Paediatrics chapters
Hereditary spherocytosis, sickle cell anaemia and red cell enzyme defects
The main inherited haemolytic anaemias of childhood: the membrane defect of hereditary spherocytosis, the haemoglobin defect of sickle cell anaemia with its crises, and the enzyme defects G6PD and pyruvate kinase deficiency, with the tests and treatment for each.
In 30 seconds
- Hereditary spherocytosis: usually autosomal dominant defect of spectrin or ankyrin; round, rigid red cells are destroyed in the spleen; anaemia, jaundice, splenomegaly, gallstones; spherocytes with increased osmotic fragility and a negative Coombs test; splenectomy after 5 years cures the anaemia.
- Sickle cell anaemia: autosomal recessive, valine takes the place of glutamic acid as the sixth amino acid of the beta chain; HbS polymerises when deoxygenated causing vaso-occlusion and haemolysis; dactylitis from about 6 months, pain crises, acute chest syndrome, splenic sequestration, parvovirus aplastic crisis, stroke, pneumococcal sepsis; give penicillin, vaccines, folic acid, hydroxyurea.
- G6PD deficiency: X-linked, commonest red cell enzyme defect; oxidant drugs, fava beans, mothballs or infection cause acute intravascular haemolysis with dark urine, Heinz bodies and bite cells; avoid triggers.
On this page
Overview
Haemolysis means red cells are destroyed before the end of their normal life of about 120 days. In children the important inherited causes fall into three groups:
- Membrane defects: hereditary spherocytosis (and elliptocytosis).
- Haemoglobin defects: sickle cell disease (and the thalassaemias, covered in their own chapter).
- Enzyme defects: G6PD deficiency and pyruvate kinase deficiency.
Features common to all haemolysis
- Pallor, jaundice (unconjugated bilirubin), splenomegaly, dark urine.
- Pigment gallstones in chronic cases, even in childhood.
- Reticulocytosis, raised LDH and unconjugated bilirubin, low haptoglobin.
- Aplastic crisis: parvovirus B19 stops red cell production for a short time, and because these cells already die early, haemoglobin falls steeply with low reticulocytes.
- Extra folic acid need, because the marrow is overworking.
| Type of haemolysis | Where cells break | Clues |
|---|---|---|
| Extravascular | Spleen and liver macrophages | Splenomegaly, jaundice (spherocytosis, sickle cell, immune) |
| Intravascular | Inside vessels | Haemoglobinuria (dark or cola-coloured urine), haemoglobinaemia (G6PD crisis) |
Hereditary spherocytosis
Genetics
- The commonest inherited abnormality of the red cell membrane and a common cause of inherited haemolytic anaemia.
- Autosomal dominant in about 75%; the rest are recessive or new mutations, so a negative family history does not exclude it.
- Defect in the membrane skeleton: most often spectrin or ankyrin (also band 3 and protein 4.2).
Pathophysiology
- The faulty skeleton cannot hold the lipid bilayer properly, so small pieces of membrane are lost.
- The cell keeps its volume but loses surface, so it becomes a sphere instead of a biconcave disc.
- Spheres are rigid and get stuck passing from the splenic cords into the sinuses.
- The spleen destroys them early.
Clinical features
- Severity varies from a mild, well-compensated state found by chance to severe transfusion-dependent anaemia.
- Newborn: anaemia and jaundice, sometimes needing phototherapy or exchange.
- Older child: pallor, intermittent jaundice, tiredness, poor exercise tolerance.
- Splenomegaly (usual).
- Pigment gallstones, possible from about 4-5 years of age.
- Aplastic crises with parvovirus; severe cases may show skull and bone marrow expansion and growth failure.
- Family history of anaemia, jaundice, gallstones, or splenectomy.
Diagnosis
- Haemoglobin usually 6-10 g/dL; reticulocytosis.
- Film: spherocytes (small, dense cells with no central pallor).
- Osmotic fragility test: spherocytes burst more easily in dilute salt solution (increased fragility); the incubated test is more sensitive.
