ABSTRACT
The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Cardiomyopathy, Dilated , Intellectual Disability , Neurodevelopmental Disorders , Animals , Humans , Mice , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Heart , Neurodevelopmental Disorders/geneticsABSTRACT
Neurofibromatosis type 1 (NF-1) microdeletion syndrome accounts for 5 to 11% of individuals with NF-1. The aim of our study was to characterize a large cohort of individuals with NF-1 microdeletion syndrome and expand its natural history. We conducted a retrospective chart review from 1994 to 2024 of individuals with NF-1 microdeletion syndrome followed at two large Neurofibromatosis Clinics. This cohort consists of 57 individuals with NF-1 microdeletion syndrome (28 type-1, 4 type-2, 2 type-3, 9 atypical deletions, and 14 indeterminate). We note 38/56 (67.9%) with describable facial features, 25/57 (43.8%) with plexiform neurofibromas, and 3/57 (5.2%) with malignant peripheral nerve sheath tumors within the observed period. The most reported neurodevelopmental manifestations from school-age or older individuals included 39/49 (79.6%) with developmental delays, 35/49 (71.4%) with expressive and/or receptive speech delays, 33/41 (80.5%) with learning difficulties, and 23/42 (54.8%) with attention-deficit/hyperactivity disorder. Full-scale IQ testing data was available for 22 individuals (range: 50-96). Of the 21 adults in this cohort, 14/21 (66.7%) graduated from high school, and 4/21 (19.0%) had some college experience. Many individuals received academic support (i.e., special education, individual education plan). In this cohort, neurocognitive outcomes in adults varied more than typically reported in the literature.
ABSTRACT
Glucosylsphingosine (lyso-GL1) is a biomarker used to monitor disease and treatment response in Gaucher disease. Data from adults show that higher values of lyso-GL1 are associated with increased disease progression, however similar data in the pediatric population is lacking. In a cohort of pediatric patients, we present a relationship between lyso-GL1 value and Gaucher type, age, and treatment response. Data from this study may serve as a reference for providers monitoring children with Gaucher disease.
Subject(s)
Gaucher Disease , Adult , Child , Humans , Gaucher Disease/drug therapy , Psychosine , Biomarkers , Enzyme Replacement TherapyABSTRACT
Nonketotic hyperglycinemia (NKH) is a relatively well-characterized inborn error of metabolism that results in a combination of lethargy, hypotonia, seizures, developmental arrest, and, in severe cases, death early in life. Three genes encoding components of the glycine cleavage enzyme system-GLDC, AMT, and GCSH-are independently associated with NKH. We report on a patient with severe NKH in whom the homozygous pathogenic variant in AMT (NM_000481.3):c.602_603del (p.Lys201Thrfs*75) and the homozygous likely pathogenic variant in GLDC(NM_000170.2):c.2852C>A (p.Ser951Tyr) were both identified. Our patient demonstrates a novel combination of two homozygous disease-causing variants impacting the glycine cleavage pathway at two different components, and elicits management- and genetic counseling-related challenges for the family.
Subject(s)
Homozygote , Hyperglycinemia, Nonketotic , Humans , Hyperglycinemia, Nonketotic/genetics , Hyperglycinemia, Nonketotic/pathology , Male , Glycine Dehydrogenase (Decarboxylating)/genetics , Aminomethyltransferase/genetics , Female , Mutation/genetics , Infant , Glycine/genetics , Infant, Newborn , Phenotype , Genetic Predisposition to Disease , Amino Acid Oxidoreductases , Multienzyme Complexes , TransferasesABSTRACT
Propionic acidemia is a metabolic condition with multiple serious acute and chronic presentations that require strict monitoring. Literature on liver function abnormalities in propionic acidemia is scarce, and the mechanism of liver impairment in this condition remains unclear. Currently, there is no indication for liver-function tests during follow-up and their clinical or prognostic utility is unknown. This study aimed to determine aminotransferase trends in individuals with propionic acidemia at a single institution. We retrospectively evaluated and classified the aminotransferases of 12 patients with propionic acidemia during hospital admissions and routine office visits. The present findings suggest that aminotransferase elevations are very common in this population and can persist beyond acute illness. During hospitalization events, aminotransferases were not a predictor of severity, duration of stay, and readmission within 1 month. Understanding aminotransferase trends in these patients will help clinicians make decisions in the acute setting and potentially in the follow-up of new therapies.
