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Diamond Blackfan disease

Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy. DBA patients have low red blood cell counts (anemia). The rest of their blood cells (the platelets and the white blood cells) are normal. A variety of other congenital abnormalities may also occur. more...

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Clinical Features

Diamond-Blackfan anemia is characterized by anemia (low red blood cell counts) with decreased erythroid progenitors in the bone marrow. This usually develops during the neonatal period. About 47% of affected individuals also have a variety of congenital abnormalities, including craniofacial malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate. Low birth weight and generalized growth retardation are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.


A diagnosis of DBA is made on the basis of anemia, low reticulocyte (immature red blood cells) counts, and diminished erythroid precursors in bone marrow. Features that support a diagnosis of DBA include the presence of congenital abnormalities, macrocytosis, elevated fetal hemoglobin, and elevated adenosine deaminase levels in red blood cells. Most patients are diagnosed in the first two years of life. However, some mildly affected individuals only receive attention after a more severely affected family member is identified. About 20-25% of DBA patients may be identified with a genetic test for mutations in the RPS19 gene.


Diamond and Blackfan described congenital hypoplastic anemia in 1938. In 1961, Diamond and colleagues presented longitudinal data on 30 patients and noted an associated with skeletal abnormalities. In 1997 a region on chromosome 19 was determined to carry a gene mutated in DBA. In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in 42 of 172 DBA patients. In 2001, it was determined that a second DBA gene lies in a region of chromosome 8 although evidence for further genetic heterogeneity was uncovered.


Approximately 10-25% of DBA cases have a family history of disease, and most pedigrees suggest an autosomal dominant mode of inheritance. The disease is characterized by genetic heterogeneity, with current evidence supporting the existence of at least three genes mutated in DBA. In 1997, a patient was identified who carried a rare balanced chromosomal translocation involving chromosome 19 and the X chromosome. This suggested that the affected gene might lie in one of the two regions that were disrupted by this cytogenetic anomaly. Linkage analysis in affected families also implicated this region in disease, and led to the cloning of the first DBA gene. About 20-25% of DBA cases are caused by mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2. Interestingly, some previously undiagnosed relatives of DBA patients were found to carry mutations. These patients also had increased adenosine deaminase levels in their red blood cells but no other overt signs of disease. A subsequent study of families with no evidence of RPS19 mutations determined that 18 of 38 families showed evidence for involvement of an unknown gene on chromosome 8 at 8p23.3-8p22. The precise genetic defect in these families has not yet been delineated. In a further 7 families, both the chromosome 19 and chromosome 8 loci could be excluded for involvement, suggesting the existence of at least one other DBA locus in the human genome.


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p53 protein overexpression in Shwachman-Diamond syndrome / In reply
From Archives of Pathology & Laboratory Medicine, 10/1/02 by Dror, Yigal

To the Editor.-We read with great interest the paper of Drs Elghetany and Alter in the April 2002 issue of the ARCHIVES.1 Shwachman-Diamond syndrome (SDS) is an autosomal recessive multisystemic disorder characterized by varying degrees of marrow failure and a high propensity for malignant myeloid transformation into myelodysplastic syndromes (MDS) and acute myeloid leukemia.2-4 The authors found p53 overexpression in bone marrow biopsies from 9 patients with SDS. None of the bone marrow biopsies from patients with acquired aplastic anemia or acquired cytopenias and none of those from individuals in the control group had overexpression of p53 protein. Very interestingly, p53 overexpression in patients with SDS was comparable to p53 results in 46 bone marrow specimens from patients with refractory anemia. Refractory anemia is a subtype of MDS.

Although neither the method for selecting patients nor the clinical phenotype of the patients was specified in the paper, the authors' work is important and furthers our understanding of the relationship between SDS and MDS. Myelodysplastic syndrome is a preleukemic, stem cell disease with peripheral blood cytopenia, ineffective hematopoiesis, and varying degrees of bone marrow cellularity and dysplasia. Shwachman-Diamond syndrome meets many of these criteria2: it is a stem cell disorder with peripheral cytopenia, ineffective hematopoiesis,5,6 and varying degrees of bone marrow cellularity, and it carries a significantly increased risk of leukemia.2-4 In addition, scattered mild dysplastic changes in the erythroid, myeloid, and megakaryocytic precursors are commonly seen on careful examination of bone marrow biopsies of patients with SDS2 and are part of the syndrome. Further, the close relationship between SDS and MDS is reflected by similar defects in marrow stromal support of normal hematopoiesis,5 increased apoptosis mediated through the Fas pathway,6 a high frequency of clonal marrow cytogenetic abnormalities,2 and as the authors showed also by a prevalence of p53 protein overexpression that is similar to that in patients with refractory anemia.1 Therefore, SDS seems to be a myelodysplastic disorder from its inception. We therefore consider SDS to be refractory anemia 2 or refractory cytopenia according to the CCC (category-cytology-- cytogenetics) classification of childhood MDS.7 When we refer to malignant myeloid transformation in SDS, we mean stages beyond refractory anemia, namely refractory cytopenia with cytogenetic abnormality, refractory anemia with ring sideroblasts, refractory anemia with dysplasia, refractory cytopenia with excess blasts, or leukemia.

