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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2001-12-0351.
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Blood, 1 July 2002, Vol. 100, No. 1, pp. 356-358
BRIEF REPORT
Hydrops fetalis-associated congenital dyserythropoietic anemia
treated with intrauterine transfusions and bone marrow
transplantation
Angel F. Remacha,
Isabel Badell,
Núria Pujol-Moix,
Juan Parra,
Eduardo Muñiz-Diaz,
Gemma Ginovart,
M. Pilar Sardà,
Angel Hernández,
Elisenda Moliner, and
Montserrat Torrent
From the Departments of Hematology, Pediatrics,
Obstetrics, and Hemotherapy, Hospital Santa Creu i Sant Pau, Barcelona,
Spain.
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Abstract |
Hydrops fetalis is rarely caused by congenital dyserythropoietic
anemia (CDA). We report a patient with hydrops fetalis as a result of
severe anemia. This patient needed intrauterine transfusions from 21 weeks of gestation until birth. The hematologic study showed an
atypical CDA (hydrops fetalis-associated CDA) characterized by
features resembling CDA type II, but negative acidified serum lysis
test (HEMPAS negative). The patient was regularly transfused for a
year, after which an allogeneic bone marrow transplantation (BMT) from
an HLA-identical sibling was successfully carried out. His actual
hemoglobin is 127 g/L, and he has not received transfusions for more
than a year. In conclusion, intrauterine transfusions and BMT could
cure an otherwise lethal atypical CDA.
(Blood. 2002;100:356-358)
© 2002 by The American Society of Hematology.
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Introduction |
Congenital dyserythropoietic anemias (CDAs) are an
uncommon inherited cause of anemia characterized by ineffective
erythropoiesis with dysplastic morphologic features. The anemia is
usually mild to moderate in patients with CDA; however, it may be more
serious and require transfusions. Anemia is rarely very severe,
resulting in fatal hydrops fetalis.
Apart from the 3 classic types of CDA (CDA type I, II, and III) defined
by Heimpel and Wendt,1 a number of CDAs are
heterogenous and cannot be included in these types. At least 3 or
4 new categories have been proposed, designated as IV (CDA with
nonspecific erythroid dysplasia), V (congenital ineffective
erythropoiesis without significant dysplasia), VI (vitamin
B12- and folate-independent megaloblastic and dysplastic
erythropoiesis), and CDA with intraerythroblastic precipitation of a
nonglobin protein, although many cases remain to be classified in a
subgroup of CDA.2
Bone marrow transplantation (BMT) has been used to treat severe
congenital erythroid disorders such as major thalassemias or
hemoglobinopathies, and BMT is now considered as a potential curative
option for many patients with transfusion-dependent disorders.
We report on a patient with hydrops fetalis as a result of a
severe transfusion-dependent CDA who was successfully treated with a BMT.
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Study design |
Hematologic parameters were determined by standard procedures,
including blood cell counts, reticulocytes, iron, vitamin
B12, folate, haptoglobin, and so forth. Other causes of
dyserythropoiesis were ruled out after studying the propositus and his
parents. Accordingly, enzyme, membrane disorders,
thalassemia-hemoglobin disorders, and sideroblastic anemia were
excluded with the use of conventional methods and genetic molecular
studies ( and  thalassemia) in the propositus and his family.
Acidified serum lysis test (Ham test), sucrose lysis test, CD55 and
CD59 glycoprotein analyses, and laboratory tests for excluding fetal
isoimmunization were performed following routine methods.
For transmission electron microscopy, bone marrow cells were
fixed with glutaraldehyde in cacodylate buffer, postfixed with osmium
tetroxide, dehydrated in ethanol, and embedded in Epon 812. The
ultrathin sections were stained with uranyl acetate and lead citrate
and were examined at 80 Kv.
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Results and discussion |
The propositus was a Gypsy boy diagnosed with hydrops fetalis as a
result of severe anemia in the prenatal diagnosis unit during an
echographic control. His parents, who were cousins, showed apparently
normal hematologic values. He was the fourth pregnancy (2 live
brothers, one dead hydropic fetus, and the patient). During the
pregnancy, the patient needed 5 intrauterine transfusions from
diagnosis at 21 weeks of gestation (intrauterine hemoglobin, 16 g/L
with marked erythroblastosis) until birth at week 34 by cesarean
section (hemoglobin, 69 g/L). Intrauterine cytogenetic study showed 46 XY chromosomes without abnormalities. Intrauterine infections were
also excluded.
