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566 Part VI: The Erythrocyte Chapter 39: The Congenital Dyserythropoietic Anemias 567

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which is absent on normal cells. Thus, the acronym HEMPAS (hemo- (Boyadjiev-Jabs syndrome). The specificity of the CDA II phenotype
lytic anemia with a positive acidified serum test) is commonly used as seems to be determined by tissue-specific expression of SEC23B versus
39
a synonym for CDA II. The technical difficulty of this test, and the fact SEC23A during erythroid differentiation. Alternatively, this specific-
that cross-testing of more than 30 normal sera is needed to obtain a ity could be explained by the presence of tissue-specific proteins (such
reliable result, has undermined its usefulness. 34 as band 3 in red blood cells) which might require high levels and full
The clinical picture of CDA II includes hemolytic anemia with mar- function of a specific COPII component to be correctly transported. 42,45
row erythroid expansion, commonly with splenomegaly, hepatomegaly, So far, more than 60 different causative mutations have been
2,8
intermittent jaundice, and cholelithiasis. 30,31 The blood film exhibits described worldwide. A genotype–phenotype correlation seems to
moderate to marked anisocytosis and anisochromia and a number of exist. Particularly, compound heterozygosity for missense and non-
spherocytes. This, along with the patient’s clinical appearance, may sense mutations tends to produce more severe clinical presentations
lead to confusion of CDA II with hereditary spherocytosis (HS; than homozygosity or compound heterozygosity for two missense
Chap. 46). However, typically in HS, the reticulocyte count in com- mutations. Homozygosity or compound heterozygosity for two non-
46
parison to hemoglobin level is higher and the serum transferrin recep- sense mutations has not been reported, suggesting it may be lethal.
tor level is lower. Moreover, the majority of HS cases are inherited as Sec23b-deficient mice (Sec23b gt/gt) have been generated and are born
autosomal dominant and, thus, a parent is likely to have findings of without anemia but die shortly after birth, with degeneration of secre-
spherocytosis on blood examination, whereas CDA II is invariably an tory organs, including the pancreas and salivary glands. 47
autosomal recessive condition. Despite these differentiating features, The disparate phenotypes in mouse and human could result from
CDA II is at times only diagnosed after the failure of splenectomy to residual SEC23B function associated with the hypomorphic mutations
normalize anemia when performed for suspected HS. In the marrow, observed in humans, or, alternatively, might be explained by species-
10 to 30 percent of intermediate and late erythroblasts have two or more specific functional differences. 48
nuclei or lobulated nuclei (see Fig. 39–2A). Karyorrhexis (fragmenta-
tion of the nucleus) is common. Gaucher-like cells may develop as a TREATMENT, COURSE, AND PROGNOSIS
result of phagocytosis of erythroblasts by macrophages. Ringed side- The clinical course of this condition is quite heterogeneous. Treatment
12
roblasts are present in severe forms. Electron microscopy shows struc- approaches depend on age, severity of phenotype and comorbidity.
tures that have been misnamed as “double membrane” (see Fig. 39–2B). Most patients have only mild or moderate anemia and do not require
These are cisternae of the endoplasmic reticulum (ER) that run along medical intervention. Approximately 10 percent of neonates need at
the red cell plasma membrane inner surface, and which contain ER-spe- least one erythrocyte transfusion, and some remain transfusion-depen-
35
cific proteins, as shown by immunochemistry labeling. Sodium dode- dent. In most adolescents and adults, transfusional needs are limited
8,31
cylsulfate polyacrylamide gel electrophoresis (SDS-PAGE), followed by to aplastic crises, pregnancy, coexistent infections, or major operations.
immunoblots, reveals the presence of calreticulin, glucose-regulated The more common, moderate forms may only be diagnosed
protein 78, and disulfide isomerase; these are specific for the ER and are in adult life because of iron overload (Chap. 43) that is consistently
not detected in normal individuals. 35 observed even in the absence of transfusions. 2,8,49 Patients with severe
The diagnostic hallmark of CDA II is analysis of erythrocyte mem- forms of CDA II may be transfusion-dependent. In some cases, severe
brane proteins by SDS-PAGE identifying narrower band size and faster phenotypes could be the result of additional genetic abnormalities, such
migration of erythrocyte anion transporters (AE1 or band 3) and band as coinheritance of glucose-6-phosphate dehydrogenase (G6PD) defi-
4.5 proteins. 36,37 Increased destruction of red blood cells in CDA II ciency or thalassemic trait. 50
is associated with hypoglycosylation of AE1, which causes clustering The iron overload is associated with high levels of growth differ-
of this protein on the red cell surface and contributes to erythrocyte entiation factor 15 (GDF15). However, GDF15 concentrations are sig-
51
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destruction in the spleen. Rare patients have been reported without nificantly lower in CDA II compared to CDA I patients, despite a similar
this characteristic SDS-PAGE pattern; it is recommended that these degree of iron overload in both patient groups. It can be speculated that
should be classified as CDA II–like conditions. additional signals may determine hepatic hepcidin expression and the
degree of iron overload in CDA II. 51
Ferritin levels should be controlled at least annually, even in
GENETICS patients with only mild anemia. Achievement of normal ferritin con-
Pathognomonic hypoglycosylation of AE1 protein is the outcome of the centrations is desirable. Iron chelation should be instituted when
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expression of the mutated gene SEC23B. 39 ferritin level exceeds 500 to 1000 cg/L (Chap. 43). If phlebotomies are
Sequencing analysis in 33 patients from 28 unrelated families tolerated, this is the preferred treatment. In instances where the patient
showed heterogeneous mutations in the SEC23B gene, either in com- cannot tolerate phlebotomy, chelating agents may be used.
pound heterozygous or homozygous states. 2,8,39 An in vitro model of Cholelithiasis and splenomegaly are common complications.
gene silencing demonstrated that suppression of SEC23B expression Coinheritance of the UGT1A (TA)7/(TA)7 genotype could account
recapitulates the cellular defects in SEC23B-silenced cells. Knockdown for the increased rate of gallstones. Cholelithiasis, which is frequent
39
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of zebrafish SEC23B also leads to aberrant erythrocyte development. 39 in all types of CDA, may require cholecystectomy; decision making
SEC23B is a cytoplasmic coat protein (COP) II component should follow therapy guidelines for cholelithiasis. Splenectomy is not
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involved in the secretory pathway of eukaryotic cells. COPII is a mul- universally recommended for CDA II or CDA I; individual decisions
tisubunit complex essential for transport of correctly folded proteins should be influenced by transfusion dependency and the presence of
from the ER toward the Golgi apparatus. This pathway is critical for a massively enlarged spleen. Generally accepted criteria for splenec-
40
membrane homeostasis, localization of proteins within cells and secre- tomy have not been defined. Splenectomy leads to a moderate, sus-
tion of extracellular factors. 40,41 tained increase in hemoglobin concentrations and decrease of serum
CDA II belongs to COPII-related human genetic disorders. bilirubin levels, but it does not prevent iron overload, and hemoglo-
42
Alterations in SAR1B, a paralogue of SEC23B, are identified as the cause bin levels postsplenectomy generally do not reach normal values. In
5,6
of chylomicron retention disease (Anderson disease), while a specific non–transfusion-dependent patients, it is advisable to follow the guide-
43
mutation in the SEC23A gene causes craniolenticulosutural dysplasia lines for mild cases of HS. 54

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