Operative Management of Extensor Carpi Ulnaris Instability: A Systematic Review.

Background Posttraumatic extensor carpi ulnaris (ECU) instability is an increasingly recognized cause of ulnar-sided wrist pain that occurs when the ECU subsheath is disrupted. Purpose The purpose of this systematic review was to assess outcomes of operatively treated posttraumatic ECU instability. Methods A systematic search of Medline, Embase, Web of Science, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases was performed using "extensor carpi ulnaris" as the keyword. Studies were systematically screened and data extracted independently by two reviewers. Results Eight retrospective studies met the inclusion criteria with a total of 97 wrists. The mean age was 32 years (13-61). Patients underwent either primary repair (40%) using sutures and anchors, or reconstruction (60%) using extensor retinaculum flaps. One study performed deepening of the osseous ulnar groove. Two studies compared preoperative and postoperative values. They both reported a significant improvement in pain scores, functional scoring instruments, satisfaction, and grip strength. The rest of the studies reported similarly favorable outcomes across the same outcomes. Concomitant pathologies were identified in 66% of the study population. Complications occurred in 9% of the sample size, including ECU tendinitis, ulnar sensory nerve irritation, and reintervention for concomitant pathology. None of the studies reported recurrence or reruptures. However, five patients (6.7%) did not return to their previous activity level. Conclusion Patients can expect favorable outcomes with a potentially low complication rate. Nevertheless, the heterogeneity of the sample population, operative techniques, and outcome measures warrant further standardized studies. Level of Evidence IV.

Proximal Row Carpectomy With Soft Tissue Interposition: A Systematic Review of Clinical Outcomes.

Proximal row carpectomy (PRC) with soft tissue interposition arthroplasty (STIA) presents an alternative approach to addressing wrist arthritis patterns involving the capitate and/or lunate fossa, in lieu of wrist arthrodesis. This systematic review aimed to evaluate clinical outcomes and techniques associated with PRC-STIA in patients with advanced wrist arthritis. We conducted a systematic review using databases including PubMed, Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials. Inclusion criteria involved articles reporting outcomes of patients who underwent PRC-STIA with at least 1 relevant outcome. The analysis encompassed 8 studies involving 106 patients (108 wrists) meeting the inclusion criteria. A majority of patients were men (69%, n = 88), with a mean age of 54.4 ± 12.7 years and an average follow-up of 4.8 ± 6.3 years. Dorsal capsule was the most commonly interposed tissue (63%, 5 out of 8 studies). Patients receiving STIA achieved comparable patient-reported outcome measures scores to those undergoing PRC alone. Postoperative pain, measured by the Visual Analog Scale, averaged 3.7 ± 0.6. The Disabilities of the Arm, Shoulder, and Hand score averaged 27.8 ± 8, while the Patient-Rated Wrist Evaluation score averaged 41.5 ± 25.9. Five complications were reported in three studies. The addition of STIA into PRC for patients with capitate and/or lunate fossa cartilage degeneration yielded outcomes akin to traditional PRC, improving wrist function, pain, and grip strength in a safe and straightforward manner. Future research should prioritize high-quality comparative studies, extended follow-up periods, and standardized core outcome measures for a more comprehensive understanding of its role in wrist arthritis treatment.

Prenatal and infantile diagnosis of craniosynostosis in individuals with RASopathies.

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.

The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy.

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.

Outcomes and Associated Extracardiac Malformations in Neonates from Colombia with Severe Congenital Heart Disease.

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.

Surgical treatment options for articular cartilage defects of the glenohumeral joint: A systematic review.