At birth his weight was 1915 g, and he showed pallor, jaundice
(maximal total bilirubin, 190 µmol/L at 4 days of life), and generalized edema. The patient required phototherapy, which was initiated at 24 hours (total bilirubin, 120 µmol/L), and mechanical ventilation during the newborn period.
In this period, an extensive study ruled out red cell enzyme, membrane,
hemoglobin, and thalassemic diseases. Tests for maternofetal isoimmunization were normal, and a bone marrow biopsy showed a normal
osteogenesis with erythroid hyperplasia, excluding an aplastic red cell
anemia. His red cells showed a normal agglutinability with anti-i
antibody, and an acidified serum lysis test was negative (HEMPAS
negative) in 3 samples and against 25 sera. At 3 months of life when
the immunohematologic study was carried out, his hemoglobin was 67 g/L,
mean corpuscular volume was 80 fL, platelets were
568 × 109/L, leucocytes were
10.2 × 109/L, including 10% of nucleated red cells, and
reticulocytes were 0.5% (0.013 × 1012/L). Red cell
morphology in peripheral blood showed scant binuclear erythroblasts
(2%) (Figure 1).
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| Figure 1.
Optical microscopy morphology of peripheral and bone marrow
hematopoiesis.
Binucleate erythroblast in peripheral blood (A). Erythroid hyperplasia
with marked abnormalities (binucleate, trinucleate, and multinucleate
late erythroblasts) (B,C,D). Abnormal erythroblasts showing anomalous
distribution of chromatin (C,D), binucleate erythroblasts, and isolated
trinuclear, tetranuclear (B), and aberrant multinuclear erythroblasts
(B,D). May-Grünwald-Giemsa stain. Original magnifications: A and
D, × 400; B, × 200; C, × 1000.
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At the age of 2 months a bone marrow examination showed erythroid
hyperplasia and markedly abnormal erythropoiesis (Figure 1), including
a substantial proportion of binuclear erythroblasts (20%) and a much
smaller proportion of trinuclear, tetranuclear, and multinuclear
erythroblasts (2%). Sideroblastic or megaloblastic anemias were ruled
out. Granulocytopoiesis and megakariocytopoiesis were normal.
Electron microscopic aberrations were more prominent in late
erythroblasts (Figure 2). The nuclear
outline was often undulated or lobulated, and the nuclear
membrane-associated heterochromatin was frequently absent over large
areas of the nuclear membrane. In some cells, the heterochromatin was
spongy and showed numerous "punched out" areas. The main
cytoplasmic anomaly was the presence of abundant cytoplasmic membranes
that are composed of excessive smooth endoplasmic reticulum. These
characteristic cisternae usually ran parallel beneath the cell outer
membrane producing the so-called "double membrane." The dilatation
of the space between the 2 layers of these cytoplasmic membranes was
frequently observed, as was the dilatation of the space of the nuclear
membrane.
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| Figure 2.
Electron micrographs of several bone marrow late
erythroblasts.
Multinucleate erythroblasts showing striking "double membranes"
with partial dilatation of the intramembranous space (A). Erythroblasts
revealing nondilated cisternae (B,C). Late erythroblast depicting
spongy heterochromatin with numerous "punched out" areas (B).
Binucleate erythroblasts showing large areas of nuclear membrane
without attached heterochromatin (C). Uranyl acetate and lead
citrate stain. Original magnification: A, × 10 600; B and C,
× 18 000).
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The patient was regularly transfused to maintain hemoglobin exceeding
80 g/L every 3 to 4 weeks for 1 year. During this year an extensive
examination did not show other dysmorphic features, and his development
was normal.