Subject(s)
Propionic Acidemia , Humans , Propionic Acidemia/genetics , Propionic Acidemia/diagnosis , Female , Male , Retrospective Studies , Child, Preschool , Child , Infant , Adolescent , Transaminases/genetics , Transaminases/blood , Liver Function Tests , Hospitalization , Liver/pathologyABSTRACT
Dandy-Walker malformation (DWM) is often sporadic, but there are a growing number of genetic disorders that have been associated with this condition. We present a female individual with a de novo variant in ABL1, c.734A>G (p.Y245), who was diagnosed prenatally with DWM. ABL1-related neurodevelopmental disorder was recently identified but brain malformations have not been well characterized to date. We reviewed the published literature and identified one additional individual with DWM and ABL1-related disorder, which suggests a possible association with this malformation.
ABSTRACT
We describe a case in which a type 1 Gaucher patient developed ichthyosis weeks after starting substrate reduction therapy (SRT) with eliglustat. There are no reports of ichthyosis in the literature in enzyme replacement or SRT for Gaucher disease. Ichthyosis is seen with type 2 and 3 Gaucher disease, but not type 1. This raises the question: Why would a patient develop ichthyosis after starting SRT?
ABSTRACT
Fetuses with RASopathies can have a wide variety of anomalies including increased nuchal translucency, hydrops fetalis, and structural anomalies (typically cardiac and renal). There are few reports that describe prenatal-onset craniosynostosis in association with a RASopathy diagnosis. We present clinical and molecular characteristics of five individuals with RASopathy and craniosynostosis. Two were diagnosed with craniosynostosis prenatally, 1 was diagnosed as a neonate, and 2 had evidence of craniosynostosis noted as neonates without formal diagnosis until later. Two of these individuals have Noonan syndrome (PTPN11 and KRAS variants) and three individuals have Cardiofaciocutaneous syndrome (KRAS variants). Three individuals had single suture synostosis and two had multiple suture involvement. The most common sutures involved were sagittal (n = 3), followed by coronal (n = 3), and lambdoid (n = 2) sutures. This case series confirms craniosynostosis as one of the prenatal findings in individuals with RASopathies and emphasizes the importance of considering a RASopathy diagnosis in fetuses with multiple anomalies in combination with craniosynostosis.
Subject(s)
Craniosynostoses , Heart Defects, Congenital , Noonan Syndrome , Infant, Newborn , Female , Humans , Pregnancy , Proto-Oncogene Proteins p21(ras)/genetics , Craniosynostoses/diagnosis , Craniosynostoses/genetics , Noonan Syndrome/diagnosis , Noonan Syndrome/genetics , Ultrasonography, PrenatalABSTRACT
Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.
Subject(s)
Costello Syndrome , Ectodermal Dysplasia , Heart Defects, Congenital , Neoplasms , Noonan Syndrome , Humans , ras Proteins/genetics , MAP Kinase Signaling System/genetics , Costello Syndrome/genetics , Neoplasms/genetics , Ectodermal Dysplasia/genetics , Noonan Syndrome/genetics , Heart Defects, Congenital/geneticsABSTRACT
Congenital heart disease (CHD) is a common structural anomaly, affecting ~ 1% of live births worldwide. Advancements in medical and surgical management have significantly improved survival for children with CHD, however, extracardiac malformations (ECM) continue to be a significant cause of morbidity and mortality. Despite clinical significance, there is limited literature available on ECM in neonates with CHD, especially from Latin America. A cross-sectional study of neonates with severe CHD evaluated by the medical-surgical board team at Fundación Cardiovascular de Colombia from 2014 to 2019 was completed to characterize morbidity, mortality, surgical outcomes, and ECM. Demographics and surgical outcomes were compared between neonates with and without ECM. Medical record data were abstracted and descriptive statistical analysis was performed. Of 378 neonates with CHD, 262 had isolated CHD (69.3%) and 116 had ECM (30.7%). The most common ECM was gastrointestinal (n = 18, 15.5%) followed by central nervous system (n = 14, 12%). Most neonates required a biventricular surgical approach (n = 220, 58.2%). Genetic testing was performed more often for neonates with ECM (n = 65, 56%) than neonates with isolated CHD (n = 14, 5.3%). Neonates with ECM had lower birth weight, longer hospital stays, and higher postsurgical complications rates. There was no difference in survival between groups. Overall, Screening for ECM in neonates with CHD is important and identification of ECM can guide clinical decision-making. These findings have important implications for pediatric healthcare providers, especially in low- and middle-income countries, where the burden of CHD is high and resources for managing CHD and extracardiac malformations may be limited.
