OVERVIEW: What every practitioner needs to know

Are you sure your patient has Diamond-Blackfan Anemia? What are the typical findings for this disease?

Diamond-Blackfan anemia (DBA) is a rare disease characterized by congential pure red cell aplasia, congenital anomalies and a predisposition to cancer.

Anemia: While anemia is frequently present at birth, hydrops fetalis is rare in these patients. Most children with DBA are diagnosed before 1 year of age. Most present with a macrocytic anemia, although some infants have been described to have normocytic anemia. Reticulocytopenia is present due to impaired production of red cells. Neutrophil and platelet counts are typically normal. Examination of the bone marrow demonstrates normal cellularity with few erythroid precursors. Fetal hemoglobin is elevated for age and erythrocyte adenosine deaminase (eADA) activity is increased.

Congenital Anomalies: The physical appearance of DBA patients is diverse, with some children with DBA having a completely normal appearance. Others have a range of congenital anomalies. A wide spectrum of anomalies has been recorded by the Diamond-Blackfan Registry (DBAR). Most common are abnormalities of the cranifacial system (e.g., hypertelorism, cleft lip and palate, microcephaly, micrognatia, low-set ears, ptosis), hands and upper extremities (e.g., hypoplastic thumbs, syndactyly), heart (e.g., ventricular septal defects, atrial septal defects, coarctation of the aorta, tetralogy of Fallot) and genitourinary track (e.g., absent kidney, horseshoe kidney and hypospadias). Approximately 20% of children with DBA will have more than one congenital anomaly.

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Cancer: Finally, children with DBA have a higher probability of cancer, most notably acute leukemias including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and a variety of solid tumors (e.g., osteogenic sarcoma, lymphoma, breast cancer and colon cancer).

What other disease/condition shares some of these symptoms?

The differential diagnosis of DBA includes transient erythroblastopenia of childhood (TEC), Shwachman-Diamond syndrome, Pearson syndrome, dyskaratosis congenita, Treacher Collins syndrome, myelodysplastic syndrome, Fanconi anemia and infection with parvovirus B19.

What caused this disease to develop at this time?

DBA is a genetic disease that most often has an autosomal dominant pattern of inheritance, although autosomal recessive cases have been suggested. In addition, many cases are the result of sporadic mutations with no one causation.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

When anemia is detected in a newborn or infant, the evaluation should include a complete history including transfusion history, complete family history and a physical examination aimed as assessing associated anomalies. Clinicians should obtain a complete blood count, reticulocyte count, hemoglobin F level, and erythrocyte ADA activity.

Children with DBA will likely have a macrocytic anemia, normal neutrophils and platelets, a very low to absent reticulocyte count, elevated hemoglobin F and increased eADA activity.

A bone marrow examination should also be performed to aid in a diagnosis of DBA. In affected children, the bone marrow will be normocellular with normal myeloid maturation, normal megakayocytes and an arrest in erythroid development with an absence of erythroid precursors.

Cytogenetics are commonly performed at diagnosis. Some patients with DBA can be identified by the finding of a translocation of the gene encoding for RSP19 and a deletion on chromosome 3q.

Finally, a confirmation of a diagnosis of DBA can be established for approximately 50% of patients through mutation analysis of 9 known “DBA genes” (RSP19, RSP24, RSP17, RSP35a, RPL5, RPL11, RPS7, RSP7, RSP26 and RSP10).

Given the differential diagnosis listed above, in cases where DBA is not clearly confirmed by these tests, additional test are performed to exclude other diagnoses. For example: diepoxybutane (DEB) or mitomycin C (MMC) assays to exclude Fanconi anemia, testing of mitochrondrial DNA deletions to exclude Pearson’s syndrome, telomere length to exclude dyskeratosis congenita and viral studies to exclude parvovirus infection.

