis (TIO) is used in children with osteogenesis imperfecta and other diseases accompanied by frequent fractures and deformities of long bones due to pathological bone tissue featuring reduced strength properties. Purpose In an animal experiment to study the growth characteristics of an intact tibia under conditions of intramedullary reinforcement with a telescopic rod. Material and methods A non‑randomized controlled study was conducted on 4 animals (puppies, littermates) that underwent TIO of the right limb tibia with a telescopic titanium rod (outer diameter of 4.2 mm) at the age of 5 months. X-ray parameters (length of the tibia, angles of inclination of the articular surfaces, telescoping magnitude) were studied before surgery, on the day of rod placement, and after the end of spontaneous growth of the segment (7 months after surgery). The contralateral left tibia served as a control, and its X-ray parameters were studied at the same time-points. Results Transphyseal reinforcement with a telescopic rod caused growth retardation with loss of length in only one case out of four (8 mm or 4.8 % of residual growth). In other cases, no difference in the length of the tibias of the right and left lower extremities was found. Eccentric insertion of the transphyseal rods into the posterior third of the distal epiphysis (due to the natural anatomy of the canine tibial shaft) formed an angular deformity during growth: a significant increase in the distal anterior and lateral tibial angles of the operated limb compared to the intact limb. The amount of divergenceof the parts of the rods was, on average, 11.3 mm. There were no cases of migration of intramedullary rods or loss of fixation of threaded sections in the epiphyses. Conclusion Under experimental conditions, the slowing down of longitudinal bone growth is not a constantly observed effect. Titanium telescopic rods are not prone to blocking during the limb growth or to losing the position of the threaded parts in the epiphyses. The eccentric passage of the rods through the growth zones causes angular deformities in the course of growth of the segment.

Humerus nail for tibial reconstruction in adolescent with osteogenesis imperfecta – A rare surgical case report

Osteogenesis Imperfecta (OI) is a rare connective tissue disorder known for excessive bone fragility caused by collagen mutations. The common orthopaedic problems related to bone fragility include frequent multiple bone fractures, progressive deformity of long bones leading to impaired ambulation. Surgical correction of long bone deformities in OI is conventionally done using distraction osteogenesis (illizarov fixator), elastic intramedullary nailing, rigid extramedullary fixation using plates, after osteotomy. Intramedullary fixation appears to be an ideal choice for correction of recurrent deformity in the long bone and the devices used previously include telescoping rods, single or dual non-elongating nails (rush nail, TENS). Recently in a case report of 3 individual patients, a humerus nail has been used to reconstruct femur in adolescents with OI. We report a case of humerus nailing for reconstruction of tibia in an adolescent OI male with excellent outcomes which is first of its kind and not reported previously by any other authors.

Towards collision detection in foot and ankle deformity correction using parallel external fixator: A novel analytical approach

Gradual correction using external fixator has been advocated as a minimally invasive solution for limb deformity and is widely used in the clinic. This treatment manner requires a long-term distraction process, which is guided by a preplanned correction path. However, bone cross-section (BCS) collision and soft tissue (ST)-distraction rod (DR) collision may occur on the path and then affect the continuity of the process. Thus, collision detection should be carried out before performing distraction. Existing detection solutions do not simultaneously consider these two types of collisions, and primarily target long-bone deformity. To solve these issues, taking more complex foot and ankle deformity as the research object, a novel analytical detection approach is proposed in this paper. By modelling the contours of BCS, ST, and DRs as convex envelope planes/bodies using different spatial line styles, the spatial posture relations of their boundaries can be reproduced on the correction path, and collision detection can be transformed into the mathematical problem of calculating point-plane and point-line distances. Subsequently, two algorithms are proposed for BCS and ST-DR collision detections, and adjustment strategies are provided to resolve algorithm anomalies. Clinical case simulation proves the effectiveness and applicability of the approach. Since the detection is used for pre-distraction prediction rather than real-time monitoring, the correction path with potential collision risk can be re-planned before distraction, and finally, guarantees the safety of gradual correction.

Profilin-1 negatively controls osteoclast migration by suppressing the protrusive structures based on branched actin filaments.

Profilin-1 (Pfn1), an evolutionarily conserved actin-binding protein, is an important regulator of the cytoskeleton. We previously reported the osteoclast-specific Pfn1-conditional knockout (cKO) mice had postnatal osteolytic phenotype with craniofacial and long-bone deformities associated with increased migration of cultured osteoclasts. We hypothesized the increased cellular processes structured with branched actin filaments may underlies the mechanism of increased bone resorption in these mutant mice. The morphological structure and cell migration of the cultured osteoclasts were analyzed using fluorescent microscopy and time-lapse image capturing. Fractional migration distances, as well as the index of protrusive structures (%-PB) that evaluates relative border length of the protrusion were compared between the cells from control and Pfn1-cKO mice. Time-lapse image analysis showed that %-PB was significantly larger in Pfn1-cKO osteoclasts. In addition, the fractional migration distance was positively correlated with the index. When the branched actin filament organization was suppressed by chemical inhibitors, the osteoclast migration was declined. Importantly, the suppression was more extensive in Pfn1-cKO than in control osteoclasts. Our results indicated the causative involvement of the increased branched actin filament formation at least in part for their excessive migration. Our findings provide a mechanistic rationale for testing novel therapeutic approaches targeting branched actin filaments in osteolytic disorders.

3D-printed Cutting Guides for Lower Limb Deformity Correction in the Young Population.

