Genotype-Phenotype Correlations in 293 Russian Patients with Causal Fabry Disease Variants.

BACKGROUND: Fabry disease (FD) is a rare hereditary multisystem disease caused by variants of the GLA gene. Determination of GLA gene variants and identification of genotype-phenotype correlations allow us to explain the features of FD associated with predominant damage of one or another system, both in the classical and atypical forms of FD, as well as in cases with late manifestation and involvement of one of the systems. METHODS: The study included 293 Russian patients with pathogenic variants of the GLA gene, which were identified as a result of various selective screening programs. Screening was carried out for 48,428 high-risk patients using a two-step diagnostic algorithm, including the determination of the concentration of the biomarker lyso-Gb3 as a first-tier test. Screening of atypical FD among patients with HCM was carried out via high-throughput sequencing in another 2427 patients. RESULTS: 102 (0.20%) cases of FD were identified among unrelated patients as a result of the study of 50,855 patients. Molecular genetic testing allowed us to reveal the spectrum and frequencies of 104 different pathogenic variants of the GLA gene in 293 examined patients from 133 families. The spectrum and frequencies of clinical manifestations in patients with FD, including 20 pediatric patients, were described. Correlations between the concentration of the lyso-Gb3 biomarker and the type of pathogenic variants of the GLA gene have been established. Variants identified in patients with early stroke were described, and the association of certain variants with the development of stroke was established. CONCLUSIONS: The results of a large-scale selective FD screening, as well as clinical and molecular genetic features, in a cohort of 293 Russian patients with FD are described.

Sliding tracheoplasty of complete tracheal cartilage rings in children.

INTRODUCTION: Complete tracheal rings are a rare malformation that occurs in 1 out of 100,000 live births. It is rare, isolated tracheal or tracheobronchial anomaly developed due to abnormal cartilage growth with formation of complete ring and often resulting in airway stenosis. Slide tracheoplasty, as it was originally described by Tsang et al. and popularized by Grillo et al., overlaps stenotic segments of trachea, shortening trachea itself, thus, doubling the circumference and diameter of the stenotic area. MATERIALS AND METHODS: We have performed slide tracheoplasty in 12 children during the period of 2019-2021 in thoracic surgery department of our center. Median age was 15 ± 21,1 months (2 months-6 years),median weight - 8,04 ± 4,75 kg (3-20,7 kg),tracheal lumen varied from 2.5 to 3.0 mm, stenosis length - from 40 to 70% of the trachea length. RESULTS: Slide tracheoplasty was performed using central veno-arterial extracorporeal membrane oxygenation in 7 cases and using cardiopulmonary bypass in 5 cases. Concomitant heart disease was revealed in 5 children (pulmonary artery sling in 3 cases, ventricular septal defects - 1, aberrant subclavian artery -1). 5 children underwent one-stage correction of VSD: plastic VSD -1; left pulmonary artery reimplantation - 3; subclavian artery reimplantation - 1. All patients were on mechanical ventilation for 4,3 ± 2,78 days at postoperative period. Patients were discharged 16,3 ± 5,14 days after surgery. Satisfactory result of treatment in the form of respiratory failure relief was achieved in 10 patients. It was possible to increase the trachea lumen from 1.5 to 2 times in all cases. There were 2 (16,6%) fatal cases due to sepsis and multi-organ failure development. CONCLUSIONS: Children with complete tracheal rings are very complicated patients with various comorbidities. Despite the advances in medicine, sometimes it is impossible to save lives of these children. The use of extracorporeal circulation (ECMO and bypass) allows us to safely perform reconstructive surgery on the trachea and save the child from respiratory failure manifestations. If needed, simultaneous correction of heart and tracheal defects is possible. Slide tracheoplasty allows to increase trachea lumen at least in 1.5-2 times. Mechanical ventilation is an unfavorable predictive factor for the outcomes of congenital tracheal stenosis management. LEVEL OF EVIDENCE: III.

Our experience of using Losartan for esophageal stenosis in children with dystrophic form of congenital epidermolysis bullosa.

INTRODUCTION: Dystrophic epidermolysis bullosa (DEB) is one of the most severe forms of congenital epidermolysis bullosa and characterized by the formation of many surgical complications. Esophageal stenosis is a common complication of DEB and occurs in almost 76% of cases. Balloon dilatation (BD) under X-ray control is the main therapeutic technique, however conservative treatment is necessary to prevent restenosis. The use of the drug losartan is promising due to its antifibrotic effect through the suppression of transforming growth factor-ß1 (TGF-ß1). PURPOSE: To evaluate the efficacy of losartan in the prevention of restenosis after BD of esophageal stenosis in children with DEB. MATERIALS AND METHODS: The study included 19 children from 2 to 16 years old (mean age 9.2 ± 3.58 years) with DEB and X-ray confirmed esophageal stenosis. All children underwent BD. In the main group 9 children after BD have received losartan, in the control group of 10 children - only standard therapy. The observation period was 12 months. RESULTS: In the main group, 1 child (11.1%) required repeated dilatation, in the control group - 4 children (40%). Indicators of nutritional deficiency (THINC scale) and the disease severity index (EBDASI) were significantly lower in the group of children treated with losartan. No undesirable actions of the drug were recorded. CONCLUSIONS: In this study losartan showed its safety, contributed to a decrease in the restenosis frequency and an improvement in the nutritional status of children with DEB after BD. However, further studies are required to confirm its effectiveness. LEVEL OF EVIDENCE: IV.