- Coombs (direct antiglobulin) test negative: this rules out immune haemolysis, which also produces spherocytes.
- Raised unconjugated bilirubin, low haptoglobin; ultrasound for gallstones.
Exam trap
Spherocytes and abnormal osmotic fragility are also seen in immune haemolysis, including ABO haemolytic disease of the newborn. A negative Coombs test and the family history point to hereditary spherocytosis.
Management
- Folic acid daily (Akbar: 1 mg) to support the marrow.
- Transfusion for severe anaemia or aplastic crisis.
- Splenectomy corrects the anaemia and stops haemolysis, although the spherocytes remain on the film. It also lowers the risk of gallstones.
- Delay until after 5 years (Akbar: 5-6 years) to reduce the risk of overwhelming post-splenectomy sepsis.
- Give pneumococcal, meningococcal and Hib vaccines before surgery.
- Give oral penicillin prophylaxis afterwards (Akbar: penicillin V into adult life).
- Partial splenectomy may help younger children while keeping some splenic immune function.
- Cholecystectomy if symptomatic gallstones.
Memory hook
Spherocytosis = Spleen: the spleen destroys the cells, and removing it cures the anaemia.
Sickle cell anaemia
Inheritance and molecular defect
- Autosomal recessive. Homozygous HbSS is sickle cell anaemia; one gene gives sickle cell trait (HbAS).
- A point mutation in the beta globin gene swaps the sixth amino acid of the beta chain, glutamic acid, for valine.
- Other sickle syndromes: HbSC disease and HbS-beta thalassaemia.
Pathophysiology: vaso-occlusion
- When deoxygenated, HbS polymerises into long fibres and distorts the cell into a sickle shape.
- Repeated sickling makes cells rigid and fragile: chronic haemolysis.
- Sickled cells block small vessels: ischaemia, infarction and pain.
- Sickling is triggered by hypoxia, acidosis, dehydration, fever, infection and cold.
Clinical features
- Well for the first months because of protective HbF; problems begin from about 4-6 months.
- Chronic haemolytic anaemia (haemoglobin about 6-10 g/dL), jaundice, flow murmur, delayed growth and puberty.
- Spleen: enlarged in infancy, then repeated infarction leaves it small and fibrotic (autosplenectomy) by early childhood, so it is not palpable later.
- Functional asplenia from early infancy: very high risk of pneumococcal and Hib sepsis and meningitis, and Salmonella osteomyelitis. Fever above 38.5°C is an emergency.
The crises
| Crisis | What happens | Key points |
|---|---|---|
| Dactylitis (hand-foot syndrome) | Painful symmetrical swelling of hands and feet | Often the first sign, in infants and toddlers; infarction of metacarpals and metatarsals |
| Vaso-occlusive (painful) crisis | Pain in long bones, back, chest or abdomen | The commonest crisis; lasts about 2-7 days |
| Acute chest syndrome | Fever, chest pain, cough, hypoxia, new infiltrate on chest X-ray | A leading cause of death; infection or infarction in the lung |
| Splenic sequestration | Sudden pooling of blood in a rapidly enlarging spleen | Haemoglobin falls by 2 g/dL or more, hypovolaemic shock; reticulocytes high; mainly young children |
| Aplastic crisis | Parvovirus B19 halts red cell production | Falling haemoglobin with low reticulocytes |
| Haemolytic crisis | Faster haemolysis | May go with G6PD deficiency or infection |
Other complications
- Stroke: overt stroke in about 8-10% (sudden weakness, seizures, altered consciousness); silent infarcts in about 20%. Transcranial Doppler screening identifies children at risk.
- Priapism, avascular necrosis of the femoral head, leg ulcers in older patients.
- Kidney: haematuria, papillary necrosis, inability to concentrate urine (so they dehydrate easily).
- Gallstones, retinopathy, chronic lung disease and pulmonary hypertension, cardiomyopathy.
- Iron overload and red cell antibodies in children who receive many transfusions.
Investigations
- Haemoglobin low, reticulocytes markedly raised.
