Albertine Donker

Rare Inherited Iron and Heme-related Anemias 93 3 INTRODUCTION Anemia in children, adolescents and adults is commonly encountered in general clinical practice. Multiple causes exist, but with a thorough history, physical examination and limited laboratory evaluations a specific diagnosis can often be established. A standard diagnostic approach is to classify anemia as microcytic (MCV< 80 fL), normocytic or macrocytic (MCV> 98 fL). Nutritional iron deficiency, iron loss by gastro-intestinal disease, iron malabsorption, hemoglobinopathies, including some thalassemia syndromes, and severe anemia of chronic disease are the primary causes of microcytic anemias. In case of normocytic anemia, hemolysis, anemia of chronic disease or bone marrow pathology should be considered. Macrocytic anemias are often caused by toxic agents such as alcohol, deficiency of folic acid and/or vitamin B12 or less frequently by myelodysplastic syndrome. However, some patients with microcytic anemias remain unexplained by the above- mentioned categorization. In these cases: i) elevation of ferritin and/or transferrin saturation (TSAT), ii) low TSAT in combination with low- normal ferritin levels (> 20 µg/L), suggest a genetic disorder of iron metabolism or heme synthesis. The family history, an anemia that is refractory or incompletely responsive to iron supplementation and additional features such as neurologic disease and skin photosensitivity may also be indicative of these disorders. During recent years, defects in genes with roles in systemic and cellular iron metabolism and heme synthesis have been identified to be involved in the pathogenesis of these genetic anemias. 1-4 We recommend integrating these clinical and molecular insights in daily practice, to avoid unnecessary delay in diagnosis, invasive or costly diagnostic tests and harmful treatments. Importantly, in some genetic anemias, such as the sideroblastic anemias, iron overload is of greater consequence than the anemia itself. 3,5 Unrecognized tissue iron loading might lead to severe morbidity and even mortality, underscoring the need for accurate and timely diagnosis of these disorders. In this article we present an evidence-basedmultidisciplinary guideline for the diagnosis and treatment of 12 disorders of microcytic anemia due to defects in 13 different genes leading to genetic disorders of iron metabolism and heme synthesis. We included the disorder associated with a defect in SLC40A1 ( or ferroportin-1) in this guideline , since in