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Upshaw-Schulman syndrome (USS) is caused by severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency due to homozygous or compound heterozygous mutations in the ADAMTS13 gene. Previous studies suggest three possible disease mechanisms: (1) reduced secretion of ADAMTS13 variants, (2) impaired proteolytic activity, (3) defective biosynthesis due to nonsense-mediated decay. Expression studies have failed to establish a clear genotype/phenotype correlation that could explain the significant variability in the age of onset and patients' clinical courses. In this study, we investigated ADAMTS13 sequence variations in 30 USS patients and identified 31 disease-causing mutations; among them 10 novel variants. While none of the recombinant proteins exhibited significant retention in the endoplasmic reticulum, secretion and activity analysis revealed defective release for all but one missense mutant. The latter exhibited normal secretion but impaired activity due to inactivation of the catalytic domain. Truncated mutants showed secretion and residual activity even though the patients suffered from a severe phenotype. The expression systems which we used may not be appropriate here, as they do not assess nonsense-mediated decay causing degradation of mRNA. In some patients, phenotypic severity could be explained by the combined effects of two mutations. Genetic screening in combination with in vitro characterization of ADAMTS13 variants from both alleles is a valuable tool to predict the phenotypic severity of USS. When necessary, supplementary methods, such as kinetics under flow conditions and mRNA processing assays, can be included. Such data are helpful to identify patients who are at high risk for severe attacks and therefore might benefit from prophylactic treatment., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Schattauer GmbH Stuttgart.)

Sickle cell disease is among hereditary diseases with evidence that early diagnoses and treatment improves the clinical outcome. So far sickle cell disease has not been included in the German newborn screening program despite immigration from countries with populations at risk. To determine the birth prevalence we tested 17,018 newborns. High pressure liquid chromatography and subsequent molecular-genetic testing were used for the detection and confirmation of hemoglobin variants. The frequency of sickle cell disease-consistent genotypes was one in 2,385 newborns. Duffy-blood group typing showed evidence that affected children were likely of Sub-Saharan ancestry. An inclusion of sickle cell disease into the German newborn screening seems reasonable., (© 2015 Wiley Periodicals, Inc.)

Intracranial hemorrhage of term neonates with severe von Willebrand disease type 3 and near normal delivery have not been published to date. We report on a term newborn with severe type 3 VWD who suffered a large intracranial bleeding presumably subsequent to sinus venous thrombosis. This case is remarkable in two aspects: i) with respect to the low risk of perinatal intracranial hemorrhage even in neonates with VWD type 3 and ii) since VWD type 3 with factor VIII:C levels < 5 IU/dl does not seem to protect from thromboembolism. Guidelines for the management of hemophilia advise atraumatic delivery of neonates with known or suspected bleeding disorders, however primary caesarean section in the absence of complications is not obligatory. To answer the question whether the presented case could have an impact on the recommended management we carried out a worldwide survey including 24 participating specialized centers. Except a single case from Sweden of a female neonate with VWD type 3 who also had an inhibitor against VWF no further cases were reported to us. We conclude that CNS bleeding in term neonates with severe VWD type 3 is a rare event that requires additional risk factors for manifestation. Therefore, the amendment of current guidelines does not seem to be mandatory.

von Willebrand disease (VWD), the most common inherited bleeding disorder, is very heterogeneous, both in its phenotype and genotype. One particular molecular mechanism of VWD is due to recombination events between the true gene and its pseudogene on chromosome 22. We assessed the frequency and extension of such events in 50 multi-ethnic index patients with severe VWD type 3 and in five index patients with VWD type 2M Vicenza. One additional unclassified patient had been diagnosed with possible VWD in Russia solely on a clinical basis. Gene conversions, previously thought to be rare events, were identified in >10% of our study population: in six multi-ethnic patients with severe VWD type 3, in one patient with VWD type 2M Vicenza and the Russian patient was finally diagnosed with VWD type 2B New York/Malmoe. Our results suggest a significant contribution of this particular molecular mechanism to the manifestation of VWD. The location of the gene conversions, their extension and their occurrence as homozygous, compound heterozygous or heterozygous mutations determines the resulting phenotype.