- Film: sickle cells and numerous target cells.
- Haemoglobin electrophoresis or HPLC is essential to confirm the exact type: in HbSS there is no HbA, HbS about 85-95% and HbF about 5-15%.
- Newborn screening in high-risk populations allows early penicillin and vaccines.
| Genotype | HbA | HbS | Picture |
|---|---|---|---|
| AS (trait) | 55-60% | 40-45% | Usually no symptoms; haematuria possible |
| SS (anaemia) | 0 | 85-95% | Severe haemolytic anaemia and crises |
| SC disease | 0 | 45-50% (plus HbC) | Moderate anaemia, retinopathy |
High-yield
Haemoglobin electrophoresis (or HPLC) is required to confirm sickle cell disease and to tell SS from AS, SC and S-beta thalassaemia.
Management
Prevention (comprehensive care)
- Daily oral penicillin from diagnosis in infancy.
- Vaccines: pneumococcal, Hib, hepatitis B and influenza.
- Folic acid.
- Avoid dehydration, hypoxia, chilling and acidosis; treat fever urgently with antibiotics.
- Hydroxyurea: raises HbF, which reduces painful crises, dactylitis and acute chest syndrome; it can be used from infancy (Akbar starts at 15-20 mg/kg once daily).
- Chronic transfusion after a stroke (or abnormal Doppler) to keep HbS below 30%.
Acute crises
- Pain: fluids, adequate analgesia (NSAIDs and opioids; fear of addiction is overrated), oxygen if hypoxic.
- Acute chest syndrome: oxygen, fluids, analgesia, antibiotics, bronchodilators, transfusion (exchange transfusion only rarely); incentive spirometry helps prevent it.
- Sequestration and aplastic crises: red cell transfusion.
- Priapism: oxygen, fluids, analgesia, transfusion.
Cure: haematopoietic stem cell transplantation.
High-yield
Sickle cell anaemia = asplenia. Every child needs penicillin prophylaxis and vaccines, and fever is treated as an emergency.
Exam trap
In an aplastic crisis the reticulocyte count is low; in a sequestration crisis it is high and the spleen is suddenly big.
G6PD deficiency
Genetics and epidemiology
- The commonest red cell enzyme defect causing haemolysis.
- X-linked recessive: mainly boys; heterozygous girls are occasionally affected.
- Common where malaria is or was endemic, including Pakistan and the Mediterranean; deficiency gives some protection against malaria.
- Variants: the African (A−) variant causes self-limited episodes; the Mediterranean variant is more severe and causes favism.
Pathophysiology
- G6PD is the first enzyme of the hexose monophosphate shunt, which makes NADPH.
- NADPH keeps glutathione reduced, protecting the cell from oxidants.
- Without it, an oxidant stress oxidises haemoglobin, which precipitates as Heinz bodies.
- The spleen removes the Heinz bodies, leaving bite cells; badly damaged cells burst inside vessels.
- Older red cells have the least enzyme, so they are destroyed first.
Triggers
| Group | Examples |
|---|---|
| Antibacterials | Sulphonamides, co-trimoxazole, dapsone, nitrofurantoin, nalidixic acid, chloramphenicol |
| Antimalarials | Primaquine, chloroquine |
| Others | Aspirin (high dose), methylene blue, vitamin K analogues, probenecid |
| Chemicals and foods | Naphthalene (mothballs), fava beans |
| Illness | Infection (the commonest trigger in children), diabetic ketoacidosis, hepatitis |
Clinical features
- Newborn: neonatal jaundice, sometimes severe enough to need exchange transfusion.
- Acute haemolytic episode: 24-48 hours after exposure, sudden pallor, jaundice and dark (cola-coloured) urine from haemoglobinuria; can cause shock or kidney injury.
- Normal between episodes.
- A rare chronic form causes ongoing non-spherocytic haemolytic anaemia.
Diagnosis
- Falling haemoglobin; haemoglobinuria; raised unconjugated bilirubin; low haptoglobin.
