Paediatrics chapters
Approach to anaemia and Diamond-Blackfan anaemia
How to define and classify anaemia in a child by red cell size and reticulocyte count, what the history, examination and first tests tell you, and how congenital red cell aplasia (Diamond-Blackfan anaemia) differs from transient erythroblastopenia.
- Anaemia is a haemoglobin more than 2 SD below the mean for age and sex; normal values change a lot in infancy, with a physiological nadir at 8-10 weeks.
- Classify by MCV (microcytic, normocytic, macrocytic) and by the reticulocyte count (high = haemolysis or bleeding; low = poor production).
- Diamond-Blackfan anaemia is congenital pure red cell aplasia in early infancy: macrocytic anaemia, low reticulocytes, normal white cells and platelets, raised HbF and red cell ADA, physical anomalies (triphalangeal thumb); treat with steroids, transfusion or stem cell transplant.
On this page
Overview
Anaemia is one of the commonest problems in paediatric practice, and it is a sign, not a diagnosis. The cause is found by putting together the child's age, the diet and family history, the examination, and three simple tests: the haemoglobin with red cell indices, the reticulocyte count and the blood film.
This chapter covers the general approach and the rare but frequently examined congenital hypoplastic anaemia (Diamond-Blackfan anaemia), together with its main look-alike, transient erythroblastopenia of childhood.
Normal values change with age
Blood production begins in the yolk sac at about 3 weeks of gestation, moves to the liver by about 2 months, and shifts to the bone marrow from about 5-6 months of fetal life. Fetal haemoglobin (HbF, α2γ2) dominates before birth and falls to adult levels (under 2%) by about 1 year, as HbA (α2β2) takes over.
After birth the oxygen level rises, erythropoietin output stops and red cell production pauses. With rapid growth and the shorter life of fetal red cells (about 60 days), haemoglobin drops to a low point at 8-10 weeks: the physiological nadir. It is lower in preterm infants.
| Age | Mean haemoglobin (g/dL), Akbar |
|---|---|
| 1-3 days (term) | 18.5 |
| 1 month | 14 |
| 2-6 months | 11.5 |
| 6 months-2 years | 12 |
| 2-6 years | 12.5 |
| 6-12 years | 13.5 |
After puberty boys keep a haemoglobin about 1.5-2 g/dL higher than girls because of androgens (Nelson).
Definition
- Anaemia is a haemoglobin or haematocrit more than 2 standard deviations below the mean for the child's age and sex.
- A physiological definition also exists: in cyanotic heart disease or lung disease, a "normal" haemoglobin may still be too low for the tissues.
- The haemoglobin can mislead: dehydration concentrates the blood and hides anaemia, fluid overload dilutes it, and after an acute bleed the fall may take several days to show.
A child who has just bled heavily can have a normal haemoglobin at first; the drop appears only as the plasma volume is restored.
Classification
By red cell size (MCV)
| Group | Main causes |
|---|---|
| Microcytic, hypochromic | Iron deficiency, thalassaemia, lead poisoning, anaemia of chronic inflammation, sideroblastic anaemia, copper deficiency |
| Normocytic | Acute blood loss, haemolysis, anaemia of chronic disease, renal failure, marrow infiltration (leukaemia), aplastic anaemia, transient erythroblastopenia |
| Macrocytic | Vitamin B12 and folate deficiency (megaloblastic), Diamond-Blackfan anaemia, Fanconi anaemia, liver disease, hypothyroidism, drugs such as phenytoin |
By marrow response (reticulocyte count)
- High reticulocytes: the marrow is working hard, so red cells are being lost or destroyed. Think of bleeding or haemolysis (membrane defects, enzyme defects, haemoglobinopathies, immune or mechanical destruction).
- Low or normal reticulocytes: production is inadequate. Think of nutritional deficiency, marrow failure or infiltration, or a very recent event before the marrow has had time to respond.
The hypochromic microcytic anaemias of childhood are mostly iron deficiency and thalassaemia; the macrocytic ones are mostly B12 and folate deficiency.
Clinical features
Symptoms and general signs
- Many children are asymptomatic; chronic anaemia is remarkably well tolerated.
- Tiredness, irritability, poor feeding, headache, breathlessness, poor exercise tolerance.
- Pallor, tachycardia, a systolic flow murmur and, when severe, high-output heart failure.
