Diagnosis and Treatment of Rare Microcytic Anemias

Guideline Watch |
March 31, 2014

Diagnosis and Treatment of Rare Microcytic Anemias

  1. David Green, MD, PhD

Evidence-based guidelines for diagnosing and treating these rare diseases

  1. David Green, MD, PhD

Sponsoring Organization: Dutch Working Group from the Laboratory of Genetic Endocrine and Metabolic Diseases, Radboud University Medical Center

Target Population: Hematologists, oncologists, and pediatricians

Background and Objective

Genetic disorders of iron metabolism and heme synthesis are usually associated with microcytic anemias (mean cellular volume, <80 fl). These anemias are characterized by an increase in ferritin and/or transferrin saturation (TS) or low TS in combination with a low or normal ferritin level. Now, experts from the Netherlands have developed practice guidelines to help clinicians and patients make clinical decisions regarding these rare disorders by describing a number of generally accepted approaches for their diagnosis and treatment. The methodology was based upon the AGREE II criteria, and evidence supporting the guidelines was derived from an extensive review of the literature.

Recommendations for Diagnosis and Treatment

The recommendations are organized by the type of defect as follows:

Low Iron Bioavailability

  • Disorders: Iron refractory iron deficiency anemia [IRIDA], ferroportin disease, and aceruloplasminemia

  • Diagnosis: The affected genes are TMPRSS6, SLC40A1, and CP. TS is low in IRIDA but normal or high in ferroportin disease; aceruloplasminemia is associated with neurologic disease.

  • Treatment: Oral or intravenous iron is given for IRIDA, ferroportin disease is treated by phlebotomy, and aceruloplasminemia is treated by chelation.

Defective Iron Acquisition

  • Disorders: Hypotransferrinemia, anemia with iron loading, and sideroblastic anemia

  • Diagnosis: The affected genes are TF, DMT1, and STEAP3. Hepcidin is low in hypotransferrinemia but normal in the other two disorders. Ringed sideroblasts are observed in the bone marrow of patients with sideroblastic anemias.

  • Treatment: Hypotransferrinemia is treated by infusions of plasma or apotransferrin, and the anemia of iron loading might respond to oral iron. Transfusion and erythropoietin are given for sideroblastic anemia due to mutations in STEAP3.

Defects in Heme Synthesis or Iron-Sulfur Cluster Biogenesis

  • Disorders: Sideroblastic anemias and erythropoietic porphyrias

  • Diagnosis: The affected genes are SLC25A38, ABCB7, ALAS2, GLRX5 in the sideroblastic anemias and FECH, ALAS2, UROS, and GATA1in the porphyrias. ABCB7 and ALAS2 are X-linked and ABCB7 is associated with ataxia. Hemolysis occurs with mutations in UROS and GATA1.

  • Treatment: Stem-cell transplantation is needed for the severe anemia associated with mutations in SLC25A38, whereas patients with X-linked sideroblastic anemia due to ALAS2 might respond to oral pyridoxine.


The disorders described in these guidelines are usually considered after the more common causes of anemia have been excluded. The evidence-based guidelines provided by the authors should assist clinicians in reaching the correct diagnosis and selecting the appropriate therapy for these rare diseases.

Editor Disclosures at Time of Publication

  • Disclosures for David Green, MD, PhD at time of publication Consultant / Advisory board Altor Bioscience Grant / research support NIH


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