Three-dimensional (3D) virtual surgical planning technology has advanced applications in the correction of deformities of long bones by enabling the production of 3D stereolithographic models, patient-specific instruments and surgical-guiding templates. Herein, we describe the implementation of this technology in young patients who required a corrective osteotomy for a complex 3-plane (oblique plane) lower-limb deformity. A total of 17 patients (9 males, average age 14.7 y) participated in this retrospective study. As part of preoperative planning, the patients' computerized tomographic images were imported into a post-processing software, and virtual 3D models were created by a segmentation process. Femoral and tibial models and cutting guides with locking points were designed according to the deformity correction plan. They were used for both planning and as intraoperative guides. Clinical parameters, such as blood loss and operative time were compared with a traditional surgical approach group. All osteotomies in the 3D group were executed with the use intraoperative customized cutting guides which matched the preoperative planning simulation and allowed easy fixation with prechosen plates. Surgical time was 101±6.2 minutes for the 3D group and 126.4±16.1 minutes for the control group. The respective intraoperative hemoglobin blood loss was 2.1±0.2 and 2.5+0.3 g/dL.Clinical and radiographic follow-up findings showed highly satisfactory alignment of the treated extremities in all 3D intervention cases, with an average time-to-bone union (excluding 2 neurofibromatosis 1 patients) of 10.3 weeks (range 6 to 20 wk). The use of 3D-printed models and patient-specific cutting guides with locking points improves the clinical outcomes of osteotomies in young patients with complex bone deformities of the lower limbs. Level III.

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.

Brittle Bone Brothers: Osteogenesis Imperfecta Conventional Serial Case

Osteogenesis Imperfecta is a hereditary connective tissue disorder due to COL1A1/2 mutation causing gene defect encoding proteins to metabolize collagen. The skeletal manifestation of OI causing bone incompetence, hence the name brittle bone disease. Here we report three cases of OI type IV in adults. Skeletal conventional X-rays were performed to all patients and all of them has similar results such as bowing deformities of long bones, old union and some non-union fractures with extreme angulation and severe osteoporosis. OI are classified based on skeletal structure, sclera colorization, dentinogenesis, and functional metabolic defect genetically. OI type I and IV can live until adults; also, the same type of OI can be found in siblings. Skeletal conventional X-rays can solely make the diagnosis.

A Novel IFITM5 Variant Associated with Phenotype of Osteoporosis with Calvarial Doughnut Lesions: A Case Report

Osteogenesis imperfecta (OI) and other decreased bone density disorders comprise a heterogeneous group of heritable diseases with skeletal fragility. Recently, it was discovered that mutations in SGMS2, encoding sphingomyelin synthetase 2, result in aberrant sphingomyelin metabolism and lead to a novel form of OI termed osteoporosis with calvarial doughnut lesions (OP-CDL) with moderate to severe skeletal fragility and variable cranial hyperostotic lesions. This study describes a Japanese family with the skeletal phenotype of OP-CDL. The affected individuals have moderately severe, childhood-onset skeletal fragility with multiple long-bone fractures, scoliosis and bone deformities. In addition, they exhibit multiple CDLs or calvarial bumps with central radiolucency and peripheral radiopacity. However, SGMS2 sequencing was normal. Instead, whole-exome sequencing identified a novel IFITM5 missense mutation c.143A>G (p.N48S) (classified as a VUS by ACMG). IFITM5 encodes an osteoblast-restricted protein BRIL and a recurrent c.-14C>T mutation in its 5' UTR region results in OI type V, a distinctive subtype of OI associated with hyperplastic callus formation and ossification of the interosseous membranes. The patients described here have a phenotype clearly different from OI type V and with hyperostotic cranial lesions, feature previously unreported in association with IFITM5. Our findings expand the genetic spectrum of OP-CDL, indicate diverse phenotypic consequences of pathogenic IFITM5 variants, and imply an important role for BRIL in cranial skeletogenesis.

4-PBA Treatment Improves Bone Phenotypes in the Aga2 Mouse Model of Osteogenesis Imperfecta.

ABSTRACTOsteogenesis imperfecta (OI) is a genetically heterogenous disorder most often due to heterozygosity for mutations in the type I procollagen genes, COL1A1 or COL1A2. The disorder is characterized by bone fragility leading to increased fracture incidence and long‐bone deformities. Although multiple mechanisms underlie OI, endoplasmic reticulum (ER) stress as a cellular response to defective collagen trafficking is emerging as a contributor to OI pathogenesis. Herein, we used 4‐phenylbutiric acid (4‐PBA), an established chemical chaperone, to determine if treatment of Aga2 +/− mice, a model for moderately severe OI due to a Col1a1 structural mutation, could attenuate the phenotype. In vitro, Aga2 +/− osteoblasts show increased protein kinase RNA‐like endoplasmic reticulum kinase (PERK) activation protein levels, which improved upon treatment with 4‐PBA. The in vivo data demonstrate that a postweaning 5‐week 4‐PBA treatment increased total body length and weight, decreased fracture incidence, increased femoral bone volume fraction (BV/TV), and increased cortical thickness. These findings were associated with in vivo evidence of decreased bone‐derived protein levels of the ER stress markers binding immunoglobulin protein (BiP), CCAAT/−enhancer‐binding protein homologous protein (CHOP), and activating transcription factor 4 (ATF4) as well as increased levels of the autophagosome marker light chain 3A/B (LC3A/B). Genetic ablation of CHOP in Aga2 +/− mice resulted in increased severity of the Aga2 +/− phenotype, suggesting that the reduction in CHOP observed in vitro after treatment is a consequence rather than a cause of reduced ER stress. These findings suggest the potential use of chemical chaperones as an adjunct treatment for forms of OI associated with ER stress. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).