Does this child have both beta and alpha thalassemia trait?

Here’s how readers responded to a You Make the Call question about a diagnosis of beta and alpha thalassemia trait.

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Since the A2 and F were both elevated, you have evidence for beta thalassemia trait in the presence of the hypochromasia. I am not sure why the alpha chain test was requested, assuming we got the reason for the hypochromasia and microcytosis. I think having the two mutations is possible. It is supposed to make the imbalance in the chains less prominent. Out of curiosity, I would check a complete blood count on both parents and if both have hypochromic microcytic picture, then I would do Hgb evaluation – one will be consistent with beta and the other is normal – this may confirm the issue. I have two siblings with beta thalassemia trait but also have duplication of the alpha chains (4 on each chromosome 16). They both have a beta thalassemia major phenotype.

Hassan M. Yaish, MD
University of Utah
Salt Lake City, UT

The child needs beta gene molecular testing to determine if he is also a carrier for beta thalassemia, as well as for one alpha gene loss. We also need to see the red blood cell and mean corpuscular volume values, as well as iron testing.

Geoffrey Wool, MD, PhD
University of Chicago
Chicago, IL

The gene deletion confirms the alpha thalassemia heterozygosity, and the high Hgb A2 confirms the beta thalassemia heterozygosity, but the microcytosis suggests underlying iron deficiency. A beta thalassemia homozygosity can be excluded because the Hgb is within normal.

The combination between alpha and beta thalassemia heterozygosities is usually normocytic. A beta globin gene sequence and blood irons/ferritin can confirm the diagnosis.

Alex Felice, MD, PhD
University of Malta

Single alpha chain deletion does not usually produce anemia or microcytosis unless something else is going on. I suspect the described patient may have an abnormality in the beta-gamma gene complex, perhaps a deletion or non-functional fusion. Why not do genetic studies of this complex?

Malcolm Vye, MD
Retired Hematopathologist
Evanston, IL

Single gene alpha thalassemia mutation is not usually associated with either microcytosis or an elevation in either Hgb F or Hgb A2. I would favor this patient having both alpha thalassemia – silent carrier and a beta-positive thalassemia trait.

James L. Harper, MD
University of Nebraska Medical Center
Omaha, NE

The child has one single alpha gene deletion, and that doesn’t have much effect on hemogram. Though his Hgb electrophoresis is suggestive of beta trait, his Hgb F level is high. There may be coexistent Xmnl mutation. Again, he has normal reticulocyte count. In my opinion, this child should be considered as beta trait only.

Debmalya Bhattacharyya, MD
Kolkata, India

I would answer yes, since the patient has an elevated Hgb A2 and a markedly decreased mean corpuscular volume. The latter is usually not that low – single gene deletion alpha thalassemia usually causes only a mild decrease in mean corpuscular volume.

Donald I. Feinstein, MD
USC University Hospital, Keck Medical Center of USC
Los Angeles, CA

I strongly favor concurrent alpha and beta thalassemia traits. First of all, the degree of microcytosis is not explained by a single alpha gene deletion. In addition, Hgb A2 would be expected to be decreased in association with alpha gene deletions sufficient to cause microcytosis. Conversely, in beta thalassemia trait Hgb A2 is generally increased as a relative percentage, as is seen in this case. Since alpha and beta thalassemia traits are relatively common in certain populations (such as Southeast Asians), it would not be surprising to find cases of both occurring in the same individual.

Kristina Davis, MD

The hemoglobin electrophoresis is consistent with beta thalassemia trait. The single alpha gene deletion is consistent with the “clinically silent” alpha gene deletion. If there were two alpha genes deleted, then the results would be considered alpha thalassemia trait. This thalassemia pattern could explain the low mean corpuscular volume (MCV), but I would recommend evaluation for iron deficiency and perhaps lead intoxication, and there may be more abnormalities leading to a low MCV.

Joan C. Gill, MD
Medical College of Wisconsin, Comprehensive Center for Bleeding Disorders, BloodCenter of Wisconsin
Milwaukee, WI

[This is] beta thalassemia trait with persistence of Hgb F.

