Complex analysis of the national Hereditary angioedema cohort in Slovakia - Identification of 12 novel variants in SERPING1 gene.

Background: Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterised by acute episodes of non-pruritic skin and submucosal swelling caused by increase in vascular permeability. Objective: Here we present the first complex analysis of the National HAE Slovakian cohort with the detection of 12 previously un-published genetic variants in SERPING1 gene. Methods: In patients diagnosed with hereditary angioedema caused by deficiency or dysfunction of C1 inhibitor (C1-INH-HAE) based on clinical manifestation and complement measurements, SERPING1 gene was tested by DNA sequencing (Sanger sequencing/massive parallel sequencing) and/or multiplex ligation-dependent probe amplification for detection of large rearrangements. Results: The Slovakian national cohort consisted of 132 living patients with confirmed HAE. We identified 51 index cases (32 families, 19 sporadic patients/112 adults, 20 children). One hundred seventeen patients had HAE caused by deficiency of C1 inhibitor (C1-INH-HAE-1) and 15 patients had HAE caused by dysfunction of C1 inhibitor (C1-INH-HAE-2). The prevalence of HAE in Slovakia has recently been calculated to 1:41 280 which is higher than average calculated prevalence. The estimated incidence was 1:1360 000. Molecular-genetic testing of the SERPING1 gene found 22 unique causal variants in 26 index cases, including 12 previously undescribed and unreported. Conclusion: The first complex report about epidemiology and genetics of the Slovakian national HAE cohort expands the knowledge of the C1-INH-HAE genetics. Twelve novel causal variants were present in the half of the index cases. A higher percentage of inframe variants comparing to other studies was observed. Heterozygous deletion of exon 3 found in a large C1-INH-HAE-1 family probably causes the dysregulation of the splicing isoforms balance and leads to the decrease of full-length C1-INH level.

The use of ketotifen as long-term anti-inflammatory prophylaxis in children with PFAPA syndrome.

Introduction: Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) is the most frequent periodic fever syndrome in children. Its pathogenesis is still unknown, but some disease-modifying factors were observed. Several medications were tested for the long-term prophylaxis of inflammatory flares; however, none are standardly used. Methods: This prospective clinical trial enrolled 142 children (71 girls, 50%) meeting diagnostic criteria for PFAPA syndrome. We analysed selected clinical characteristics and compared laboratory parameters during the flare and attack-free period (at least two weeks after the attack). Moreover, we assessed the possible therapeutic effect of ketotifen on the duration of attack free-periods and clinical picture. Results: The mean age of patients was 6.81 ± 3.03 years and the mean age of onset of symptoms was 2.31 ± 2.02 years. No significant differences were observed between genders.We recorded a positive family history for PFAPA in 31.69% of patients. Attacks lasted for 2.8 ± 1.2 days, with intervals between attacks of 4 ± 1 weeks. We administered ketotifen in 111 (77.8%) patients, and a positive effect was observed in 86 (77.5%) of patients. We observed prolonged attack-free intervals in patients treated with ketotifen (14.7 ± 8.9 days in comparison with 4.4 ± 1.9 days before the treatment; p<0.001). The used dose of ketotifen was 0.08 ± 0.01 mg/kg/day. Mild side effects were observed in four patients (restlessness, irritability, agitation and constipation). Discussion: Our data supports the use of ketotifen for long-term prophylaxis in children with PFAPA syndrome with positive effects on the attenuation of disease activity and the prolongation of attack-free periods. Further well-designed studies should confirm the preliminary data.

Endothelial Dysfunction in Children with Juvenile Psoriatic Arthritis.

BACKGROUND: To evaluate the presence of endothelial dysfunction in Slovak children with juvenile psoriatic arthritis in the absence of classic cardiovascular risk factors in order to assess its relationship to the disease activity and disability. METHODS: 25 juvenile psoriatic arthritis patients (JPSA) and 25 healthy controls aged 6-19 years were enrolled into this study. In all subjects vascular measurements over a period of three years (January 2013 - January 2016) were performed, in accordance with the guidelines for ultrasonographic evaluation of FMD% (flow-mediated endothelial dependent vasodilatation) of the brachial artery. The measured items were compared to the variables reflecting the disease activity and disability. RESULTS: Significantly lower FMD% values in patients with JPSA when compared to healthy controls {mean(SD), median, range: 5.49% (3.77), 3.55, 0.3-13.0 vs. 9.28% (1.72), 9.3, 6.4-13.1} (p < 0.001) have been documented. Strong correlations between FMD% values and disease duration (p < 0.01), non-specific inflammatory markers levels (p < 0.001) or functional disability (p < 0.01) have been observed. Significantly lower FMD% values in patients with an early disease onset (JPSA onset < 5 years of age) when compared to the rest of JPSA group {mean (SD), median, range: 4.39% (2.47), 4.45, 0.9-13.2 vs. 6.38% (1.42), 6.3, 3.2-12.1} (p < 0.01) have also been detected. CONCLUSION: Study is the only one addressing endothelial dysfunction development in Slovak children with psoriatic arthritides. We state that endothelial dysfunction is present in these patients even during childhood and in the absence of classic cardiovascular risk factors. Its development seems to be related to an early disease onset as well as to the increased disease activity and disability. Potential genetic predictors have also been identified.