A 2-week-old female came to clinic for well-child care. She was a full-term infant who was breastfeeding and had regained her birth weight. She had no jaundice and appeared to have no problems with hearing or vision. Her parents had family support and were doing well other than being tired. Her neonatal screen had been positive for a Bart’s hemoglobin and she had a complete blood count (CBC) done at 1 week was normal for her age and a confirmatory hemoglobin electrophoresis was sent. The past medical history showed no pre- or post-natal problems. The family history was positive for Hepatitis B in the father. There was mild anemia in the family but more information was not available. The family was from Southeast Asia. The review of systems was negative.
The pertinent physical exam showed an alert infant with weight of 3834 g (50-75%, up 76g from birth weight), head circumference of 35.5 cm (50-75%) and length of 53 cm (75%). Her examination was negative. The diagnosis of a normal infant with probable alpha thalassemia was made. The state neonatal screening program had contacted the family and she already had an appointment with a hematologist. Some basic information about alpha thalassemia had been given to the family and they felt comfortable at this time with this information, especially since her CBC had been normal.
Hemoglobin is important as it is the major oxygen carrier to tissues. It is comprised of a protoporphyrin unit, elemental iron and 4 globin chains together. The globin chains are alpha (chromosome 16), beta, gamma or delta proteins (all on chromosome 11) The predominant hemoglobin is Hemoglobin A (adult) with 2 alpha and 2 beta globin chains. Minor hemoglobins are Hemoglobin F (fetal) with 2 alpha and 2 gamma globin chain and Hemoglobin A2 with 2 alpha and 2 delta globin chain. The beta gene produces 2 proteins and there can be variations of the beta gene include sickle cell, C and E.
There is a very tightly controlled ratio of production of the chains where alpha chains are matched basically 1 for 1 to the other chains. When this ratio is disrupted then disease can occurs. Thalassemia is one of the most common single-gene disorders, and often occurs in populations in the malaria belt of the world as thalassemias provides some genetic protection against this infectious disease. It is possible for two genetic mutations to occur simultaneously and to have abnormalities of both alpha and beta globin chains such as an alpha thalassemia trait and sickle cell disease.
It is estimated that alpha thalassemia is carried in more than 270 million individuals. About 300,000-400,000 severely affected infants are born every year, mainly in Asia, India, or the Middle East.
Healthy individuals have 4 alpha-globin genes (α α/ α α)
Alpha thalassemia happens when there is an absent or reduced amount of the alpha globin chains produced. Up to 4 genes can be missing and result in different disease patterns.
- 1 gene missing (- α / α α)
- Silent carrier
- Can make Hemoglobin A normally therefore individuals usually have no clinical problems and their complete blood count is usually normal or has mild decreases in the RBC mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) can be seen.
- Prognosis is excellent.
- 2 gene missing (- α / – α) or (- – / α α)
- Alpha thalassemia trait
- (- α / – α) – this is the trans isomer and is common in African Americans. A trans isomer combined with another trans isomer can only produce a patient with alpha thalassemia trait. (- α) + (- α) = (- α / – α)
- (- – / α α) is the cis isomer is more common in people of Southeast Asian, Southern Chinese, Mediterranean and Middle Eastern descent. The cis isomer is of more concern because it can lead to a 3 or 4 gene deletion if combined with another trans or cis deletion which causes severe disease or death (see below). (- -) + (- α) = (- – / – α) or (- -) + (- -) = (- – / – -)
- Can make Hemoglobin A to a great extent therefore affected individuals usually have no clinical problems but often will have changes in their complete blood count including mild anemia, decreased RBC, MCV and MCH.
- Prognosis is excellent.
- 3 gene missing (- – / – α)
- Hemoglobin H disease
- Cannot make as much Hemoglobin A, therefore there is an increase in tetramers of beta hemoglobin (also known as Hemoglobin H). Hemoglobin H has a high binding capacity for oxygen, so although it can release oxygen, it doesn’t release it efficiently to the tissues. Patients have moderate to severe anemia, low MCH and MCH and high reticulocyte counts.
- Prognosis depends on the type of hemoglobin made which varies in different populations. Complications can occur including marrow hyperplasia, aplastic or hypoplastic crises, hepatosplenomegaly, skeletal abnormalities, osteopenia, fractures, malignancies and transfusion related problems.
- Close followup is needed.
- 4 gene missing (- – / – -)
- Alpha Thalassemia Major
- Cannot make any Hemoglobin A and produces Bart’s hemoglobin or tetramers of gamma hemoglobin chains
- Causes hydrops fetalis and is incompatible with life because of inability to carry oxygen to tissues leading to high output congestive heart failure, hepatosplenomegaly, and end organ failure. Demise occurs in utero or short after birth usually.
Bart’s hemoglobin (tetramers of gamma hemoglobin chains) are produced in the neonatal period.
It can occur in silent carriers (1-2% of total hemoglobin), trait (5-15% of total hemoglobin) or Hemoglobin H (20-40% of total hemoglobin). Neonatal screening with elevated Bart’s hemoglobin can indicate probable alpha thalassemia but is not perfect. Confirmatory hemoglobin electrophoresis testing is necessary. Prenatal testing is available for at risk families usually by polymerase chain reaction testing.
Questions for Further Discussion
1. What is Cooley’s anemia?
2. What is the current role of bone marrow transplantation for thalassemia and sickle cell anemia?
- Disease: Thalassemia | Newborn Screening
- Symptom/Presentation: Abnormal Laboratory Test
- Specialty: Genetics | Hematology
- Age: Newborn
To Learn More
To view pediatric review articles on this topic from the past year check PubMed.
Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.
Information prescriptions for patients can be found at MedlinePlus for these topics: Thalassemia and Newborn Screening.
To view current news articles on this topic check Google News.
To view images related to this topic check Google Images.
Kaye CI. Newborn Screening Fact Sheets. Pediatrics 2006;118;e934.
Cheerva AC, Bleibel SA, Jones-Crawford JL. Alpha Thalassemia. Medscape.
Available from the Internet at http://emedicine.medscape.com/article/955496-overview (rev. 10/5/2011, cited 1/17/12).
Alpha Thalassemia Trait. St. Jude Children’s Research Hospital.
Available from the Internet at http://www.stjude.org/stjude/v/index.jsp?vgnextoid=d966885309c6f110VgnVCM1000001e0215acRCRD&vgnextchannel=17bfdb6324d6f110VgnVCM1000001e0215acRCRD
(rev. 2012, cited 1/17/2012).
ACGME Competencies Highlighted by Case
1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
2. Essential and accurate information about the patients’ is gathered.
3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
4. Patient management plans are developed and carried out.
5. Patients and their families are counseled and educated.
7. All medical and invasive procedures considered essential for the area of practice are competently performed.
8. Health care services aimed at preventing health problems or maintaining health are provided.
9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.
10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.
13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.
23. Differing types of medical practice and delivery systems including methods of controlling health care costs and allocating resources are known.
25. Quality patient care and assisting patients in dealing with system complexities is advocated.
26. Partnering with health care managers and health care providers to assess, coordinate, and improve health care and how these activities can affect system performance are known.
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital