Diamond Blackfan Anemia: New Paradigms for a “Not So Pure” Inherited Red Cell Aplasia

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Diamond Blackfan anemia (DBA) is a genetically and clinically heterogeneous disorder characterized by erythroid failure, congenital anomalies, and a predisposition to cancer. Faulty ribosome biogenesis is hypothesized to be the underlying defect, leading to erythroid failure due to accelerated apoptosis in affected erythroid progenitors/precursors. Since first observed in DBA, pro-apoptotic hematopoiesis has been recognized as a common mechanism for hematopoietic failure in virtually all of the inherited bone marrow failure syndromes. Inherited as an autosomal dominant trait, one of what appears to be multiple DBA genes, coding for ribosomal protein RPS19, has been cloned. The discovery of additional genes will no doubt clarify the molecular pathophysiology of this disorder. Even within families, individuals may vary dramatically as to the degree of anemia, treatment response, and the presence of congenital anomalies. The study of DBA has been facilitated by the creation of international patient registries that provide more reliable information regarding clinical presentation, genetics, and outcome, as well as descriptions of congenital malformations and cancer predisposition, than can be culled from the literature. Analysis of registry data has led to improvements in clinical care and provides patients and research specimens for clinical and laboratory investigations.

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Pathophysiology and Genetics: Is DBA a Disorder of Ribosome Biosynthesis?

A number of theories regarding the pathophysiology of DBA have been proposed and discarded.15, 16, 17, 18 Widely accepted is that the disorder results from an intrinsic cellular defect in which erythroid progenitors and precursors are highly sensitive to death by apoptosis.19, 20, 21, 22 Familial DBA appears to be inherited as an autosomal dominant. No instance of autosomal recessive inheritance has been confirmed, and apparent recessive inheritance is likely a consequence of non-penetrance2

Making the Diagnosis of Diamond Blackfan Anemia

The median age at presentation and diagnosis of classical DBA are 8 weeks (range, birth to 6 years) and 12 weeks (range, birth to 26 years), respectively.40 Ninety-three percent of DBA patients present in the first year of life, but as in the other inherited bone marrow failure syndromes, DBA may present in adulthood,52 when it is often misdiagnosed. The differential diagnosis of DBA in children presenting with red cell failure, anemia, reticulocytopenia, and decreased or absent marrow

Congenital Anomalies

Birth defects have long been known to be a feature of DBA. A distinct facial appearance and triphalangeal thumbs have been classically described in DBA as the Cathie facies56 and Aase syndrome,57 respectively. A cute snub nose and wide-spaced eyes, as originally described by Cathie, and other craniofacial anomalies, some as already discussed quite severe, are the most common physical anomalies of DBA. Abnormal thumbs are classic.58 In all, congenital anomalies were found in 30% to 47% of the

Cancer: Is DBA a Cancer Predisposition Syndrome?

At least 26 cases of cancer in patients with DBA have been reported in the literature. Sixteen were hematopoietic malignancies: 10 acute myeloid leukemia (AML), two myelodysplastic syndrome (MDS), two Hodgkin disease, one non-Hodgkin lymphoma, and one acute lymphoblastic leukemia. Ten solid tumors have been reported: three osteogenic sarcoma, two breast cancer, two hepatocellular carcinoma, and one each of gastric carcinoma, vaginal melanoma, and malignant fibrous histiocytoma.3 A number of

Corticosteroids and Red Cell Transfusions

Corticosteroids and red cell transfusions are the mainstays of therapy for DBA. Since 1951,67 it has been known that the anemia of DBA can be ameliorated by corticosteroids. The initial suggestion to use corticosteroids was based on the theory that DBA was an “allergic” disorder. The response to corticosteroids further perpetuated the erroneous notion of DBA as an autoimmune disease, even when only miniscule doses were required to maintain adequate erythropoiesis. The almost unlimited use of

Conclusions: Where Are We Going?

Progress in the understanding of the inherited bone marrow failure syndromes and in particular DBA has resulted from the combination of clinical and research laboratory science. Patient registries have permitted the more precise description of congenital anomalies, suggesting a possible connection between DBA and TCS; similarities between them strongly support their classification as disorders of ribosome biosynthesis. Other disorders have been postulated to involve defects in ribosome assembly

Acknowledgment

The progress described in this review is testament to the commitment of the patients with DBA, their families, clinicians who care for the patients, and the dedicated scientists, clinical and laboratory-based, with whom I have the privilege to work. The author would also like to thank Adrianna Vlachos, MD, Johnson Liu, MD, Hanna Gazda, MD, and Eva Atsidaftos, MA, for their invaluable advice and assistance.

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    Supported by grants from the Daniella Maria Arturi Foundation, Diamond Blackfan Anemia Foundation, Pediatric Cancer Foundation, National Institutes of Health RO1 HL 079571, and the Feinstein Institute for Medical Research at the NSLIJ General Clinical Research Center MO1 RR018535.

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