Hereditary Hemolytic Anemia in Children

1. Amit Patel.

(1. Student, International Medical University ,Bishkek, Kyrgyz Republic.)

Abstract

Hereditary hemolytic anemia (HHA) is a group of genetically determined diseases with premature erythrocyte destruction. In children, the diseases cause a significant clinical burden due to anemia, jaundice, growth retardation, and risk of gallstones and splenomegaly. The most common forms are membrane defects (hereditary spherocytosis), enzymopathies (G6PD deficiency, pyruvate kinase deficiency), and hemoglobinopathies (sickle cell disease, thalassemia). Accurate diagnosis relies on a combination of clinical, laboratory, and molecular requirements. Early diagnosis and tailored treatment will prevent morbidity and improve quality of life.

Introduction

Inherited hemolytic anemias are hereditary disorders that lead to the premature destruction of red blood cells (RBCs), which results in intermittent or chronic anemia. These conditions arise due to defects in one of three key components of the erythrocyte: the cell membrane, the structure of hemoglobin, or red cell metabolism-associated enzymes. Unlike acquired hemolytic anemias, the inherited forms are present at birth but can become clinically apparent depending on the severity of the defect. Children presenting with these conditions may exhibit pallor, jaundice, splenomegaly, and a delay in growth and development.

Etiopathogenesis

The etiopathogenesis of hereditary hemolytic anemia is classified according to the underlying defect. Membranopathies result from protein deficiencies in the erythrocyte membrane, leading to abnormal red cell shape and heightened fragility; this group includes Hereditary Spherocytosis (HS), where a deficiency of ankyrin, spectrin, or band 3 protein causes spherocytes to be sequestered and destroyed in the spleen, and Hereditary Elliptocytosis (HE), which involves spectrin or protein 4.1 mutations resulting in elliptical red blood cells. Hemoglobinopathies involve abnormal hemoglobin synthesis leading to the destruction of red blood cells; examples are Sickle Cell Disease (SCD), a mutation in the $\beta$-globin gene causing hemoglobin S and the sickling of RBCs that leads to both hemolysis and vaso-occlusion, and Thalassemias, which feature the overproduction or underproduction of $\alpha$- or $\beta$-globin chains, causing ineffective erythropoiesis and hemolysis. Enzymopathies are red cell enzyme deficiencies that impair RBC metabolism and survival, such as Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, which results in hemolysis due to oxidative stress, and Pyruvate Kinase deficiency, where unusual ATP production causes membrane instability and hemolysis. Finally, regarding Genetic Transmission, membrane disorders like HS are typically autosomal dominant, enzymopathies and severe hemoglobinopathies (e.g., PK deficiency, thalassemia major) are usually autosomal recessive, and G6PD deficiency is X-linked.

Clinical Picture

The clinical presentation of hereditary hemolytic anemias depends entirely on the severity and nature of the hemolysis. Across many types of the condition, several common features arise: anemia presents as pallor, fatigue, and growth delay; jaundice occurs due to unconjugated hyperbilirubinemia; splenomegaly develops because of increased sequestration of red blood cells; and gallstones are common, as chronic hemolysis leads to the formation of pigment stones. Specific clinical presentations vary by type: Hereditary spherocytosis is characterized by intermittent jaundice, mild to moderate anemia, and spherocytes visible on a peripheral smear. Sickle cell disease is marked by painful crises, dactylitis, recurrent infections, and a significant risk of stroke. Thalassemias often involve severe anemia, distinct skeletal deformities such as frontal bossing, and pronounced hepatosplenomegaly. Finally, G6PD deficiency typically presents as episodes of acute hemolysis that are triggered by specific drugs, infections, or ingestion of fava beans.

Diagnosis

The diagnosis of hereditary hemolytic anemia requires a combination of laboratory tests and clinical correlation. Diagnosis begins with general Laboratory Investigations. A Complete Blood Count (CBC) typically shows anemia and reticulocytosis (an increased number of immature red blood cells). The Peripheral Blood Smear is crucial for morphology, revealing characteristic cell shapes such as spherocytes (Hereditary Spherocytosis, HS), elliptocytes (Hereditary Elliptocytosis, HE), target cells (thalassemia), or sickle cells (Sickle Cell Disease, SCD). Further evidence of red blood cell destruction is supported by an elevated Reticulocyte Count, unconjugated hyperbilirubinemia from increased breakdown products, elevated Lactate Dehydrogenase (LDH), and a low Haptoglobin level. A key differentiator from acquired autoimmune anemias is the Direct Antiglobulin Test (Coombs test), which is negative in hereditary forms.Following general screening, Specific Diagnostic Tests pinpoint the underlying defect. The Osmotic Fragility Test is used for the diagnosis of HS. Hemoglobin Electrophoresis separates different hemoglobin variants and is essential for identifying thalassemias and SCD. Enzyme Assays measure the activity of specific enzymes, such as pyruvate kinase and G6PD, to diagnose enzymopathies. Finally, Molecular Genetic Testing is used to establish specific mutations in cases that are difficult to diagnose otherwise.

Differential Diagnosis

Hereditary hemolytic anemia should be distinguished from other causes of hemolysis in the pediatric population, including acquired hemolytic anemia, such as autoimmune hemolytic anemia, which can be differentiated by a positive Coombs test, as well as hemolysis due to infections like sepsis or malaria. Other causes to consider are nutritional deficiencies, particularly of folate or Vitamin B12, and hemolysis that is drug- or toxin-induced.

Treatment

reatment begins with General Measures, which include Folic acid supplementation to support the increased demands of erythropoiesis and the avoidance of specific triggers, which is particularly important in G6PD deficiency to prevent acute hemolytic episodes. Regarding Type-specific Interventions, for Hereditary Spherocytosis, mild cases require only supportive care, while severe disease is treated with splenectomy, typically performed after 5–6 years of age to minimize infection risk. For Sickle Cell Disease (SCD), treatment involves using Hydroxyurea to prevent painful crises, blood transfusions for severe anemia or stroke protection, and strict prevention of infection through vaccines and penicillin prophylaxis. Thalassemias often require regular blood transfusions, which necessitates subsequent iron chelation treatment to manage iron overload, and bone marrow transplantation is an option for selected patients. In cases of G6PD deficiency, the cornerstone of treatment is the avoidance of oxidant drugs and foodstuffs, with supportive therapy provided during hemolytic crises. Finally, for Pyruvate Kinase deficiency, splenectomy is used for severe disease, alongside general supportive treatment. Promising New Therapies are also emerging, including gene therapy for beta-thalassemia and SCD, and pharmacologic chaperones being investigated for enzyme deficiencies.

Prognosis

The prognosis for hereditary hemolytic anemia differs significantly based on the specific type and severity of the disorder. Generally, a timely detection and adequate treatment plan can significantly improve a patient's quality of life. Crucially, the long-term management involves regular monitoring for complications, which include the development of gallstones, managing iron overload (especially in transfusion-dependent patients), and preventing or quickly treating infection.

Conclusion

Inherited hemolytic anemias in children constitute a heterogeneous group of disorders with common clinical presentations but disparate molecular etiologies. Proper understanding of their etiopathogenesis, clinical presentation, and diagnostic modalities is vital to optimal management. Early diagnosis, prevention, and goal-directed treatment can reduce morbidity and improve outcomes.

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