Hereditary Spherocytosis in Children

Hereditary Spherocytosis Introduction Pathophysiology Clinical Presentation Diagnosis Management Complications Prognosis

Introduction to Hereditary Spherocytosis in Children

Hereditary Spherocytosis (HS) is a genetic disorder characterized by the production of abnormally shaped red blood cells (RBCs) that are spherical rather than biconcave discs. It is the most common inherited hemolytic anemia in individuals of Northern European descent, with an estimated prevalence of 1 in 2,000 to 1 in 5,000 people.

Key points:

• Autosomal dominant inheritance in 75% of cases; autosomal recessive in 25%
• Caused by defects in RBC membrane proteins, primarily ankyrin, spectrin, band 3, and protein 4.2
• Characterized by hemolytic anemia, jaundice, and splenomegaly
• Severity ranges from asymptomatic to severe, life-threatening anemia
• Diagnosis often made in childhood but can be delayed until adulthood in milder cases

Pathophysiology of Hereditary Spherocytosis

The underlying defect in HS involves the red blood cell membrane skeleton, leading to decreased membrane surface area relative to cell volume.

Key aspects of pathophysiology:

1. Genetic mutations:
   • ANK1 (ankyrin) - 50-60% of cases
   • SPTB (β-spectrin) - 15-30% of cases
   • SLC4A1 (band 3) - 15-20% of cases
   • EPB42 (protein 4.2) - 3-5% of cases
   • SPTA1 (α-spectrin) - <1% of cases
2. Membrane instability:
   • Defective proteins lead to weakened vertical interactions between the lipid bilayer and the spectrin-based membrane skeleton
   • Results in loss of membrane lipids and decreased surface area-to-volume ratio
3. Spherocyte formation:
   • Loss of membrane leads to spherical shape
   • Spherocytes are less deformable and more fragile than normal RBCs
4. Splenic destruction:
   • Spherocytes are trapped and destroyed in the spleen
   • Leads to extravascular hemolysis and shortened RBC lifespan (10-30 days vs. normal 120 days)
5. Compensatory erythropoiesis:
   • Increased production of RBCs in bone marrow
   • May lead to bilirubin overproduction and gallstone formation

Clinical Presentation of Hereditary Spherocytosis in Children

The clinical presentation of HS in children can vary widely, from asymptomatic to severe hemolytic anemia. Symptoms typically appear in early childhood but may be recognized at any age.

Common presenting features:

• Anemia:
  • Pallor
  • Fatigue
  • Shortness of breath
  • Tachycardia
• Jaundice:
  • Yellowing of skin and sclera
  • May be intermittent or persistent
• Splenomegaly:
  • Often palpable by age 3-5 years
  • May cause abdominal discomfort or early satiety
• Gallstones:
  • More common in older children and adolescents
  • May present with right upper quadrant pain or cholecystitis

Other potential presentations:

• Aplastic crisis:
  • Sudden worsening of anemia
  • Often triggered by parvovirus B19 infection
• Hemolytic crisis:
  • Increased hemolysis due to infection or stress
  • May require transfusion support
• Neonatal presentation:
  • Severe hyperbilirubinemia requiring exchange transfusion
  • Anemia in first few months of life

Diagnosis of Hereditary Spherocytosis

Diagnosis of HS is based on clinical presentation, family history, and laboratory findings. A stepwise approach is recommended.

Diagnostic workup:

1. Complete blood count (CBC):
   • Anemia (usually normocytic, normochromic)
   • Increased mean corpuscular hemoglobin concentration (MCHC)
   • Reticulocytosis
2. Peripheral blood smear:
   • Presence of spherocytes
   • Polychromasia (reflecting reticulocytosis)
3. Osmotic fragility test:
   • Increased RBC lysis in hypotonic solutions
   • May be normal in mild cases or neonates
4. Eosin-5'-maleimide (EMA) binding test:
   • Flow cytometry-based test
   • High sensitivity and specificity
5. Acid glycerol lysis test (AGLT):
   • Alternative to osmotic fragility test
   • More sensitive in mild cases
6. Cryohemolysis test:
   • Measures RBC lysis after cooling and rewarming
   • Useful in differentiating HS from other hemolytic anemias
7. SDS-PAGE analysis of RBC membrane proteins:
   • Identifies specific protein deficiencies
   • Not routinely performed for diagnosis
8. Genetic testing:
   • Not usually necessary for diagnosis
   • May be helpful in unclear cases or for family studies

Additional tests to assess complications:

• Liver function tests and bilirubin levels
• Abdominal ultrasound for splenomegaly and gallstones
• Folate levels

Management of Hereditary Spherocytosis in Children

Management of HS in children is tailored to disease severity and individual patient needs. The main goals are to manage anemia, prevent complications, and improve quality of life.

