Evidence of Two Novel LAMA2 Variants in a Patient With Muscular Dystrophy: Facing the Challenges of a Certain Diagnosis

BackgroundBenefits and challenges resulting from advances in genetic diagnostics are two sides of the same coin. Facilitation of a correct and timely diagnosis is paralleled by challenges in interpretation of variants of unknown significance (VUS). Focusing on an individual VUS-re-classification pipeline, this study offers a diagnostic approach for clinically suspected hereditary muscular dystrophy by combining the expertise of an interdisciplinary team.MethodsIn a multi-step approach, a thorough phenotype assessment including clinical examination, laboratory work, muscle MRI and histopathological evaluation of muscle was performed in combination with advanced Next Generation Sequencing (NGS). Different in-silico tools and prediction programs like Alamut, SIFT, Polyphen, MutationTaster and M-Cap as well as 3D- modeling of protein structure and RNA-sequencing were employed to determine clinical significance of the LAMA2 variants.ResultsTwo previously unknown sequence alterations in LAMA2 were detected, a missense variant was classified initially according to ACMG guidelines as a VUS (class 3) whereas a second splice site variant was deemed as likely pathogenic (class 4). Pathogenicity of the splice site variant was confirmed by mRNA sequencing and nonsense mediated decay (NMD) was detected. Combination of the detected variants could be associated to the LGMDR23-phenotype based on the MRI matching and literature research.DiscussionTwo novel variants in LAMA2 associated with LGMDR23-phenotype are described. This study illustrates challenges of the genetic findings due to their VUS classification and elucidates how individualized diagnostic procedure has contributed to the accurate diagnosis in the spectrum of LGMD

Impact of Endoscopic Vacuum Therapy with Low Negative Pressure for Esophageal Perforations and Postoperative Anastomotic Esophageal Leaks

Introduction: Management of esophageal anastomotic leaks (AL) and esophageal perforations (EP) remains difficult and often requires an interdisciplinary treatment modality. For primary endoscopic management, self-expanding metallic stent (SEMS) placement is often considered first-line therapy. Recently, endoscopic vacuum therapy (EVT) has emerged as an alternative or adjunct for management of these conditions. So far, data for EVT in the upper gastrointestinal-tract is restricted to single centre, non-randomized trials. No studies on optimal negative pressure application during EVT exist. The aim of our study is to describe our centre’s experience with low negative pressure (LNP) EVT for these indications over the past 5-years. Patients and Methods: Between January 2014 and December 2018, 30 patients were endoscopically treated for AL (n = 23) or EP (n = 7). All patients were primarily treated with EVT and LNP between –20 and –50 mm Hg. Additional endoscopic treatment was added when EVT failed. Procedural and peri-procedural data, as well as clinical outcomes including morbidity and mortality, were analysed. Results: Clinical successful endoscopic treatment of EP and AL was achieved in 83.3% (n = 25/30), with 73.3% success using EVT alone (n = 22/30). Mean treatment duration until leak closure was 16.1 days (range 2–58 days). Additional treatment modalities for complete leak resolution was necessary in 10% (n = 3/30), including SEMS placement and fibrin glue injection. Mean hospital stay for patients with EP was shorter with 33.7 days compared to AL with 54.4 days (p = 0.08). Estimated preoperative 10-year overall survival (Charlson comorbidity score) was 39.4% in patients with AL and 59.9% in patients with EP (p = 0.26). A mean of 5.1 EVT changes (range 1–12) was needed in EP and 3.6 changes (range 1–13) in AL to achieve complete closure, switch to other treatment modality, or reach endoscopic failure (p = 0.38). Conclusion: LNP EVT enables effective minimally – invasive endoluminal leak closure from anastomotic esophageal leaks and EP in high-morbid patients. In this study, EVT was combined with other endoscopic treatment options such as SEMS placement or fibrin glue injection in order to achieve leak or perforation closure in the vast majority of patients (83.3%). Low aspiration pressures led to slower but still sufficient clinical results

