Skeletal Abnormalities Research Articles

Relative contributions of osteal macrophages and osteoclasts to postnatal bone development in CSF1R-deficient rats and phenotype rescue following wild-type bone marrow cell transfer.

Macrophage and osteoclast proliferation, differentiation and survival are regulated by colony-stimulating factor-1 receptor (CSF1R) signaling. Osteopetrosis associated with Csf1 and Csf1r mutations has been attributed to the loss of osteoclasts and deficiency in bone resorption. Here we demonstrate that homozygous Csf1r mutation in rat leads to delayed postnatal skeletal ossification associated with substantial loss of osteal macrophages (osteomacs) in addition to osteoclasts. Osteosclerosis and site-specific skeletal abnormalities were reversed by intraperitoneal transfer of wild-type bone marrow cells (BMT) at weaning. Following BMT, IBA1+ macrophages were detected before TRAP+ osteoclasts at sites of ossification restoration. These observations extend evidence that osteomacs independently contribute to bone anabolism and are required for normal postnatal bone growth and morphogenesis.

Skeletal abnormalities in mice with Dnmt3a missense mutations

Overgrowth and intellectual disability disorders in humans are typified by length/height and/or head circumference ≥ 2 standard deviations above the mean as well as intellectual disability and behavioral comorbidities, including autism and anxiety. Tatton-Brown-Rahman Syndrome is one type of overgrowth and intellectual disability disorder caused by heterozygous missense mutations in the DNA methyltransferase 3A (DNMT3A) gene. Numerous DNMT3A mutations have been identified in Tatton-Brown-Rahman Syndrome patients and may be associated with varying phenotype severities of clinical presentation. Two such mutations are the R882H and P904L mutations which result in severe and mild phenotypes, respectively. Mice with paralogous mutations (Dnmt3aP900L/+ and Dnmt3aR878H/+) exhibit overgrowth in their long bones (e.g., femur, humerus), but the mechanisms responsible for their skeletal overgrowth remain unknown. The goal of this study is to characterize skeletal phenotypes in mouse models of Tatton-Brown-Rahman Syndrome and identify potential cellular mechanisms involved in the skeletal overgrowth phenotype. We report that mature mice with the Dnmt3aP900L/+ or Dnmt3aR878H/+ mutation exhibit tibial overgrowth, cortical bone thinning, and weakened bone mechanical properties. Dnmt3aR878H/+ mutants also contain larger bone marrow adipocytes while Dnmt3aP900L/+ mutants show no adipocyte phenotype compared to control animals. To understand the potential cellular mechanisms regulating these phenotypes, growth plate chondrocytes, osteoblasts, and osteoclasts were assessed in juvenile mutant mice using quantitative static histomorphometry and dynamic histomorphometry. Tibial growth plates appeared thicker in mutant juvenile mice, but no changes were observed in osteoblast activity or osteoclast number in the femoral mid-diaphysis. These studies reveal new skeletal phenotypes associated with Tatton-Brown-Rahman Syndrome in mice and provide a rationale to extend clinical assessments of patients with this condition to include bone density and quality testing. These findings may be also informative for skeletal characterization of other mouse models presenting with overgrowth and intellectual disability phenotypes.

Quantitative ultrasonography reveals skeletal muscle abnormalities in carriers of DMD pathogenic variants.

Carriers of DMD pathogenic variants may become symptomatic and develop muscle-related manifestations. Despite that, few studies have attempted to characterize changes in the muscles of these carriers using imaging tools, particularly muscle ultrasound (MUS). The aim of this study was to compare lower limb MUS findings in carriers of DMD pathogenic variants (cDMD) vs healthy controls. Twenty-eight women (15 cDMD and 13 controls) underwent clinical evaluation and MUS. We collected information about muscle-related symptoms and assessed muscle strength. MUS was performed by a single physician (blind to the genetic status of subjects). The following muscles were assessed: rectus femoris, sartorius, tibialis anterior, and medial gastrocnemius. For each site, we computed data on muscle thickness, cross-sectional area, sound attenuation index, and elastography. Between-group comparisons were assessed using nonparametric tests and p-values <.05 were deemed significant. None of the subjects had objective muscle weakness, but exercise intolerance/fatigue was reported by four cDMDs and only one control. Regarding MUS, sound attenuation indices were significantly higher among carriers for all muscles tested. Longitudinal and axial deep echo intensities for the rectus femoris and tibialis anterior were also higher in the cDMD group compared with controls. No significant between-group differences were noted for elastography values, muscle area, or mean echo intensities. cDMD have skeletal muscle abnormalities that can be detected using quantitative MUS. Further studies are needed to determine whether such abnormalities are related to muscle symptoms in these patients.

