Screening and counseling for thalassemia

The demography of patients with thalassemia syndromes in North America has changed.^1,2 In the past 6 months, we were asked to diagnose 4 infants, ages 1 month to 4 years, who were born with β-thalassemia major (Table 1). Included were a pair of twins (family no. 3), both of whom had inherited β-thalassemia major, with hemoglobin (Hb) levels of 55 g/L (5.5 g/dL) and 52 g/L (5.2 g/dL), respectively, at 4 years of age, when the diagnosis was made (Table 1). Their parents were not screened for their thalassemia carrier status. More recently, another couple and their 1-year-old child were referred for diagnosis. The β-thalassemia mutation in one parent was missed by the initial laboratory, and their child had inherited both parental mutations. Yet another unsuspected pregnancy with a hemoglobin Barts hydrops fetalis fetus was diagnosed only at 24 weeks of gestation. These findings suggest that many couples at risk of conceiving fetuses with these devastating hereditary diseases in the United States are not identified and provided with proper genetic counseling.

Table 1.

Hematologic results and β-globin genotypes in 3 couples and their 4 children with β-thalassemia major

Family no., characteristic	Father	Mother	Child
1
Age at diagnosis, mo	NA	NA	1
Hb, g/dL	12.6	11.0	10.6
MCV, fL	67	65	82
Hb A, %	94	93	None
Hb A2, %	5.2	5.6	None
Hb F, %	0.7	1.4	99
β-Globin genotype	Heterozygous for IVSI-1 (G > A) β0-thalassema mutation	Heterozygous for IVSI-1 (G > A) β0-thalassema mutation	Homozygous for IVSI-1 (G > A) β0-thalassema mutation
2
Age at diagnosis, mo	NA	NA	1.5
Hb, g/dL	13.7	12.4	8.7
MCV, fL	60	63	82
Hb A, %	94	94	None
Hb A2, %	5.4	5.0	None
Hb F, %	0.6	0.5	99
β-Globin genotype	Heterozygous for IVSII-654 (C > T) β+-thalassemia mutation	Heterozygous for codons 41/42 (–CTTT) β0-thalassemia mutation	Compound heterozygous for both parental β-thalassemia mutations
3
Age at diagnosis, y	NA	NA	4
Hb, g/dL	15.9	10.8	5.5; 5.2
MCV, fL	63	56	64; 64
Hb A, %	95	93	33; 34
Hb A2, %	4.1	5.7	4.9; 5.1
Hb F, %	0.2	0.6	64.4; 63.9
β-Globin genotype	Heterozygous for IVSI-6 (T > C) β+-thalassemia mutation	Heterozygous for codon 39 (CAG > TAG) β0-thalassemia mutation	Compound heterozygous for both parental β-thalassemia mutations

Both twins born to family no. 3 (values separated by semicolons in right-hand column) inherited both parental β-thalassemia mutations. The IVSI-1 (G > A) mutation is commonly found in the Indian subcontinent, the Middle East, and part of the Mediterranean region; the IVSII-654 (C > T) and codons 41/42 (–CTTT) mutations are commonly found in Southeast Asia and in China; and the IVSI-6 (T > C) and codon 39 (CAG > TAG) mutations are commonly found in the Mediterranean region.

To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.

NA indicates not applicable.

There are 270 million people who are carriers of globin gene mutations worldwide. Up to a half million infants are born annually with severe hemoglobinopathies.³ In our country, there are approximately 100 million people with ethnic backgrounds in whom carrier frequencies of hemoglobinopathies are high. Rapid, simple, and inexpensive screening tests can detect carriers of globin gene mutations, and antenatal diagnosis of these diseases is available.⁴

α-Thalassemia mutations affecting 3 α-globin genes cause Hb H disease.^4,5 Deletion of all 4 α-globin genes causes Hb Barts hydrops fetalis.^4,6 Affected fetuses die in utero during the second or third trimester of pregnancy or shortly after birth, frequently accompanied by maternal complications. The correct diagnosis is often missed.⁶ In some populations, there are 2 to 3 times as many fetuses afflicted with the Hb Barts hydrops fetalis than with β-thalassemia major.⁷

Children with β-thalassemia major require monthly blood transfusions and daily iron chelation therapy, or stem cell transplantation, to survive.^4,8 Hb E is a common variant hemoglobin in Southeast Asia, and in combination with β-thalassemia mutation can present as thalassemia major.

Thalassemia carriers do not have significant anemia, but invariably have microcytosis (MCV, < 80 fL) and hypochromia (MCH, < 27 pg). The MCVs of Hb E carriers vary from borderline low to normal values. Serum ferritin is useful to exclude iron deficiency. Hemoglobin analysis should reveal elevated Hb A₂ level (above 3.5%) in β-thalassemia carriers; while α-thalassemia carriers have normal or low Hb A₂. High-performance liquid chromatography (HPLC) can also detect Hb E and other variant hemoglobins. For individuals with complex findings, especially pregnant women, timely consultation with a hematologist or clinical geneticist is essential. To accurately assess reproductive risks and for proper genetic counseling, DNA-based genotyping is necessary in all cases.

The disease burden of Hb Barts hydrops fetalis and β-thalassemia major is great. The costs to care for patients with β-thalassemia major are substantial. Until a cure for these diseases is available, providing counseling for couples at risk, preferably before pregnancy, to allow them to make an informed reproductive decision is the best option.^9,10 Education for frontline health care providers, obstetricians, and HMOs is necessary. Funding and strategy for community-wide preventive efforts, especially among recent immigrants, ought to be made a top priority.

Note added in proof. A fetus in distress was delivered by cesarian birth late in the third trimester. He succumbed within hours after delivery. DNA-based diagnostics confirmed that the newborn had Hb Barts hydrops fetalis syndrome, with deletion of all four α-globin genes (--^SEA/--^SEA).