Diamond-Blackfan anemia

What every physician needs to know:

Diamond-Blackfan anemia (DBA) is a severe red cell (erythroid) aplasia that usually presents soon after birth. Congenital abnormalities of the head and neck (hypertelorism, cleft or high arched palate, microcephaly, micrognathia), thumb and other organs such as kidneys and or heart may be present. Importantly, DBA usually presents as a pure red cell aplasia with a severe often macrocytic anemia, but normal platelet and leukocyte counts. Although DBA can present at any age, 90% of patients present during the first year of life.

Are you sure your patient has Diamond-Blackfan anemia? What should you expect to find?

  • Anemia, usually severe
  • Reticulocytopenia
  • Macrocytosis
  • Increased red cell adenosine deaminase (ADA)
  • Normal platelet and leukocyte counts
  • Bone marrow erythroid hypoplasia with normal myelopoiesis and megakaryocytes

Beware of other conditions that can mimic Diamond-Blackfan anemia:

DBA must be differentiated from transient erythroblastosis of childhood (TEC), a pure red cell aplasia that usually occurs in slightly older children (6 months to 4 years) and is not associated with congenital defects. The anemia is usually normocytic and can follow an unidentified virus infection. Recovery with a reticulocytosis usually occurs in 1-2 months, and transfusion may be necessary.

Parvovirus B19 (fifth disease) can also cause red cell aplasia, but a significant anemia is only seen in children with an underlying hemolytic anemia and shortened red cell survival, such as hereditary spherocytosis or sickle-cell disease. Other virus infections including human immunodeficiency virus as well as bacterial infections, drugs and toxins should be ruled out.

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Inherited bone marrow failure syndromes that can mimic DBA include Pearson syndrome (severe hypoplastic anemia with ring sideroblasts and exocrine pancreatic deficiency), cartilage hair hypoplasia, Fanconi anemia and Shwachman-Diamond syndrome, all of which can be associated with a macrocytic anemia, although other clinical features should, in most cases, make the distinction easy.

Which individuals are most at risk for developing Diamond-Blackfan anemia:

Forty to 45% of cases are familial, and almost always show a dominant pattern of inheritance. Because expressivity of the DBA phenotype is very broad, even in familial cases with the identical mutation, subtle evidence of anemia in first degree relatives should be sought, for example, transfusion for anemia during pregnancy or unexplained anemia as a child. In addition, characteristic congenital abnormalities such as: low birth weight, short stature, upper limb abnormalities especially of the thumb, head and neck anomalies, and renal defects may provide clues to the diagnosis.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Complete blood count with reticulocyte count

Severe anemia, often macrocytic and normochromic. Leukocytes and platelets normal. Reticulocytopenia.

Red cell adenosine deaminase

This enzyme may be markedly increased in DBA (greater than 3 SD above mean). It is very important to remember to obtain this test before transfusion.

Bone marrow aspirate and biopsy

Normocellular marrow with marked reduction of erythroid precursors of all stages of maturation, although a few pronormoblasts may be present. Myeloid precursors are normal, as are megakaryocytes.

Hemoglobin electrophoresis

Fetal hemoglobin (HbF) can be increased.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of Diamond-Blackfan anemia?

Radiology of hands and arms

Abnormalities of radii, thumbs (triphalangeal, duplex, bifid).

Renal ultrasound

Horseshoe or absent kidney.


Ventricular septal defect (VSD), atrial septal defect (ASD), coarctation of the aorta, and complex cardiac abnormalities.

If you decide the patient has Diamond-Blackfan anemia, what therapies should you initiate immediately?

Severe anemia is a frequent presenting feature, and cautious transfusion of packed red blood cells is often the most urgent first line treatment and used to maintain the hemoglobin during the first year of life.

More definitive therapies?

Steroids (prednisone) can induce remission in approximately 75% of patients. Because of concerns about steroids and growth retardation during infancy, a trial of prednisone (2mg/kg/day) for 3 weeks, followed by a slow taper to an acceptable dose (equal to or less than 0.5mg/kg daily or 1mg/kg on alternate days), is frequently begun only at age 1 year.

Patients who fail steroid treatment (non-responders or those in whom an unacceptably high steroid dose is necessary to maintain the hemoglobin) should be weaned off steroids and will require regular blood transfusions at approximately 4 to 6 week intervals.

Discussion with a hematopoietic stem cell transplant (HSCT) unit experienced in transplanting patients with bone marrow failure should be instigated for transfusion dependent patients who have an human leukocyte antigens (HLA) compatible and genetically unaffected sibling donor. The Diamond Blackfan Anemia Registry (DBAR) reported 73% survival for matched sibling donors at 5 years, compared with 17% for unrelated donors. Results were best for patients transplanted at less than 10 years of age without significant iron overload.

What other therapies are helpful for reducing complications?

Transfusion dependent patients need to be carefully monitored for iron overload, so that chelation can be started at the appropriate time. Ferritin measurements are not a good indicator of total body iron burden, but can be used as a rough guide (1,000 to 1,500µg/L as a starting point), as can a calculation of total packed red blood cells (PRBC) transfused (170 to 200mL/kg).

Liver biopsy is the gold standard (normal 3 to 7mg/g dry weight, with high risk greater than 15mg/g dry weight). A objective non-invasive approach such as magnetic susceptometry (SQUID [superconducting quantum interference device] is a very sensitive magnetometer, used to measure extremely subtle magnetic fields, but is not widely available) or cardiac and hepatic T2* MRI (weighted magnetic resonance scans use a gradient echo sequence, with long echo time [TE] and long repetition time [TR]) are the much preferred current approaches. Adequate chelation is an essential aspect of management and will usually rely on deferoxamine (desferal [Novartis]), administered subcutaneously by pump 4 to 6 nights/week over 8 to 12 hours, or deferasirox (exjade [Novartis]), an oral iron chelator that can be given once daily.

