eMedicine Specialties > Pediatrics: General Medicine > Hematology

Hemoglobin H Disease

Alexandra C Cheerva, MD, Associate Professor of Pediatrics, Hematology/Oncology Division, Director of Pediatric Blood and Marrow Transplantation, University of Louisville; Attending Staff, Section of Pediatric Hematology and Oncology, Kosair Children's Hospital
Ashok B Raj, MD, Associate Professor, Section of Pediatric Hematology and Oncology, Department of Pediatrics, Kosair Children's Hospital, University of Louisville

Updated: Jul 16, 2009

Introduction

Background

Thalassemia is one of the world's most common single-gene disorders. The hallmark of the thalassemia syndromes is decreased or absent synthesis of one or more globin chains. a -Thalassemia is the decreased production of a ₂ -globin or a ₁ -globin gene products.^{[1 ]}Individuals with thalassemia syndrome are most often of African, Asian, Mediterranean, or Middle Eastern descent. Mutations and gene deletions causing the thalassemia genotype have arisen independently in different populations but then have propagated by means of natural selection. Thus, the thalassemias are more prevalent in regions in which malaria is endemic because the RBC phenotype confers some protection against malaria.^{[2 ]}However, individuals with b -thalassemia syndromes have somewhat better protection against malaria.

Pathophysiology

The a -thalassemia syndromes are a group of hereditary anemias of varying clinical severity. They are caused by deficient expression in one or more of the two a -globin genes on chromosome 16 and are characterized by the absence or reduced synthesis of a -globin chains. Healthy individuals have 2 a -globin genes on each chromosome 16 (aa/aa).

α-chain genes in duplication on chromosome 16 pairing with non-α chains to produce various normal hemoglobins.

Two genotypes (--/aa and -a/-a) are associated with the a -thalassemia trait. The genotypes are termed either the cis form if both a ₂ -globin and a ₁ -globin genes are deleted on the same chromosome (--/aa) or the trans form if the 2 a ₂ -globin genes of both alleles of chromosome 16 are deleted but the a ₁ -globin genes are intact (-a/-a).

In both cases, 2 a -globin genes are inactivated. The (--SEA) type of a -thalassemia deletion removes both a -globin genes in cis, is common in Southeast Asia, and is the most common cause for hemoglobin H disease and hydrops fetalis in that part of the world. Nondeletional forms of a -thalassemia in which the a -globin genes are intact are caused by mutations similar to those causing b -thalassemia and are relatively uncommon.

Hemoglobin H disease is usually observed in individuals from Southeast Asia who have deletions of both a -globin genes on one allele and a deletion of only one a -globin gene on the other allele. The deletions result in hemoglobin H (b ₄), which is characterized by a high b -globin– a -globin synthetic ratio and a 2-fold to 5-fold excess in b -globin production. The excess b chains aggregate into tetramers, which account for 5-30% of the hemoglobin level in patients with hemoglobin H disease.^{[3 ]}

Hemoglobin H has a high affinity for oxygen and has no Bohr effect or heme-heme interaction; therefore, hemoglobin H ineffectively supplies oxygen to the tissues under physiologic conditions. Patients with significant amounts of hemoglobin H have a defect in oxygen-carrying capacity that is more severe than that expected on the basis of the hemoglobin concentration. Red cells that contain hemoglobin H are sensitive to oxidative stress; thus, they may be more susceptible to hemolysis when oxidants such as sulfonamides are administered.

Aging erythrocytes contain more precipitated hemoglobin H than younger erythrocytes; therefore, aging erythrocytes are removed from the circulation prematurely. Thus, hemoglobin H disease is primarily a hemolytic disorder. When bone marrow cells are examined, hemoglobin H inclusions are rare, and erythropoiesis is apparently effective. Erythroid hyperplasia can result in typical structural bone abnormalities with marrow hyperplasia, bone thinning, maxillary hyperplasia, and pathologic fractures.

