Albertine Donker

Chapter 1 36 OUTLINE AND AIMS OF THIS THESIS We aim to increase awareness among clinicians and to facilitate them to accurately and timely diagnose these rare disorders in order to optimize management and to prevent not effective or even harmful treatments. To achieve this aim, this thesis explores clinical, genetic and diagnostic aspects of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis. PART I: LITERATURE AND CLINICAL STUDIES In Chapter 2 we review the literature on developmental aspects of systemic iron metabolism, summarize the physiologic changes in iron homeostasis that occur during the journey from fetus to adult and identify research gaps on this topic. Therewith we aim to contribute to a better understanding of pediatric genetic disorders of iron metabolism or heme synthesis. As a first step to improve the clinical management of microcytic anemias due to iron metabolism and heme synthesis, we explored the literature on clinical, biochemical and genetical studies of these disorders. In Chapter 3 we present evidence- based multidisciplinary guidelines for the diagnosis and treatment of 12 disorders of microcytic anemia that result from defects in 13 different genes and that lead to genetic disorders of iron metabolism and heme synthesis. We briefly discuss pathogenesis, epidemiology, clinical presentation, diagnosis and treatment, and also provide recommendations on family screening. 141 In the next chapters we describe case series for a disorder of iron metabolism (IRIDA) and a disorder of heme synthesis (XLSA), respectively. In Chapter 4 we assess clinical presentation, disease severity, response to (oral) iron supplementation and genotype-phenotype correlation of a case series of Dutch IRIDA patients, in order to get more insight in the clinical and genetic nature of this anemia. 142 In Chapter 5 we discuss the pathogenicity of the non-synonymous TMPRSS6 changes c.757A>G (p.Lys253Glu, rs2235324) and c.2207 T>C (p.Val736Ala, rs855791) in response to a paper on a suggested IRIDA case of de Nie et al . 143,144 In Chapter 6 we present clinical and genetic data of Dutch XLSA patients. 145