Morphological Parameters of the Hip Joint and Its Relation to Gender, Joint Side and Age—A CT-Based Study

Background: Physiological reference values for morphological parameters of the hip (MPH) are of clinical importance for the treatment of painful, degenerated or fractured hip joints, as well as to detect morphological deformities, which could result in early osteoarthritis of the hip. Currently, sufficient data for MPH are lacking. Therefore, it remains unclear if age-dependent alterations in adult hip morphology are physiological and if there are side- and gender-dependent differences. The aim of the study was to analyze MPH according to gender, side and age in a large-scaled cohort by CT scans. Methods: A total of 1576 hip joints from 788 patients (female: 257, male: 531; mean age: 58.3 years (±18.9; 18–92 years)) were analyzed by CT. For all hips, acetabular anteversion (AcetAV); lateral centrum edge angle (LCE); acetabular index (AI); femoral neck version (FNV); centrum-collum-diaphyseal angle (CCD); and anterior alpha angle (AαA) were measured. Results: The mean values in this cohort were: AcetAV 20.5° (±6.9); LCE 40.8° (±8.8); AI 0.3° (±5.3); FNV 11.0° (±9.8); CCD 129.9° (±7.4); and AαA 41.2° (±7.7). There was a detectable side-specific difference for AcetAV (p = 0.001); LCE (p p p p = 0.37). There was a significant correlation between age and AcetAV (r = 0.17; p p p p p p = 0.79). Conclusions: There are side-, gender- and age-specific alterations in hip morphology, which have to be considered in treating hip joint pathologies

Physiological Offset Parameters of the Adult Shoulder Joint—A MRI Study of 800 Patients

Background: Humeral offset (HO) and glenoidal offset (GO) are important morphological parameters in diagnostics and therapy for shoulder pathologies. However, physiological reference values have not yet been sufficiently determined. The aim of the present study was to establish physiological reference values for shoulder offset parameters (SOPs). Methods: MRI images of the shoulder joints of 800 patients (mean age: 50.13 years [±16.01]) were analysed retrospectively. HO, GO, lateral glenoidal humeral offset (LGHO), humeral shaft axis offset (HAO) and cortical offset (CO) were measured. SOPs were examined for associations with age, gender, side and osteoarthritis. Results: The mean HO was 26.19 (±2.70), the mean GO was 61.79 (±5.67), the mean LGHO was 54.49 (±4.69), the mean HAO was 28.17 (±2.82) and the mean CO was 16.70 (±3.08). For all SOPs, significantly higher values were measured in male shoulders. There was a significantly (p < 0.001) higher mean value for HO, GO and LGHO in right shoulders. There was a significant correlation between age and LGHO, and HAO and CO, but not between age and HO or GO. Shoulders with osteoarthritis and non-osteoarthritis did not differ in the mean value of HO, GO, LGHO and HAO, except for CO (p = 0.049). Conclusion: Reference values for SOPs in the adult shoulder joint were determined for the first time. Significant gender-specific differences were found for all measured SOPs. In addition, it was seen that for some SOPs, the joint side and the patient’s age has to be taken into account in shoulder diagnostics and surgery

Comparing Apparent Diffusion Coefficient and FNCLCC Grading to Improve Pretreatment Grading of Soft Tissue Sarcoma—A Translational Feasibility Study on Fusion Imaging

Histological subtype and grading are cornerstones of treatment decisions in soft tissue sarcoma (STS). Due to intratumoral heterogeneity, pretreatment grading assessment is frequently unreliable and may be improved through functional imaging. In this pilot study, 12 patients with histologically confirmed STS were included. Preoperative functional magnetic resonance imaging was fused with a computed tomography scan of the resected specimen after collecting core needle biopsies and placing radiopaque markers at distinct tumor sites. The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading criteria of the biopsies and apparent diffusion coefficients (ADCs) of the biopsy sites were correlated. Concordance in grading between the specimen and at least one biopsy was achieved in 9 of 11 cases (81.8%). In 7 of 12 cases, fusion imaging was feasible without relevant contour deviation. Functional analysis revealed a tendency for high-grade regions (Grade 2/3 (G2/G3)) (median (range) ± standard deviation: 1.13 (0.78–1.70) ± 0.23 × 10−3 mm2/s) to have lower ADC values than low-grade regions (G1; 1.43 (0.64–2.03) ± 0.46 × 10−3 mm2/s). In addition, FNCLCC scoring of multiple tumor biopsies proved intratumoral heterogeneity as expected. The ADC appears to correlate with the FNCLCC grading criteria. Further studies are needed to determine whether functional imaging may supplement histopathological grading