We have recently analyzed bone marrow mononuclear cells from 11 patients with SDS (2 had a clonal marrow cytogenetic abnormality), and we did not find mutations in exons 2 through 11 of the p53 gene.2 Therefore, p53 protein overexpression in SDS can result from either upregulation of the functional p53 gene (as the authors postulated) or posttranslational modification of the protein, rendering it more stable than the wild type protein, which normally cannot be detected.


Marrow Failure and Myelodysplasia Programme

Division of Hematology/ Oncology

The Hospital for Sick Children and the University of Toronto

Toronto, Ontario, Canada M5G 1X8

1. Elghetany MT, Alter BP. p53 Protein overexpression in bone marrow biopsies of patients with Shwachman-Diamond syndrome has a prevalence similar to that of patients with refractory anemia. Arch Pathol Lab Med. 2002;126:452-455.

2. Dror Y, Durie P, Ginzberg H, et al. Clonal evolution in marrows of patients with Shwachman-Diamond syndrome: a prospective 5-year follow-up study. Exp Hematol. 2002;30:659-669.

3. Mack DR, Forstner GG, Wilschanik M, Freedman MH, Durie PR. Shwachman syndrome: exocrine pancreatic dysfunction and variable phenotypic expression. Gastroenterology. 1996;111:15931602.

4. Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P. Haematological abnormalities in Shwachman-Diamond syndrome. Br] Haematol. 1996;94: 279-284.

5. Dror Y, Freedman MH. Shwachman-Diamond syndrome: an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. Blood 1999;94:3048-3054.

6. Dror Y, Freedman MH. Shwachman-Diamond syndrome marrow cells show abnormally increased apoptosis mediated through the Fas pathway. Blood. 2001;97:3011-3016.

7. Mandel K, Dror Y, Poon A, Freedman MH. Practical classification of pediatric MDS. J Pediatr Hematol Oncol. 2002;24:343-352.

In Reply.-We thank Dr Dror for his comments in support of our recent article.1 Our patients were unselected, and included all of those whose samples were available between November 1999 and November 2000. None of the patients with Shwachman-Diamond syndrome (SDS) had cytogenetic clones, and their bone marrow morphology did not show significant dysplastic features. Thus, p53 overexpression was the hallmark of the similarity between SDS and refractory anemia (RA). Dr Dror raises the interesting question regarding the relationship between this syndrome and RA. Although we agree with Dr Dror that SDS shares common features with RA, it may not be appropriate to classify all patients with this syndrome as having RA at the time of diagnosis. Other bone marrow failure syndromes, such as Fanconi anemia and Diamond-Blackfan anemia, share some features with RA as well.2,3 We are concerned that labeling SDS as RA may prompt an aggressive mode of treatment that may not be supported by data other than these similarities. Moreover, there are some indications that myelodysplastic syndromes evolving from an inherited bone marrow disease may not have the same biological behavior as primary myelodysplastic syndromes in children.4 Longterm prospective studies and the continued search for an underlying molecular defect for SDS should shed some light on this rare disease and its relationship to RA.


Department of Pathology

University of Texas Medical Branch

Galveston, TX 77555-0743


Division of Cancer Epidemiology and Genetics

National Cancer Institute Bethesda, MD 20892

1. Elghetany MT, Alter BP. p53 protein overexpression in bone marrow biopsies of patients with Shwachman-Diamond syndrome has a prevalence similar to that of patients with refractory anemia. Arch Pathol Lab Med. 2002;126:452-455.

2. Alter BP, Caruso JP, Drachtman RA, Uchida T, Velagaleti GVN, Elghetany MT Fanconi anemia: myelodysplasia as a predictor of outcome. Cancer Genet Cytogenet. 2000;117:125-131.

3. Perdahl, EB, Naprstek BL, Wallace WC, Lipton JM. Erythroid failure in Diamond-Blackfan anemia is characterized by apoptosis. Blood. 1994;83:645650.

4. Novitzky N, Prindall G. Myelodysplastic syndromes in children: a critical review of the clinical manifestations and management. Am J Hematol. 2000;63:212-222.

Copyright College of American Pathologists Oct 2002
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