Algorithm for differential diagnosis of Anemia Thrombocytopenia Congenital Dyserythropoietic Anaemias (CDA) Hb < 2SD

Reduced or normal reticulocyte count

Elevated MCV Normal MCV Reduced MCV

Exclude other causes of microcytic Exclude other causes of macrocytic anemias: Exclude other causes of anemias: Thalassemias, ACD, Sideroblastic Megaloblastic Anemias (Vit B12/ Folate deficiency), normocytic anemias: Hemolytic Anemia Anemias, Lead poisoning, Infections Hemolytic Anemia, MDS, Gilbert Syndrome, (Hereditary spherocytosis), Aplastic Anemias, Exclude other causes of thrombocytopenias: Infections, Liver disease, hypothyroidism. ACD, MDS, Gilbert Syndrome, Infections Wiskott–Aldrich syndrome and others

Clinical suspicion: Clinical suspicion: Clinical suspicion: Clinical suspicion: Clinical suspicion: CDA I CDA II CDA III CDA IV XLTDA

Bone marrow: dysplastic Bone marrow: incompletely Giant multinucleated Bone marrow: Binucleated Bone marrow: Bone marrow: tri- and multi- erythropoiesis, with megaloblastic divided cells; binucleated erythroblasts (up to 12 nuclei) erythroblasts; (10-30%) and rarely multinucleated nucleated erythroblasts features, nuclear irregularities, (3-7%); thin chromatin bridges between abnormal megakaryocytes. late polychromatic erythroblasts Electron microscopy: invagination bi and multi-nucleation; ineffective pairs of erythroblasts. Electron microscopy: double Biochemical diagnosis: of nuclear membrane, intra-nuclear megakaryopoiesis with atypical Electron microscopy: “swiss cheese High serum thymidine kinase plasma membrane in erythroblasts precipitated material and nuclear micro-megakaryocytes. appearance” of the erythroblasts Additional features: Biochemical diagnosis: blebbing. Additional features: HPFH, heterochromatin Gammopathies, multiple myeloma, hypoglycosylation of AE1 Additional features: HPFH β-thalassemia-like anemia, easily Additional features: 1/3 cases retinal angioid streaks Test HAM positive bruising, criptorquidia with malformations

Molecular diagnosis: Molecular diagnosis: Molecular diagnosis: Molecular diagnosis: Molecular diagnosis: - CDAN1 (AR) - SEC23B (AR) - KIF23 (AD) - KLF1 (AD) - GATA1 (X-linked) - C15ORF41 (AR)

CDA Congenital dyserythropoietic Anaemia MDS Myelodisplastic Syndrome ACD Anaemia of chronic disease HPFH Hereditary persistence of fetal hemoglobin

Provided by Dr. Mayka Sanchez & Dr. Achille Iolascon D·IRON ®