Congenital Dyserythropoietic Anemia Type I

A 4-month-old boy was referred due to pallor. Initial Hb was 9 gr/dl. Which worsened at about 8 months to 4.9 gr. Physical exam: Normal growth and development and splenomegaly. He received twice transfusions at infancy .. Overall 4 times until 6 years of age. PBS: Non significant, anisocytosis and poikilocytosis Reticulocytes: 2% - 7%, Serum ferritin: 150-200, LFT: Nl MCV and MCH: Nl Hb electrophoresis: Nl Osmotic fragility: Nl CBC of parents: Nl BM: erythroid hyperplasia, dyserythropoiesis and binucleated and multinucleated erythroblasts with few internuclear bridges. Ring sideroblast: Negative HEMPAS test: Positive

Congenital Congenital dyserythropoietic dyserythropoietic anemia anemia Four major forms of CDA and several minor subgroups have been identified. Shared clinical symptoms : Anemia of variable degree, intermittent jaundice, hepatomegaly, splenomegaly, cholelithiasis, and iron overload. Additionally, extramedullary hematopoiesis presenting as a paravertebral mass may be observed in all types of CDAs.

Differential diagnosis of CDA Differential diagnosis of CDA oThalassemia syndromes oHemoglobin C oCertain unstable hemoglobins oHereditary sideroblastic anemias oHereditary persistence of fetal hemoglobin oRed blood cell membrane defect oVitamin B12 or folate deficiency oIron deficiency oliver disease oHeavy metal poisoning oMDS

Congenital Dyserythropoietic Anemia Type I o Incidence of CDA type I: about 1/100,000 per year. Most patients: diagnosis is made during childhood and adolescence. Anemia is moderate, with a mild macrocytosis and frequent eliptocytes. o Newborns: small stature, hepatosplenomegaly, jaundice, pulmonary hypertension, abnormal liver tests, and rarely, transient thrombocytopenia. o RBC transfusions are often required for newborns and infants but occasionally necessary later in life. o Splenomegaly is evident in 80% to 90% of adult patients. o Occasionally, severe erythroid hyperplasia may cause skeletal deformities such as frontal bossing or paravertebral tumors secondary to extramedullary hematopoiesis. o Iron overload with increased ferritin levels is frequent even in untransfused patients. Increased iron loading is due to the fact that hepcidin levels are reduced in CDA type I . o Congenital abnormalities are associated with some CDA type I cases and include abnormalities of the fingers, toes, and wrists; short stature; pigeon chest deformity; deformity of the hips, vertebral bodies, and ribs; abnormal skin pigmentation; congenital ptosis; and deafness.

Laboratory Findings of CDA type I o The anemia in CDA type I is moderate, Hb between 6.6 -11.6 g/dl. o Red cell morphology: macrocytosis, severe anisopoikilocytosis, and basophilic stippling. o Inappropriate suppression of hepcidin, high levels of serum hemojuvelin have been described in patients with CDA I and II, probably contributing to secondary hemochromatosis o BM shows erythroid hyperplasia with megaloblastic changes. o Diagnostic of CDA type I is the finding of inter nuclear chromatin bridges which is seen in about 0.6% to 2.8% of the early and late polychromatic erythroblasts. o The characteristic electron microscopic abnormality in CDA type I is a spongy Swiss-cheese appearance of heterochromatin in up to 60% of intermediate and late erythroblasts.

Inheritance of CDA 1 Inheritance of CDA 1 (CDAN1A) is caused by homozygous or compound heterozygous mutation in the gene encoding codanin-1 (CDAN1) on chromosome 15q15. (CDAN1B) is caused by mutation in the C15ORF41 gene on chromosome 15q14.

Clinical Management of CDA Clinical Management of CDA oTreatment is essentially symptomatic. oSplenectomy results in hematologic improvement in some patients with CDA type II; oTransfusion independence was achieved in one patient with CDA type IV in whom splenectomy was performed. oSplenectomy in CDA does not have a beneficial effect on iron overload. oThe benefit of splenectomy in other forms of CDA is controversial. oPatients with CDA type I show hematologic improvement and a reduction in iron overload in response to recombinant interferon alfa.

Clinical Management of CDA Clinical Management of CDA Successful treatment with allogeneic HSCT in combination with intensive iron chelation therapy has been reported in severely affected patients with CDA. In contrast to other IBMFS, CDA is not associated with a significantly increased risk for leukemia or cancer.

Congenital Congenital Dyserythropoietic Dyserythropoietic Anemia Type II Anemia Type II oIncidence of CDA type II is about 1 in 100,000 per year, with more than 300 reported cases o CDA type II is the most frequent form of CDA. oCDA type II is also known as hereditary erythroblastic multinuclearity with a positive acidified serum lysis test (HEMPAS) oThe extent of anemia in patients with CDA type II varies from mild to severe. oAbout 10% of patients require red cell transfusions in infancy and childhood but rarely thereafter. oSplenomegaly and the development of gallstones are common.

Congenital Congenital Dyserythropoietic Dyserythropoietic Anemia Type II Anemia Type II Extramedullary hematopoiesis with the development of paravertebral tumors is rare. Progressive iron overload is seen even in untransfused patients, and liver cirrhosis secondary to iron overload develops in about 20%. Dysmorphic features appear to be less common than in CDA type I. Mental retardation has been reported in some patients with CDA type II.

Laboratory Findings Laboratory Findings of CDA type II of CDA type II o Hemoglobin in patients with CDA type II is generally between 8-11 g/dL, with a normal MCV. o Red cells are usually normocytic, with moderate to marked anisocytosis, anisochromasia, and poikilocytosis (including teardrop-shaped poikilocytes); occasional basophil stippling cells; and a few circulating NRBC. oThere is erythroid hyperplasia in the bone marrow, with 10% to 35% of binucleate erythroblasts and, rarely, multinucleate late polychromatic erythroblasts. oPseudo-Gaucher macrophages may be found in the majority of cases.

oRed cells of most patients with CDA type II are lysed in the acidified serum lysis test (Ham test) when mixed with fresh ABO-compatible normal sera but not the patient s own serum. oThe reactive sera contain a naturally occurring IgM antibody that recognizes an antigen present on CDA type II cells but not on normal cells. oCDA type II red cells show increased agglutinability with anti-i antibody. oIn contrast to RBC from patients with PNH, which lyse in the acidified serum lysis test even with autologous serum because of complement activation, CDA type II cells lyse because of persistence of the HEMPAS antigen on their surfaces. oThus CDA type II cells do not lyse in the sucrose lysis test.

Inheritance of CDA type II Inheritance of CDA type II CDAN2 is caused by mutation in the SEC23B gene on chromosome 20p11

Congenital Congenital Dyserythropoietic Dyserythropoietic Anemia Type III Anemia Type III oCDA type III is rare, with about 60 cases reported, the majority in Sweden. Both familial and sporadic cases have been reported. In familial cases the inheritance pattern is AD. oSplenomegaly was present in some patients but not in others. oIn contrast to CDA types I and II, iron overload seems not to be clinically significant in patients with familial CDA type III, most likely because of intravascular hemolysis and iron loss by hemosiderinuria. oVisual disturbances with macular degeneration and angioid streaks and myeloma have been described in individual families. oSporadic CDA type III cases are clinically heterogeneous. Hepatosplenomegaly and significant iron overload have been described in some.

Laboratory Findings in CDA type III Laboratory Findings in CDA type III oAnisopoikilocytosis, basophilic stippling and very large RBCs may be found in the peripheral blood smear. oSerum thymidine kinase activity is elevated in most patients with CDA III. oIn families with hemosiderinuria, iron deficiency may be found. oBM contains multinucleate and mononucleate erythroblasts. Other dysplastic changes include basophilic stippling, nuclear lobulation, and karyorrhexis. oErythroblasts show a variety of nonspecific ultrastructural abnormalities, intranuclear clefts, karyorrhexis, abnormalities in the nuclear membrane, and large autophagic vacuoles.

Congenital Congenital Dyserythropoietic Dyserythropoietic Anemia Type IV Anemia Type IV CDA IV is exceedingly rare; only four patients have been described. All have severe hemolytic anemia with hyperbilirubinemia, a markedly elevated fetal hemoglobin of 40% or higher, iron overload, and marrow showing moderate dyserythropoiesis. Additional features include splenomegaly and growth delay. One case of CDA IV was associated with additional complex congenital anomalies. Patients with CDA IV have a specific red cell phenotype that is Co(a-b-), In(b-), and LW(ab-) and not the In(Lu). Additional characteristics of CDA IV are : low or lack of expression of CD44 and AQP1, as well as low expression of BCAM and ICAM4. Some patients also have persistent expression of embryonic globins.

Inheritance of Inheritance of Congenital Congenital Dyserythropoietic Dyserythropoietic Anemia Type III and IV Anemia Type III and IV CDAN3 maps to chromosome 15q21. CDAN4 is caused by mutation in the KLF1 gene on chromosome 19p13.

A 13-month-old boy infant was referred with a course of fever of 15 days duration, GE, cytopenia and splenomegaly from Hamedan. He was born from a non-consanguineous parent with normal birth weight. Was admitted in Infectious department. Fever, cytopenia, splenomegaly was present. Preliminary w/o for infectious diseases were neg. EBV and CMV/PCR: Neg Serum Ferritin: 28900 ng/ml, TG: 303 mg/dl, Fibrinogen: Nl BMA and biopsy: many macrophages showing hemophagocytosis

He was diagnosed with HLH. Treatment with HLH-94 protocol was started along with IVIG. He got afebrile very soon in a few days. All parameters normalized within 2 weeks. He was discharged and genetic study was performed for the patient. A nonsense variant ( c.987T> G) in hemizygote state for XIAP gene ( Exon 4) on X-chromosome was detected as a mostly pathogen gene. He was diagnosed as XLP-2 syndrome.

oXLP1 is estimated to occur in about 1 per million males worldwide. oXLP2 is less common, occurring in about 1 per 5 million males.