Treatment options:

1. Supportive care:
   • Folic acid supplementation (especially in moderate to severe cases)
   • Iron supplementation if deficient (caution in those post-splenectomy)
   • Education about avoiding oxidative stressors
2. Transfusion therapy:
   • Reserved for severe anemia or aplastic crisis
   • Aim to maintain hemoglobin above 7-8 g/dL
3. Splenectomy:
   • Considered in moderate to severe cases
   • Usually delayed until 6-9 years of age if possible
   • Laparoscopic approach preferred
   • Partial splenectomy may be an option in young children
4. Management of aplastic crisis:
   • Supportive care and transfusions as needed
   • Isolation to prevent spread of parvovirus B19
5. Cholecystectomy:
   • For symptomatic gallstones
   • Often performed at the time of splenectomy
6. Immunizations:
   • Ensure up-to-date vaccinations, especially if considering splenectomy
   • Pneumococcal, meningococcal, and Haemophilus influenzae type b vaccines

Monitoring:

• Regular follow-up with hematologist
• Periodic CBC and reticulocyte count
• Annual abdominal ultrasound for gallstones
• Growth and development assessment

Complications of Hereditary Spherocytosis

Children with HS may experience various complications related to chronic hemolysis and treatment.

Common complications:

• Gallstones:
  • Due to increased bilirubin production
  • Risk increases with age
  • May require cholecystectomy
• Aplastic crisis:
  • Usually triggered by parvovirus B19 infection
  • Can lead to severe, life-threatening anemia
• Hemolytic crisis:
  • Triggered by infections, stress, or oxidative agents
  • May require transfusion support
• Iron overload:
  • More common in transfusion-dependent patients
  • May require chelation therapy
• Folate deficiency:
  • Due to increased erythropoiesis
  • Can exacerbate anemia
• Growth delay:
  • May occur in severe, untreated cases
  • Usually resolves with appropriate management

Post-splenectomy complications:

• Overwhelming post-splenectomy infection (OPSI):
  • Life-threatening sepsis
  • Risk highest in young children
  • Requires prompt antibiotic treatment
• Thrombotic complications:
  • Increased risk of venous thromboembolism
  • May require anticoagulation in high-risk cases
• Pulmonary hypertension:
  • Rare but serious complication
  • Regular echocardiographic screening recommended

Prognosis of Hereditary Spherocytosis in Children

The prognosis for children with HS is generally good, especially with appropriate management. Life expectancy is typically normal.

Factors affecting prognosis:

• Disease severity:
  • Mild cases may not require intervention
  • Severe cases may need more intensive management
• Timing of diagnosis and treatment:
  • Early diagnosis allows for proactive management
  • Delayed diagnosis may lead to more complications
• Compliance with treatment:
  • Regular follow-up and adherence to recommendations improve outcomes
• Splenectomy:
  • Often leads to significant improvement in anemia
  • May increase risk of infections and thrombotic complications

Long-term considerations:

• Quality of life:
  • Most patients lead normal lives with minimal limitations
  • Regular medical care and monitoring required
• Fertility and pregnancy:
  • Generally not affected
  • May require closer monitoring during pregnancy
• Psychosocial aspects:
  • Importance of education and support for patients and families
  • Transition of care from pediatric to adult services
• Long-term complications:
  • Need for ongoing monitoring of post-splenectomy patients
  • Potential for iron overload in transfusion-dependent cases

Research and future directions:

• Gene therapy approaches in development
• Improved understanding of genotype-phenotype correlations
• Novel treatments targeting RBC membrane stability

Hereditary Spherocytosis in Children

1. Question: What is the primary defect in hereditary spherocytosis? Answer: Abnormalities in red blood cell membrane proteins, particularly spectrin, ankyrin, band 3, or protein 4.2
2. Question: What is the characteristic shape of red blood cells in hereditary spherocytosis? Answer: Spherical shape with decreased surface area-to-volume ratio
3. Question: What is the most common inheritance pattern of hereditary spherocytosis? Answer: Autosomal dominant (75% of cases)
4. Question: Which protein defect is most commonly associated with hereditary spherocytosis? Answer: Ankyrin defects (40-50% of cases)
5. Question: What is the primary clinical manifestation of hereditary spherocytosis in children? Answer: Hemolytic anemia of variable severity
6. Question: How does hereditary spherocytosis affect red blood cell membrane stability? Answer: It decreases membrane stability, leading to increased fragility and splenic sequestration
7. Question: What is the most common complication of hereditary spherocytosis in children? Answer: Gallstones (cholelithiasis)
8. Question: Which laboratory finding is characteristic of hereditary spherocytosis? Answer: Increased osmotic fragility of red blood cells
9. Question: What is the gold standard diagnostic test for hereditary spherocytosis? Answer: Eosin-5-maleimide (EMA) binding test
10. Question: What is the primary treatment for moderate to severe hereditary spherocytosis in children? Answer: Splenectomy (often partial splenectomy in young children)
11. Question: How does hereditary spherocytosis affect red blood cell lifespan? Answer: It significantly shortens red blood cell lifespan due to increased splenic destruction
12. Question: What is the role of the spleen in the pathophysiology of hereditary spherocytosis? Answer: The spleen selectively traps and destroys spherocytes, exacerbating hemolysis
13. Question: Which complication is associated with severe forms of hereditary spherocytosis in neonates? Answer: Severe neonatal jaundice requiring exchange transfusion
14. Question: How does hereditary spherocytosis affect reticulocyte count? Answer: Reticulocyte count is typically elevated due to compensatory erythropoiesis
15. Question: What is the most common extramedullary hematopoietic site in severe hereditary spherocytosis? Answer: Paravertebral masses
16. Question: How does hereditary spherocytosis affect mean corpuscular hemoglobin concentration (MCHC)? Answer: MCHC is typically increased due to cellular dehydration
17. Question: What is the primary difference between hereditary spherocytosis and hereditary elliptocytosis? Answer: Spherocytes are the predominant cell shape in spherocytosis, while elliptocytes are predominant in elliptocytosis
18. Question: Which diagnostic test is used to assess red cell deformability in hereditary spherocytosis? Answer: Osmotic gradient ektacytometry
19. Question: How does hereditary spherocytosis affect iron metabolism? Answer: It can lead to iron overload due to increased erythropoiesis and transfusions
20. Question: What is the role of erythropoietin levels in hereditary spherocytosis? Answer: Erythropoietin levels are typically elevated due to chronic hemolysis
21. Question: How does hereditary spherocytosis affect red blood cell deformability? Answer: It significantly decreases red blood cell deformability due to loss of membrane surface area
22. Question: What is the primary indication for splenectomy in hereditary spherocytosis? Answer: Moderate to severe anemia, growth retardation, or symptomatic splenomegaly
23. Question: How does hereditary spherocytosis affect the spleen? Answer: It leads to splenomegaly due to increased red blood cell sequestration and destruction
24. Question: What is the primary difference between mild and severe forms of hereditary spherocytosis? Answer: The degree of membrane protein deficiency and resulting clinical manifestations
25. Question: How does hereditary spherocytosis affect bilirubin levels? Answer: Bilirubin levels are typically elevated due to increased hemolysis
26. Question: What is the role of the band 3 protein in normal red blood cells? Answer: It functions as an anion exchanger and provides structural support to the membrane
27. Question: How does hereditary spherocytosis affect red blood cell hydration? Answer: It causes cellular dehydration due to loss of membrane surface area
28. Question: What is the primary reason for folic acid supplementation in hereditary spherocytosis? Answer: To support increased erythropoiesis and prevent megaloblastic anemia
29. Question: How does hereditary spherocytosis affect the mean corpuscular volume (MCV)? Answer: MCV is typically normal or slightly decreased
30. Question: What is the role of the acidified glycerol lysis test (AGLT) in diagnosing hereditary spherocytosis? Answer: It assesses red cell fragility and can be used as a screening test
31. Question: How does partial splenectomy differ from total splenectomy in treating hereditary spherocytosis? Answer: Partial splenectomy reduces hemolysis while maintaining some splenic immune function

Further Reading

Additional Resources for Hereditary Spherocytosis in Children

• How I manage hereditary spherocytosis - Blood Journal
• Hereditary Spherocytosis - StatPearls
• Guidelines for the diagnosis and management of hereditary spherocytosis – 2011 update - British Journal of Haematology
• Hereditary spherocytosis - Nature Reviews Disease Primers
• Hereditary spherocytosis - UpToDate (subscription required)