Pediatrics

Hemoglobinopathies

OVERVIEW: What every practitioner needs to know

Are you sure your patient has a hemoglobinopathy? What are the typical findings for this disease?

The term hemoglobinopathy refers to a number of inherited disorders that result from mutations in the globin (alpha, beta, or gamma) genes. These mutations result in either reduced production or altered structure of the hemoglobin (Hb) molecule. Many variant Hbs function normally and are of no clinical consequence but may be discovered on routine newborn screening. Other hemoglobinopathies can produce clinical disorders, most commonly sickle cell disease and thalassemia syndromes.

Beta globin mutations, which cause sickle cell disease and beta-thalassemia typically have no symptoms in the neonatal period because of the high level of fetal hemoglobin (Hb F) and low level of adult Hb at birth. These conditions are often diagnosed because of abnormal newborn screening results.

Alpha globin gene deletions may present in the neonatal period with anemia and/or relative microcytosis (unaffected newborns have an elevated mean corpuscular volume compared with adults); severity is based on the number of alpha genes affected (1-4 ). Severe anemia and hydrops fetalis (generalized edema, ascites, pleural and pericardial effusions) result when no functional alpha genes are present (typically 4 genes deleted), whereas mild anemia with red cell microcytosis, often in the absence of clinical symptoms, is seen when two or three alpha genes are nonfunctional.

An alpha globin gene mutation found (Hb Hasharon) produces an unstable Hb that causes hemolysis in the neonatal period. Symptoms include pallor and jaundice.

Gamma globin gene mutations may present with symptoms in the neonatal period. These symptoms include pallor, jaundice/hyperbilirubinemia, splenomegaly, and cyanosis.

Fetal hemoglobin mutations

Hb F is composed of two alpha and two gamma globin chains. At birth, the majority of Hb production is Hb F, whereas small amounts of adult Hb are present. Gamma globin gene mutations are uncommon and include:

Mutations that lead to the production of an unstable Hb and hemolysis (e.g., Hb F Poole). Symptoms include jaundice, pallor, and tea-colored urine. The hemolytic anemia is often mild to moderate.

Mutations that cause cyanosis (e.g., Hb FM-Osaka, Hb FM-Fort Ripley, Hb F-Circleville, and Hb F Toms River). These mutations either cause increased methemoglobin (formed when iron in heme is oxidized from the ferrous (Fe+2) to the ferric (Fe+3) state) or increased oxygen affinity of the abnormal Hb. Neonates present with cyanosis but are otherwise clinically well. There is often a family history of neonatal cyanosis that resolves over the first two months of life. It is important to make the diagnosis to avoid unnecessary diagnostic procedures and treatments.

What other disease/condition shares some of these symptoms?

Anemia with microcytosis can be caused by iron deficiency from chronic fetal-maternal bleeding.

Hb F mutations that produce an unstable Hb and hemolysis are rare, and in the absence of a family history of such a mutation, other causes should be considered first.

Causes of anemia and hyperbilirubinemia in the neonate include the following:

Hemolytic disease of the newborn from ABO, Rh, or minor blood group incompatibility

Red blood cell enzyme deficiencies, including glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency

Red blood cell membrane defects, including hereditary spherocytosis and hereditary elliptocytosis

Infantile pyknocytosis (a rare disorder that causes transient neonatal hemolytic anemia with pyknocytes on peripheral blood smear)

Rare anemias such as congenital dyserythropoietic anemias

Sepsis

Causes of cyanosis include the following:

Hypoxemia/pulmonary disease

Cardiac disease

Methemoglobinemia (methemoglobin reductase deficiency, toxin-induced production of methemoglobin)

What caused this disease to develop at this time?

Globin gene mutations are inherited

Neonates produce mostly Hb F(composed of two alpha and two gamma globin molecules) rather than the adult form of Hb (composed of two alpha and two beta globin chains).

Beta globin mutations (sickle cell disease, beta-thalassemias), although present at birth, usually are not symptomatic in the neonatal period. During the first 6 months of life, gamma globin (Hb F) production wanes and is replaced by beta globin production. Thus symptoms of beta-hemoglobinopathies typically develop after the first few months of life. These disorders are often discovered on newborn screening.

Alpha globin gene mutations or deletions can be detected in the neonatal period because Hb F is composed of alpha and gamma globin chains. Because alpha globin is also present in the adult form of Hb, these abnormalities will persist after the switch from fetal to adult Hb production occurs.

Most mutations in alpha-thalassemia are large deletions. In alpha-thalassemia, two alpha genes may be deleted on the same chromosome (common in Asians) or one of the two alpha genes on a chromosome may be deleted (common in Africans).

Hb H disease (three missing alpha genes) is most common in people of Southeast Asian descent.

When four alpha genes are deleted (no alpha globin production), severe anemia develops in utero and generally leads to fetal hydrops and death unless in utero transfusions are administered.