- Film: Heinz bodies (special stain, first few days), bite (blister) cells.
- Reticulocytes may be low for the first 3-4 days, then rise.
- G6PD enzyme assay confirms the diagnosis, but it can be falsely normal during or just after an episode because the oldest, most deficient cells have been destroyed and young reticulocytes have more enzyme. Repeat in a few weeks, or test the mother.
Management
- Stop the offending drug and treat infection.
- Hydration (and urine alkalinisation) to protect the kidneys from haemoglobin.
- Blood transfusion if anaemia is severe or the circulation is compromised.
- Most episodes are self-limiting.
- Prevention: give the family a list of drugs, foods and chemicals to avoid.
High-yield
A boy with sudden dark urine and jaundice a day or two after co-trimoxazole, primaquine or mothballs, with bite cells, has G6PD deficiency until proved otherwise.
Pyruvate kinase deficiency
- Much less common; usually autosomal recessive.
- Defect in glycolysis leads to ATP depletion and a rigid cell that the spleen destroys.
- Chronic haemolytic anaemia with jaundice and splenomegaly; not made worse by oxidants.
- Aplastic crises can be life-threatening.
- Splenectomy reduces the anaemia and transfusion needs.
| Feature | G6PD deficiency | Pyruvate kinase deficiency |
|---|---|---|
| Pathway | Hexose monophosphate shunt (NADPH) | Glycolysis (ATP) |
| Inheritance | X-linked | Autosomal recessive |
| Pattern | Episodic, triggered by oxidants | Chronic |
| Film | Heinz bodies, bite cells | Non-specific |
| Splenectomy | Not helpful | Helpful |
Exam focus
Expect: inheritance of each disorder (spherocytosis AD, sickle cell AR, G6PD X-linked); the spectrin or ankyrin defect and osmotic fragility test with negative Coombs test; timing of splenectomy and pre-splenectomy vaccines; the valine-for-glutamic-acid mutation at position 6; dactylitis as the earliest sickle feature; types of crisis, especially parvovirus aplastic crisis and splenic sequestration; acute chest syndrome; penicillin prophylaxis, vaccines and hydroxyurea; G6PD triggers (sulphonamides, primaquine, fava beans, naphthalene), haemoglobinuria, Heinz bodies and bite cells, and why the assay may be normal during an attack.
Quick revision
- Haemolysis: pallor, jaundice, splenomegaly, gallstones, reticulocytosis, low haptoglobin.
- Parvovirus B19: aplastic crisis in any chronic haemolysis.
- Spherocytosis: AD, spectrin/ankyrin, spherocytes, raised osmotic fragility, Coombs negative.
- Splenectomy after 5 years: vaccines before, penicillin after; spherocytes persist.
- Sickle: Glu to Val at beta-6, AR; HbF protects for the first months.
- Dactylitis first; pain crisis commonest; acute chest syndrome; sequestration with shock.
- Penicillin, vaccines, folic acid, hydroxyurea; transfuse for stroke to keep HbS below 30%.
- G6PD: X-linked; oxidant drugs, fava beans, mothballs, infection; Heinz bodies, bite cells.
- G6PD assay can be normal right after haemolysis; repeat later.
- PK deficiency: AR, chronic, not oxidant-triggered, splenectomy helps.
Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).
FAQ
Why is splenectomy delayed until after 5 years in hereditary spherocytosis?
Young children without a spleen are at high risk of overwhelming infection with encapsulated bacteria, and older children respond better to the pneumococcal vaccine.
Why do sickle cell symptoms start only after a few months of age?
Fetal haemoglobin, which does not sickle, protects the baby until it falls during the first months of life.
Why must children with sickle cell anaemia take penicillin?
Their spleen stops working early in life, so they cannot clear pneumococci and other encapsulated bacteria; daily penicillin and vaccines prevent fatal sepsis.
Why might a G6PD test be normal in a child who has just had a haemolytic episode?
The oldest, most deficient red cells have already been destroyed and the young cells that remain have more enzyme, so the test should be repeated a few weeks later.