Subject(s)
Heart Defects, Congenital , Infant, Newborn , Humans , Child , Colombia/epidemiology , Cross-Sectional Studies , Retrospective Studies , Heart Defects, Congenital/epidemiology , Heart Defects, Congenital/surgery , Genetic TestingABSTRACT
PURPOSE: The purpose of this systematic review is to examine the outcomes, complications, and potential advantages of using anatomical interlocking intramedullary nails (IMN) in the treatment of radius and ulnar shaft diaphyseal fractures in adults. METHODS: Medline, Embase, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched between January 2000 and January 2023. Studies meeting criteria were observational or randomized controlled trials evaluating outcomes in IMN for adult diaphyseal forearm fractures. Standardized data extraction was performed and a quality assessment tool was used to evaluate individual study methodology. Descriptive statistics for interventions, functional outcomes, and complications were reported. Meta-analysis was performed for patient-reported outcome measures and operative time. RESULTS: A total of 29 studies involving 1268 patients were included with 764 (60%) undergoing IMN, 21% open reduction and internal fixation (ORIF), and 9% hybrid fixation. There was no significant difference between groups in DASH and Grace-Eversmann scores. Operative time was significantly shorter in IMN compared with ORIF. The DASH scores were: 13.1 ± 6.04 for IMN, 10.17 ± 3.98 for ORIF, and 15.5 ± 0.63 in hybrids. Mean operative time was 65.3 ± 28.7 in ORIF and 50.8 ± 17.7 in IMN. Complication rates were 16.7% in the IMN group, 14.9% in ORIF, and 6.3% in hybrid constructs. There were 11 cases of extensor pollicis rupture in the IMN group. Average IMN pronation and supination were 78.3° ± 7.9° and 73° ± 5.0°, respectively. Average ORIF pronation and supination was 82.15° ± 1.9° and 79.7° ± 4.5°, respectively. CONCLUSIONS: Similar functional outcomes and complication rates along with shorter operative times can be achieved with IMN compared with ORIF. The use of IMN is promising, however, higher quality evidence is required to assess appropriate indications, subtle differences in range of motion, implant-related complications, and cost-effectiveness. Trail Registration PROSPERO (International Prospective Register of Systematic Reviews) (ID: CRD42022362353).
Subject(s)
Bone Nails , Fracture Fixation, Intramedullary , Radius Fractures , Ulna Fractures , Humans , Fracture Fixation, Intramedullary/methods , Fracture Fixation, Intramedullary/instrumentation , Fracture Fixation, Intramedullary/adverse effects , Radius Fractures/surgery , Ulna Fractures/surgery , Adult , Diaphyses/surgery , Diaphyses/injuries , Postoperative Complications , Treatment Outcome , Operative TimeABSTRACT
Liver transplantation risks transferring a genetic defect in metabolic pathways, including the urea cycle. We present a case of pediatric liver transplantation complicated by metabolic crisis and early allograft dysfunction (EAD) in a previously healthy unrelated deceased donor. Allograft function improved with supportive care, and retransplantation was avoided. Because hyperammonemia suggested an enzymatic defect in the allograft, genetic testing from donor-derived deoxyribonucleic acid revealed a heterozygous mutation in the ASL gene, which encodes the urea cycle enzyme argininosuccinate lyase. Homozygous ASL mutations precipitate metabolic crises during fasting or postoperative states, whereas heterozygous carriers retain sufficient enzyme activity and are asymptomatic. In the described case, postoperative ischemia/reperfusion injury created a metabolic demand that exceeded the enzymatic capacity of the allograft. To our knowledge, this is the first report of an acquired argininosuccinate lyase deficiency by liver transplantation and underscores the importance of considering occult metabolic variants in the allograft during EAD.
