Diamond-Blackfan Anaemia

Also written as Congenital pure red cell aplasia.

Diamond-Blackfan anaemia (DBA) is a congenital pure red‑cell aplasia presenting in infancy with macrocytic anaemia, low reticulocytes and often physical anomalies. Diagnosis relies on blood film, marrow findings and exclusion of other causes.

Definition and diagnosis

DBA is a rare inherited disorder of erythropoiesis characterised by failure of red‑cell precursors, leading to macrocytic anaemia with a reticulocyte count <1 %. Diagnosis requires a peripheral smear, bone‑marrow biopsy showing paucity of erythroid precursors, and exclusion of other causes of normocytic or macrocytic anaemia.

• Full blood count: Is there anaemia and what is the red cell size? Low Hb with MCV >100 fL suggests macrocytic anaemia.
• Reticulocyte count: Is marrow production adequate? <1 % indicates underproduction.
• Peripheral blood smear: Are red cells macrocytic with anisopoikilocytosis? Confirms macrocytosis, looks for nucleated RBCs.
• Bone‑marrow aspirate/biopsy: Is erythropoiesis reduced? <5 % erythroid precursors confirms pure red‑cell aplasia.
• Genetic testing (RPS19, RPL5, etc.): Does the patient have a known DBA mutation? Positive result supports diagnosis; unavailable? rely on clinical criteria.

• Macrocytic anaemia (MCV >100 fL)
• Reticulocyte count <1 %
• Bone‑marrow: <5 % erythroid precursors, normal myeloid and megakaryocytic lines

Severity and staging

Severity is graded by transfusion dependence and haemoglobin level. The International DBA Registry uses three grades: mild (Hb ≥ 9 g/dL, no transfusion), moderate (Hb 7‑9 g/dL, occasional transfusion), severe (Hb < 7 g/dL or regular transfusion).

• Mild: Hb ≥ 9 g/dL, no transfusion
• Moderate: Hb 7‑9 g/dL, intermittent transfusion
• Severe: Hb < 7 g/dL or chronic transfusion

Causes, most likely first

Most DBA cases are due to ribosomal protein gene mutations (≈ 70 %). In low‑resource settings, secondary pure red‑cell aplasia from parvovirus B19 infection must be considered, especially in children with sickle cell disease or HIV.

• Inherited ribosomal protein mutations (RPS19, RPL5, RPL11…)
• Acquired parvovirus B19 infection
• Other viral infections (HIV, hepatitis B)
• Drug‑induced marrow suppression (chloramphenicol, antiretrovirals)

How it presents

Infants present with pallor, poor feeding, tachycardia and growth failure. Physical anomalies occur in ~ 50 % (triphalangeal thumbs, craniofacial dysmorphism, cardiac defects). In low‑resource settings, presentation may be delayed until severe anaemia forces presentation.

• Pallor, fatigue, tachycardia
• Macrocytosis on smear
• Congenital anomalies (thumb, facial, cardiac)
• Failure to thrive

Investigations

Focus on confirming pure red‑cell aplasia, ruling out infection, and identifying associated anomalies.

• Serology for parvovirus B19 IgM: Is the anaemia infection‑related? Positive IgM indicates acute B19 infection, treat supportively.
• HIV test: Is HIV contributing? Positive test prompts antiretroviral review and infection control.
• Echocardiogram (if cardiac anomaly suspected): Are there structural heart defects? Detects VSD, ASD that may need referral.
• Renal ultrasound (if renal malformation suspected): Any renal anomaly? Guides multidisciplinary care.
• Serum ferritin / transferrin saturation: Is iron overload present from transfusions? Elevated ferritin >1000 µg/L indicates need for chelation.

Red flags and complications

Untreated severe anaemia can cause high‑output cardiac failure. Chronic transfusion leads to iron overload, endocrine dysfunction, and liver disease. There is an increased risk of malignancy (especially AML).

• Heart failure signs (edema, hepatomegaly)
• Iron overload (ferritin >1000 µg/L)
• Progressive cytopenias
• Development of malignancy

Management

Initial management aims to stabilise anaemia, then address the underlying defect. Corticosteroids are first‑line; if ineffective, consider chronic transfusion with iron chelation. In selected patients, hematopoietic stem‑cell transplantation (HSCT) offers cure.

• If no response after 8 weeks, start regular packed RBC transfusion (aim Hb > 9 g/dL).
• Deferoxamine or deferasirox for ferritin > 1000 µg/L – prevents organ damage.
• HSCT for severe, steroid‑refractory cases – curative but requires donor and supportive care.

Follow-up and prevention

Regular monitoring of haemoglobin, growth, cardiac status and iron load is essential. Vaccination against parvovirus B19 is not available; educate families on infection avoidance and prompt treatment of febrile illnesses.

• Hb and reticulocyte count every 3 months
• Ferritin every 6 months; start chelation if >1000 µg/L
• Annual cardiac echo if transfusion dependent
• Growth chart review at each clinic visit

Often confused with

Conditions that also cause macrocytic anaemia with low reticulocytes.

• Transient erythroblastopenia of childhood (post‑viral, self‑limited)
• Vitamin B12/folate deficiency (dietary, malabsorption)
• Aplastic anaemia (pancytopenia, not isolated red‑cell line)

Where results can mislead

In early disease, reticulocyte count may be borderline, and marrow may appear normal; reliance on a single smear can miss subtle erythroid hypoplasia.

• Normal MCV early in disease – do not rule out DBA
• Transient rise in reticulocytes after infection – re‑check after 2 weeks

Questions an examiner may ask

• A 6‑month‑old infant presents with pallor and macrocytic anaemia; bone‑marrow shows absent erythroid precursors. What is the most likely diagnosis and why? — Diamond‑Blackfan anaemia; isolated red‑cell aplasia, macrocytosis, low retic.
• How would you differentiate DBA from transient erythroblastopenia of childhood? — Duration (DBA chronic), congenital anomalies, marrow findings, need for steroids/transfusion.
• A child with known DBA is now requiring weekly transfusions. What complication must you screen for and how? — Iron overload; check serum ferritin >1000 µg/L and start chelation.
• What is the first‑line pharmacologic therapy for DBA and what monitoring is required? — Prednisone; monitor blood pressure, glucose, and response after 8 weeks.
• In a low‑resource hospital without genetic testing, which clinical features help you confirm DBA? — Macrocytic anaemia, retic <1 %, congenital anomalies, marrow erythroid hypoplasia.
• A patient with DBA develops fever and sudden drop in Hb; what urgent investigation is needed? — Parvovirus B19 PCR/IgM; acute infection can cause aplastic crisis.
• Why is HSCT not always the immediate choice for DBA in East Africa? — Limited donor registries, high infection risk, need for intensive supportive care.
• What red‑flag symptom would prompt immediate referral to a tertiary centre? — Signs of high‑output cardiac failure or severe iron overload.

When to seek help

• Signs of cardiac failure (tachypnoea, edema, hepatomegaly)
• Severe anaemia with Hb < 5 g/dL
• Rapidly rising ferritin >2000 µg/L

Quick questions

Why is reticulocyte count crucial?

It distinguishes underproduction (low retic) from loss or destruction, pointing to marrow failure.

Can DBA be cured without HSCT?

Most patients require lifelong therapy; HSCT offers cure but is limited by donor availability and resources.

What is the role of steroids?

They can increase residual erythropoiesis in ~ 30 % of patients, delaying or avoiding transfusion dependence.