The oral phenotype and dental management in patients with maple syrup urine disease; case report and scoping review

Background and objectivesThe literature about oral manifestations and dental management in maple syrup urine disease (MSUD) is sparse. The aim of this report is to present a new case of MSUD with special emphasis on oral findings and to review the relevant literature.MethodA case report of a 4-year-old boy with MSUD was described according to the CARE guidelines for describing case reports. Scoping review of relevant literature was performed, according to the PRISMA-ScR guidelines, by searching PubMed, Medline, Embase, and the grey literature for articles describing dental management and/or oral manifestations in MSUD.ResultsThe initial search identified 219 articles, but only 4 met the inclusion criteria. Rampant caries and plaque induced gingivitis were the main oro-dental findings in MSUD. Other oral findings included enamel hypoplasia, skeletal abnormalities, and abnormal oral behaviors. Disease-related factors appeared to play a major role in the development of the observed oral phenotype.ConclusionOral health in MSUD seems to be influenced by the reliance on semi-synthetic diet and associated neurocognitive complications. Tailored oral health promotional interventions should be included in the multidisciplinary management of patients with MSUD.

Rhodamine B, an organic environmental pollutant induces reproductive toxicity in parental and teratogenicity in F1 generation in vivo

This study investigated the reproductive toxicity of rhodamine B in zebrafish and its transgenerational effects on the F1 generation. In silico toxicity predictions revealed high toxicity of rhodamine B, mainly targeting pathways associated with the reproductive and endocrine systems. In vivo experiments on zebrafish demonstrated that rhodamine B exposure at a concentration of 1.5 mg/L led to significant impairments in fecundity parameters, particularly affecting females. Histopathological analysis revealed distinct changes in reproductive organs, further confirming the reproductive toxicity of rhodamine B, with females being more susceptible than males. Gene expression studies indicated significant suppression of genes crucial for ovulation in rhodamine B-treated female fish, highlighting hormonal imbalance as a potential mechanism of reproductive toxicity. Furthermore, bioaccumulation studies showed the presence of rhodamine B in both adult fish gonads and F1 generation samples, suggesting transgenerational transfer of the dye. Embryotoxicity studies on F1 generation larvae demonstrated reduced survival rates, lower hatching rates, and increased malformations in groups exposed to rhodamine B. Moreover, rhodamine B induced oxidative stress in F1 generation larvae, as evidenced by elevated levels of reactive oxygen species and altered antioxidant enzyme activity. Neurotoxicity assessments revealed reduced acetylcholinesterase activity, indicating potential neurological impairments in F1 generation larvae. Additionally, locomotory defects and skeletal abnormalities were observed in F1 generation larvae exposed to rhodamine B. This study provides comprehensive evidence of the reproductive toxicity of rhodamine B in adult zebrafish and its transgenerational effects on the F1 generation.

Mechanistic interplay of dual environmental stressors: Bisphenol-A and cadmium-induced ovarian follicular damage and hepatocyte dysfunction in vivo

This study investigates the individual and combined toxic effects of Bisphenol A (BPA) and Cadmium (Cd) in zebrafish, recognizing the complex mixture of pollutants organisms encounter in their natural environment. Examining developmental, neurobehavioral, reproductive, and physiological aspects, the study reveals significant adverse effects, particularly in combined exposures. Zebrafish embryos exposed to BPA + Cd exhibit synergistically increased mortality, delayed hatching, and morphological abnormalities, emphasizing the heightened toxicity of the combination. Prolonged exposure until 10 days post-fertilization underscores enduring effects on embryonic development. BPA and Cd induce oxidative stress, as evidenced by increased production of reactive oxygen species and lipid peroxidation. This oxidative stress disrupts cellular functions, affecting lipid metabolism and immune response. Adult zebrafish exposed to BPA and Cd for 40 days display compromised neurobehavioral functions, altered antioxidant defenses, and increased oxidative stress, suggesting potential neurotoxicity. Additionally, disruptions in ovarian follicle maturation and skeletal abnormalities indicate reproductive and skeletal impacts. Histological analysis reveals significant liver damage, emphasizing the synergistic hepatotoxicity of BPA and Cd. Molecular assessments further demonstrate compromised cellular defense mechanisms, synaptic function, and elevated cellular stress and inflammation-related gene expression in response to combined exposures. Bioaccumulation analysis highlights differential tissue accumulation patterns. In conclusion, this study provides comprehensive insights into the multifaceted toxicological effects of BPA and Cd in zebrafish, raising concerns about potential adverse impacts on environmental ecosystems and human health.