Finally, since many cases of DBA have a autosomal dominant inheritance pattern that has variable penetrance and expression, parents and siblings should be similarly evaluated with a complete history, physical examination, CBC, reticulocyte count, hemoglobin F, eADA and genotyping when indicated. In cases where allogeneic hematopoietic stem cell transplantation is anticipated using an HLA-matched related donor, it is imperative that the potential donor undergo a full diagnostic evaluation to exclude DBA prior to stem cell transplantation.

Would imaging studies be helpful? If so, which ones?

Radiographs of the skeleton (especially of the upper extremities) can help to define congenital anomalies of the skeletal system. Similarly, ultrasound and echocardiograms can aid in the identification of genitourinary and cardiac abnormalities.

If you are able to confirm that the patient has Diamond-Blackfan anemia, what treatment should be initiated?

DBA is a rare and complex disease. Children suspected or confirmed to have this diagnosis should be referred to a center with multi-disciplinary expertise in the care of children with DBA and other marrow failure syndromes.

There are three major approaches to the treatment of children with DBA: red blood cell (RBC) transfusions, corticosteroids and allogeneic hematopoietic stem cell transplantation. The timing and relationship between RBC transfusions, corticosteroids and allogeneic transplantation is complex and dependent upon a number of factors, including age, transfusion requirements and corticosteroid response.

Red Blood Cell Transfusions

Chronic RBC transfusions are a mainstay of therapy for DBA, with most patients receiving transfusions every 3-5 weeks with a goal of maintaining the hemoglobin level higher than 8 grams/dl. Based on the child’s growth and function, hemoglobin values may need to be higher for some patients (e.g., 9 grams/dl). Given the chronic nature of these red cell transfusions, iron overload becomes problematic, so careful monitoring of serum ferritin levels and other parameters indicative of iron overload (e.g., magnetic resonance determinations of liver, heart and pancreas iron, liver biopsies, etc.) are necessary.

Pediatric hematologists with expertise in the treatment of DBA will frequently begin iron chelation with intravenous or oral agents after 15 red cell transfusions, or after the age of 2 years. Intravenous chelation frequently necessitates the implantation of non-metallic ports that are MRI-compatible.


Corticosteroid therapy is attempted in virtually all DBA patients, although RBC transfusion may be used primarily in the first year of life to minimize corticosteroid-associated toxicities in newborns, including significant growth disturbances.

Prednisone or prednisolone at a dose of 2 mg/kg per day is used for a 4 week trial period. A steroid response is typically detectable within a week in steroid-responsive cases. DBA patients can exhibit variable responses to steroid treatment including: unresponsive disease, responsive disease with “remission” after discontinuation of steroids, responsive disease after taper but with a need for “low dose” maintenance therapy, responsive disease but a requirement for high dose steroids, and an initial response with a later loss of response despite increased doses of steroids.

Presently, clinicians are not able to predict an individual patients’ pattern of response based on known prognostic factors. The overall goal is to use the minimal dose of corticosteroid that results in a hemoglobin response. It is imperative that growth charts be carefully maintained. In addition, as a result of immune suppression associated with higher doses of steroids, physicians should consider prophylaxis for Pneumocystis jirovecii.

Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic transplantation from HLA-matched related and unrelated donors is indicated for children with DBA who are steroid unresponsive and transfusion dependent. Recent data suggest a better outcome when allogeneic transplantation occurs between the ages of 3-9 years. In the event a family member is HLA-matched, it is imperative that the potential for DBA be fully assessed prior to the use of related donors.

Most transplants to date for DBA have used myeloablative conditioning regimens, although more recently, non-myeloablative approaches have been studied, especially for patients with pre-existing organ damage due to iron overload. All stem cell sources have been utilized, including bone marrow, peripheral blood stem cells and cord blood.

Current results suggest an excellent outcome (survival exceeding 90% with related donors, and more recently, with the use of well-matched unrelated donors with survival in approximately 85%. As with Fanconi anemia, some parents have chosen to use preimplantation genetic diagnosis to create donors who are HLA-matched and who do not have DBA.

