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540 Part VI: The Erythrocyte Chapter 36: Pure Red Cell Aplasia 541

CLINICAL FEATURES Red cell transfusions should be leukocyte depleted to avoid allo-
Approximately one-third of patients are diagnosed at birth or within immunization (see Chap. 138). Erythrocytes are administered with the
a few weeks of delivery, and almost all are identified within the first goal of eliminating symptoms and permitting normal growth and sex-
year of life. Considerable variations are noted with regard to sever- ual development, usually achieved by maintaining hemoglobin levels
31
ity of phenotype, ranging from hydrops fetalis 32,33 to presentation in between 7 and 9 g/dL (70 to 90 g/L). 43
adulthood, when diagnosis is inferred from associated physical anom- Glucocorticoids are effective in many patients. Although the
alies. No sex predominance exists. Increased rates of prematurity in mechanism of action of glucocorticoids in this disease is not under-
5,34
patients and of miscarriages in families have been inferred from col- stood, their toxicities are substantial, and a response is not predictable.
lected cases. Symptoms of anemia in early childhood include pallor, Once the diagnosis is established, prednisone is administered orally at 2
35
35,44,45
apathy, poor appetite, and “failure to thrive.” Physical anomalies occur mg/kg daily in three or four divided doses. A reticulocyte response
in about a third of cases; most frequent is craniofacial dysmorphism, is seen in the majority of patients 1 to 4 weeks later, followed by a rise in
the classic appearance described by Cathie is “tow-colored hair, snub hemoglobin level. Once the hemoglobin level reaches 9 to 10 g/dL (90 to
36
nose, wide set eyes, thick upper lips, and an intelligent expression.” Mal- 100 g/L), very slow reduction of the glucocorticoid dose is undertaken
formations of the thumbs and short stature are frequent, followed by by decreasing the number of daily doses. When a single daily dose is
abnormalities of the urogenital system, web neck, and skeletal and car- achieved, an alternate-day schedule is adopted. In general, severe ane-
diac defects. 11,31,37 These physical anomalies are less prevalent than the mia can be avoided with continued glucocorticoid administration. The
abnormalities seen in Fanconi anemia (FA). maintenance dose may be low (1 to 2 mg/day). Some patients may toler-
ate complete withdrawal of prednisone, but relapse is frequent and most
responders become glucocorticoid dependent. A variety of patterns
LABORATORY FEATURES of response have been described, ranging from prompt recovery and
35
The degree of anemia is highly variable at diagnosis. Erythrocytes may apparent cure to refractoriness after a long period of responsiveness.
be macrocytic or normocytic. Reticulocytopenia is profound. The mar- Conversely, a second trial of glucocorticoids years after an apparent
row, which usually is devoid of red blood cell precursors, may show therapeutic failure may be successful. In a series of 76 patients followed
small numbers of megaloblastoid early erythroid cells with apparent for many years, 59 were treated with prednisone; 31 initially responded,
44
“maturation arrest.” Platelets are normal or elevated. Leukocytes may be and two of the 25 who initially failed later responded. Glucocorticoid
normal or slightly decreased at presentation. Neutrophils often decline responsiveness is strongly associated with better survival, and patients
with age, and in adult survivors neutropenia occasionally is severe who require low doses of prednisone, or those few who spontaneously
enough to predispose to fatal infection. 38 remit, may have normal life expectancies. Long-term use of high-dose
Erythrocyte adenosine deaminase level is elevated in approxi- prednisone results in significant toxicity, including some combination
mately 75 percent of patients but also may be increased in other aregen- of growth retardation, cushingoid facies, buffalo hump, osteoporosis,
erative anemias of childhood. Serum erythropoietin level, serum iron aseptic necrosis of the hip and fractures, diabetes, hypertension, and
39
level, and total iron-binding capacity are high. Ferritin level increases as cataracts. Red cell transfusions with iron chelation may be preferable to
patients receive multiple transfusions and develop iron overload if they such an outcome.
are not treated with chelation therapy. Allogeneic stem cell marrow transplantation, when successful, is
curative (Chap. 23), but the procedure has not been widely applied to
DIFFERENTIAL DIAGNOSIS children responding to medical measures. The median life expectancy

The characteristic triad consists of the clinical diagnostic features of ane- of patients requiring transfusions and iron chelation is 30 to 40 years.
mia, reticulocytopenia, and a paucity or absence of erythroid precur- A less-favorable outcome is related to poor compliance and cardiac
46
sors in the marrow. These findings may be supplemented by increased and hepatic disease from iron overload. Because of the morbidity and
activity of red cell adenosine deaminase and ribosomal gene mutation mortality associated with allogeneic stem cell transplant, most patients
analysis. FA can be excluded by cytogenetic analyses under clastogenic have been transplanted late in their disease course, after large numbers
stress and determination of FA gene mutations (Chap. 35). Transient of transfusions, accumulation of heavy iron loads, and alloimmuniza-
erythroblastopenia of childhood, which unusually occurs in the first tion. Despite the poor predictive factors, 15 of 19 patients of the first
year of life, is established by spontaneous recovery. When presentation published series of cases survived 5 months to many years posttrans-
47
37
occurs at older ages, the distinction between inherited and acquired plant. Comparable survival rates have been reported from European
48
aplastic anemia can be difficult : family history, physical anomalies, and and Japanese registries. Stem cell transplantation from unrelated stem
40
47,49
characteristic cytogenetic enzymatic, or genetic findings implicate and cell donors or use of cord blood stem cells has been less successful.
indicate an inherited disorder. Recurrent red cell aplasia despite full engraftment was reported in one
child after transplantation. 50
Other therapies have not gained wide acceptance despite prom-
THERAPY, COURSE, AND PROGNOSIS ising pilot studies, including interleukin-3 (IL-3), high-dose methyl-
51
Untreated inherited pure red cell aplasia is fatal; death results from severe prednisolone, cyclosporine and other immunosuppressive agents, 53,54
52
55
anemia and congestive heart failure. Transfusions, glucocorticoids, and and prolactin induction by metoclopropamide. Leucine, which is
56
9,41
allogeneic stem cell transplantation are of proven efficacy. Predictors effective in animal models, is in clinical trials.
of glucocorticoid administration in glucocorticoid responsive patients With better survival, the risk of late development of leukemia has
include older age at presentation, a family history, and a normal platelet become apparent. 14,43 Four of 76 patients followed at Children’s Hospital
count. Younger age at presentation and premature birth correlate with in Boston died of acute myelogenous leukemia, with a calculated rela-
continued red cell transfusion dependence. Supportive care consists tive risk of greater than 200 times expected. 44
42
of red cell transfusions. To avoid transfusional hemosiderosis, chelation Gene transfer in vitro has functionally corrected cells defective in
57
with desferrioxamine should be initiated early (Chap. 43). Injury to vis- RSP19, and in animal models corrected cells show improved erythro-
ceral organs from iron overload has been a major cause of death in the poiesis and a survival advantage in vivo offering the possibility of gene
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past. therapy.
Kaushansky_chapter 36_p0539-0548.indd 540 9/17/15 6:15 PM