Diamond Blackfan anemia: a model for the translational approach to understanding human disease

Abstract

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome. As with the other rare inherited bone marrow failure syndromes, the study of these disorders provides important insights into basic biology and, in the case of DBA, ribosome biology; the disruption of which characterizes the disorder. Thus DBA serves as a paradigm for translational medicine in which the efforts of clinicians to manage DBA have informed laboratory scientists who, in turn, have stimulated clinical researchers to utilize scientific discovery to provide improved care. In this review we describe the clinical syndrome Diamond Blackfan anemia and, in particular, we demonstrate how the study of DBA has allowed scientific inquiry to create opportunities for progress in its understanding and treatment.

Keywords::

• Diamond Blackfan anemia
• GATA1
• MDM2
• p53
• pure red cell aplasia
• ribosomal proteins
• ribosome biosynthesis
• ribosomopathy

Acknowledgements

The authors express their gratitude to the DBA patients, their families and their physicians for their support in the research and their contribution of data to the DBA Registry. The authors also acknowledge many colleagues who worked tirelessly to understand DBA as well as the collaborators in the Intramural Research Programs of the National Cancer Institute and the National Human Genome Research Institute.

This work is or has been supported by grants from the National Heart Lung and Blood Institute (R01HL079571, R109MOHLKE), the Centers for Disease Control and Prevention, the Pediatric Cancer Foundation, the Diamond Blackfan Anemia Foundation and the Daniella Maria Arturi Foundation.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Diamond Blackfan anemia (DBA) usually presents in infancy with severe anemia but only rarely in utero. Occasional patients present as adults.

• The classical diagnostic criteria for DBA are: normochromic, usually macrocytic and occasionally normocytic anemia developing in early childhood; reticulocytopenia; normocellular bone marrow with normal appearing myeloid and megakaryocyte lineages with a selective deficiency of erythroid precursors; normal granulocyte count with occasional mild-to-moderate neutropenia and infrequently severe neutropenia; and normal platelet count or thrombocytosis, or occasionally clinically insignificant thrombocytopenia.

• The differential diagnosis of DBA includes predominantly transient erythroblastopenia of childhood and parvovirus B19-induced erythroid failure in immunodeficient patients.

• Multiplex family pedigrees are consistent with autosomal dominant, X-linked and autosomal recessive inheritance. Autosomal recessive inheritance has not been genetically confirmed.

• The majority of cases result from ribosomal protein (RP) haploinsufficiency (autosomal dominant) as a consequence of a mutation or deletion in 1 of 10 genes encoding RPs. Rare cases as a consequence of mutations in GATA1 (X-linked) have been described. The etiology still remains to be identified in about 30% of the total cases.

• Birth defects are found in approximately 50% of patients. Although there are no genotype–phenotype correlations for steroid responses, remission or cancer predisposition, mutations in RPL5, RPS26 or RPL11 are associated with particular anomalies in the face and hands.

• Current treatment of DBA is suboptimal relying upon only corticosteroids, transfusions/iron chelation or hematopoietic stem cell transplantation. The prognosis depends upon response to treatment with patients responsive to non-toxic doses of corticosteroids having a better prognosis than transfusion-dependent patients. The results for stem cell transplantation are best for young patients transplanted with a matched sibling donor. The results for matched unrelated transplants have improved considerably since 2000.

• The relationships between RP haploinsufficiency with the DBA phenotype remain obscure. Although the knockout of p53 in animal and cellular models ameliorates the hematopoietic phenotype, the predilection for red cell failure is yet to be adequately explained.

Notes

^†Typically found in, although not restricted to, adults.

^‡Although most single large-scale deletions in mitochondrial DNA are sporadic, single deletions can be transmitted through the germline in rare cases.