Frequency

United States

Frequency of a -thalassemia is low among whites. Among blacks, the frequency of the a -thalassemia trait is relatively high (20-30%), but the trait usually consists of the loss of only a single a -globin gene on each allele, and hemoglobin H disease is rare. In North America, many multicultural communities are growing, and these populations have increased frequencies of thalassemia syndromes.

In some ethnic groups, such as the Southeast Asian population, in particular, and Mediterranean populations, hemoglobin H and hemoglobin Bart (g ₄) disease are common because of the frequent co-inheritance of one allele lacking both a -globin genes and the other allele lacking one a -globin gene. The high frequency of hemoglobin Constant Spring in the Southeast Asian population can lead to the hemoglobin H (--/-aCS) phenotype, which involves an elongated form of a -globin.^{[4,1 ]}

International

a -thalassemia is perhaps the most common single-gene disorder in the world. The frequency of a -thalassemia alleles is 5-10% in persons from the Mediterranean basin, 20-30% in portions of West Africa, and as high as 60-80% in parts of Saudi Arabia, India, Thailand, Papua New Guinea, and Melanesia. In Thailand, which has a population of 62 million people, approximately 7000 infants are born each year with hemoglobin H disease. The frequency of heterozygote carrier status among the Chinese population has been reported to vary from 5-15%. The frequency of a -thalassemia is less than 0.01% in Great Britain, Iceland, and Japan.^{[5,6 ]}

Mortality/Morbidity

The degree of anemia varies, and morbidity and mortality are largely related to the degree. In some families, a syndrome of hemoglobin H disease and varying degrees of mental retardation has been reported. As a result of multiple blood transfusions, consequences of iron overload on the heart, liver, and other organs may be present, and these can contribute to morbidity and mortality.

Race

a -thalassemia occurs in individuals of all ethnic backgrounds but particularly those of African, Asian, Central American, Mediterranean, and Middle Eastern descent. Emigration from regions in which carrier frequency is high increases the presence of thalassemia syndromes in other parts of the world. Indeed, the disorders are increasing in frequency in North America and Europe.

Sex

Males and females are equally affected.

Age

Hemoglobin H disease occurs in persons of all ages. Neonates with hemoglobin H disease often have anemia, with severely hypochromic RBCs, and high levels of hemoglobin Bart (g ₄). This is in contrast to neonates with b -chain disease, who often have no anemia, although they may have hypochromic RBCs. This is because a -chains are required for production of all forms of hemoglobin, whereas b -chains are found only in the adult form of hemoglobin, hemoglobin A (HbA). In the fetus and neonate, most hemoglobin is hemoglobin F (HbF), which is composed of 2 a -chains and 2 g -chains.

Clinical

History

Symptoms of hemoglobin H disease (HbH disease) are consistent with a chronic hemolytic anemia and include episodes of severe pallor and anemia. Infections, fever, ingestion of oxidative compounds, or drug use may precipitate hemolytic episodes, and patients may require transfusions. Generally, hemoglobin H disease is thought to be a mild disorder. However, because of the marked variability in degree of anemia, patients may range from asymptomatic to needing periodic transfusions to having severe anemia with hepatomegaly and splenomegaly. Some patients may also suffer hydrops fetalis syndrome in utero. Pregnancy may also be a special circumstance, in which patients may develop severe anemia and require transfusions.^{[4 ]}

Physical

Findings at physical examination are consistent with those of chronic hemolytic anemia and include pallor, jaundice, hepatosplenomegaly, folic acid deficiency, pigment gallstones, leg ulcers, and increased susceptibility to infection.

Causes

The disorder is inherited in a complex autosomal recessive manner; therefore, males and females are equally affected. Individuals with deletions of one or two a -globin genes have no clinical manifestations, whereas individuals with deletions of all 4 a -globin genes usually die in utero of hydrops fetalis.

Differential Diagnoses

Anemia, Acute
Anemia, Chronic
Thalassemia
Thalassemia Intermedia

Other Problems to Be Considered

Autoimmune hemolytic anemia
Nonimmune hemolytic anemia
Iron deficiency anemia
Hydrops fetalis

Workup

Laboratory Studies

The following studies are indicated in hemoglobin H disease (HbH disease):

• CBC and reticulocyte counts: Moderately severe hemolytic anemia is present, with hypochromia and microcytosis. Often, mild-to-moderate reticulocytosis is present. The higher the reticulocyte count, the more severe the hemolysis.
• Hemoglobin electrophoresis: Results indicate the presence of hemoglobin H, as well as typical findings of adult hemoglobin A (HbA), hemoglobin A₂, and hemoglobin F (HbF) concentrations.
• Serum iron, total iron binding capacity, and ferritin analysis: Exclude iron deficiency because it may be present in patients with thalassemia. In the setting of undiagnosed disease, iron deficiency also can cause microcytosis, which must be excluded. In older patients or in individuals who have received transfusions, closely monitor ferritin levels. Once the ferritin level is greater than 1000 ng/mL, consider beginning chelation therapy with deferoxamine. Iron deficiency may result in a misleading hemoglobin electropheresis finding due to suppression of hemoglobin production.
• Newer DNA-based techniques using polymerase chain reaction (PCR) may be used for globin-chain analysis. The techniques can be helpful in some cases in which both the patient's and parents' a -chain configurations are elucidated exactly, which can be useful in predicting the risk that a couple's future offspring will be affected.

Imaging Studies

• Ultrasonography of the liver, gallbladder, and spleen frequently reveals gallstones, which consist of pigment resulting from hemolysis.
• Hepatomegaly was in 70% of 502 patients in Thailand, 60% of 153 patients in Sardinia, and 14% of 88 patients in Taiwan.
• Splenomegaly is also common in hemoglobin H disease and was found in 79% of patients in Thailand, 60% in Sardinia, and 47% in Taiwan.

Treatment

Medical Care

• General supportive care in hemoglobin H disease (HbH disease) includes transfusions, which may be needed periodically or in periods of severe anemia, such as during parvovirus infections. Guidelines for transfusion in neonates and older children have been established.^{[7 ]}Usually, patients with hemoglobin H disease live fairly normal lives and require few transfusions. Hemoglobin levels usually range from 7-10 g/dL. Transfusion therapy is reserved for patients with severe anemia (usually <7 g/dL) and symptomatic anemia. Hemolytic episodes may be triggered either by drug use or by infection. The use of special RBC units (eg, washed, irradiated, leucocyte depleted) usually is not required.
• Carefully document iron deficiency with laboratory testing prior to the administration of supplemental iron. Many patients with apparent iron deficiency can have iron overload (hemachromatosis), the effects of which can contribute to morbidity and mortality.
• In very severe cases, allogeneic bone marrow transplantation may be considered, which is curative, since the hematopoietic system of the patient is replaced by that of the donor. A sibling who is fully matched for human leukocyte antigen (HLA) and who is, at most, a carrier for a -thalassemia (deletion of 2 a -globin genes) is the most suitable donor. However, because of the toxicity of the procedure, bone marrow transplantation should be limited to the most severely affected patients.

Surgical Care

• Splenectomy may be beneficial in some patients. Usually, splenectomy is reserved for patients with symptoms of hypersplenism, as reflected by leukopenia, thrombocytopenia, and worsening anemia or, in patients who were previously stable, development of a transfusion requirement.

Consultations

• Patients with hemoglobin H disease usually undergo close follow-up monitoring by a hematologist who can coordinate care and treat the patient during acute hemolytic and anemic episodes.

Diet

• In patients with elevated ferritin levels, the diet should be low in iron.

Medication

In general, no medications are needed in hemoglobin H disease (HbH disease); however, if the reticulocyte count is elevated, supplement the diet with folic acid. If a patient has an elevated ferritin level, consider chelation therapy with deferoxamine (Desferal) or deferasirox (Exjade). Deferasirox is preferred because it is orally administered, whereas deferoxamine is administered intravenously or subcutaneously.

Vitamins

This is a supplement with folic acid, a vitamin necessary for red blood cell production.

Folic acid (Folvite)

Necessary coenzyme for nucleoprotein synthesis and maintenance in patients with erythropoiesis.

