What are the causes, clinical severity, diagnostic work‑up, and management of α‑thalassemia due to deletion or mutation of the α2‑globin gene?

Alpha-2 Poly A1 Thalassemia: Clinical Overview

Understanding the Genetic Defect

Alpha-2 poly A1 thalassemia is caused by non-deletional mutations affecting the α2-globin gene, which can occur on normal chromosomes or on fusion genes (such as the -α3.7 fusion gene), with critical reproductive implications when mutations are located on fusion genes. 1

The α2-globin gene mutations represent a distinct subset of α-thalassemia that differs from the more common large deletions:

• Non-deletional mutations (point mutations, small insertions/deletions) affect the α2-globin gene and can produce abnormal or reduced α-globin chains 1, 2
• These mutations may co-exist with deletional mutations on the same chromosome, creating compound heterozygous states with severe clinical consequences 1
• When a non-deletional mutation occurs on a -α3.7 fusion gene (rather than a normal α gene), this functionally creates an α0 allele (αα/-), carrying significant reproductive risk for Hemoglobin Bart's hydrops fetalis 1

Clinical Severity Spectrum

Silent Carrier State (Single Gene Affected)

• Typically asymptomatic with normal or near-normal hemoglobin levels 3, 4
• May show minimal microcytosis (MCV slightly reduced) 5, 4
• No treatment required, only genetic counseling 4

Alpha Thalassemia Trait (Two Genes Affected)

• Mild microcytic anemia that is often asymptomatic 3, 4
• Key diagnostic clue: significant microcytosis (MCV <80 fL) with normal or elevated ferritin, distinguishing it from iron deficiency 5, 4
• Patients with non-deletional mutations on fusion genes may show more pronounced microcytosis than expected for a simple two-gene deletion 1
• No treatment needed; monitoring only 4

Hemoglobin H Disease (Three Genes Affected)

• Moderate to severe hemolytic anemia with variable transfusion requirements 3, 4
• CBC monitoring every 3-6 months is recommended to assess hemolytic anemia progression and transfusion needs 5
• Treatment includes transfusions for symptomatic anemia, iron chelation for iron overload, and hydroxyurea in select cases 4, 6
• Complications include bone marrow expansion, extramedullary hematopoiesis, and iron deposition in organs 4

Alpha Thalassemia Major (Four Genes Affected - Bart's Hydrops Fetalis)

• Uniformly fatal without intervention, presenting as severe non-immune hydrops fetalis in late second or early third trimester 7, 5
• Accounts for 28-55% of non-immune hydrops cases in Southeast Asian populations 5
• Intrauterine transfusion remains investigational and is not routinely recommended outside research protocols 5

Diagnostic Work-Up

Initial Screening

Begin with parental MCV screening: values <80 fL suggest possible α-thalassemia carrier status and warrant further investigation 5

Laboratory Evaluation

• Complete blood count showing microcytic anemia (low MCV) with normal or elevated ferritin distinguishes thalassemia from iron deficiency 4
• Hemoglobin electrophoresis may show characteristic patterns but cannot definitively diagnose α-thalassemia 4
• DNA testing for deletions and point mutations is the definitive diagnostic test to identify the specific genetic defect 5

Critical Diagnostic Step for Non-Deletional Mutations

When a patient with α-thalassemia trait shows more severe microcytosis than expected from a single deletion, α1 and α2 globin gene sequencing must be performed using gene-specific primers to determine if the mutation is on a normal gene or a fusion gene 1

• Standard sequencing may miss the precise location of mutations on fusion genes 1
• Separate α1-specific primers are needed to distinguish mutations on the α1 gene from those on the -α3.7 fusion gene 1
• This distinction is critical: mutations on fusion genes create functional α0 alleles with risk of Bart's hydrops fetalis in offspring 1

Prenatal Diagnosis

• When both parents are carriers, prenatal diagnosis via amniocentesis or fetal blood sampling is recommended to detect severe forms 5
• Middle cerebral artery Doppler ultrasound assesses for fetal anemia in suspected hydrops fetalis cases 5
• Ethnicity must be considered in the diagnostic approach, as α-thalassemia is most prevalent in Southeast Asian, Mediterranean, Middle Eastern, and African populations 5

Management Approach

By Clinical Severity

Silent Carriers and Trait:

• No treatment required 4
• Genetic counseling regarding reproductive risks 5
• Avoid unnecessary iron supplementation 4

Hemoglobin H Disease:

• Regular CBC monitoring every 3-6 months 5
• Red blood cell transfusions for symptomatic anemia 4, 6
• Iron chelation therapy when iron overload develops (from hemolysis, increased intestinal absorption, or transfusions) 4, 6
• Hydroxyurea may be beneficial in select cases 4
• Monitor for complications: skeletal abnormalities, endocrine dysfunction, cardiac and hepatic iron deposition 4

Alpha Thalassemia Major:

• Prenatal counseling when both parents are at-risk carriers 5
• Intrauterine transfusion is not standard of care outside research settings 5
• Hematopoietic stem cell transplantation offers potential cure but remains investigational 6

Reproductive Counseling

Cascade testing is recommended: test the affected family member first to identify the specific mutation, then perform targeted testing of at-risk relatives 5

Critical reproductive risk scenario: When a non-deletional mutation is located on a -α3.7 fusion gene (creating a functional αα/- genotype), there is a 25% risk of Bart's hydrops fetalis if the partner is also a carrier of an α0 allele 1

Common Pitfalls

• Failing to recognize that significant microcytosis in a patient with presumed two-gene deletion may indicate a non-deletional mutation requiring specialized sequencing 1
• Misdiagnosing α-thalassemia trait as iron deficiency and prescribing unnecessary iron supplementation 4
• Not using α1-specific primers to accurately localize mutations to fusion genes versus normal genes, missing critical reproductive risks 1
• Overlooking ethnicity in the diagnostic approach, leading to missed diagnoses in high-risk populations 5
• Assuming all α-thalassemia trait cases have identical reproductive risks without confirming the specific genetic defect 1