Hemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show recessive inheritance carriers are... Show moreHemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show recessive inheritance carriers are usually clinically silent. Programmes for preconception and antenatal carrier screening, with the option of prenatal diagnosis are considered beneficial in many endemic countries. With the development of genetic tools such as Array analysis and Next Generation Sequencing in addition to state of the art screening at the hematologic, biochemic and genetic level, have contributed to the discovery of an increasing number of rare rearrangements and novel factors influencing the disease severity over the recent years. This review summarizes the basic requirements for adequate carrier screening analysis, the importance of genotype-phenotype correlation and how this may lead to the unrevealing exceptional interactions causing a clinically more severe phenotype in otherwise asymptomatic carriers. A special group of patients are beta-thalassemia carriers presenting with features of beta-thalassemia intermedia of various clinical severity. The disease mechanisms may involve duplicated alpha-globin genes, mosaic partial Uniparental Isodisomy of chromosome 11p15.4 where the HBB gene is located or haplo-insufficiency of a non-linked gene SUPT5H on chromosome 19q, first described in two Dutch families with beta-thalassemia trait without variants in the HBB gene. Show less
Mekelenkamp, H.; Zanten, H. van; Vries, M. de; Lankester, A.; Smiers, F.; SCORE Consortium 2021
Hematopoietic stem cell transplantation decision-making for hemoglobinopathy patients is a complex process, and it remains difficult for health care professionals to decide whether and when a... Show moreHematopoietic stem cell transplantation decision-making for hemoglobinopathy patients is a complex process, and it remains difficult for health care professionals to decide whether and when a hematopoietic stem cell transplantation should be offered. Gaining insight into health care professionals' considerations is required to understand and optimize this decision-making process. A qualitative interview study using semi-structured interviews with eighteen health care professionals. Data were thematically analyzed. Two main themes emerged from the data: (1) Experiencing the influence of a frame of reference and (2) Feeling responsible for a guided decision-making. The frame of reference, meaning the health care professionals' knowledge and experiences regarding hematopoietic stem cell transplantation, influenced the guided decision-making process. Subsequently, three subthemes evolved from the second theme: (a) weighing up disease severity against possible complications, (b) making an effort to inform, and (c) supporting the best fitting decision for the individual patient. The health care professionals' frame of reference determined the hematopoietic stem cell transplantation decision-making process. This demands reflection on the health care professionals' own frame of reference and its influence on decision-making. Furthermore, reflection on the frame of reference is needed by exchange of knowledge and experiences between referring and referred-to healthcare professionals in an open and two-way direction. The transplantation teams have a responsibility of keeping the frame of reference of their referring colleagues up to date and referring health care professionals should share their feelings regarding hematopoietic stem cell transplantation. To guide patients, a shared decision-making approach is supportive, in which eliciting the patients' preferences is highly important. Health care professionals can refine the decision-making process by guiding patients in eliciting their preferences and including these in the decision. Show less
During the last few years, next-generation sequencing (NGS) has undergone a rapid transition from a research setting to a clinical application, becoming the method of choice in many clinical... Show moreDuring the last few years, next-generation sequencing (NGS) has undergone a rapid transition from a research setting to a clinical application, becoming the method of choice in many clinical genetics laboratories for the detection of disease-causing variants in a variety of genetic diseases involving multiple genes. The hemoglobinopathies are the most frequently found Mendelian inherited monogenic disease worldwide and are composed of a complex group of disorders frequently involving the inheritance of more than one abnormal gene. This review aims to present the role of NGS in both screening and pre- and post-natal diagnostics of the hemoglobinopathies, and the added value of NGS is discussed based on the results described in the literature. Overall, NGS has an added value in large-scale high throughput carrier screening and in the complex cases for which common molecular techniques have some inadequacies. It is proven that the majority of thalassemia cases and Hb variants can be diagnosed using routine analysis involving a combined approach of hematology, hemoglobin separation, and classical DNA methods; however, we conclude that NGS can be a useful addition to the existing methods in the diagnosis of these disorders. Show less
Background While multiple studies have examined the cost of health care for one aspect of sickle cell disease care, few have focussed on the overall cost of comprehensive care for sickle cell... Show moreBackground While multiple studies have examined the cost of health care for one aspect of sickle cell disease care, few have focussed on the overall cost of comprehensive care for sickle cell disease. Methods We conducted a retrospective cohort study of children with sickle cell disease treated in a comprehensive care centre from 1 January 2015 to 31 December 2016. Health care utilisation of included patients was based upon data from two main sources. The clinical practice guideline was used to determine the expected resource use of routine comprehensive care (planned elective care), and the financial claims database was used to estimate real-world resource use associated with acute and inpatient care (additional care). Results A total of 125 children with sickle cell disease were analysed. Expenditures for these patients averaged euro5049 [standard deviation (SD) euro1634] per child per year. Total yearly costs per patient varied considerably, ranging from euro669 to euro84 010, and less than 15% of patients were responsible for 50% of the health care costs. The majority (37%) of costs was associated with inpatient hospital care, which increased by age group, 27% with diagnostics, 19% with treatment, 11% with outpatients' visits and 6% with emergency care. Conclusion We have described real-world resource use and expenditures for children with sickle cell disease in a European comprehensive care centre. It seems that costs of a comprehensive approach with effective management in the outpatient setting is favourable when compared to episodic health care. Show less
Stroke risk in children with sickle cell disease (SCD) is currently assessed with routine transcranial Doppler ultrasound (TCD) measurements of blood velocity in the Circle of Willis (CoW). However... Show moreStroke risk in children with sickle cell disease (SCD) is currently assessed with routine transcranial Doppler ultrasound (TCD) measurements of blood velocity in the Circle of Willis (CoW). However, there is currently no biomarker with proven prognostic value in adult patients. Four-dimensional (4D) flow magnetic resonance imaging (MRI) may improve risk profiling based on intracranial haemodynamics. We conducted neurovascular 4D flow MRI and blood sampling in 69 SCD patients [median age 15years (interquartile range, IQR: 12-50)] and 14 healthy controls [median age 21years (IQR: 18-43)]. We measured velocity, flow, lumen area and endothelial shear stress (ESS) in the CoW. SCD patients had lower haematocrit and viscosity, and higher velocity, flow and lumen area, with lower ESS compared to healthy controls. We observed significant age-related decline in haemodynamic 4D flow parameters; velocity (Spearman's =-036 to -061), flow (=-026 to -052) and ESS (=-014 to -054) in SCD patients. Further analysis in only adults showed that velocity values were similar in SCD patients compared to healthy controls, but that the additional 4D flow parameters, flow and lumen area, were higher, and ESS lower, in the SCD group. Our data suggest that 4D flow MRI may identify adult patients with an increased stroke risk more accurately than current TCD-based velocity. Show less