Gamma globin gene mutations will present in the neonatal period because the majority of the Hb that is produced is Hb F. The abnormalities will improve, however, over the first few months of life as the switch to production of adult Hb occurs.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Complete Blood Count (CBC)

Mild anemia and microcytosis are seen when three alpha genes are missing and the mean corpuscular Hb is also reduced. Red blood cell morphologic analysis shows anisocytosis and hypochromia. The CBC may be normal in the neonatal period of show mild microcytosis with or without mild anemia when two alpha genes are missing (alpha-thalassemia trait).

With Hb F mutations leading to unstable Hbs, anemia (often normocytic for age) with reticulocytosis can be seen. The percentage of nucleated red blood cells may also be elevated.

Some Hb F mutations that cause cyanosis also can cause a hemolytic anemia, with mild anemia and reticulocytosis.

Chemistry Panel

Total bilirubin, indirect bilirubin, lactate dehydrogenase, and aspartate transaminase levels may be elevated resulting from hemolysis with HbF mutations that produce an unstable Hb.

Hemoglobin Identification and Quantitation

A number of techniques can be used to identify and quantify abnormal Hbs, including cellulose acetate and agarose gel electrophoreses, high-performance liquid chromatography, and Isoelectric focusing. The latter two tests are used in most newborn screening programs. Some abnormal Hbs can be identified with these techniques, whereas others may not be identified, as the band runs with a normal Hb band.

In sickle cell disease, a pattern of FS (homozygous SS disease or S-beta 0 thalassemia) or FSC (SC disease) or FSA (S-beta+ thalassemia) is demonstrated.

With beta-thalassemia major, an "F" only pattern is seen (no Hb A production), although children with beta+ mutations may demonstrate some Hb A (FA pattern).

With alpha gene deletions, gamma globin tetramers (Hb Barts) are demonstrated. Quantifying the amount of Hb Barts in the newborn provides an estimate, although not precise, of the number of missing alpha globin genes.

  • One alpha gene missing: 1%-2% Hb Barts

  • Two alpha genes missing: 2%-10% Hb Barts

  • Three alpha genes missing: 20%-30% Hb Barts

  • Four alpha genes missing: greater than 80% Hb Barts

Some gamma globin gene mutations will produce an altered electrophoretic mobility. The abnormal Hb often composes between 5% and 30% of the Hb.

Methemoglobin level will be elevated in some gamma globin mutations that cause cyanosis.

Oxygen hemoglobin dissociation curve (P50) may be helpful to demonstrate increased oxygen affinity for globin gene mutations that cause cyanosis.

Special tests using heat stability or isopropanol may be used to detect unstable hemoglobins.

DNA analysis of the globin gene can be used to confirm the mutation.

Would imaging studies be helpful? If so, which ones?

Imaging studies are generally not helpful. Chest radiography and echocardiography may be used in the evaluation of a cyanotic infant to assess for cardiopulmonary disease.

If you are able to confirm that the patient has a hemoglobinopathy, what treatment should be initiated?

For sickle cell disease, penicillin prophylaxis (125 mg orally twice daily) should be initiated by the time the infant is 2-3 months old. The child should be referred to a sickle cell program if available. Early counseling includes discussion of the hyposplenia and risk of infection, importance of timely immunizations, and demonstration of splenic palpation, as well as genetic counseling.

Neonates with beta-thalassemia require close follow-up over the first years of life for growth and development, development of facial bony changes (maxillary hyperplasia and frontal bossing) and monitoring of the Hb level. Symptoms often develop between 3 and 18 months as Hb F production wanes and the child becomes more anemic. Indications to start regular transfusion therapy include persistent anemia (hemoglobin <7 g/dL), poor growth, or complications of ineffective erythropoiesis. Iron therapy is not helpful and could contribute to the development of iron overload over time.

For neonates with one or two alpha genes missing, no special treatment is needed. Iron therapy is not necessary.

Neonates with Hb H disease (three missing alpha genes) or Hb H Constant Spring (two alpha genes missing and one alpha-Constant Spring mutation) generally do not require treatment in the neonatal period. These children will need to be followed for growth and development and periodic Hb measurements over time. Hb H Constant Spring is generally associated with a more severe anemia and clinical course than that of Hb H disease. Iron therapy is not helpful. Genetic counseling should be provided for parents.

Neonates with functional Hb F mutations will improve as Hb F production wanes.

For unstable Hb F or alpha globin mutations, children should be monitored for the development of hyperbilirubinemia and treated with phototherapy as needed. Simple or exchange transfusion are uncommonly needed but should be considered for significant hyperbilirubinemia, for low or rapidly falling Hb, or if symptoms of worsening anemia develop (such as tachycardia, S3 gallop). The transfused, normal red blood cells will not undergo hemolysis. The CBC should be followed closely.

For Hb F mutations that cause cyanosis, no specific treatment is needed.

What are the adverse effects associated with each treatment option?

Transfusion therapy carries the risk of infectious disease transmission, transfusion reactions, and fluid overload. The development of red blood cell alloantibodies are uncommon in the neonate. Repeated transfusions can lead to the development of iron overload over many years.

