Eyrich and Schlegel contributed equally to this work.
Successful treatment of an infant with CDA type II by intrauterine transfusions and postnatal stem cell transplantation
Version of Record online: 3 OCT 2013
© 2013 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Pediatric Blood & Cancer
Volume 61, Issue 4, pages 743–745, April 2014
How to Cite
Braun, M., Wölfl, M., Wiegering, V., Winkler, B., Ertan, K., Bald, R., Schwarz, K., Heimpel, H., Eyrich, M. and Schlegel, P.G. (2014), Successful treatment of an infant with CDA type II by intrauterine transfusions and postnatal stem cell transplantation. Pediatr. Blood Cancer, 61: 743–745. doi: 10.1002/pbc.24786
Disclosure Statement: M.B. is a fellow of the Else-Kröner-Forschungskolleg Würzburg for Translational Immunology. The other authors declare no competing financial interests.
Conflict of Interest: Nothing to Report.
- Issue online: 6 FEB 2014
- Version of Record online: 3 OCT 2013
- Manuscript Accepted: 26 AUG 2013
- Manuscript Received: 15 MAY 2013
- congenital dyserythropoietic anemia type II;
- fetal hydrops;
- unrelated HSCT
Congenital dyserythropoietic anemias are rare hematological disorders leading to ineffective erythropoiesis with chronic anemia, complicated by iron overload. Here we present a remarkable clinical course of an infant with CDA type II who first presented as a severe fetal hydrops, requiring serial intrauterine red cell transfusions. While postnatal transfusion dependency persisted, the patient was successfully transplanted with a myeloablative conditioning regimen and peripheral blood stem cells of a matched donor. We believe that allogeneic HSCT is a reasonable therapeutic approach for patients with very severe CDA, even if only a matched unrelated donor is available. Pediatr Blood Cancer 2014;61:743–745. © 2013 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.
congenital dyserythropoietic anemia
hematopoeietic stem cell transplantation
Congenital dyserythropoietic anemias (CDA) are rare inherited hematological disorders characterized by an ineffective erythropoiesis leading to a variable degree of persistent anemia. In 1968, one of the authors, Heimpel and Wendt , described a classification of three main types, which is still in use today. The three types differ in their morphological findings of the dyserythropoiesis in the respective bone marrow aspirates and in their clinical presentation. For CDA type I, approximately 150 cases have been reported, for type II more than 300 cases are known, type III is rare and shows autosomal dominant inheritance [2, 3].
Patients with CDA type II present with hemoglobin level between 8 and 11 g/dl, jaundice and splenomegaly. Approximately 8–10% of patients with CDA type II require red cell transfusions [2, 3]. Most of the patients, even those without the need for red cell transfusions develop iron overload throughout their life-time , thus requiring phlebotomy or chelation therapy to minimize organ damage. Though CDA II can become symptomatic early in childhood, antenatal anemia manifesting itself as fetal hydrops has only rarely been reported [3-6].
We describe a patient who had been diagnosed with fetal hydrops and cardiomegaly at 20 + 0th weeks gestational age. At this time her hemoglobin was 1.5 mg/dl, requiring emergency intrauterine blood transfusion. Her condition was stabilized by serial intrauterine blood transfusions (intervals one to maximum 4 weeks, 8 transfusions total), the last of which was performed 9 days before birth. She was born at 33 + 5th gestational age by elective caesarean section. No history of anemia, or consanguinity was present within the German family. The period of postnatal adaptation was uneventful; WBC and platelet counts were unremarkable at all times, but reticulocyte count was continuously inadequate compared to the degree of the anemia (Table I). Hemolytic anemias as well as infections or rare hematological disorders, for example, Fanconi Anemia were ruled out; additional investigations directed towards hemoglobinopathies or membrane defects were unremarkable. Meanwhile transfusion dependency persisted. Bone marrow aspiration at the age of 6 and again at 9 months showed typical findings of CDA type II (1). Genetic analysis revealed a heterozygous mutation of SEC23B gene (exon 4: c.325G > A p.Glu109Lys); a second SEC23B mutation was not detected. Due to the severe clinical course, allogeneic HSCT as a potential curative approach was discussed with the parents, and, since no sibling donor was available, a HLA-matched unrelated donor (10/10 loci) was selected.