Spinal Manifestations of Skeletal Dysplasia: A Practical Guide for Clinical Diagnosis.

Skeletal dysplasias are a group of genetic conditions defined by atypical bone or cartilage growth and development. Skeletal abnormalities include short stature, limb deformity, joint contracture, and spinal deformity. Over 90% of disorders have a known genetic mutation that can definitively determine the diagnosis. As patients may present with a primary spinal concern, a careful clinical and radiographic evaluation can allow the physician to develop a working diagnosis to guide additional evaluation. Spinal manifestations include scoliosis and kyphoscoliosis, cervical instability, cervical kyphosis, thoracolumbar kyphosis, spinal stenosis, and atypical vertebral body morphology. An understanding of the affected conditions, prevalence, and natural history of these radiographic findings aids the orthopaedic surgeon in establishing a diagnosis and guides appropriate orthopaedic care.

Global Map of Skeletal and Dental Malocclusion Prevalence: From Classes to Continents

Malocclusion, ranked by the WHO as the third most critical oral health concern, impacts 39% to 93% of adolescents and teenagers worldwide, exhibiting variations influenced by age and ethnicity. Across sagittal, transverse, and vertical orientations, malocclusion poses physiological and social challenges, with 46% experiencing negative lifestyle impacts. To assess global prevalence and characteristics, Authors reviewed articles on skeletal abnormalities and malocclusions from the early 1990s to September 2023. Criteria included English-language research studies or meta-analyses focusing on Class I, Class II, and Class III malocclusions, malocclusion incidence, and dental anomalies such as open bite, deep bite, overjet, crowding, spacing, and crossbite. Prevalence globally varied for Class I (1.7-93.6%), Class II (7.4-84.0%), Class III (0.8-72.1%), and Angle Class I (0.5- 31 39.1%). Deep bite incidence ranged from 8.4% to 51.5%, influenced by ethnic and gender cofounders. Geographic variations were attributed to genetic and environmental factors, alongside methodological disparities, and categorization issues. Ambiguities in malocclusion prevalence arose from diverse research methodologies. Orthodontic epidemiology urgently requires standardized guidelines accepted by academia and professional groups to provide reliable data for healthcare recommendations. Geographic variations, influenced by genetic and environmental factors, contribute to the diverse prevalence of malocclusion globally. Methodological disparities and categorization issues create challenges, necessitating urgent development of standardized guidelines for orthodontic epidemiology. These guidelines, embraced by academia and professional groups, are crucial for providing accurate data to inform healthcare recommendations.

A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder

PurposeFem1 homolog B (FEM1B) acts as a substrate recognition subunit for ubiquitin ligase complexes belonging to the CULLIN 2-based E3 family. Several biological functions have been proposed for FEM1B, including a structurally resolved function as a sensor for redox cell status by controlling mitochondrial activity, but its implication in human disease remains elusive. MethodsTo understand the involvement of FEM1B in human disease, we made use of Matchmaker exchange platforms to identify individuals with de novo variants in FEM1B and performed their clinical evaluation. We performed functional validation using primary neuronal cultures and in utero electroporation assays, as well as experiments on patient’s cells. ResultsFive individuals with a recurrent de novo missense variant in FEM1B were identified: NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln) (FEM1BR126Q). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells. In addition, the individuals’ cells exhibited signs of oxidative stress and induction of type I interferon signaling. ConclusionOverall, our data indicate that p.(Arg126Gln) induces aberrant FEM1B activation, resulting in a gain-of-function mechanism associated with a severe syndromic developmental disorder in humans.