What are the possible outcomes of hemoglobinopathies?

Families can be reassured that cyanosis or hemolysis related to gamma globin gene mutations will resolve over the first couple of months of life.

With alpha thalassemia, families can be reassured that one or two alpha gene deletions have no clinical consequences for the child. Hemoglobin H disease (three alpha gene deletions) will be present lifelong but generally causes a mild to moderate anemia. Worsening hemolysis can be seen at times of acute illnesses. Follow-up by a hematologist is recommended. Four alpha gene deletions is very serious and will require treatment with lifelong red blood cell transfusions and iron chelation therapy or curative therapy with stem cell transplantation.

Beta globin gene mutations, although asymptomatic in the neonate, will produce symptoms in older infants and throughout life. Follow-up by a hematologist is necessary. Depending on the severity, lifelong transfusions and chelation therapy are often needed, or curative treatment with stem cell transplantation may be required.

What causes this disease and how frequent is it?

Alpha-thalassemia is found most commonly in individuals of Asian and African background. The prevalence of alpha-thalassemia trait in the United States is estimated to be 2%-3% in those of African descent and 5%-15% in those of Southeast Asian background. Hb H disease is most common in individuals of Asian ethnicity (because two alpha gene deletions on the same chromosome [cis] is more common in this population). In the California State newborn screening program, Hb H disease affected about 1/15,000 births.

Beta-thalassemia is common in individuals of Mediterranean, African, and Asian descent, and sickle cell disease is highly prevalent in sub-Saharan Africa, but also occurs in the Middle East, India, and the Mediterranean. Beta-thalassemia affects hundreds of thousands of individuals worldwide. The prevalence in the United States is unknown, but it is estimated to affect about 1000 individuals.

In the United States, most individuals with sickle cell disease are of African or Hispanic descent. The true prevalence of sickle cell disease (all types) in the United States is unknown but is thought to affect close to 100,000 individuals. Through newborn screening programs, the prevalence of sickle cell disease (all types) is estimated at about 1/365 births.

Gamma globin and alpha globin mutations that cause unstable Hbs or cyanosis are very rare. Hb Hasharon, an alpha globin variant, is most common in the Ashkenazi Jewish population.

How can hemoglobinopathies be prevented?

Genetic counseling can be provided to at-risk couples.

For gamma globin gene mutations, the disease is mild, and often counseling is merely aimed at educating family members so that needless testing can be avoided in future offspring.

Partners of women who either have thalassemia or sickle cell disease or are carriers of beta-thalassemia trait, sickle trait, Hb C or E trait, alpha thal trait (in cis configuration) and for certain other variant Hbs should be tested to determine if the couple is at risk of having a child with clinically significant disease. Beta-thalassemia combined with another beta-thalassemia gene or Hb E gene can all cause thalassemia major. Similarly, the combination of Hb S with Hb S, C, beta thalassemia, and certain other variants, causes clinically significant sickle cell disease. Genetic counseling is imperative. New in vitro fertilization techniques that use preimplantation testing and implant only unaffected embryos can be performed. Chorionic villus sampling and amniocentesis also can be used to diagnosis at-risk fetuses.

What is the evidence?

Information of the clinical presentation of Hb H disease and newborn screening can be found in the following references:

Lal, A, Goldrich, ML, Haines, DA. "Heterogeneity of hemoglobin H disease in childhood". N Engl J Med. vol. 364. 2011. pp. 710-8.

Kemper, AR, Knapp, AA, Metterville, DR. "Weighing the evidence for newborn screening for hemoglobin H disease". J Pediatr. vol. 158. 2011. pp. 780-3.

Information on Hb F mutations are limited to case reports, including the following references:

Crowley, MA, Mollan, TL, Abdulmalik, OY. "A hemoglobin variant associated with neonatal cyanosis and anemia". N Engl J Med. vol. 364. 2011. pp. 1837-43.

Lee-Potter, JP, Deacon-Smith, RA, Simpkiss, MJ. "A new cause of haemolytic anemia in the newborn. A description of an unstable fetal haemoglobin: F Poole, alpha2-G-gamma2 130 tryptophan yields glycine". J Clin Pathol. vol. 28. 1975. pp. 317-20.

The following reference provides information about laboratory investigation for hemoglobinopathies:

Kutlar, F. "Diagnostic approach to hemoglobinopathies". Hemoglobin. vol. 31. 2007. pp. 243-50.

Ongoing controversies regarding etiology, diagnosis, treatment

Controversy exists about whether routine newborn screening for Hb H disease should be performed. Some argue that early detection of Hb H disease does not alter the early treatment course and that many children have minimal clinical symptoms over time. Others argue that the newborn period provides a unique opportunity for screening for Hb Barts (which decreases over the first few months of life as Hb F production wanes) and that identification of affected children will allow education of families about signs of anemia and assessment of splenomegaly. Screening programs often will use a cutoff of 25% Hb Barts to report Hb H disease to limit the rate of false-positive results.

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