Albertine Donker

Chapter 3 94 animal models mutations in this gene cause a microcytic anemia, 6 and narrative reviews classified the related human disease as a microcytic anemia, 1 despite the fact that our literature review showed that microcytic anemia is rarely reported in these patients. We also included (normocytic) patients with XLDPP, since this disorder is a variant of erythropoietic protoporphyria, a disease with patients presenting with microcytic anemia. We describe themethodology used, provide a short and illustrated introduction in iron homeostasis ( Figure 1 ) and briefly discuss the pathogenesis, epidemiology, clinical presentation, diagnosis, and treatment. We present i) case tables comprising characteristics of the individual patients described in the literature ( Supplement 1, online) , except for patients with loss-of-function defects in ALAS2 and defects in SLC40A1 , UROS and FECH because of their relatively high prevalence, ii) evidence-based conclusions and related references ( Supplement 2, online ), iii) recommendations including advice on family screening ( Table 1 ), and iv) results of literature analysis on prevalence of anemia in patients with defects in SLC40A1 ( Supplement 3 ). To facilitate the clinician, a table summarizing the characteristics of the disorders ( Table 2 ) and a flow chart ( Figure 2 ) to aid the diagnosis of the relevant diseases are included. Methodology This guideline has been developed to assist clinicians and patients in the clinical decision-making process for rare anemia due to genetic disorders of iron metabolism and heme synthesis by describing a number of generally accepted approaches for the diagnosis and treatment of these disorders. For the development of this evidence-based guideline, the working group adopted themethodology described in theMedical specialist guidelines 2.0 of the Netherlands Association of Medical Specialists. 7 This methodology is based upon the international AGREE II criteria for assessing the quality of guidelines (http://www.agreetrust.org ). 8 In short, the development of the guideline was started by formulating a number of starting questions ( Supplement 4 ). Each question guided a systematic literature review in both Medline and Embase up to December 2010, using MESH headings and free text words related to the name of the predefined genes and disease of interest (see “definitions” below), and disease specific symptoms. In addition, we retrieved more recent original and review articles by using the same key words for searching PubMed and checked the references of the obtained papers. Searches were limited to those written in English, German, French and Dutch. Searches were not limited in time.