Albertine Donker

Summary 337 10 After depicting the physiology of systemic and cellular iron homeostasis and heme synthesis, we discuss the clinical sequelae of a defective systemic iron homeostasis or heme synthesis in terms of iron deficiency and iron overload, with a focus on IRIDA and XLSA. PART I: LITERATURE AND CLINICAL STUDIES In Chapter 2 we narratively reviewed the critical roles of iron during the different phases of childhood and the developmental aspects of iron homeostasis throughout the journey from fetus to adult. The aimof this reviewwas to increase the understanding of iron biology from fetal life to adulthood since this is essential for the timely and accurate diagnosis of both genetic and acquired iron disorders in childhood. We assessed the importance of iron for the growth of the body and the accompanying increase of circulating blood volume and bone mass, for the maturation of the central nervous system, the immune system and the gut microbiota. We reviewed the current knowledge on the systemic iron homeostasis from fetus to infant to middle-aged child to adolescent. After extensive exploration of the literature, we concluded that many questions remain on iron handling in childhood and on the ideal iron status for the different iron-demanding tissues in the growing and developing child. Understanding the way the human body prioritizes and distributes iron between the erythroblasts in the bone marrow, the brain and other iron-dependent organs systems during the different phases of development from fetus to adult is limited. Moreover, the lack of appropiate biomarkers for the various iron-consuming organs, and especially the central nervous system, hampers adequate assessment of iron status of the different iron-containing compartments. This limited understanding of iron physiology of childhood complicates the diagnosis and management of both acquired iron disorders as iron deficiency (anemia), anemia of inflammation or iron loading due to ineffective erythropoiesis and also anemias due to genetic disorders of iron metabolism. We proposed research ideas addressing these knowledge gaps regarding iron and iron handling in childhood, the assessment of body iron status and the treatment of iron deficiency, some of which are adressed in this thesis (establishment of hepcidin reference values in children, Chapter 7 ). Chapter 3 is a systematic review of the literature on microcytic anemias due to a genetic disorder of iron metabolism or heme synthesis, with the intention to develop evidence-based and multidisciplinary guidelines that assist the clinician in the diagnosis and treatment of these rare disorders and provide recommendations on