Clinical phenotype in genetically confirmed von Willebrand disease type 2N patients reflects a haemophilia A phenotype.

INTRODUCTION: Von Willebrand disease (VWD) type 2N is characterized by a defective binding of factor VIII (FVIII) to von Willebrand factor (VWF) resulting in diminished plasma FVIII levels and a clinical phenotype mimicking mild haemophilia A. Several mutations in the FVIII binding site of VWF have been reported. AIM: This study aims to examine the effect of genotype on clinical phenotype in a cohort of VWD 2N patients. METHODS: Patients with at least one genetically confirmed 2N mutation were selected retrospectively from a cohort of patients with suspected VWD. Clinical and laboratory phenotypes including bleeding scores (BS) were obtained and analysed. RESULTS: Forty-two VWD 2N patients with a mean age of 44 years were included. Eleven patients were homozygous or compound heterozygous (genetically confirmed group) and 31 patients were heterozygously affected (carriers group). Statistically significant differences between genetically confirmed VWD 2N patients and carriers were found in FVIII activity, VWF antigen levels, VWF-FVIII binding capacity, FVIII/VWF antigen ratio (all P<0.001), VWF-ristocetin activity (p=0.001) and VWF collagen binding (P = 0.002). Median BS was 6 in genetically confirmed VWD 2N patients compared with 3 in carriers (P = 0.047). Haemarthrosis, muscle haematomas and postpartum haemorrhage were only reported in genetically confirmed 2N patients. CONCLUSION: Phenotypic analysis showed that all laboratory parameters are lower in genetically confirmed VWD 2N patients compared with heterozygous 2N carriers. The clinical phenotype in genetically confirmed VWD 2N patients is comparable to mild haemophilia A patients and more severe than heterozygous 2N carriers.

X-linked sideroblastic anaemia due to ALAS2 mutations in the Netherlands: a disease in disguise.

BACKGROUND: X-linked sideroblastic anaemia (XLSA; OMIM#300751) is the most common inherited form of sideroblastic anaemia and is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene (ALAS2). This gene encodes for aminolevulinic acid synthase 2 (ALAS2), the catalytic enzyme involved in the first en rate-limiting step of haem biosynthesis.1-3 The disorder is characterised by mostly mild hypochromic microcytic anaemia with bone marrow ring sideroblasts. Even untransfused patients with mild or no anaemia are at risk for severe systemic iron overload due to ineffective erythropoiesis. To date, 61 different ALAS2 mutations have been reported in 120 families with XLSA. Descriptions of molecularly confirmed case series from the Netherlands, however, are lacking. METHODS: We reviewed age of presentation, clinical and biochemical features, ALAS₋2 defects and treatment characteristics of 15 Dutch patients from 11 unrelated families diagnosed with XLSA. RESULTS AND CONCLUSIONS: In one family a novel pathogenic c.1412G>A (p.Cys471Tyr) mutation was found. All other families shared the previously described c.1355G>A (p.Arg452His) mutation. Haplotype analysis in seven probands with the p.Arg452His mutation strongly suggests that six of them were ancestrally related. Nevertheless, their phenotype was very different. Our patients illustrate the phenotypical heterogeneity in the presentation of XLSA patients, the effectiveness of treatment regimens and the various pitfalls associated with the diagnosis, follow-up and treatment of the disease. A timely diagnosis avoids unnecessary investigations and allows adequate treatment that can prevent systemic iron load with subsequent severe life-threatening complications. Therefore, we suggest considering XLSA in both male and female patients with unexplained iron overload and÷or (mild) microcytic anaemia, also at older age.

Bone cysts in patients with afibrinogenaemia: a literature review and two new cases.

Afibrinogenaemia is an autosomal recessive disease with an estimated prevalence of approximately one in a million. The most common symptoms of afibrinogenaemia are umbilical cord bleeding, bleeding into skin, mouth, muscles, gastrointestinal and genitourinary tracts and the central nervous system. Other recognized complications include; haemarthroses, spontaneous splenic rupture, epistaxis, menorrhagia, recurrent abortion and venous and arterial thromboembolism. Bone cysts have also been described as a rare complication of afibrinogenaemia. The aim of this study was to conduct a systematic literature review, summarize the reported cases and to report two new cases. Three electronic databases were searched for relevant publications: PubMed, Medline and EMBASE. The following search criteria were used: '(bone cysts OR intraosseous haematoma OR intraosseous haemorrhage) AND (afibrinogenaemia OR fibrinogen deficiency)'. The reference lists of the selected papers were searched for more relevant literature. In total, eight patients had bone cysts as complication of afibrinogenaemia and six of them suffered from pain in their extremities. Bone cysts were primarily located in the vicinity of the cortex or trabeculae in the diaphysis of the long bones, especially in the femora, tibiae and humeri. Some were regressive, probably due to reactive bone remodelling. A number of cysts were filled with serosanguinous fluid. It might be useful to check for bone cysts when patients with congenital afibrinogenaemia complain of 'rheumatic' pains in their extremities. Whole body magnetic resonance imaging is the diagnostic imaging technique of choice. Recurrent episodes of pain, but not radiological deterioration, appear to benefit from prophylactic therapy with fibrinogen concentrate.