Subject(s)
Argininosuccinic Aciduria , Humans , Child , Mutation , Argininosuccinic Aciduria/genetics , Liver , Allografts , UreaABSTRACT
Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.
Subject(s)
Carcinogenesis/genetics , Mitogen-Activated Protein Kinase 1/genetics , Neurodevelopmental Disorders/genetics , Noonan Syndrome/genetics , Child, Preschool , Female , Humans , MAP Kinase Signaling System/genetics , Male , Mutation, Missense/genetics , Neurodevelopmental Disorders/pathology , Noonan Syndrome/physiopathology , Phenotype , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Signal Transduction , Exome Sequencing , ras Proteins/geneticsABSTRACT
PURPOSE: Transformer2 proteins (Tra2α and Tra2ß) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder. METHODS: A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA sequencing and western blot analyses of Tra2ß-1 and Tra2ß-3 isoforms from patient-derived cells were performed. Tra2ß1-GFP, Tra2ß3-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells. RESULTS: All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2ß-3 isoform. All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2ß-1 isoform, whereas they increased the expression of the Tra2ß-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2ß-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2ß-1. CONCLUSION: Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2ß protein.
Subject(s)
Autism Spectrum Disorder , Intellectual Disability , Neurodevelopmental Disorders , Humans , Alternative Splicing , RNA-Binding Proteins/genetics , HEK293 Cells , Protein Isoforms/genetics , Intellectual Disability/genetics , Neurodevelopmental Disorders/genetics , Serine-Arginine Splicing Factors/genetics , Serine-Arginine Splicing Factors/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolismABSTRACT
PURPOSE: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder. METHODS: Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae. RESULTS: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans. CONCLUSION: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.
Subject(s)
Classical Lissencephalies and Subcortical Band Heterotopias , Intellectual Disability , Lissencephaly , Neurodevelopmental Disorders , Humans , Animals , Mice , Brain/abnormalities , Lissencephaly/genetics , Intellectual Disability/genetics , 14-3-3 Proteins/geneticsABSTRACT
The repeated evolution of phenotypes provides clear evidence for the role of natural selection in driving evolutionary change. However, the evolutionary origin of repeated phenotypes can be difficult to disentangle as it can arise from a combination of factors such as gene flow, shared ancestral polymorphisms or mutation. Here, we investigate the presence of these evolutionary processes in the Hawaiian spiny-leg Tetragnatha adaptive radiation, which includes four microhabitat-specialists or ecomorphs, with different body pigmentation and size (Green, Large Brown, Maroon, and Small Brown). We investigated the evolutionary history of this radiation using 76 newly generated low-coverage, whole-genome resequenced samples, along with phylogenetic and population genomic tools. Considering the Green ecomorph as the ancestral state, our results suggest that the Green ecomorph likely re-evolved once, the Large Brown and Maroon ecomorphs evolved twice and the Small Brown evolved three times. We found that the evolution of the Maroon and Small Brown ecomorphs likely involved ancestral hybridization events, while the Green and Large Brown ecomorphs likely evolved through novel mutations, despite a high rate of incomplete lineage sorting in the dataset. Our findings demonstrate that the repeated evolution of ecomorphs in the Hawaiian spiny-leg Tetragnatha is influenced by multiple evolutionary processes.
Subject(s)
Gene Flow , Polymorphism, Genetic , Phylogeny , Hawaii , PhenotypeABSTRACT
Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood.
Subject(s)
Zinc Finger Nucleases , HumansABSTRACT
Objective: To evaluate the use of telemedicine as a collaboration tool between a pediatrician and subspecialists looking to address challenges, such as the lack of health care specialists, which are present in the Dominican Republic. Study design: During this 6-year study, 65 patients were evaluated by a medical team consisting of a local pediatrician and 17 subspecialists from a leading academic medical center in the Unites States. Patient's age ranged from 2 months to 16 years of age (mean 8 years old). The most common reasons for referral were masses or malignancies, vascular malformations, urogenital anomalies, stuttering, and cochlear implant programming. Results: A total of 39 out of 65 cases (60%) carried an initial diagnosis. Of the 65 cases, a change in medical management occurred in 92.31% of cases (60 cases). There was no change in medical diagnosis or treatment in 5 of 65 cases (8%). Conclusion: This protocol exhibited high patient satisfaction with the technology and platform and direct patient savings from transportation costs. It also demonstrated the importance of thorough diagnosis in providing appropriate treatment and solutions. Telemedicine use in comparable practices should be studied further to aid in the development of policies for the diagnosis and management of chronic illnesses that require referrals to subspecialists.