What are the adverse effects associated with each treatment option?

Red Cell Transfusions

The most significant toxicities associated with chronic RBC transfusions are related to iron overload which can lead to cirrhosis of the liver, hemsiderosis of the heart, insulin dependent diabetes mellitus, hypothyroidism and hypoparathyroidism.


Long-term treatment with corticosteroids can cause hypertension, hyperglycemia, cataracts, avascular necrosis of the bone, pathological fractures, growth retardation and serious infections.

Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation is associated with a significant risk of morbidity and mortality, including, but not limited to: death, bleeding, infection, graft-versus-host disease and secondary malignancies.

What are the possible outcomes of Diamond-Blackfan anemia?

Approximately 20% of patients with DBA will enter a “remission” (defined as 6 months of a normal hemoglobin level without treatment) by adulthood. In some patients, this state of remission is longstanding, whereas in others, there may have repeated periods of remission.

Actuarial surival for DBA patients as reported by the DBA Registry is approximately 75% at 40 years of age. Survival is highest among steroid responders and lowest among those who undergo allogeneic transplantation.

What causes this disease and how frequent is it?

Diamond-Blackfan is a one of a number of emerging disorders characterized by ribosomal dysgenesis, now often referred to as “ribosomopathies”. In approximately half of cases, DBA results from haploinsufficiency of ribosomal proteins. The proteins affected include either the 40S or 60S ribosomal subunit. Currently, nine DBA genes have been identified, including RSP19, RSP24, RSP17, RSP35a, RPL5, RPL11, RPS7, RSP7, RSP26 and RSP10.

The pathophysiology is not currently well defined, but it is increasingly apparent that p53 activation likely plays a central role. Other than an association between mutations in RPL5 or RPL11 and craniofacial abnormalities, genotype:phenotype correlations are not yet clearly defined.

Most often DBA has an autosomal dominant pattern of inheritance, although cases thought to be autosomal recessive have been suggested. Many cases are the result of sporadic mutations.

How do these pathogens/genes/exposures cause the disease?

The pathogenesis of DBA is not clear, but the current understanding of the disease is described above.

How can Diamond-Blackfan anemia be prevented?

As with most genetic diseases, there are no known methods to prevent the disease. However, after a family has one affected child, preimplantation genetic testing can be used to select for blastocysts without DBA and in some cases, for HLA in efforts to create sibling donors. Genetic counseling is a critically important aspect of care for parents with affected children.

What is the evidence?

Ball, S. “Diamond Blackfan anemia”. American Society of Hematology Education Program Book. 2011. pp. 487-91.

Draptchinskaia, N, Gustavsson, P, Adnersson, B. “The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia”. Nature Genetics.. vol. 21. 1999. pp. 169-75.

Dutt, S, Narla, A, Lin, K. “Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells”. Blood. 2011. pp. 2567-76.

Ellis, SR, Gleizes, P-E. “Diamond Blackfan anemia: ribosomal proteins going rogue”. Seminars in Hematology. vol. 48. 2011. pp. 89-96.

Sieff, CA, Yang, J, Merida-Long. “Pathogenesis of the erythroid failure in Diamond Blackfan anaemia”. British Journal of Haematogy. vol. 148. 2010. pp. 611-22.

Vlachos, A, Ball, S, Dahl, N. “Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference”. British Journal of Haematology. vol. 142. 2008. pp. 859-76.

Narla, A, Vlachos, A, Nathan, DG. “Diamond Blackfan anemia treatment: past, present and future”. Seminars in Hematology. vol. 48. 2011. pp. 117-23.

Vlachos, A, Muir, E. “How I treat Diamond-Blackfan anemia”. Blood. vol. 116. 2011. pp. 3715-3723.

Vlachos, A, Federman, N, Reyes-Haley, C. “Hematopoietic stem cell transplantation for Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry”. Bone Marrow Transplantation. vol. 27. 2001. pp. 381-6.