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384 Part IV Disorders of Hematopoietic Cell Development

appears to be autosomal recessive in some cases but possibly autoso- differ from CDA by the presence of marked microcytosis with elevated
mal dominant or X-linked in others. In CDA group V, the BM levels of hemoglobin A 2, HbF, or both.
macrophages engulf morphologically normal but functionally abnor-
mal erythroblasts.
Therapy and Prognosis
CDA Group VI. This group is characterized by marked macrocytosis
(MCV 119–125 fL) with little or no anemia and grossly megaloblas- In general, the CDAs are associated with a favorable long-term
tic erythropoiesis. There may be mild jaundice and an increased prognosis. For example, CDA I can be diagnosed late in life. One
serum bilirubin. The differential diagnosis includes orotic aciduria reported case was associated with a relatively benign course over a
and thiamine-responsive anemia. Vitamin B 12 and RBC folate levels 30-year follow-up. Clinical manifestations of the CDAs may include
are normal. intermittent jaundice and dark urine caused by increased hemoglobin
catabolism or signs and symptoms of anemia. Rarely, hyperbilirubi-
CDA Group VII. These patients have severe transfusion-dependent nemia without anemia may be the initial presentation of CDA
anemia from birth, marked erythroid hyperplasia, normoblastic or patients. Cholelithiasis may be present as a consequence of chronic
nonspecific dysplastic changes, markedly abnormal nuclear shapes in hyperbilirubinemia.
many erythroblasts, and intraerythroblastic inclusions resembling Anemia is typically mild in most cases of CDA and requires no
precipitated α-globin chains. The inclusions do not react with intervention, but in more severe presentations, especially those
monoclonal antibodies against α- and β-globin chains. The diagnosis requiring transfusional support, splenectomy may be beneficial. Most
requires the exclusion of β-thalassemia trait in the parents. of the experience showing an improvement in hemoglobin levels after
splenectomy has been in CDA II; the benefit of splenectomy in CDA
Unclassified CDA Cases I is less clear. Splenectomy may cause a persistent thrombocytosis in
Unclassifiable cases of CDA have been reported with lifelong anemia CDA types I and II and contribute to the development of Budd-
that was probably inherited. These cases were characterized by marked Chiari syndrome and portal vein thrombosis.
aniso- and poikilocytosis and occasional teardrop and fragmented Treatment of all forms of CDA with androgens, corticosteroids,
erythrocytes in the peripheral blood. Hyperplastic BM showed mega- vitamin E, vitamin B 12 , folic acid, pyridoxine, or iron is ineffective
loblastoid features without multinuclearity or ringed sideroblasts, but in ameliorating the anemia. Iron therapy is also contraindicated
a case with prominent ringed sideroblasts was also described. Unlike because of the underlying propensity for hemosiderosis secondary to
classical CDA, neutropenia or thrombocytopenia has been observed ineffective erythropoiesis, transfusional iron overload, increased gut
in some of these patients. Cytogenetic studies of BM revealed no iron absorption, and downregulation of the primary regulator of iron
clonal chromosomal abnormalities. Reticulocyte response to anemia absorption, hepcidin. Even if regular RBC transfusions are not initi-
was absent or inappropriately low in all. Most studies of parents failed ated, patients should be routinely monitored for evidence of iron
to reveal abnormalities, suggesting an autosomal recessive mode of overload. Iron chelation with daily subcutaneous infusions of defer-
transmission. oxamine (Desferal) has been underused in CDA even though deaths
have been recorded from hemochromatosis. The value of the oral iron
Variant CDAs Associated With Specific Gene Mutations chelator deferasirox (Exjade) has not been defined yet for the CDAs.
GATA1 is a transcription factor closely linked with erythropoiesis and Phlebotomy has been carried out to remove iron in selected CDA
megakaryopoiesis. The Val205Met mutation in the GATA1 gene patients, but this could result in a worsening of the anemia and theo-
underlies a CDA with dyserythropoiesis and thrombocytopenia. retically enhance gut iron absorption. An additional concern is that
The KLF1 gene encodes an erythroid transcription factor. A CDA patients seem predisposed to hepatic cirrhosis irrespective of
specific mutation of KLF1 produced a severe form of CDA with body iron burden. The pathogenesis of this is unclear.
basophilic stippling of polychromatic erythroblasts and erythrocytes, Interferon-α-2a or INF-α-2b therapy given two or three times a
marked abnormalities of nuclear shape, and increased expression of week or peg-INF-α-2a once a week, increase hemoglobin levels and
embryonic and HbF. decrease iron overload in most patients with CDA I who require
A case of hereditary cryostomatocytosis and dyserythropoiesis was repeated transfusions for moderately severe anemia. Erythrokinetic
caused by a de novo erythroid anion exchanger band 3 mutation. studies demonstrate a striking reduction of ineffective erythropoiesis
The BM morphology showed dyserythropoiesis characteristic of in patients receiving INF, and electron microscopy shows a reduction
CDA I and CDA II. in nuclear structural abnormalities. INF therapy should also be
Mutant MVK resulted in mevalonate kinase deficiency, dyseryth- considered in moderately anemic CDA I patients before treatment of
ropoietic anemia, and BM findings similar to those in CDA II. iron overload with phlebotomy. Patients with CDA II do not respond
A syndrome of dyserythropoietic anemia, exocrine pancreatic to INF-α.
insufficiency, and calvarial hyperostosis was caused by a mutation in Hematopoietic stem cell transplantation has been curative in a few
COX412, a gene highly expressed in BM. severe cases of CDA, including transfusion-dependent CDA type I,
CDA type II, Ham test–negative “CDA type II,” and an unclassifi-
able CDA.
Differential Diagnosis Asymptomatic extramedullary hematopoiesis may mimic tumors
of the mediastinum, abdomen, and vertebral column. Because of the
Marrow erythroblast multinuclearity is seen with other hematologic increased RBC production that occurs, the development of sites of
disorders, but these can be readily distinguished from CDA. The extramedullary hematopoiesis may result in an amelioration of the
megaloblastic anemias have a different clinical presentation and are degree of anemia. Technetium-99m sulfur colloid scintigraphy is
identified in the laboratory by the presence of hypersegmented useful in delineating the extent of these regions.
neutrophils, decreased RBC folate values, or reduced serum levels of
vitamin B 12. The MDS may manifest as an isolated refractory anemia,
but they often present with bi- or trilineage cytopenias that contrast Future Directions
sharply with CDA. The MDS subsets may also show BM granulocytic
and megakaryocytic morphologic abnormalities, the presence of Identification of the various mutant genes for the CDA types will
myeloblasts, ringed sideroblasts, and clonal cytogenetic changes. facilitate a more precise classification than the phenotype-based
Erythroleukemia (AML, M6) is another cause of marked dyseryth- system used currently. The wild-type protein product of the CDA
ropoiesis, but typically there is pancytopenia, the erythroblasts are genes requires further research to clarify their function in health and
avidly positive for the periodic acid–Schiff stain, and the BM cells their role in producing CDA when mutated. Strategies are required
may show a clonal cytogenetic marker. The β-thalassemia syndromes for managing iron overload similar to those for DBA and thalassemia