Hemoglobin Lepore syndrome

Overview

Hemoglobin Lepore syndrome is a rare inherited blood disorder characterized by the presence of an abnormal hemoglobin variant called Hemoglobin Lepore. This variant results from a fusion between the delta (δ) and beta (β) globin genes, producing a hybrid globin chain. The syndrome presents with clinical features similar to beta-thalassemia, ranging from mild anemia in carriers to moderate or severe anemia in individuals with two copies of the Lepore gene. It is most often found in individuals of Mediterranean, Middle Eastern, or South Asian descent.

Causes

Hemoglobin Lepore syndrome is caused by a genetic mutation involving an unequal crossover between the beta and delta globin genes on chromosome 11 during meiosis. This results in the formation of a hybrid δβ-globin gene that produces the abnormal Hemoglobin Lepore protein. The condition is inherited in an autosomal recessive pattern:

• Heterozygous individuals: Carry one copy of the mutated gene and usually have mild or no symptoms

• Homozygous individuals or compound heterozygotes: Inherit two defective genes (or one Lepore gene and one beta-thalassemia gene), leading to a more severe, thalassemia-like anemia

Symptoms

Symptoms vary based on whether the individual is a carrier or has a more severe form of the disease:

• Heterozygotes: Usually asymptomatic or have mild microcytic anemia

• Homozygotes or compound heterozygotes:

  • Moderate to severe anemia

  • Fatigue and weakness

  • Pallor

  • Jaundice

  • Enlarged spleen (splenomegaly)

  • Delayed growth in children

  • Facial bone changes and other skeletal abnormalities (in severe cases)

Diagnosis

Diagnosis of Hemoglobin Lepore syndrome involves a combination of blood tests and genetic studies:

• Complete blood count (CBC): Shows microcytic, hypochromic anemia

• Peripheral blood smear: Reveals target cells, anisopoikilocytosis, and other thalassemia-like features

• Hemoglobin electrophoresis: Detects the presence of Hemoglobin Lepore and reduced levels of normal HbA

• High-performance liquid chromatography (HPLC): Quantifies hemoglobin fractions and helps distinguish from other hemoglobinopathies

• DNA analysis: Confirms the presence of the delta-beta hybrid gene

Family studies may also help in confirming inheritance patterns and carrier status.

Treatment

Treatment depends on the severity of the condition. Mild cases may require no treatment beyond monitoring, while more severe forms may need intervention:

• Folic acid supplementation: Supports red blood cell production

• Blood transfusions: In cases of moderate to severe anemia

• Iron chelation therapy: If transfusions lead to iron overload

• Splenectomy: May be considered if the spleen becomes overly enlarged and contributes to anemia

• Genetic counseling: Recommended for affected families and carriers

Routine vaccinations and infection prevention are important in patients with splenomegaly or after splenectomy.

Prognosis

The prognosis for individuals with Hemoglobin Lepore syndrome varies by severity. Carriers generally have a normal lifespan and no complications. Those with homozygous or compound heterozygous forms may experience a clinical course similar to beta-thalassemia intermedia or major, requiring ongoing medical care. With appropriate treatment, most patients can manage symptoms effectively and maintain a good quality of life. Early diagnosis and personalized management are key to improving outcomes.