Subject(s)
Telemedicine , Child , Humans , Infant , Referral and Consultation , Chronic Disease , Costs and Cost Analysis , Patient SatisfactionABSTRACT
PURPOSE: Distal radius fractures involving the volar rim are a subset of unstable and extremely distal fractures involving the volar lunate and/or scaphoid facets. Volar rim fractures (VRF) are challenging to manage and different treatment options have been described. This study aimed to compare outcomes and assess the rates of complications and implant removal for different treatment methods of wrist fractures involving VRF. METHODS: A systematic review of studies published in MEDLINE, EMBASE, Web of Science and Cumulative Index to Nursing and Allied Health literature (CINAHL) was conducted to assess the operative outcomes of VRF. Data on patient demographics, implant usage, postoperative outcomes, complications, and implant removal were compiled. RESULTS: Twenty-six studies met the inclusion criteria with a total of 617 wrists. The most commonly used implants were 2.4 mm variable-angle volar rim plate (DePuy Synthes) (17.5%), Acu-Loc II (Acumed) (14%) and standalone hook plates (13%). The average outcome measures were Q-DASH (10.9 ± 7), MWS (85.8 ± 7.5), PRWE (15.9 ± 12.1), and DASH (14 ± 8.5). The overall complication rate was 14% (n = 87), with 44% (n = 38) involving flexor tendon problems. The implant removal rate was 22%, with routine removal being performed in 54% and non-routine removal in 46% of cases. CONCLUSION: The current treatment of VRF yields favorable functional outcomes across different treatment options. However, these fractures have a high rate of complications and re-interventions, particularly for symptomatic implants. LEVEL OF EVIDENCE: Therapeutic IV.
Subject(s)
Radius Fractures , Wrist Fractures , Wrist Injuries , Humans , Radius Fractures/surgery , Fracture Fixation, Internal/adverse effects , Fracture Fixation, Internal/methods , Wrist Injuries/surgery , Tendons , Bone Plates , Range of Motion, ArticularABSTRACT
The MAPK pathway is a major growth signal that has been implicated during the development of progenitors, neurons, and glia in the embryonic brain. Here, we show that the MAPK pathway plays an important role in the generation of distinct cell types from progenitors in the ventral telencephalon. Our data reveal that phospho-p44/42 (called p-ERK1/2) and the ETS transcription factor Etv5, both downstream effectors in the MAPK pathway, show a regional bias in expression during ventral telencephalic development, with enriched expression in the dorsal region of the LGE and ventral region of the MGE at E13.5 and E15.5. Interestingly, expression of both factors becomes more uniform in ventricular zone (VZ) progenitors by E18.5. To gain insight into the role of MAPK activity during progenitor cell development, we used a cre inducible constitutively active MEK1 allele (RosaMEK1DD/+) in combination with a ventral telencephalon enriched cre (Gsx2e-cre) or a dorsal telencephalon enriched cre (Emx1cre/+). Sustained MEK/MAPK activity in the ventral telencephalon (Gsx2e-cre; RosaMEK1DD/+) expanded dorsal lateral ganglionic eminence (dLGE) enriched genes (Gsx2 and Sp8) and oligodendrocyte progenitor cell (OPC) markers (Olig2, Pdgfrα, and Sox10), and also reduced markers in the ventral (v) LGE domain (Isl1 and Foxp1). Activation of MEK/MAPK activity in the dorsal telencephalon (Emx1cre/+; RosaMEK1DD/+) did not initially activate the expression of dLGE or OPC genes at E15.5 but ectopic expression of Gsx2 and OPC markers were observed at E18.5. These results support the idea that MAPK activity as readout by p-ERK1/2 and Etv5 expression is enriched in distinct subdomains of ventral telencephalic progenitors during development. In addition, sustained activation of the MEK/MAPK pathway in the ventral or dorsal telencephalon influences dLGE and OPC identity from progenitors.