Physiological Femoral Condylar Morphology in Adult Knees—A MRI Study of 517 Patients

Background: In the age of individualised arthroplasty, the question arises whether currently available standard implants adequately consider femoral condylar morphology (FCM). Therefore, physiological reference values of FCM are needed. The aim was to establish physiological reference values for anterior (ACO) and posterior condylar offset (PCO) as well as for the length of the medial (LMC) and lateral femoral condyles (LLC). Methods: The knee joints of 517 patients (mean age: 52.3 years (±16.8)) were analysed retrospectively using MRI images. Medial (med) and lateral (lat) ACO and PCO, as well as LMC and LLC, were measured. All FCM parameters were examined for association with age, gender, side and osteoarthritis. Results: Mean ACOmed was 2.8 mm (±2.5), mean ACOlat was 6.7 mm (±2.3), mean PCOmed was 25.7 mm (±4.6), mean PCOlat was 23.6 mm (±3.0), mean LMC was 63.7 mm (±5.0) and mean LLC was 64.4 mm (±5.0). Except for PCOmed, the mean values of all other FCM parameters were significantly higher in male knees compared to female knees. ACOmed and PCOmed showed significant side-specific differences. There were no significant differences in relation to age and osteoarthritis. Conclusion: The study showed significant differences in FCM side- and gender-specifically in adult knees. These aspects should be considered in the discussion of individual and gender-specific knee joint replacement

Assessment of esophagogastric junction morphology by dynamic real-time MRI: comparison of imaging features to high-resolution manometry

Purpose!#!To assess the esophagogastric junction (EGJ) on real-time MRI and compare imaging parameters to EGJ morphology on high-resolution manometry (HRM).!##!Methods!#!A total of 105 of 117 eligible patients who underwent real-time MRI and high-resolution manometry for GERD-like symptoms between 2015 and 2018 at a single center were retrospectively evaluated (male n = 57; female n = 48; mean age 52.5 ± 15.4 years). Real-time MRI was performed at a median investigation time of 15 min (1 frame/40 ms). On HRM, EGJ morphology was assessed according to the Chicago classification of esophageal motility disorders. Real-time MRI was performed at 3 T using highly undersampled radial fast low-angle shot acquisitions with NLINV image reconstruction. A 10 mL pineapple juice bolus served as oral contrast agent at supine position. Real-time MRI films of the EGJ were acquired during swallowing events and during Valsalva maneuver. Anatomic and functional MRI parameters were compared to EGJ morphology on HRM.!##!Results!#!On HRM, n = 42 patients presented with EGJ type I (40.0%), n = 33 with EGJ type II (31.4%), and n = 30 with EGJ type III (28.6%). On real-time MRI, hiatal hernia was more common in patients with EGJ type III (66.7%) than in patients with EGJ type I (26.2%) and EGJ type II (30.3%; p < 0.001). Sliding hiatal hernia was more frequent in patients with EGJ type II (33.3%) than in patients with EGJ type III (16.7%) and EGJ type I (7.1%; p = 0.017). The mean esophagus-fundus angle of patients was 85 ± 31° at rest and increased to 101 ± 36° during Valsalva maneuver.!##!Conclusion!#!Real-time MRI is a non-invasive imaging method for assessment of the esophagogastric junction. Real-time MRI can visualize dynamic changes of the EGJ during swallowing events