Background: Many joint-preserving surgical interventions for cartilage defects of the knee have been adapted for use in the shoulder; however, there still exists no clear consensus for treatment. Thus, the purpose of this systematic review was to evaluate the outcomes of different interventions in patients with focal chondral lesions of the glenohumeral joint. Methods: A literature search was conducted using PubMed, Embase, and Medline. Patients who underwent a joint-preserving surgical procedure to treat a focal chondral defect of the glenoid, humeral head or both were included. Patients treated for diffuse cartilage defects or with shoulder arthroplasty were excluded. Results: Ten studies were included, with follow-up data available for 194 shoulders. Eight joint-preserving procedures were evaluated, with microfracture being the most common. One study evaluating microfracture reported significant improvements in patient-reported outcomes at short-term and long-term follow-up compared to preoperative scores. Across all studies, 32 patients underwent subsequent shoulder surgery, with 22 being arthroplasties. Conclusions: We found improvements in patient-reported and functional outcomes across all studies. Although joint-preserving procedures have shown reasonable outcomes for focal chondral defects of the glenohumeral joint, long-term outcomes remain unknown, and the progression of osteoarthritis remains a concern. Higher quality evidence is required to make definitive recommendations. Level of Evidence: IV.

Multiple paths toward repeated phenotypic evolution in the spiny-leg adaptive radiation (Tetragnatha; Hawai'i).

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.

The role of preoperative opioid use in shoulder surgery-A systematic review.

Background: Emerging evidence suggests preoperative opioid use may increase the risk of negative outcomes following orthopedic procedures. This systematic review evaluated the impact of preoperative opioid use in patients undergoing shoulder surgery with respect to preoperative clinical outcomes, postoperative complications, and postoperative dependence on opioids. Methods: EMBASE, MEDLINE, CENTRAL, and CINAHL were searched from inception to April, 2021 for studies reporting preoperative opioid use and its effect on postoperative outcomes or opioid use. The search, data extraction and methodologic assessment were performed in duplicate for all included studies. Results: Twenty-one studies with a total of 257,301 patients were included in the final synthesis. Of which, 17 were level III evidence. Of those, 51.5% of the patients reported pre-operative opioid use. Fourteen studies (66.7%) reported a higher likelihood of opioid use at follow-up among those used opioids preoperatively compared to preoperative opioid-naïve patients. Eight studies (38.1%) showed lower functional measurements and range of motion in opioid group compared to the non-opioid group post-operatively. Conclusion: Preoperative opioid use in patients undergoing shoulder surgeries is associated with lower functional scores and post-operative range of motion. Most concerning is preoperative opioid use may predict increased post-operative opioid requirements and potential for misuse in patients. Level of evidence: Level IV, Systematic review.

Operative treatment of distal radius fractures involving the volar rim-A systematic review of outcomes and complications.

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.

Motor Function and Physiology in Youth With Neurofibromatosis Type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic neurocutaneous disorder commonly associated with motor and cognitive symptoms that greatly impact quality of life. Transcranial magnetic stimulation (TMS) can quantify motor cortex physiology, reflecting the basis for impaired motor function as well as, possibly, clues for mechanisms of effective treatment. We hypothesized that children with NF1 have impaired motor function and altered motor cortex physiology compared to typically developing (TD) control children and children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Children aged 8-17 years with NF1 (n = 21) were compared to children aged 8-12 years with ADHD (n = 59) and TD controls (n = 88). Motor development was assessed using the Physical and Neurological Examination for Subtle Signs (PANESS) scale. The balance of inhibition and excitation in motor cortex was assessed using the TMS measures short-interval cortical inhibition (SICI) and intracortical facilitation (ICF). Measures were compared by diagnosis and tested using bivariate correlations and regression for association with clinical characteristics. RESULTS: In NF1, ADHD severity scores were intermediate between the ADHD and TD cohorts, but total PANESS scores were markedly elevated (worse) compared to both (P < 0.001). Motor cortex ICF (excitatory) was significantly lower in NF1 than in TD and ADHD (P < 0.001), but SICI (inhibitory) did not differ. However, in NF1, better PANESS scores correlated with lower SICI ratios (more inhibition; ρ = 0.62, P = 0.003) and lower ICF ratios (less excitation; ρ = 0.38, P = 0.06). CONCLUSIONS: TMS-evoked SICI and ICF may reflect processes underlying abnormal motor function in children with NF1.

Change in Gustilo-Anderson classification at time of surgery does not increase risk for surgical site infection in patients with open fractures: A secondary analysis of a multicenter, prospective randomized controlled trial.