Mário Sérgio Fernandes

Yes – both alpha and beta thalassemia – Hgb A2 is elevated indicating beta thalassemia. More profound microcytosis than expected and gene mutation (so alpha thalassemia). Normal Hgb because it is a balanced mutation.

Payal Desai, MD
Director of the Ohio State University Adult Sickle Cell Program
Columbus, OH

Gap-PCR looks like the best technique.

Alan B. Grosbach, MD
UF & Shands Breast Center
Gainesville, FL

The microcytosis with normal hemoglobin suggests thalassemia rather than iron deficiency. The elevated Hgb A2 and Hgb F suggest beta-thalassemia trait. The alpha globin one-gene deletion is consistent with alpha thalassemia silent carrier. So this child has alpha thalassemia silent carrier/beta thalassemia minor.

Marion A. Koerper, MD
UCSF School of Medicine
San Francisco, CA

The child is probably an alpha + beta thalassemia carrier. This is due to the fact that his blood count indicated increased microcytes and the Hgb electrophoresis results showed low Hgb A but increased Hgb A2 and Hgb F, which is a suggestive of beta thalassemia, but it is minor because the child is asymptomatic, no hemolysis and hemoglobin and reticulocyte count are normal. Again, the alpha thalassemia gene testing also revealed a single alpha gene deletion which indicates alpha thalassemia minor contributing to the low Hgb A.

Renate Asare

This is very challenging. If inheritance of both alpha and beta thalassemia trait balances the alpha to beta chain ratio, then there is no microcytosis and no anemia, and the two traits cancel each other out.

However, to develop microcytosis, high Hgb A2 and high Hgb F, there must be a beta chain deficiency, so the child must have an abnormally low alpha to beta chain ratio, defining a thalassemia state.

If the patient genetically lacks one alpha gene, it must be functionally an insufficiently severe alpha thalassemia trait to balance the beta thalassemia trait in this patient. This could be possible with a single alpha gene deletion, since a two-alpha gene deletion might more appropriately balance a severe beta chain mutation.

Iron deficiency does not appear to be a confounding issue, because it would cause the Hgb A2 to be artifactually low, and it instead appears to be high in conjunction with high Hgb F.

So it does appear that this patient has inherited both alpha thalassemia trait and beta thalassemia trait.

A strong, but not foolproof, way to assess this would be to obtain CBC and Hb electrophoresis from both parents.  It would help even more to obtain CBC and Hb electrophoresis from any siblings.

Gregory J. Kato, MD
Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh
Pittsburgh, PA

The boy has beta thalassemia trait and is an alpha-thalassemia silent carrier (therefore also alpha thalassemia trait). The beta-thalassemia trait can be further confirmed by molecular mutation analysis if available

[It is] important for his next generation depending on the genotype of his spouse/significant other, [as there is] potential for his child to have beta thalassemia major if spouse/significant other has beta-thalassemia trait; and for hemoglobin H disease if spouse/significant other has 2 alpha-globin gene deletion (in the cis position). Thus his future spouse/significant other should be tested for alpha and beta thalassemia problem for genetic and prenatal counseling.

Man-Chiu Poon, MD
Department of Medicine, University of Calgary

Yes, it is likely that this child has both alpha and beta thalassemia trait. In our routine diagnostic service we see about 10 to 20 percent of patients with beta thalassemia trait who also have alpha thalassemia.

How can I tell?

  1. The patient has an Hgb A2 of 4.6% consistent with beta thalassemia trait.
  2. Coexistent alpha and beta thalassemia will have the effect of normalizing red cell indices, so this patient is likely to have beta zero thalassemia.
  3. We routinely screen all couples for hemoglobin alpha (HBA) gene deletions when performing molecular workup for beta thalassemia prenatal diagnosis.

We performed prenatal diagnosis in a twin pregnancy, finding one fetus normal and the other fetus predicted to develop beta thalassemia major. The affected fetus had also inherited a 3.7 kB deletion. The parents opted to continue the pregnancy. At two years, the affected child remains transfusion free.

Catherine Nicholls, MSc, MHGSA
Genetics and Molecular Pathology Directorate
South Australia

This child has one alpha gene missing and probably a beta that mutation. Not anemic due to balanced reduction in both alpha and beta globin gene.

Sanjay Shah, MD
Phoenix Children’s Hospital