The patient had the main features of the atypical CDA, causing severe
transfusion-dependent anemia presenting as hydrops fetalis. Cantù-Rajnoldi et al3 reviewed the characteristics of
5 cases and suggested the name of "hydrops fetalis-associated
congenital dyserythropoietic anaemia." The hematologic findings are
very similar in all cases, including a CDA II-like erythroblast
morphology with a negative Ham test. Typically, the family history
revealed repeated abortions and consanguinity. All patients who have
survived are transfusion dependent.3
BMT is a potential curative treatment in patients with many hematologic
severe diseases, including erythroid disorders such as major
thalassemia, severe hemoglobinopathies, and so forth. The results are
excellent when the procedure was carried out as early as possible and
from an HLA-matched sibling. Thus, BMT is an alternative to regular
transfusions and chelation treatment.4 In this regard, a
BMT from his HLA-matched 12-year-old brother was carried out, although
at that time the literature did not contain reports of the results of
BMT in patients with CDA.
At the age of 13 months the BMT was carried out. The patient was
O, Rh (M), and the serology for
cytomegalovirus was positive. His 12-year-old brother was also O,
Rh (M+) and positive for cytomegalovirus.
Both boys were HLA identical (A, B, and DRB1). Donor blood counts were
normal (hemoglobin, 140 g/L; mean corpuscular volume, 86 fL; platelets,
220 × 109/L; and leucocytes, 5.9 × 109/L),
as was his bone marrow including erythroid cells.
The conditioning treatment was oral busulfan (16 mg/kg over 4 days) and intravenous cyclophosphamide (200 mg/kg over 4 days). Cyclosporine A was used for graft-versus-host disease prophylaxis until
day +30 in continuous infusion and after this date orally until 9 months after BMT. A total number of 7.7 × 108/kg
mononuclear cells or 16.7 × 106/kg CD34+
cells were infused on October 27, 2000. The hemopoietic reconstitution was observed on day +12 for neutrophils and on +29 for platelets.
The patient has not shown acute or chronic graft-versus-host disease
complications. As for transplant-related complications during the BMT
procedure, the propositus only showed transient arterial hypertension
related to cyclosporine and a respiratory tract infection without a
known microorganism.
A total chimerism was demonstrated by a DNA study from day +11 to day
+236. Mixed chimerism persists now at day +391 in T lymphocytes (58%
donor) and in granulocytes (52% donor). However, red blood cells
belong to the donor (M+), and the patient did not require
more transfusions since day +30. The patient is now 3 years old, his
current hemoglobin is 127 g/L, and he has not received red cell
transfusion for more than a year.
To our knowledge, this patient is the first in which a severe
transfusion-dependent CDA that caused hydrops fetalis has been treated
with intrauterine transfusions and BMT. This case raises the
possibility of a curative treatment for patients with this rare
disease. During the follow-up of our patient, a patient with a
classical CDA type II in association with beta-thalassemia trait and
severe iron overload was successfully treated with a BMT.5
| |
Footnotes |
Submitted December 28, 2001; accepted March 1, 2002.
Prepublished
online as Blood First Edition Paper, April 17, 2002;
DOI 10.1182/blood-2001-12-0351.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Angel F. Remacha, Department of Hematology,
Hospital de Sant Pau, Avinguda Padre Claret 167, Barcelona 08025, Spain.
| |
References |
1.
Heimpel H, Wendt F.
Congenital dyserythropoietic anemia with karyorrexis and multinuclearity of erythroblasts.
Helv Med Acta.
1968;34:103-112[Medline]
[Order article via Infotrieve].
2.
Wickramasinghe SN.
Dyserythropoiesis and congenital dyserythropoietic anaemias.
Br J Haematol.
1997;98:785-797[CrossRef][Medline]
[Order article via Infotrieve].
3.
Cantù-Rajnoldi A, Zanella A, Conter U, et al.
A severe transfusion-dependent congenital dyserythropoietic anaemia presenting as hydrops fetalis.
Br J Haematol.
1997;96:530-533[CrossRef][Medline]
[Order article via Infotrieve].
4.
Lucarelli G, Galimberti M, Giardini C, et al.
Bone marrow transplantation in thalassemia: the experience of Pesaro.
Ann N Y Acad Sci.
1998;850:270-275[CrossRef][Medline]
[Order article via Infotrieve].
5.
Iolascon A, Sabato V, de Mattia D, Locatelli F.
Bone marrow transplantation in a case of severe, type II congenital dyserythropoietic anaemia (CDA II).
Bone Marrow Transplant.
2001;27:213-215[CrossRef][Medline]
[Order article via Infotrieve].
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Abstract
Introduction