|Age||Birth||12 weeks||7 Months||11 Months (prior to transplant)||17 Months (6 months after transplant)||29 Months (18 months after transplant)|
|Reticulocyte (% of total RBC count)||1.7||1.7||0.6||2.1||1.7|
|Total bilirubin (mg/dl)||5.4||n.a.||1.0||1.2||0.2||0.3|
|Cumulative number of red cell transfusions||8||13||16||18|
|Donor chimerism (% donor cells)||100||100|
Except for the hematological system the pre-transplant evaluation showed no relevant pathological findings, especially no signs of organ damage due to iron overload. Laboratory findings showed an elevated ferritin serum value (404 µg/L) and a transferrin saturation of 87%. HSCT was performed at the age of 11 months. The conditioning regimen consisted of busulfan (4 × 1 mg/kg/day i.v. × 4 days, day −8 until −5), cyclophosphamide (60 mg/kg/day × 2 days, day −4,−3), melphalan (100 mg/m2 on day −2). GvHD-prophylaxis comprised of ATG (antithymocyte globulin, rabbit, 10 mg/kg/day × 3 days, day −3 to −1), CSA starting on day −3 and methotrexate (10 mg/m2/day) on days +1 and +3. The girl was transplanted with G-CSF-mobilized PBSC. The graft contained 6.1 × 108 WBC/kg, 6.55 × 106 CD34+ cells/kg and 3.2 × 108 CD3+ T-cells/kg. Engraftment (ANC > 500/µl) was achieved on day +22, hemoglobin levels started to increase on day +20. The patient could be discharged on day +28 without any signs of GvHD.
With a follow-up of 24 months post-transplant, our patient is alive and well and shows normal neurological development. Hemoglobin levels and reticulocyte counts are within normal range (Table I). Subsequent bone marrow aspirates confirmed full donor chimerism with normal hematopoiesis in all three lineages.
We describe a female patient with CDA type II, who presented with fetal hydrops and was successfully treated by serial intrauterine transfusions followed by postnatal transplantation from an unrelated donor. There have been only few reports on HSCT in CDA of all three subtypes [4, 6-11], seven out of nine were matched sibling donor transplantations, one was haploidentical . In the group of patients with CDA type II, only three patients are reported to have undergone allogeneic HSCT thus far. Of these, only one received a graft from a matched unrelated donor . In the previous report the authors had used a modified Pesaro “protocol 26,” originally intended for patients with high risk thalassemia . Their regimen was chosen due to the already existing end organ damage caused by iron overload. The protocol we chose is in use for HSCT in patients with inborn errors of metabolism or immunodeficiencies. With this myeloablative regimen our patient experienced little toxicity and engrafted well.
Genetic analysis revealed a heterozygous SEC23B mutation (c.325G > A), which has been identified as one of the more frequent mutations causing CDA type II. This mutation leads to a missense codon and is present in around 30% of patients with CDAII . A heterozygous state for SEC23B mutations is seen in approximately 10–15% [13, 14]. How heterozygosity can be reconciled with the severe clinical course of our patient still remains an open question. RNA analysis of pretransplant peripheral blood leukocytes revealed a heterozygous status with both alleles being expressed at about the same level, which makes a DNA deletion or regulatory defect of the wildtype allele in these cell populations highly unlikely. Peripheral blood genomic DNA analysis of the parents showed a wildtype sequence of the complete paternal SEC23B gene, while the mother had the same heterozygous mutation of SEC23B as our patient, despite having never had a history of anemia. There are several possible explanations: although more theoretical, there could be a uniparenteral disomy of the maternal allele or an epigenetic regulatory defect of the fathers SEC23B allele only present in erythroid precursors. More likely, there are yet unidentified mutations or epigenetic alterations in (a) SEC23B unrelated gene(s) associated with dyserythropoiesis, which lead to aggravation of the CDAII phenotype. The apparent discrepancy between the mothers phenotype, having no anemia as well as a mild to moderate anemia in known patients with CDAII with the heterozygous mutation of c.325G>A and the severe phenotype of our patient show that the molecular pathogenesis of CDAII is at least in some cases more complex than known to date.
However, the positive outcome of this case is remarkable, as fetal hydrops by itself is a life threatening condition often leading to intrauterine death. While treatment with intrauterine transfusions for patients with fetal hydrops due to for example, rhesus incompatibility is eventually curative, patients with dyserythropoiesis and a severe clinical phenotype require a red cell transfusion program, eventually leading to iron overload and organ damage. Considering that transplantation related mortality in children has decreased significantly particularly when using a matched unrelated donor [15, 16], HSCT may be a therapeutic option for severe clinical CDA. Furthermore, if no sibling donor is available, a matched unrelated donor may represent a reasonable alternative.
M.B. wrote the manuscript, M.B., M.W., B.W., M.E. and P.G.S. were considerably involved during the HSCT and follow up and reviewed the manuscript, K.E. and R.B. conducted the intrauterine transfusions, K.S. and V.W. performed the genetic analysis, K.S. helped interpreting the genetic analysis, H.H. did the reference assessment for the bone marrow aspirates and reviewed the manuscript.
CDA-UPN 0298/01 in the German CDA Registry.