Introduction: Open fractures represent a major source of morbidity. Surgical site infections (SSIs) after open fractures are associated with a high rate of reoperations and hospitalizations, which are associated with a lower health-related quality of life. Early antibiotic delivery, typically chosen through an assessment of the size and contamination of the wound, has been shown to be an effective technique to reduce the risk of SSI in open fractures. The Gustilo-Anderson classification (GAC) was devised as a grading system of open fractures after a complete operative debridement of the wound had been undertaken but is commonly used preoperatively to help with the choice of initial antibiotics. Incorrect preoperative GAC, leading to less aggressive initial management, may influence the risk of SSI after open fracture. The objectives of this study were to determine (1) how often the GAC changed from the initial to definitive grading, (2) the injury and patient characteristics associated with increases and decreases of the GAC, and (3) whether a change in GAC was associated with an increased risk of SSI. Methods: Using data from the FLOW trial, a large multicenter randomized study, we used descriptive statistics to quantify how frequently the GAC changed from the initial to definitive grading. We used regression models to determine which injury and patient characteristics were associated with increases and decreases in GAC and whether a change in GAC was associated with SSI. Results: Of the 2420 participants included, 305 participants had their preoperative GAC change (12.6%). The factors associated with upgrading the GAC (from preoperative score to the definitive assessment) included fracture sites other than the tibia, bone loss at presentation, width of wound, length of wound, and skin loss at presentation. However, initial misclassification of type III fractures as type II fractures was not associated with an increased risk of SSI (P = 0.14). Conclusions: When treating patients with open fracture wounds, surgeons should consider that 12% of all injuries may initially be misclassified when using the GAC, particularly fractures that have bone loss at presentation or those located in sites different than the tibia. However, even in misclassified fractures, it did not seem to increase the risk of SSI.

International Pediatric Multidisciplinary Management Using Telemedicine to Promote Equitable Care.

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.

The management of fracture related infections: What practices can be supported by high-level evidence?

Fracture related infections (FRIs) are a disabling condition causing significant concern within the orthopaedic community. FRIs have a huge societal and economic burden leading to prolonged recovery times and the potential for becoming chronic conditions or being life-threatening. Despite its importance in our field, the surgical community has just recently agreed on a definition which, added to the lack of surgical trials assessing preventive and treatment interventions have limited our understanding and precipitated wide variations in surgeons' practice. This article aims to review the current practices that can be supported with high-quality evidence. Currently, we have a limited body of high-quality evidence on FRI prevention and treatment. A handful of measures have proven effective, such as the use of prophylactic antibiotics, the use of saline and low pressure as the preferred irrigation solution and the safety of delaying initial surgical débridement more than 6 hours without impacting infection rates for open fracture wounds débridement. Future multicentre trials, properly powered, will shed light on current areas of controversy regarding the benefit of different preoperative and perioperative factors for the prevention and treatment of FRIs. Higher quality evidence is needed to guide surgeons to offer an evidence-based approach to prevent FRI occurrence and to treat patients suffering from them.

Arrhythmia Burden and Heart Rate Response During Exercise in Anderson-Fabry Disease.

Patients with Anderson-Fabry disease (AFD) have an elevated incidence of resting arrhythmias and ischemic heart disease, but their exercise arrhythmia burden and ischemic changes are not well understood. In addition, little research has been done on heart rate recovery in these patients. We retrospectively reviewed charts of patients with AFD who underwent maximal effort cardiopulmonary exercise testing (CPET) (n=44; 38.2 ± 13.8 yr; 23 men) from 2012 through 2018. Electrocardiographic, Holter monitoring, echocardiographic, cardiac magnetic resonance imaging, and patient demographic data were collected. No patient had adverse events that necessitated CPET termination, whereas 25 (57%) had ectopy during CPET, including 3 (7%) with frequent premature atrial contractions and 5 (11%) with frequent premature ventricular contractions. The ectopic burden was higher during resting electrocardiographic monitoring before exercise. In addition, 7 patients (16%) had pathologic ST-segment or T-wave changes on CPET, defined as ST-segment changes ≥2 mm. Among the patients who had concurrent cardiac magnetic resonance findings with their CPET (n=27), ST-segment or T-wave changes were associated with left ventricular myocardial mass (r=0.43, P=0.02). Chronotropic incompetence was seen during CPET in 28 patients (64%); however, only 2 patients (4%) had abnormal heart rate recovery at 1 minute. This study shows that patients with AFD can safely undergo exercise testing but have a high incidence of exercise-induced arrhythmias and ischemic changes. Ischemic electrocardiographic changes during exercise testing are associated with myocardial mass. Despite the chronotropic incompetence associated with AFD, heart rate recovery appears to be generally preserved in these patients.