Dosing

Adult

1-3 mg/d PO/IV/IM/SC

Pediatric

0-12 months: 0.5-1 mg/d PO/IV/IM/SC
1-10 years: Up to 1 mg/d PO/IV/IM/SC
>11 years: Administer as in adults

Interactions

Increase in seizure frequency and subtherapeutic levels with concurrent phenytoin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Pregnancy category C if >0.8 mg/d; benzyl alcohol may be present as preservative and is associated with fatal gasping syndrome in premature infants; resistance to treatment may occur in patients with alcoholism and other vitamin deficiencies

Chelation agents

Iron overload (usually from multiple transfusions) may require chelation therapy, which usually begins when the ferritin level is greater than 1000 ng/mL.

Deferoxamine mesylate (Desferal)

Freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. Excreted in urine and bile and discolors the urine red. Readily chelates iron from ferritin and hemosiderin but not transferrin. Most effective when provided to the circulation continuously by means of infusion. May be administered by IM injection, slow infusion, SC bolus, or continuous infusion. Does not effectively chelate other trace metals of nutritional importance.

Dosing

Adult

Acute iron intoxication: 1 g IM followed by 500 mg 4 h and 8 h later; may repeat with 500 mg IM q4-12h; not to exceed 6 g/d
Alternative: 1 g IV at a rate not exceeding 15 mg/kg/h followed by 500 mg q4h for 2 doses; administer additional IV infusion slowly over 24 h; not to exceed 6 g/d

Pediatric

<3 years: Not established
>3 years:
IM: 50 mg/kg IM initially; not to exceed 1 g/dose; may repeat with half dose 4h and 8h later; similar IM doses can be administered at q4h for next 24 h if clinical findings warrant
IV: 20 mg/kg IV initially over 1-2 min followed by an infusion of 60 mg/kg over 6-8 h; rapid injection can cause hypotension; if clinically indicated, additional therapy can be administered
IM in most circumstances
SC: 20-50 mg/kg/d SC continuous infusion over 8-12 h; not to exceed 2 g/d

Interactions

Concomitant administration with prochlorperazine can cause transient loss of consciousness

Contraindications

Documented hypersensitivity; absence of acute iron poisoning; severe renal disease and anuria (consider dose reduction after loading dose)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Tachycardia, hypotension, and shock may occur with chronic therapy (can increase cardiovascular collapse due to iron toxicity); adverse effects in GI tract include abdominal discomfort, nausea, vomiting, and diarrhea (may increase symptoms of acute iron toxicity); flushing; fever; rapid IV injection can cause hypotension

Deferasirox (Exjade)

Tab for oral susp. PO iron chelation agent demonstrated to reduce liver iron concentration in adults and children who receive repeated RBC transfusions. Binds iron with high affinity in a 2:1 ratio. Approved to treat chronic iron overload due to multiple blood transfusions. Treatment initiation recommended with evidence of chronic iron overload (ie, transfusion of about 100 mL/kg packed RBCs [about 20 U for 40-kg person] and serum ferritin level consistently >1000 mcg/L).

Dosing

Adult

Initial: 20 mg/kg PO qd on empty stomach 30 min ac; calculate dose to nearest whole tablet
Maintenance: Adjust dose by 5- to 10-mg/kg/d increments q3-6mo according to serum ferritin level trends; not to exceed 30 mg/kg/d
Note: Dissolve tab completely in water, orange juice, or apple juice, then immediately drink susp; resuspend any remaining residue in small volume of liquid and swallow

Pediatric

<2 years: Not established
>2 years: Administer as in adults

Interactions

Data limited; do not take with aluminum-containing antacids

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include diarrhea, nausea, abdominal pain, headache, pyrexia, cough, and rash; may increase serum creatinine and hepatic enzyme levels; decrease dose with persistent elevation of serum creatinine level; may cause auditory and visual disturbances; slight decreases in serum copper and zinc levels may occur; dissolve tab completely in water, orange juice, or apple juice and drink resulting susp immediately (do not swallow tab whole, do not chew or crush); measure serum ferritin levels monthly and adjust dose q3-6mo based on serum ferritin trends

Follow-up

Further Outpatient Care

• Pay close attention to iron overload in patients with hemoglobin H disease (HbH disease).
• Even patients who have not received a large number of transfusions may have elevated total body iron loads and may require chelation therapy.