What should you tell the patient and the family about prognosis?

Overall actuarial survival is 75% at age 40 years. Steroid responsiveness confers a significant survival benefit, compared with transfusion dependent patients. Hematopoietic stem cell transplantation (HSCT) can be curative, and the best results have been reported for matched sibling grafts; matched unrelated donor HSCT are not as successful. Treatment related causes of death include: infection (Pneumocystis jiroveci in patients on a high-steroid dose), complications of iron overload, or HSCT. There is an increased risk of malignancy (leukemia, myelodysplastic syndrome, and sarcoma) and also evolution to aplastic anemia.

“What if” scenarios.

Infants and children with suspected DBA should be referred to a pediatric hematology program with expertise in the diagnosis and management of bone marrow failure disorders. Management can then be continued in partnership with the center of expertise.

Steroid dose

A trial of prednisone or prednisolone should only be started at 1 year of age, because of concerns about growth delay in infancy. A dose of 2mg/kg day for 3 weeks should be sufficient to determine responsiveness, and can be started 10 to 14 days after the previous transfusion, in an attempt to avoid the need for another transfusion, yet still allow sufficient time to monitor a reticulocyte and hemoglobin response before the next transfusion is due. If a response is observed (reticulocytosis, Hb climbs to the 9 to 10g/dL range), the daily dose should be gradually tapered to 1mg/kg/day and then the alternate day dose should be tapered and stopped, to give a daily dose of 0.5mg/kg/day (1mg/kg/d on alternate days). Then, this alternate day dose can be slowly reduced. If the Hb falls between visits then the dose is too low, and one should return to the previous dose.

Patients who do not respond in 3 weeks should be tapered over a few weeks and the steroid treatment stopped. Patients should not be maintained on steroids if a dose of prednisone greater than 0.5mg/kg/day is required.

Transfusional iron overload

Iron accumulation in patients on chronic transfusions should be carefully monitored in collaboration with a center expert in the management of iron overload.


Around half of DBA patients have a mutation in one of tendifferent ribosomal protein (RP) genes (Figure 1), which usually result in haploinsufficiency of the protein, although there is evidence that certain RPS19 point mutations can act in a dominant negative manner. Mutations in RP genes result in a block in ribosomal RNA (ribonucleic acid)biogenesis, and different mutations show varying stages at which processing of the primary ribosomal RNA transcript is arrested. Current evidence shows that nucleolar stress from mutations in RP genes results in stabilization of p53 (protein 53) levels by inhibition of the normal HDM (human double minute, also called MDM in reference to murine data [mouse double minute]) mediated degradation pathway, leading to cell death by apoptosis.

Figure 1n
Diamond-Blackfan anemia, gene mutations.

What other clinical manifestations may help me to diagnose Diamond-Blackfan anemia?

A careful family history is essential. Since DBA is either sporadic or dominantly inherited, information about anemia during childhood, transfusions, and complications of pregnancy in first degree relatives may offer clues, as may the presence in family members of congenital anomalies associated with DBA. Figure 2 indicates the congenital abnormalities that are described in DBA. Interestingly, 60S ribosomal protein L5 (RPL5)and 60S ribosomal protein L11 (RPL11) mutations have been associated with specific congenital anomalies. Low birth weight may occur in 25% cases.

Craniofacial abnormalities are most common, and include hypertelorism, broad flat nasal bridge, and high arched or cleft palate. It is essential to examine the thumb. While a bifid and triphalangeal thumb would be obvious, as would radial abnormalities, more subtle abnormalities such as flattening of the thenar eminence may be present. Renal and cardiac defects may also be present, and once the diagnosis of DBA is made, patients should undergo renal imaging and an echocardiogram.

Figure 2n
Congenital abnormalities in Diamond-Blackfan anemia

What other additional laboratory studies may be ordered?

Genetic mutation analysis of known common RP genes can be obtained by sequencing through either commercial laboratories such as GeneDx, or through research laboratories. The latter can be more comprehensive, but will take longer and identified mutations will then require confirmation in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory.

What’s the evidence?

Vlachos, A, Ball, S, Dahl, N. “Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference”. Br J Haematol. vol. 142. 2008. pp. 859-876. [Consensus document by clinicians expert in the management of patients with DBA.]

Lipton, JM, Atsidaftos, E, Zyskind, I, Vlachos, A. “Improving clinical care and elucidating the pathophysiology of Diamond Blackfan anemia: an update from the Diamond Blackfan Anemia Registry”. Pediatr Blood Cancer. vol. 46. 2006. pp. 558-564. [Example of DBA Registry data on US patients with DBA followed for several years. Other registries in Europe provide valuable information.]

Draptchinskaia, N, Gustavsson, P, Andersson, B. “The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia”. Nat Genet. vol. 21. 1999. pp. 169-175. [First publication to establish RPS19 as the ribosomal protein (RP) gene mutated in approximately 25% patients. This is also the first publication demonstrating that mutations in RP genes can cause human disease.]

Gazda, HT, Sheen, MR, Vlachos, A. “Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients”. Am J Hum Genet. vol. 83. 2008. pp. 769-780. [This paper establishes mutations in RPL5 and RPL11 as the second and third most common RP genes mutated in DBA after RPS19, and shows for the first time genotype-phenotype correlations.]

Narla, A, Ebert, BL. “Ribosomopathies: human disorders of ribosome dysfunction”. Blood. vol. 115. 2010. pp. 3196-3205. [Review of the bone marrow failure and other disease caused by mutations in genes associated with ribosomal biogenesis, and a common pathogenetic mechanic involving p53 mediated apoptosis.]