School-aged children after the end of successful treatment of non-central nervous system cancer: longitudinal assessment of health-related quality of life, anxiety and coping.

The aim of the study was to investigate: (1) health-related quality of life (HRQoL) and anxiety in school-aged cancer survivors during the first 4 years of continuous remission after the end of treatment; and (2) correlations of disease-related coping with HRQoL and anxiety. A total of 76 survivors aged 8-15 years completed questionnaires about HRQoL, anxiety and disease-related cognitive coping at one to five measurement occasions. Their HRQoL was compared with norm data, 2 months (n = 49) and 1 year (n = 41), 2 years (n = 41), 3 years (n = 42) and 4 years (n = 27) after treatment. Through longitudinal mixed models analyses it was investigated to what extent disease-related cognitive coping was associated with HRQoL and anxiety over time, independent of the impact of demographic and medical variables. Survivors reported worse Motor Functioning (HRQoL) 2 months after the end of treatment, but from 1 year after treatment they did no longer differ from the norm population. Lower levels of anxiety were associated with male gender, being more optimistic about the further course of the disease (predictive control) and less searching for information about the disease (interpretative control). Stronger reliance on the physician (vicarious control) was associated with better mental HRQoL. As a group, survivors regained good HRQoL from 1 year after treatment. Monitoring and screening survivors are necessary to be able to trace the survivors at risk of worse HRQoL.

Participation and risk-taking behaviour in sports in children with haemophilia.

The aim of this study was to investigate participation in sports activities and risk-taking behaviour in children with haemophilia and the relationship to personal and health related factors. Ninety-nine children (mean age 12.6 years) completed questionnaires regarding participation in sports and physical education, medication, health related quality of life, and perceived motor competence. Furthermore, weight, height, active range of motion, pain, and muscle strength were assessed. Based on a risk exposure factor (REF) we defined subgroups with low, medium, and high risk when participating in sport. Most children participate in sport five times a week (mean 140 min per week), and little absence during school sports was reported. In general, prophylaxis was not tailored to sport activities. Boys with haemophilia preferred other sports than their Dutch contemporaries. The top-5 being soccer, swimming, tennis, gymnastics, and cardio-fitness for the former; soccer, gymnastics, tennis, hockey, and swimming for the latter. Significant differences between the low risk group and both other groups were found for sport intensity, total energy expenditure (EE) and average risk factor (ARF), however the medium and high-risk groups did not differ in ARF. REF and sport participation increased associated with increasing interest in athletic and motor activities. No significant differences were found between REF groups regarding age, Z-BMI, Z-AROM, Z-Muscle force, and the presence of painful joints. As in normal peers motivation to participate in sport depends upon the enthusiasm and interest, in children with haemophilia choice of sports differs, probably related to sport advice.

[Rituximab instead of splenectomy in 4 children with chronic or refractory autoimmune haemolytic anaemia]. / Rituximab in plaats van splenectomie bij 4 kinderen met chronische of refractaire auto-immune hemolytische anemie.

4 children, a boy aged 10 years and 3 girls aged 3, 3, and 16 years, suffering from chronic or refractory autoimmune haemolytic anaemia (AIHA), who were dependent on high doses of steroids and were refractory to immunosuppressants, were treated with rituximab at a dose of 375 mg/m2 once a week for 3 or 4 weeks as an alternative to splenectomy. Rituximab is a monoclonal anti-CD20 antibody that prevents the production ofautoantibodies by selective destruction of B-lymphocytes. Haemoglobin levels increased and the parameters of chronic haemolysis (reticulocyte count, lactate dehydrogenase activity, bilirubin concentration) decreased to normal values. 3 patients were taken off corticosteroids completely; 1 of these was also no longer dependent on blood transfusions. Circulating B-lymphocytes were absent for 6 to 15 months after the treatment and the rituximab was well-tolerated. During the treatment, immunoglobulins were substituted and infectious complications were not seen. Rituximab was valuable in the treatment of chronic or refractory AIHA and eliminated the need for splenectomy. 1 patient did not respond to rituximab.