Zebrafish as a model to investigate a biallelic gain-of-function variant in MSGN1, associated with a novel skeletal dysplasia syndrome

Background/ObjectivesRare genetic disorders causing specific congenital developmental abnormalities often manifest in single families. Investigation of disease-causing molecular features are most times lacking, although these investigations may open novel therapeutic options for patients. In this study, we aimed to identify the genetic cause in an Iranian patient with severe skeletal dysplasia and to model its molecular function in zebrafish embryos.ResultsThe proband displays short stature and multiple skeletal abnormalities, including mesomelic dysplasia of the arms with complete humero-radio-ulna synostosis, arched clavicles, pelvic dysplasia, short and thin fibulae, proportionally short vertebrae, hyperlordosis and mild kyphosis. Exome sequencing of the patient revealed a novel homozygous c.374G > T, p.(Arg125Leu) missense variant in MSGN1 (NM_001105569). MSGN1, a basic-Helix–Loop–Helix transcription factor, plays a crucial role in formation of presomitic mesoderm progenitor cells/mesodermal stem cells during early developmental processes in vertebrates. Initial in vitro experiments show protein stability and correct intracellular localization of the novel variant in the nucleus and imply retained transcription factor function. To test the pathogenicity of the detected variant, we overexpressed wild-type and mutant msgn1 mRNA in zebrafish embryos and analyzed tbxta (T/brachyury/ntl). Overexpression of wild-type or mutant msgn1 mRNA significantly reduces tbxta expression in the tailbud compared to control embryos. Mutant msgn1 mRNA injected embryos depict a more severe effect, implying a gain-of-function mechanism. In vivo analysis on embryonic development was performed by clonal msgn1 overexpression in zebrafish embryos further demonstrated altered cell compartments in the presomitic mesoderm, notochord and pectoral fin buds. Detection of ectopic tbx6 and bmp2 expression in these embryos hint to affected downstream signals due to Msgn1 gain-of-function.ConclusionIn contrast to loss-of-function effects described in animal knockdown models, gain-of-function of MSGN1 explains the only mildly affected axial skeleton of the proband and rather normal vertebrae. In this context we observed notochord bending and potentially disruption of pectoral fin buds/upper extremity after overexpression of msgn1 in zebrafish embryos. The latter might result from Msgn1 function on mesenchymal stem cells or on chondrogenesis in these regions. In addition, we detected ectopic tbx6 and bmp2a expression after gain of Msgn1 function in zebrafish, which are interconnected to short stature, congenital scoliosis, limb shortening and prominent skeletal malformations in patients. Our findings highlight a rare, so far undescribed skeletal dysplasia syndrome associated with a gain-of-function mutation in MSGN1 and hint to its molecular downstream effectors.

Clinical manifestations and genetic mutation analysis of patients with mucopolysaccharidosis type VII in China

ObjectiveThis study aimed to explore the clinical and genetic features of Chinese patients with mucopolysaccharidosis type VII (MPS VII), thereby improving early detection, disease management, and patient outcomes. MethodsA retrospective review of medical records for five patients presenting with coarse facial features, rib protrusion, chest deformities, and scoliosis was conducted. Exome sequencing was employed to identify causative genetic mutations. ResultsThe study comprised five patients (four males, one female) with disease onset at six months of age (range: 0–1.5 years). Common symptoms included coarse facial features, skeletal abnormalities, delayed motor and language development, and intellectual disability. Approximately 80% of the patients exhibited multiple skeletal dysplasias, enlarged adenoids or tonsils, and snoring; 60% had hernias; 40% reported hearing loss and hepatosplenomegaly. Less frequent manifestations were short stature, valvular heart disease, non-immune hydrops fetalis, and corneal opacity. All patients demonstrated elevated urine glycosaminoglycans levels and absent β-glucuronidase activity in leukocytes. Exome sequencing identified compound heterozygous mutations in the GUSB gene in all four tested patients, uncovering seven mutations in total, three of which were novel (c.189G > A, c.869C > T, and c.1745 T > C). Furthermore, prenatal diagnosis through chorionic villus sampling in subsequent pregnancies of one patient's mother revealed both fetuses had normal β-glucuronidase activity and no disease-causing mutations in the GUSB gene. ConclusionThe study's patients all presented with classic symptoms of MPS VII due to β-glucuronidase deficiency, with three new pathogenic mutations identified in the GUSB gene. Genetic counseling and prenatal testing were highlighted as crucial for disease prevention.