- How urgently to act (including transfusion) depends on the cardiovascular state, not on the number alone.
Clues in the history
| Clue | Points to |
|---|---|
| Diet of mainly cow's milk | Iron deficiency |
| Goat's milk | Folate deficiency |
| Strict vegetarian (vegan) diet or mother | Vitamin B12 deficiency |
| Pica | Iron deficiency, lead poisoning |
| Jaundice in the family, early cholecystectomy or splenectomy in a relative | Inherited haemolysis (spherocytosis) |
| Consanguinity, affected cousins | Thalassaemia and other recessive disorders |
| Boys affected through the mother | X-linked: G6PD deficiency |
| Oxidant drugs (sulphonamides, antimalarials) | G6PD haemolysis |
| Phenytoin, methotrexate | Folate deficiency |
| Chronic diarrhoea | Malabsorption of iron, folate or B12 |
| Bleeding, bruising, recurrent infection | Marrow failure or leukaemia |
Clues on examination
| Finding | Think of |
|---|---|
| Jaundice, splenomegaly | Haemolysis |
| Frontal bossing, prominent cheekbones, big spleen | Thalassaemia major |
| Koilonychia (spoon nails), angular stomatitis | Iron deficiency |
| Glossitis, posterior column signs, vitiligo | Vitamin B12 deficiency |
| Absent thumbs, café-au-lait spots, short stature | Fanconi anaemia |
| Triphalangeal thumb, cleft lip, shield chest | Diamond-Blackfan anaemia |
| Petechiae, lymph nodes, liver and spleen enlarged | Leukaemia or marrow infiltration |
| Poor growth | Chronic disease |
First investigations
- Full blood count with indices (MCV, MCH, MCHC, RDW), white cell and platelet counts.
- Reticulocyte count.
- Peripheral blood film: hypochromic microcytes (iron deficiency), target cells (thalassaemia), spherocytes, sickle cells, bite or blister cells (G6PD), fragmented cells (haemolytic uraemic syndrome), blasts (leukaemia).
- Look at all three cell lines: if white cells and platelets are also low, the problem is in the marrow, not only the red cell line.
- Signs of haemolysis: raised unconjugated bilirubin and LDH, low haptoglobin.
- Stool for occult blood, because bleeding must be looked for in every anaemic child.
- Then targeted tests: iron studies, haemoglobin electrophoresis, B12 and folate, Coombs test, G6PD assay, bone marrow.
In anaemia of inflammation, hepcidin rises and traps iron in macrophages, so serum iron is low but ferritin is normal or high. Giving iron blindly to a systemically ill child is not advised.
Pallor and jaundice together suggest haemolysis; pallor with petechiae and organomegaly suggests marrow infiltration.
Congenital hypoplastic anaemia: Diamond-Blackfan anaemia
What it is
Diamond-Blackfan anaemia (DBA) is a rare, lifelong congenital failure of red cell production: a pure red cell aplasia. Only the erythroid line is affected; white cells and platelets are normal. It is classed among the inherited bone marrow failure syndromes, and mutation analysis can support the diagnosis.
Clinical features
- Presents at birth or in the first few months with pallor, severe anaemia and sometimes heart failure; about 90% are diagnosed before 1 year (Nelson).
- About half have physical anomalies (Akbar):
- Craniofacial (the commonest): microcephaly, wide-set eyes, snub nose, high-arched or cleft palate, cleft lip.
- Thumbs: triphalangeal thumb, flat thenar eminence; the radial pulse may be absent.
- Short stature (more than a third), webbed neck, shield chest.
- Eye (glaucoma, cataract, squint) and kidney anomalies.
DBA = "Don't Build Any" red cells, but white cells and platelets are fine.
Laboratory findings
| Test | Result in DBA |
|---|---|
| Haemoglobin | Low, often severe |
| MCV | Raised (macrocytic), though without megaloblastic features |
| Reticulocytes | Very low |
| White cells and platelets | Normal |
| HbF | Raised |
| Red cell adenosine deaminase (ADA) | Raised |
| Fetal "i" antigen on red cells | Present |
| Bone marrow | Red cell precursors absent or very scanty; other lines normal |
Raised red cell ADA is the key test that separates DBA from transient erythroblastopenia of childhood (TEC), where ADA is normal.
Differential diagnosis
- Transient erythroblastopenia of childhood (usually older, see below).
