Marjon H. Cnossen

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Deletions spanning the neurofibromatosis type 1 gene: Implications for genotype-phenotype correlations in neurofibromatosis type 1?

Neurofibromatosis type 1 (NF1) is an autosomal‐dominant disorder characterized by abnormalities of tissues predominantly derived from the neural crest. Symptoms are highly variable and severity cannot be predicted, even within families. DNA of 84 unrelated patients with NF1, unselected for clinical features or severity, were screened with intragenic polymorphic repeat markers and by Southern analysis with cDNA probes. Deletions of the entire gene were detected in five patients from four unrelated families. Their phenotype resembled that of five previously reported patients with deletions, including intellectual impairment and dysmorphic features, but without an excessive number of dermal neurofibromas. This report supports the hypothesis that large deletions spanning the entire NF1 gene may lead to a specific phenotype. Hum Mutat 9:458–464, 1997

A prospective 10 year follow up study of patients with neurofibromatosis type 1

OBJECTIVE To establish the prevalence and incidence of symptoms and complications in children with neurofibromatosis type 1 (NF1) and to assess possible risk factors for the development of complications. DESIGN A 10 year prospective multidisciplinary follow up study. PATIENTS One hundred and fifty children diagnosed with NF1 according to criteria set by the National Institutes of Health. RESULTS In 62 of 150 children (41.3%) complications were present, including 42 (28.0%) children with one complication, 18 (12.0%) with two complications, and two (1.3%) with three complications (mean (SD) duration of follow up 4.9 (3.8) years). Ninety five of the 150 children presented without complications (follow up, 340.8 person-years). The incidence of complications was 2.4/100 person-years in this group. An association was found between behavioural problems and the presence of complications. CONCLUSION This is the largest single centre case series of NF1 affected children followed until 18 years of age. Children with NF1, including those initially presenting without complications, should have regular clinical examinations.

Paediatric arterial ischaemic stroke: functional outcome and risk factors

Aim  To study functional outcome in children aged 1 month to 18 years after paediatric arterial ischaemic stroke (PAIS) and to identify risk factors influencing their quality of life.

Reduced prevalence of arterial thrombosis in von Willebrand disease

High von Willebrand factor (VWF) levels are an established risk factor for arterial thrombosis, including coronary heart disease and ischemic stroke. It has been hypothesized that von Willebrand disease (VWD) patients are protected against arterial thrombosis; however, this has never been confirmed in clinical studies.

Diagnosis and management of haemophilia

#### Summary points Haemophilia, which means love (“philia”) of blood (“haemo”), is associated with prolonged and excessive bleeding. It is a hereditary disorder of haemostasis that occurs in one in 5000 men (prevalence of 10 in 100 000 people) and is caused by a deficiency of clotting factor VIII (in haemophilia A) or factor IX (in haemophilia B) as a result of defects in the F8 and F9 genes. Basic knowledge of the inheritance and management of haemophilia is essential for a broad group of healthcare workers, because severe or even life threatening bleeding can be prevented if the condition is adequately diagnosed and promptly treated. Furthermore, in women carriers who have an affected fetus, special precautions are needed to prevent perinatal bleeding in both the mother and the newborn baby. This review presents current recommendations for the diagnosis and management of haemophilia, which are generally based on observational studies and case series because few randomised clinical trials have been published in this relatively rare disease. #### Sources and selection criteria We searched Medline and the Cochrane Database of Systematic …

Minor disease features in neurofibromatosis type 1 (NF1) and their possible value in diagnosis of NF1 in children < or = 6 years and clinically suspected of having NF1. Neurofibromatosis team of Sophia Children's Hospital.

OBJECTIVE: To establish the frequency of minor disease features in children with neurofibromatosis type 1 (NF1) and to evaluate the value of minor disease features in children < or = 6 years with a suspected diagnosis of NF1, considering that the disease is virtually 100% penetrant at 6 years of age. DESIGN: During this 10 year, prospective, multidisciplinary, follow up study, 209 children suspected of having NF1 were examined; 150 were diagnosed with NF1 and 59 were not. The present analysis included children in whom NF1 was considered to be present at 6 years of age (n=85) and children without NF1 at 6 years of age (n=42). RESULTS: The minor disease features macrocephaly (52.9%), short stature (24.7%), hypertelorism (63.5%), and thorax abnormalities (37.6%) were highly prevalent in children with NF1 and significantly associated with a diagnosis of NF1 at 6 years of age. In addition, the mean number of minor disease features was significantly higher in children with NF1 at 6 years of age compared to the group without a diagnosis at 6 years of age (mean 1.8 v 0.8, p<0.001). Moreover, children with three or more minor disease features were all diagnosed with NF1 under the age of 6 years. Multivariate analysis using a logistic regression model showed that macrocephaly, short stature, hypertelorism, and thorax abnormalities were all independently associated with the presence of NF1 at 6 years of age. CONCLUSION: In children with insufficient diagnostic criteria aged < or = 6 years, documentation of minor disease features may be a helpful aid in predicting the diagnosis of NF1 in years to come.

Age dependency of coagulation parameters during childhood and puberty

Summary.  Background:  Use of age‐adjusted reference values is crucial for correct diagnosis and management of thrombotic and hemorrhagic disease in children. They vary with utilized reagents and analyzers.

von Willebrand disease and aging: an evolving phenotype

Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant.

CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease

von Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWF gene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown.