Paroxysmal Nocturnal Hemoglobinuria in Children

Topic Name Introduction Pathophysiology Clinical Presentation Diagnosis Treatment Prognosis

Introduction to Paroxysmal Nocturnal Hemoglobinuria in Children

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis. While primarily affecting adults, PNH can occur in children and adolescents, presenting unique diagnostic and management challenges.

Key points:

• Incidence: Approximately 1-1.5 cases per million population per year
• Pediatric cases: Account for about 10% of all PNH cases
• Age of onset: Can occur at any age, but pediatric cases typically present in late childhood or adolescence
• Gender distribution: Equal in children, unlike adult PNH which has a slight female predominance

Pathophysiology of Pediatric PNH

The underlying mechanism of PNH in children is similar to that in adults, involving a somatic mutation in the PIGA gene of hematopoietic stem cells.

Key aspects of pathophysiology:

1. PIGA gene mutation:
   • Located on the X chromosome
   • Encodes an enzyme essential for the synthesis of glycosylphosphatidylinositol (GPI) anchors
2. GPI anchor deficiency:
   • Results in the absence of GPI-anchored proteins on cell surfaces
   • Affects complement regulatory proteins CD55 and CD59
3. Complement-mediated hemolysis:
   • Lack of CD55 and CD59 leads to increased susceptibility to complement attack
   • Results in chronic intravascular hemolysis
4. Bone marrow failure:
   • Often associated with pediatric PNH
   • May precede or coincide with PNH diagnosis

Clinical Presentation in Pediatric PNH

The clinical manifestations of PNH in children can be variable and may differ from adult presentations. Awareness of these differences is crucial for early diagnosis and management.

Common presenting features:

• Anemia: Often the initial presenting symptom
  • May be accompanied by fatigue, weakness, and pallor
  • Can be severe and require transfusions
• Hemoglobinuria: Less common in children compared to adults
  • May be intermittent or absent
  • When present, often noticed as tea-colored urine
• Thrombosis: Less frequent in pediatric PNH but can occur
  • Intra-abdominal and cerebral venous thromboses are most common
  • Can be life-threatening
• Bone marrow failure: More common in pediatric PNH
  • May present as aplastic anemia or myelodysplastic syndrome
  • Can precede the diagnosis of PNH
• Abdominal pain: Common in both pediatric and adult PNH
  • Often associated with hemolytic episodes
  • May be severe and mimic acute abdomen
• Other symptoms:
  • Dyspnea
  • Dysphagia
  • Erectile dysfunction (in adolescent males)
  • Growth retardation
  • Recurrent infections

Note: The classic triad of hemolytic anemia, pancytopenia, and thrombosis is less common in pediatric PNH compared to adult cases. A high index of suspicion is necessary for timely diagnosis.

Diagnosis of Pediatric PNH

Diagnosing PNH in children can be challenging due to its rarity and variable presentation. A combination of clinical suspicion and laboratory tests is essential for accurate diagnosis.

Diagnostic approach:

1. Clinical history and physical examination:
   • Assess for symptoms of anemia, hemoglobinuria, and thrombosis
   • Look for signs of bone marrow failure
2. Laboratory tests:
   • Complete blood count (CBC): Anemia, thrombocytopenia, neutropenia
   • Reticulocyte count: Usually elevated
   • Lactate dehydrogenase (LDH): Markedly elevated
   • Haptoglobin: Decreased or undetectable
   • Direct antiglobulin test (DAT): Negative
   • Urinalysis: Hemoglobinuria (if present)
3. Flow cytometry: Gold standard for PNH diagnosis
   • Detects absence of GPI-anchored proteins (CD55 and CD59) on erythrocytes, granulocytes, and monocytes
   • Quantifies the size of the PNH clone
   • High sensitivity can detect small PNH clones (<1%)
4. Bone marrow examination:
   • Not essential for PNH diagnosis but important to assess for associated bone marrow failure
   • May show hypocellularity or features of myelodysplasia
5. Genetic testing:
   • PIGA gene sequencing: Not routinely performed but can confirm diagnosis in challenging cases
   • May be useful in familial cases or for research purposes

Differential diagnosis: Consider other causes of hemolytic anemia, thrombosis, and bone marrow failure, including:

• Autoimmune hemolytic anemia
• Hereditary spherocytosis
• Thrombotic thrombocytopenic purpura
• Aplastic anemia
• Myelodysplastic syndrome

Treatment of Pediatric PNH

Management of PNH in children requires a multidisciplinary approach and should be tailored to the individual patient's needs. Treatment goals include reducing hemolysis, preventing thrombosis, and managing symptoms.

Treatment options:

1. Complement inhibition:
   • Eculizumab: Humanized monoclonal antibody against C5
     • Approved for use in children with PNH
     • Reduces intravascular hemolysis and risk of thrombosis
     • Dosing based on body weight
     • Requires meningococcal vaccination prior to initiation
   • Ravulizumab: Long-acting C5 inhibitor
     • Approved for adults, studies ongoing in pediatric population
     • Allows for less frequent dosing compared to eculizumab
2. Supportive care:
   • Red blood cell transfusions: For severe anemia
   • Folic acid supplementation: To support erythropoiesis
   • Iron supplementation: If iron deficient
   • Management of pain and other symptoms
3. Anticoagulation:
   • For patients with thrombosis or at high risk
   • Low molecular weight heparin or warfarin
   • Careful monitoring required due to increased bleeding risk
4. Hematopoietic stem cell transplantation (HSCT):
   • Potentially curative option
   • Considered in severe cases or those with significant bone marrow failure
   • Risk-benefit ratio must be carefully evaluated
5. Management of bone marrow failure:
   • May require immunosuppressive therapy (e.g., anti-thymocyte globulin, cyclosporine)
   • Consider HSCT in severe cases
6. Emerging therapies:
   • Proximal complement inhibitors (e.g., pegcetacoplan)
   • Small molecule inhibitors of complement
   • Gene therapy approaches

Monitoring: Regular follow-up is essential to assess treatment response, monitor for complications, and adjust therapy as needed. This includes:

• Regular blood counts and hemolysis markers
• Flow cytometry to monitor PNH clone size
• Screening for thrombosis
• Assessment of quality of life and growth in children

Prognosis of Pediatric PNH

The prognosis of PNH in children has improved significantly with the advent of complement inhibitor therapy. However, it remains a chronic condition requiring long-term management.

Factors influencing prognosis:

• PNH clone size: Larger clones generally associated with more severe disease
• Presence of bone marrow failure: Can significantly impact outcomes
• Thrombotic events: Major cause of morbidity and mortality
• Access to treatment: Availability of complement inhibitors has dramatically improved outcomes
• Age at diagnosis: Earlier diagnosis and treatment may lead to better long-term outcomes

Long-term outcomes:

• Survival rates have significantly improved with complement inhibitor therapy
• Quality of life can be substantially improved with appropriate management
• Some patients may experience spontaneous remission, but this is rare
• HSCT offers potential cure but carries significant risks
• Long-term effects of chronic complement inhibition in children are still being studied

Follow-up and transition of care: As pediatric patients with PNH transition to adulthood, careful planning and coordination between pediatric and adult hematology teams is essential to ensure continuity of care.

Paroxysmal Nocturnal Hemoglobinuria in Children

1. QUESTION: What is the primary defect in Paroxysmal Nocturnal Hemoglobinuria (PNH)?
   ANSWER: Deficiency of GPI-anchored proteins on blood cells
2. QUESTION: Which gene mutation is responsible for PNH?
   ANSWER: PIGA gene mutation
3. QUESTION: What is the typical age of onset for PNH in children?
   ANSWER: Adolescence or young adulthood
4. QUESTION: Which of the following is NOT a classic symptom of PNH?
   ANSWER: Joint pain
5. QUESTION: What is the primary mechanism of hemolysis in PNH?
   ANSWER: Complement-mediated destruction of red blood cells
6. QUESTION: Which test is considered the gold standard for diagnosing PNH?
   ANSWER: Flow cytometry
7. QUESTION: What percentage of cells typically need to be affected for clinical manifestations of PNH to occur?
   ANSWER: Greater than 10%
8. QUESTION: Which of the following is a common complication of PNH?
   ANSWER: Thrombosis
9. QUESTION: What is the most common site of thrombosis in PNH patients?
   ANSWER: Hepatic veins (Budd-Chiari syndrome)
10. QUESTION: Which of the following laboratory findings is characteristic of PNH?
    ANSWER: Elevated serum lactate dehydrogenase (LDH)
11. QUESTION: What is the primary treatment for PNH?
    ANSWER: Complement inhibitor therapy (e.g., eculizumab)
12. QUESTION: Which of the following is NOT a common indication for initiating treatment in PNH?
    ANSWER: Asymptomatic disease
13. QUESTION: What is the mechanism of action of eculizumab in treating PNH?
    ANSWER: Inhibition of terminal complement activation
14. QUESTION: Which vaccination is crucial before starting eculizumab therapy?
    ANSWER: Meningococcal vaccine
15. QUESTION: What is the only potentially curative treatment for PNH?
    ANSWER: Allogeneic hematopoietic stem cell transplantation
16. QUESTION: Which of the following is a risk factor for developing PNH?
    ANSWER: Aplastic anemia
17. QUESTION: What is the typical pattern of hemoglobinuria in PNH?
    ANSWER: Intermittent and often nocturnal
18. QUESTION: Which of the following is NOT a typical finding in the urine of PNH patients?
    ANSWER: Proteinuria
19. QUESTION: What is the estimated incidence of PNH?
    ANSWER: 1-2 cases per million population per year
20. QUESTION: Which of the following cell lines is typically NOT affected in PNH?
    ANSWER: Lymphocytes
21. QUESTION: What is the role of CD55 and CD59 proteins in normal red blood cells?
    ANSWER: Protection against complement-mediated lysis
22. QUESTION: Which of the following is a potential complication of chronic hemolysis in PNH?
    ANSWER: Pulmonary hypertension
23. QUESTION: What is the term for the presence of free hemoglobin in the urine?
    ANSWER: Hemoglobinuria
24. QUESTION: Which of the following is NOT a typical feature of bone marrow in PNH patients?
    ANSWER: Fibrosis
25. QUESTION: What is the typical life expectancy of untreated PNH patients?
    ANSWER: 10-15 years from diagnosis
26. QUESTION: Which of the following is a potential trigger for hemolytic episodes in PNH?
    ANSWER: Infections
27. QUESTION: What is the term for the presence of red blood cells with varying sensitivity to complement?
    ANSWER: PNH mosaicism
28. QUESTION: Which of the following is NOT a typical laboratory finding in PNH?
    ANSWER: Elevated white blood cell count
29. QUESTION: What is the role of iron supplementation in PNH patients?
    ANSWER: To treat iron deficiency due to chronic hemolysis and urinary iron loss
30. QUESTION: Which of the following is a potential long-term complication of PNH?
    ANSWER: Chronic kidney disease

Further Reading

• How I treat paroxysmal nocturnal hemoglobinuria (Blood Journal)
• Paroxysmal nocturnal hemoglobinuria in pediatric patients (Pediatric Blood & Cancer)
• Diagnosis and management of paroxysmal nocturnal hemoglobinuria in childhood and adolescence (Pediatric Blood & Cancer)
• Paroxysmal Nocturnal Hemoglobinuria (New England Journal of Medicine)