The surgical management of distal triceps tendon ruptures: a systematic review.

BACKGROUND: Distal triceps tendon ruptures (DTTRs) are highly uncommon injuries and can be treated with surgical repair. The purpose of this review was to compare the outcomes and complications of various surgical techniques used for primary repair of DTTRs. METHODS: The electronic databases MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched from data inception to October 15, 2020. The Methodological Index for Non-randomized Studies tool was used to assess study quality. Data are presented descriptively. RESULTS: A total of 19 studies were identified, comprising 560 patients (565 triceps tendons), of whom 78.6% were male patients. The mean age was 46.1 ± 8.4 years, and the mean follow-up period was 31.8 ± 21.0 months. The overall complication rate across all DTTR repair procedures was 14.9%. The distribution of complications for each technique was 29.2% for the direct repair technique, 15.2% for the transosseous technique (transosseous suture), and 7.7% for the suture anchor technique. Common complications include ulnar neuropathies, infections, and pain. The overall rerupture rate for transosseous suture, suture anchor, and direct repair was 4.3% (n = 12), 2.1% (n = 3), and 0% (n = 0), respectively. Patients undergoing DTTR repair experience significant improvements postoperatively regarding pain, strength, and range of motion. CONCLUSIONS: Patients undergoing DTTR experience improvements in postoperative outcomes; however, there is a moderate reported risk of rerupture or complication. Owing to the heterogeneity in rupture patterns, surgical procedures, and outcome measures, it is difficult to ascertain the superiority of one surgical technique over another. Future studies should use large prospective cohorts and long-term follow-up to determine more accurate complication rates and outcome scores.

Craniosynostosis is a feature of Costello syndrome.

Costello syndrome (CS) is an autosomal dominant disorder caused by pathogenic variants in HRAS. Craniosynostosis is a known feature of other RASopathies (Noonan and cardiofaciocutaneous syndromes) but not CS. We describe four individuals with CS and craniosynostosis and present a summary of all previously reported individuals with craniosynostosis and RASopathy.

Helicobacter pylori virulence factors: relationship between genetic variability and phylogeographic origin.

BACKGROUND: Helicobacter pylori is a pathogenic bacteria that colonize the gastrointestinal tract from human stomachs and causes diseases including gastritis, peptic ulcers, gastric lymphoma (MALT), and gastric cancer, with a higher prevalence in developing countries. Its high genetic diversity among strains is caused by a high mutation rate, observing virulence factors (VFs) variations in different geographic lineages. This study aimed to postulate the genetic variability associated with virulence factors present in the Helicobacter pylori strains, to identify the relationship of these genes with their phylogeographic origin. METHODS: The complete genomes of 135 strains available in NCBI, from different population origins, were analyzed using bioinformatics tools, identifying a high rate; as well as reorganization events in 87 virulence factor genes, divided into seven functional groups, to determine changes in position, number of copies, nucleotide identity and size, contrasting them with their geographical lineage and pathogenic phenotype. RESULTS: Bioinformatics analyses show a high rate of gene annotation errors in VF. Analysis of genetic variability of VFs shown that there is not a direct relationship between the reorganization and geographic lineage. However, regarding the pathogenic phenotype demonstrated in the analysis of many copies, size, and similarity when dividing the strains that possess and not the cag pathogenicity island (cagPAI), having a higher risk of developing gastritis and peptic ulcer was evidenced. Our data has shown that the analysis of the overall genetic variability of all VFs present in each strain of H. pylori is key information in understanding its pathogenic behavior.