Fetal Warfarin Syndrome - A Case Report

Fetal warfarin syndrome (FWS) or warfarin embryopathy also known as “Di Sala syndrome” is a rare fetal anomaly which occurs as a result of fetal exposure to warfarin during the early stages of pregnancy. FWS is characterised by nasal hypoplasia and skeletal abnormalities, including short limbs and digits and stippled epiphyses. Here we present a case of foetal embryopathy due to warfarin use in a female with an unplanned pregnancy while taking warfarin for cerebral venous thrombosis. The case was reported in Adverse Drug Reaction (ADR) Monitoring centre in August 2023. The purpose of this case report is to caution all the clinicians particularly obstetricians regarding the fetal abnormalities of warfarin. If the mother had history of warfarin usage, paediatricians should also be vigilant regarding the possibility of congenital warfarin syndrome in the newborn.&#x0D; Warfarin is an oral anticoagulant drug that decreases the production of clotting factors (II, VII, IX, X) which are vitamin K-dependent. Warfarin is used in the treatment of patients with thromboembolic disorders and in patients who are predisposed to the development of thrombus. Especially those people with prosthetic heart valves, those who have had ischemic stroke and atrial fibrillation. Warfarin is a teratogen which can cross the placental barrier and cause harm to the developing foetus.[1] Warfarin causes inhibition of clotting factors leading to internal bleeding of the fetus, while inhibition of osteocalcin retards bone growth. In addition to birth defects, warfarin can induce spontaneous abortion, premature delivery, neonatal death and even congenital anomalies known as fetal warfarin syndrome.[2] The risk of teratogenicity is not predictable with any dose of warfarin. The first case of embryopathy due to warfarin was reported by Di Sala in 1966 hence, it is also known as Di Sala syndrome.[3,4] Warfarin leads to embryopathy which is characterized by the abnormalities of cartilages and bones known as chondrodysplasia punctata.[5] Almost 6% of babies born to mothers treated with warfarin during the first trimester have a pattern of congenital anomalies like nasal hypoplasia and stippling of vertebrae or bony epiphyses.[6] So, warfarin is contraindicated during pregnancy.&#x0D; Here we present a case of foetal embryopathy due to warfarin use in a female with an unplanned pregnancy while taking warfarin for cerebral venous thrombosis. This form of stroke is relatively rare and underdiagnosed which accounts for 0.5%-1% of all strokes mostly occurring in young adults, especially in women. Pregnancy, use of oral contraceptive pills (OCPs), puerperium, malignancies and other conditions with hypercoagulable states have been recognised as predisposing risk factors.[7] The conventional therapy for venous thromboembolism includes treatment with parenteral low-molecular-weight heparin (LMWH) and the vitamin K antagonist warfarin.[7]

Clinical and genetic analysis of trichohepatoneurodevelopmental syndrome caused by a CCDC47 variant

Trichohepatoneurodevelopmental syndrome is an extremely uncommon autosomal recessive disorder resulting from variants in the CCDC47 gene, which encodes a Ca2+-binding endoplasmic reticulum (ER) transmembrane protein. To date, only four patients with CCDC47 deficiency have been reported, all of them with homozygous truncating CCDC47 variants. For this study, a Chinese family was recruited, which included a patient diagnosed with trichohepatoneurodevelopmental syndrome. Whole exome sequencing (WES) identified the proband's novel homozygous CCDC47 variation (NM_020198: c.634C > T(p.Arg212*). The variant was confirmed to be segregating in the proband and her unaffected relatives through Sanger sequencing. The patient described exhibited a clinical phenotype similar to that of patients with the CCDC47 variant. Compared to reported cases with CCDC47 pathogenic variants, our patients showed a novel complication of hearing impairment. In addition, brain abnormalities, small feet, bilateral hip dislocation, hip dysplasia, overlapping toes, pectus excavatum, scoliosis and narrow chest were not observed in our patient. We also examined five different variations and their corresponding phenotypes from five patients, both in current and previous research. Although some clinical manifestations of trichohepatoneurodevelopmental syndrome were highly variable, the most common phenotypes observed in these patients include microcephaly, profound intellectual disability, severe global development delay, pronounced growth restriction, hypotonia, woolly hair, facial dysmorphism, respiratory and visual abnormalities, gastrointestinal abnormalities, liver dysfunction, pruritus, skeletal and limb abnormalities, congenital heart defects and immunodeficiency. The present report is the first of a Chinese infant with homozygous variant in the CCDC47 gene. We expanded the genetic and phenotypic spectrum associated with trichohepatoneurodevelopmental syndrome.

Impaired endochondral ossification in a skeletally immature dog: implications for femoral cleft formation and suspected incomplete femoral ossification.

Historically, knowledge regarding congenital skeletal malformations in canines is poor. The Nomina Embryologica Veterinaria does not currently list any dysmorphia related to distal femoral fusion, and there is a significant absence of comprehensive descriptions of congenital defects in the veterinary literature. This paper reports on the radiographic and computed tomography (CT) characteristics of a skeletal abnormality in a seven-month-old crossbreed dog that presented for chronic right pelvic limb lameness as a result of secondary developmental patella luxation. Successful resolution of the lameness was achieved through concurrent surgical correction of the patella luxation and distal femoral cleft.

Bone and bone derived factors in kidney disease.

Purpose of review: Mineral and bone disorder (MBD) is a prevalent complication in chronic kidney disease (CKD), significantly impacting overall health with multifaceted implications including fractures, cardiovascular events, and mortality. Despite its pervasive nature, effective treatments for CKD-MBD are lacking, emphasizing the urgency to advance understanding and therapeutic interventions. Bone metabolism intricacies, influenced by factors like 1,25 dihydroxy vitamin D, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), along with intrinsic osseous mechanisms, play pivotal roles in CKD. Skeletal abnormalities precede hormonal changes, persisting even with normalized systemic mineral parameters, necessitating a comprehensive approach to address both aspects. Recent findings: In this review, we explore novel pathways involved in the regulation of systemic mineral bone disease factors, specifically examining anemia, inflammation, and metabolic pathways. Special emphasis is placed on internal bone mechanisms, such as hepatocyte nuclear factor 4α, transforming growth factor-β1, and sclerostin, which play crucial roles in the progression of renal osteodystrophy. Summary: Despite advancements, effective treatments addressing CKD-MBD morbidity and mortality are lacking, necessitating ongoing research for novel therapeutic targets.

Pinoresinol diglucoside mitigates dexamethasone-induced osteoporosis and chondrodysplasia in zebrafish

BackgroundThe global increase in the aging population has led to a higher incidence of osteoporosis among the elderly. ObjectiveThis study aimed to evaluate the protective properties of pinoresinol diglucoside (PDG), an active constituent of Eucommia ulmoides, against dexamethasone-induced osteoporosis and chondrodysplasia. MethodsA zebrafish model of osteoporosis was established by exposing larval zebrafish to dexamethasone. The impact of PDG on bone mineralization was assessed through alizarin red and calcein staining. Alkaline phosphatase activity was quantified to evaluate osteoblast function. The influence of PDG on chondrogenesis was estimated using alcian blue staining. Fluorescence imaging and motor behavior analysis were employed to assess the protective effect of PDG on the structure and function of dexamethasone-induced skeletal teratogenesis. qPCR determined the expression of osteogenesis and Wnt signaling-related genes. Molecular docking was used to assess the potential interactions between PDG and Wnt receptors. ResultsPDG significantly increased bone mineralization and corrected spinal curvature and cartilage malformations in the zebrafish model. Furthermore, PDG enhanced swimming abilities compared to the model group. PDG mitigated dexamethasone-induced skeletal abnormalities in zebrafish by upregulating Wnt signaling, showing potential interaction with Wnt receptors FZD2 and FZD5. ConclusionPDG mitigates dexamethasone-induced osteoporosis and chondrodysplasia by promoting bone formation and activating Wnt signaling.

Novel OBSL1 Variant in a Chinese Patient with 3M Syndrome and the c.458dupG Mutation May Be a Potential Hotspot Mutation in the Chinese Population.

3M syndrome is an autosomal recessive disorder characterized by short stature and skeletal developmental abnormalities. In this study, a Chinese patient with 3M syndrome was presented. A novel OBSL1 (obscurin-like 1 gene) variant was found. The patient is a 2-year-old girl who presented with short stature and had intrauterine growth retardation and low birth weight. Gene analysis revealed compound heterozygote mutations in the OBSL1 gene: c.458dupG (p.L154Pfs*100) and c.427dupG (p.A143Gfs*111). The c.427dupG mutation is novel. The c.458dupG mutation has been documented in 5 cases, occurring only in Chinese individuals, indicating ethnic specificity. In cases of short-statured children presenting intrauterine growth retardation, low birth weight, and skeletal developmental abnormalities, 3M syndrome should be considered. The c.458dupG mutation might be a hotspot mutation in the Chinese population.

