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CHAPTER 36 Gasser first reported a response of a patient to glucocorticoids in 1951,
3
and Diamond and associates presented a series of treated patients.
4
PURE RED CELL APLASIA Genetic linkage studies have identified etiologic mutations in ribosomal
protein genes. Hundreds of cases have been reported, and many
5–9
10
excellent reviews have been published. Although Joseph was the first
to describe the disorder, the anemia invariably is referred to as either
Neal S. Young Blackfan-Diamond or Diamond-Blackfan anemia.
ETIOLOGY AND PATHOGENESIS
SUMMARY An annual incidence of 5 cases per 1 million livebirths has been esti-
mated from registry data. Well-characterized pedigrees are consistent
11
Pure red cell aplasia is the diagnosis applied to isolated anemia secondary with an autosomal dominant or, less often, recessive inheritance pat-
to failure of erythropoiesis. Cardinal findings are a low hemoglobin level tern. Sporadic cases are seen most frequently. Retrospective studies may
combined with reticulocytopenia and absent or extremely infrequent mar- reveal subtle hematologic or biochemical lesions, or an abnormal gene,
row erythroid precursor. Historical names for pure red cell aplasia include in an affected parent or another relative without clinical anemia. 12
erythroblast hypoplasia, erythroblastopenia, red cell agenesis, hypoplastic ane- Recent genetic studies have led to the characterization of
mia, and aregenerative anemia. Aplastic anemia confers the same meaning, Diamond-Blackfan anemia as a disease of ribosomal biogenesis. 5–7,13,14
of course, but is applied to pancytopenia and an empty marrow (Chap. 35). Linkage analyses of several dozen European families mapped to a site on
15
Pure red cell aplasia was first separated from aplastic anemia by Kaznelson chromosome 19q13 and the finding of a translocation in one individ-
ual allowed cloning of the ribosomal protein S19 (RPS19) gene, which
in 1922. The association of red cell aplasia and thymoma interested physi- encodes a protein involved in ribosome assembly. Most mutations
5–9
cians in the 1930s and ultimately led to laboratory studies linking pure red are whole gene deletions, translocations or truncations; this pattern
cell aplasia to immune mechanisms, including the early identification of suggests a mechanism of haploinsufficiency, and RPS19 behaves as a
antierythroid precursor cell antibodies by Krantz and later characterization dominant gene. (Disruption of both copies of the gene in the mouse
16
of T cells that inhibited erythropoiesis. Red cell aplasia as an acute and life- prevents implantation. ) RPS19 mutations occur in approximately 25
17
threatening complication of sickle cell disease and other hemolytic anemias was percent of patients with inherited red cell aplasia 16,18 ; and mutations sub-
recognized in the 1940s, presaging the role of a specific virus in the etiology of sequently have been identified in multiple other ribosomal biogenesis
both acute and chronic erythropoietic failure. Despite its infrequency, pure red genes (RPS10, RPS26 particularly) in other cases. 16,19,20 More recently, a
cell aplasia has been a subject of much laboratory research because of its link globin transcription factor 1 (GATA1) gene mutation was identified in a
to an immune mechanism of erythropoietic failure and as a manifestation of Diamond-Blackfan kindred, implicating a signal transduction pathway
21
parvovirus B19 infection and viral destruction of red cell progenitors. However, of erythroid differentiation as also causative of the syndrome. Experi-
ments have implicated RPS14 in one of the myelodysplastic syndromes
because of its infrequency, pure red cell aplasia has not been the subject of large characterized by loss of 5q. 22
or controlled clinical trials; as a result, therapeutic recommendations are based Precisely how defects in ribosomal protein genes cause consti-
on single cases or small series. Table 36–1 lists a practical classification of pure tutional red cell aplasia is uncertain. Historically, Diamond-Blackfan
red cell aplasia. anemia has been characterized by diminished erythroid progenitor cell
numbers (colony forming unit–erythroid [CFU-E] and burst-forming
unit–erythroid [BFU-E]). 23,24 In cell culture, early, erythropoietin-
independent erythropoiesis is relatively normal; the major defect is in
INHERITED PURE RED CELL APLASIA the late stage of erythropoietin-dependent erythroid cell expansion and
25
(DIAMOND-BLACKFAN ANEMIA) maturation. A defect in late erythroid differentiation is compatible
with the classic findings of macrocytosis and increased hemoglobin F
DEFINITION AND HISTORY expression in inherited red cell aplasia. Granulopoiesis in the colony-
forming unit–granulocyte-macrophage assay and the earlier hemato-
Anemia in infancy and early childhood associated with absent reticu- poietic progenitors as measured in vitro by long-term culture-initiating
locytes in the blood and erythroid precursor cells in the marrow was cell assay (an assay for an early multipotential hematopoietic progeni-
described by Joseph in 1936 as a “failure of erythropoiesis” and by tor) frequently are abnormal, but to a lesser degree than are CFU-E and
1
Diamond and Blackfan in 1938 as “congenital hypoplastic anemia.” BFU-E. In a zebrafish model, deficiency of rps19 in early embryogen-
2
26
esis caused a decrease in erythrocytes and also physical anomalies. In
27
tissue culture experiments, silencing of RPS19 profoundly affects ery-
thropoietic differentiation and, to lesser degrees, myelopoiesis. 28,29 Both
Acronyms and Abbreviations: B19, primate erythroparvovirus 1; BFU-E, burst- in vivo and in vitro models have implicated accumulation in the cell
forming unit–erythroid; CD20, a cluster of differentiation molecule expressed on of free ribosomal proteins, which modulates the inhibitory activity of
the surface of all mature B cells; CFU-E, colony-forming unit–erythroid; CLL, chronic regulators of tumor protein p53, leading to p53 stabilization and apop-
lymphocytic leukemia; FA, Fanconi anemia; GATA1 gene, globin transcription factor tosis. The specificity of this molecular defect for the erythroid pathway
30
1; HLA, human leukocyte antigen; Ig, immunoglobulin; IL, interleukin; LGL, large may be a result of the extreme requirement of red cell progenitors and
granular lymphocytic leukemia; RPS14 and RPS19 genes, ribosomal protein S14 and precursors for ribosome biogenesis.
S19 genes; STAT3 gene, signal transducer and activator of transcription 3 gene; T cell, Despite responsiveness of patients to glucocorticoids, there is lit-
thymus-derived lymphocyte. tle evidence of an immune mechanism, cellular or humoral, underlying
inherited red cell aplasia.

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