Generation of a Mouse Model to Study the Noonan Syndrome Gene Lztr1 in the Telencephalon.

The leucine zipper-like transcriptional regulator 1 (Lztr1) is a BTB-Kelch domain protein involved in RAS/MAPK pathway regulation. Mutations in LZTR1 are associated with cancers and Noonan syndrome, the most common RASopathy. The expression and function of Lztr1 in the developing brain remains poorly understood. Here we show that Lztr1 is expressed in distinct regions of the telencephalon, the most anterior region of the forebrain. Lztr1 expression was robust in the cortex, amygdala, hippocampus, and oligodendrocytes in the white matter. To gain insight into the impact of Lztr1 deficiency, we generated a conditional knockout (cKO) restricted to the telencephalon using Foxg1 IREScre/+. Lztr1 cKOs are viable to postnatal stages and show reduced Lztr1 expression in the telencephalon. Interestingly, Lztr1 cKOs exhibit an increase in MAPK pathway activation in white matter regions and subsequently show an altered expression of stage-specific markers in the oligodendrocyte lineage with increased oligodendrocyte progenitor cells (OPCs) and decreased markers of oligodendrocyte differentiation. Moreover, Lztr1 cKOs also exhibit an increased expression of the astrocyte marker GFAP. These results highlight the generation of a new mouse model to study Lztr1 deficiency in the brain and reveal a novel role for Lztr1 in normal oligodendrocyte and astrocyte development in the telencephalon.

UBA2 variants underlie a recognizable syndrome with variable aplasia cutis congenita and ectrodactyly.

PURPOSE: The human chromosome 19q13.11 deletion syndrome is associated with a variable phenotype that includes aplasia cutis congenita (ACC) and ectrodactyly as specific features. UBA2 (ubiquitin-like modifier-activating enzyme 2) lies adjacent to the minimal deletion overlap region. We aimed to define the UBA2-related phenotypic spectrum in humans and zebrafish due to sequence variants and to establish the mechanism of disease. METHODS: Exome sequencing was used to detect UBA2 sequence variants in 16 subjects in 7 unrelated families. uba2 loss of function was modeled in zebrafish. Effects of human missense variants were assessed in zebrafish rescue experiments. RESULTS: Seven human UBA2 loss-of-function and missense sequence variants were detected. UBA2-phenotypes included ACC, ectrodactyly, neurodevelopmental abnormalities, ectodermal, skeletal, craniofacial, cardiac, renal, and genital anomalies. uba2 was expressed in zebrafish eye, brain, and pectoral fins; uba2-null fish showed deficient growth, microcephaly, microphthalmia, mandibular hypoplasia, and abnormal fins. uba2-mRNAs with human missense variants failed to rescue nullizygous zebrafish phenotypes. CONCLUSION: UBA2 variants cause a recognizable syndrome with a wide phenotypic spectrum. Our data suggest that loss of UBA2 function underlies the human UBA2 monogenic disorder and highlights the importance of SUMOylation in the development of affected tissues.

Everolimus for severe arrhythmias in tuberous sclerosis complex related cardiac rhabdomyomas.

Intracardiac rhabdomyoma is the most common primary cardiac tumor in children. Most cases are associated with tuberous sclerosis complex (TSC). Most of them are asymptomatic in the neonate and do not require treatment. However, some develop cardiovascular symptoms such as arrhythmias, heart failure, and ventricular inflow/outflow tract obstruction in the neonatal period with early death. Many of these tumors are not candidates for surgical resection and medical management is limited. Treatment with mammalian target of rapamycin (mTOR) inhibitor is currently approved for the management of central nervous tumors and angiomyolipoma in TSC. Two patients with malignant arrhythmias related to nonsurgical multiple rhabdomyomas associated with TSC who were successfully treated with an mTOR inhibitor were described. Everolimus therapy showed significant regression of rhabdomyomas with rapid improvement of arrhythmias and heart failure prior to tumor shrinkage.