Digital pathology-based artificial intelligence models for differential diagnosis and prognosis of sporadic odontogenic keratocysts

Odontogenic keratocyst (OKC) is a common jaw cyst with a high recurrence rate. OKC combined with basal cell carcinoma as well as skeletal and other developmental abnormalities is thought to be associated with Gorlin syndrome. Moreover, OKC needs to be differentiated from orthokeratinized odontogenic cyst and other jaw cysts. Because of the different prognosis, differential diagnosis of several cysts can contribute to clinical management. We collected 519 cases, comprising a total of 2 157 hematoxylin and eosin-stained images, to develop digital pathology-based artificial intelligence (AI) models for the diagnosis and prognosis of OKC. The Inception_v3 neural network was utilized to train and test models developed from patch-level images. Finally, whole slide image-level AI models were developed by integrating deep learning-generated pathology features with several machine learning algorithms. The AI models showed great performance in the diagnosis (AUC = 0.935, 95% CI: 0.898–0.973) and prognosis (AUC = 0.840, 95%CI: 0.751–0.930) of OKC. The advantages of multiple slides model for integrating of histopathological information are demonstrated through a comparison with the single slide model. Furthermore, the study investigates the correlation between AI features generated by deep learning and pathological findings, highlighting the interpretative potential of AI models in the pathology. Here, we have developed the robust diagnostic and prognostic models for OKC. The AI model that is based on digital pathology shows promise potential for applications in odontogenic diseases of the jaw.

Альфа-маннозидоз: путь к диагнозу ультраредкого заболевания

Alpha-mannosidosis is a rare autosomal recessive hereditary disease characterized by lysosomal accumulation of olygosaccharides in various tissues due to deficiency of alpha-mannosidase. Low enzyme activity results from homozygous or compound heterozygous mutations of the MAN2B1 gene. Clinical manifestations of alpha-mannosidosis usually develop in childhood or adolescence and include facial deformity (Hurler-like phenotype), mental retardation, progressive sensorineural hearing loss, skeletal abnormalities, neurological and psychiatric disorders, and ocular disease. Demonstration of low activity of acid alpha-mannosidase in dried blood spots and genetic testing can be used for diagnosis. The authors present the case report of alpha-mannosidosis and discuss its pathogenesis, clinical signs and symptoms and approaches to treatment including the long-term enzyme replacement therapy with velmanasa alfa.

Correcting for asymmetry of the proximal tibial epiphysis is warranted to determine postoperative alignment deviations in kinematic alignment from planned alignment of the tibial component on the native tibia

BackgroundIn total knee arthroplasty, unrestricted kinematic alignment aims to restore pre-arthritic lower limb alignment and joint lines. Joint line orientations of the contralateral healthy proximal tibia might be used to evaluate accuracy of tibial component alignment post-operatively if asymmetry is minimal. Our objective was to evaluate left-to-right asymmetry of the proximal tibial epiphysis in posterior tibial slope and varus-valgus orientation as related to unrestricted kinematic alignment principles. MethodsHigh resolution CT images (0.5 mm slice thickness) were acquired from bilateral lower limbs of 11 skeletally mature subjects with no skeletal abnormalities. Images were segmented to generate 3D tibia models. Asymmetry was quantified by differences in orientations required to shape-match the proximal epiphysis of the mirror 3D tibia model to the proximal epiphysis of the contralateral 3D tibia model. FindingsSystematic and random differences (i.e. mean ± standard deviation) in tibial slope and varus-valgus orientation were − 0.8° ± 1.2° and − 0.2° ± 0.8°, respectively. Ninety five percent confidence intervals on the means included 0° indicating that systematic differences were minimal. InterpretationSince random differences due to asymmetry are substantial in relation to random surgical deviations from pre-arthritic joint lines previously reported, post-operative computer tomograms of the contralateral healthy tibia should not be used to directly assess accuracy of tibial component alignment on a group level without correcting for differences in tibial slope and varus-valgus orientation due to asymmetry.