- Fanconi anaemia and Shwachman-Diamond syndrome (other inherited marrow failure syndromes, which affect more than one cell line).
- Parvovirus B19 red cell aplasia, especially in a child with chronic haemolysis.
- Anaemia of renal failure, hypothyroidism.
Management
- Corticosteroids (prednisolone) stimulate red cell production: about 80% respond according to Akbar, 50-66% according to Nelson. Responders usually need treatment for a long time.
- Regular red cell transfusion for those who do not respond, with iron chelation to prevent iron overload.
- Haematopoietic stem cell transplantation is the only cure.
- Spontaneous remission occurs in a minority.
- Long-term follow-up is needed because there is a higher risk of leukaemia and other blood cancers.
Transient erythroblastopenia of childhood (TEC)
- The commonest acquired red cell aplasia of childhood.
- A temporary suppression of red cell production in a previously healthy child, usually aged 6 months to 3 years (Nelson: up to 5 years, most over 1 year), often after a viral infection.
- Normocytic anaemia with low reticulocytes; no haemolysis, no lymph nodes or organ enlargement; Coombs test negative.
- Normal HbF, normal i antigen and normal red cell ADA.
- Marrow (if done) shows isolated absence of red cell precursors.
- Recovers on its own in about 4-8 weeks; a rise in reticulocytes heralds recovery. Transfuse only if the anaemia causes cardiovascular strain.
| Feature | Diamond-Blackfan anaemia | TEC |
|---|---|---|
| Age at onset | Birth to first months; 90% under 1 year | 6 months to 3-5 years |
| Cause | Congenital marrow failure | Post-viral, acquired |
| Physical anomalies | About half | None |
| MCV | High | Normal |
| HbF, i antigen | Raised, present | Normal, absent |
| Red cell ADA | Raised | Normal |
| Course | Lifelong | Recovers in weeks |
| Treatment | Steroids, transfusion, stem cell transplant | Observation, transfusion only if needed |
Both DBA and TEC cause anaemia with low reticulocytes and normal white cells and platelets. Age, MCV, anomalies, HbF and ADA separate them.
Expect: the definition of anaemia (2 SD below the mean for age and sex); the physiological nadir at 8-10 weeks; how MCV and reticulocyte count classify anaemia; dietary and family clues (cow's milk, goat's milk, vegan diet, consanguinity, X-linked G6PD); examination clues such as frontal bossing, koilonychia and absent or triphalangeal thumbs; and a young infant with macrocytic anaemia, reticulocytopenia, normal white cells and platelets and a thumb anomaly, which is Diamond-Blackfan anaemia treated first with steroids; and its distinction from transient erythroblastopenia by age, MCV, HbF and red cell ADA.
Quick revision
- Anaemia: Hb more than 2 SD below the mean for age and sex.
- Physiological nadir at 8-10 weeks; deeper in preterm babies.
- Microcytic: iron deficiency, thalassaemia. Macrocytic: B12, folate, DBA, Fanconi.
- High reticulocytes: haemolysis or bleeding. Low: production failure.
- Check all three cell lines; pancytopenia means a marrow problem.
- DBA: pure red cell aplasia in infancy, macrocytic, low reticulocytes, raised HbF and red cell ADA.
- DBA anomalies: craniofacial, triphalangeal thumb, short stature.
- DBA treatment: steroids, then transfusion with chelation; stem cell transplant cures; leukaemia risk.
- TEC: older child, normocytic, normal ADA, recovers in 4-8 weeks.
Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).
FAQ
Why is a haemoglobin of 10 g/dL normal at 2 months but abnormal at 8 years?
Haemoglobin falls after birth to a physiological low point at about 8-10 weeks, then rises through childhood, so every result must be compared with the normal range for that age.
What does a low reticulocyte count tell you in an anaemic child?
It means the marrow is not producing enough red cells, so the cause is a production problem such as nutritional deficiency, red cell aplasia or marrow failure, rather than bleeding or haemolysis.
Which test best separates Diamond-Blackfan anaemia from transient erythroblastopenia?
Red cell adenosine deaminase, which is raised in Diamond-Blackfan anaemia and normal in transient erythroblastopenia; a raised HbF and macrocytosis also favour Diamond-Blackfan anaemia.
Can Diamond-Blackfan anaemia be cured?
Steroids control it in many children, but the only cure is haematopoietic stem cell transplantation.