Deterrence/Prevention

• Prenatal testing is available for families at risk (eg, parents are members of ethnic groups with the highest carrier rates). Globin-chain analysis can be performed by means of polymerase chain reaction (PCR) testing.^{[8 ]}
• Although neonatal screening is not sufficient in the diagnosis hemoglobin H disease, patients with the disease at birth have large amounts of hemoglobin Bart (g ₄), which is detectable with neonatal screening.

Prognosis

• The risk of severe anemia and the need for transfusions are lifelong.

Patient Education

• Educate patients and their parents regarding hemoglobin H disease.
• Genetic counseling is important for parents of a child with hemoglobin H disease. Parents must understand the risk that future children may have hemoglobin H disease and other, possibly more severe, thalassemia syndromes.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize this type of anemia as a genetic condition and to properly inform parents and patients of the potential to have children with hemoglobin H disease (HbH disease) or other thalassemia syndromes
• Failure to confirm iron deficiency anemia using laboratory testing in a patient with hemoglobin H disease may lead to continuation of supplemental iron therapy for an extended period (usually >3 mo), which may lead to secondary hemachromatosis. If iron overload continues longer than 1-2 years, it can lead to damage in multiple organs, including cardiac, hepatic, and endocrine dysfunction.

Special Concerns

• Pregnancy: During pregnancy, iron and folic acid deficiencies can alter the mean corpuscular volume (MCV). As a result, thalassemia may be difficult to diagnose or exclude during pregnancy. If a strong suspicion exists and if a definitive answer is required, polymerase chain reaction (PCR) should be performed for globin-chain analysis. Pregnant women with hemoglobin H disease require special care because those women with severe anemia may have serious health problems during their pregnancy and this may adversely affect the health of their fetuses. The incidence of low birth weight is also high in women with hemoglobin H disease and severe anemia.^{[9,10 ]}
• Geriatric patients: A particularly severe acquired form of hemoglobin H disease may occur in elderly men with clonal myeloproliferative diseases. In these patients, hemoglobin H levels may be as high as 60%. Extremely low a -chain– b -chain synthetic ratios may be present, and low a -globin messenger RNA levels are found in bone marrow cells. Hemolytic disease caused by hemoglobin H disease may wax and wane with the course of the myeloproliferative disease.
• a -thalassemia/mental retardation (ATR) syndromes:
  • In the ATR-16 syndrome, affected children have chromosomal rearrangements involving the short arm of chromosome 16 telomere, which includes the a -globin complex. This results in monosomy for the 16p telomere, and the a -thalassemia phenotype. If an affected child also inherits a single a -globin gene deletion from the other parent, hemoglobin H disease results. These children may also have mental retardation and other congenital anomalies thought to be due to deletions of dose-sensitive genes on chromosome 16p.
  • The ATR-X syndrome is an X-linked disorder caused by mutations of the ATRX gene located on chromosome Xq13.3. It is more frequent than the ATR-16 syndrome. Males who are affected usually have severe intellectual and physical handicaps and other congenital anomalies. Skeletal deformities are present in as many as 90% of patients. The a -thalassemia phenotype varies, with hemoglobin H inclusion bodies found in 0-32% of circulating erythrocytes.

Multimedia

Media file 1: α-chain genes in duplication on chromosome 16 pairing with non-α chains to produce various normal hemoglobins.

References

1. Chui DH. Alpha-thalassemia: Hb H disease and Hb Barts hydrops fetalis. Ann N Y Acad Sci. 2005;1054:25-32. [Medline].

2. Danquah I, Mockenhaupt FP. Alpha(+)-thalassaemia and malarial anaemia. Trends Parasitol. Nov 2008;24(11):479-81. [Medline].

3. Liu YT, Old JM, Miles K, et al. Rapid detection of alpha-thalassaemia deletions and alpha-globin gene triplication by multiplex polymerase chain reactions. Br J Haematol. Feb 2000;108(2):295-9. [Medline].

4. Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. Feb 1 2003;101(3):791-800. [Medline]. [Full Text].

5. Casas-Castaneda M, Hernandez-Lugo I, Torres O, et al. Alpha-thalassemia in a selected population of Mexico. Rev Invest Clin. Sep-Oct 1998;50(5):395-8. [Medline].

6. Ko TM, Hwa HL, Liu CW, et al. Prevalence study and molecular characterization of alpha-thalassemia in Filipinos. Ann Hematol. Aug 1999;78(8):355-7. [Medline].

7. [Guideline] Gibson BE, Todd A, Roberts I, et al. Transfusion guidelines for neonates and older children. Br J Haematol. Feb 2004;124(4):433-53. [Medline]. [Full Text].

8. Liu JZ, Yan M, Wang LR, et al. Molecular prenatal diagnosis of alpha-thalassemia using real-time and multiplex polymerase chain reaction methods. Hemoglobin. 2008;32(6):553-60. [Medline].

9. Tongsong T, Srisupundit K, Luewan S. Outcomes of pregnancies affected by hemoglobin H disease. Int J Gynaecol Obstet. Mar 2009;104(3):206-8. [Medline].

10. Tantiweerawong N, Jaovisidha A, Israngura Na Ayudhya N. Pregnancy outcome of hemoglobin H disease. Int J Gynaecol Obstet. Sep 2005;90(3):236-7. [Medline].

11. Chan V, Yam I, Chen FE, Chan TK. A reverse dot-blot method for rapid detection of non-deletion alpha thalassaemia. Br J Haematol. Mar 1999;104(3):513-5. [Medline].

12. Dondorp AM, Chotivanich KT, Fucharoen S, et al. Red cell deformability, splenic function and anaemia in thalassaemia. Br J Haematol. May 1999;105(2):505-8. [Medline].

13. Doridot V, Sibony O, Luton D, et al. Antenatal diagnosis of Bart's hydrops fetalis [correction of homozygous alpha thalassemia]. A case report. Fetal Diagn Ther. Mar-Apr 1999;14(2):122-4. [Medline].

14. Hunt JA, Lee L, Donlon TA, Hsia YE. Determination of the breakpoint of the common alpha-thalassaemia deletion in Filipinos in Hawaii. Br J Haematol. Feb 1999;104(2):284-7. [Medline].

15. Leder A, Wiener E, Lee MJ, et al. A normal beta-globin allele as a modifier gene ameliorating the severity of alpha-thalassemia in mice. Proc Natl Acad Sci U S A. May 25 1999;96(11):6291-5. [Medline].

16. Li D, Liao C, Li J, Xie X, Huang Y, Zhong H. Detection of alpha-thalassemia in beta-thalassemia carriers and prevention of Hb Bart's hydrops fetalis through prenatal screening. Haematologica. May 2006;91(5):649-51. [Medline].

Keywords

hemoglobin H disease, alpha-thalassemia syndrome, α-thalassemia syndrome, HbH disease, chronic hemolytic anemia, genetic disorder, thalassemia, anemia, alpha-globin gene, globin protein, malaria protection, alpha-globin chains, jaundice, hepatosplenomegaly, folic acid deficiency, iron deficiency, hydrops fetalis, marrow hyperplasia, bone thinning, maxillary hyperplasia, anemia, treatment, diagnosis

Contributor Information and Disclosures

Author

Alexandra C Cheerva, MD, Associate Professor of Pediatrics, Hematology/Oncology Division, Director of Pediatric Blood and Marrow Transplantation, University of Louisville; Attending Staff, Section of Pediatric Hematology and Oncology, Kosair Children's Hospital
Alexandra C Cheerva, MD is a member of the following medical societies: American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, International Pediatric Transplant Association, and Kentucky Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Ashok B Raj, MD, Associate Professor, Section of Pediatric Hematology and Oncology, Department of Pediatrics, Kosair Children's Hospital, University of Louisville
Ashok B Raj, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and Kentucky Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories
Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Afshin Ameri, MD to the development and writing of this article.

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