Incidence of inhibitor development in PUPs with severe Haemophilia A in the CEE region between 2005 and 2015.

INTRODUCTION: This study analyses real-world data on 144 previously untreated patients (PUPs) with severe Haemophilia A, from seven countries in Central and Eastern Europe (CEE: Bulgaria, Croatia, Czech Republic, Hungary, Latvia, Serbia, and Slovenia), over a period of 11 years. It analyses the risk factors associated with development of inhibitors to factor VIII concentrates. METHODS: Cox proportional hazard models were used to estimate the hazard risk of factors possibly influencing the development of inhibitors. Patients were followed for up to 100 exposure days (EDs). RESULTS: Cumulative inhibitor incidence at the time of 100 EDs was 18.7%, slightly lower than the 25-35% incidence reported in most studies. Of PUPs who developed inhibitors, a majority (56%) developed them within the first 20 EDs and 88% by the 50th ED. FVIII class (recombinant or plasma-derived) did not influence the inhibitors' incidence rate (p = 0.64). We found a significant protective effect of prophylaxis compared to on-demand treatment (p = 0.003). PUPs who had an intensive peak treatment during the first 50 EDs were at significantly higher risk for inhibitor development (HR (95% CI) 5.3 (2.3-12.5), p < 0.001). CONCLUSION: Inhibitors are and will continue to be the most significant complication of haemophilia treatment with factor concentrates. This is particularly true for haemophilia A. In our cohort, we were able to show that the treatment regimen used during first 50EDs influenced significantly the inhibitor risk, but the class of the factor concentrate did not play an important role. Real world data will remain one of the important resources for improving our knowledge of haemophilia.

Carrier and prenatal diagnostic strategy and newly identified mutations in Hungarian haemophilia A and B families.

Deficiencies of blood coagulation factors VIII and IX (haemophilia A and haemophilia B) represent the most common inherited bleeding disorders with a wide range of causative mutations. Carrier and prenatal diagnostics are preferably performed by direct mutation detection; however, in certain situations, indirect family studies may also be useful. We aimed to utilize a combination of direct and indirect techniques for carrier and prenatal diagnostics in both haemophilias in a single national centre. Two hundred and eleven haemophilia A families were investigated by screening for inversions of introns 1 and 22, and by family studies using polymorphic markers. Twenty-eight haemophilia A and 39 haemophilia B families were investigated by Sanger-sequencing of the coding regions. Among severe haemophilia A families, frequencies of intron 22 and 1 inversions were 82 out of 145 (57%) and two out of 145 (1.4%). Sequencing of the entire coding region of the respective factor gene was performed and 12 (haemophilia A) and 5 (haemophilia B) previously unpublished disease-causing mutations were identified. For genetic markers used for haemophilia A indirect family testing, heterozygosity rates varied between 137 out of 327 [42% intragenic BclI restriction fragment length polymorphism (RFLP], 168 out of 254 (66% intragenic F8Civs13CA) and 202 out of 261 (77% extragenic DXS15CA) with a combined rate of 92% (intragenic markers) and 97% (all three markers). For male fetuses, prenatal diagnostics was provided to 43 haemophilia A families (n = 22 with direct mutation detection and n = 21 by indirect family testing) and to three haemophilia B families. The combination of direct and indirect molecular genetics approaches is a successful and cost-effective approach to provide carrier and prenatal diagnostics and risk assessment for inhibitor formation.

[Association of occipital encephalocele with vesicoureteral reflux]. / Encephalokele társulása súlyos vesicoureteralis refluxszal.

Occipital encephalocele was associated with vesicoureteral reflux and agenesis of the os coccygeum in a small-for-gestational age newborn girl. The symptoms did not correspond to any of the syndromes with encephalocele. The present observation and data of the literature suggest that the significance of vesicoureteral reflux in syndrome diagnosis is generally underestimated.