Diagnostic Considerations

The differential diagnoses will depend on the presentation, and patients fall into three clinical categories.

Asymptomatic patients in childhood or later, with mild microcytic hypochromic anemia

Alpha- and beta-thalassemia trait need to be differentiated from iron-deficiency anemia, which is the most common cause of microcytic hypochromic anemia in children. Assessment of the patient's nutritional and family history must be included in this differentiation. A review of the complete blood count (CBC) can be diagnostic, owing to the fact that in thalassemia trait the anemia is mild (usually Hb >9-10 g/dL), with the RBC count elevated and the mean corpuscular volume (MCV) significantly decreased. This discordance is reflected in the Mentzer index, where MCV/RBC is less than 13 in patients with thalassemia trait.

In iron-deficiency anemia, Hb electrophoresis results can be misleading, since the production of HbA₂ is suppressed; if there is a strong clinical suspicion, the test should be repeated after the iron-deficiency anemia has been treated. Confirmation of alpha-thalassemia trait can be hard, since Hb electrophoresis is normal, but commercially available polymerase chain reaction (PCR) screening for α-globin 3.7 kb and 4.2 kb deletions has made it easier to screen for patients who are α⁺ thalassemia carriers, with these individuals commonly being of African or Middle Eastern origin.^[2]

Patients with severe hemolytic anemia presenting a few months after birth, or in early childhood.

The concern in this category would be severe beta thalassemia (major or intermedia) or alpha thalassemia (HbH disease). For patients who are transfusion dependent, congenital dyserythropoietic anemia and Diamond-Blackfan anemia should be in the differential. For patients who are not transfusion dependent, Gaucher disease and other storage disorders, as well as malignant osteopetrosis, should be considered. In almost all cases, review of the red cell indices, peripheral blood smear, and Hb electrophoresis, of the child and parents, is usually adequate to reveal the diagnosis. Rarely does any other testing need to be done.

HbH disease can be diagnosed based on inclusions in the RBCs (Heinz bodies), provided a supravital stain is performed, but on Hb electrophoresis, the HbH band tends to be unstable and can be missed. Patients with HbH disease have more than 20% Hb Bart at birth, which allows diagnosis in a newborn screening program.^[20]

Patients stillborn with hydrops fetalis

Homozygous α⁰ thalassemia is not compatible with life (unless intrauterine blood transfusion is administered, which is a rare situation), and a stillbirth with Hb Bart hydrops fetalis usually occurs. Other causes of immune and nonimmune hydrops fetalis should be differentiated from alpha-thalassemia major, a condition that is commonly encountered in Southeast Asia and southern China but is rarely seen outside those regions.^[15]

Differential Diagnoses

Workup

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Media Gallery

Alpha chain genes in duplication on chromosome 16 pairing with non-alpha chains to produce various normal hemoglobins.
Alpha and beta globin genes (chromosomes 16 and 11, respectively).
Various mutations in the beta gene that result in beta thalassemia.
Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball appearance).
Peripheral blood film in Cooley anemia.
Peripheral blood film in thalassemia minor.
Peripheral blood film in hemoglobin H disease in a newborn.
Peripheral blood in iron deficiency anemia.
The classic "hair on end" appearance on plain skull radiographs of a patient with Cooley anemia.
Excessive iron in a bone marrow preparation.

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Author

Hassan M Yaish, MD Medical Director, Intermountain Hemophilia and Thrombophilia Treatment Center; Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology, Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center

Hassan M Yaish, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Michigan State Medical Society, New York Academy of Sciences

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology, American Federation for Clinical Research, Council on Medical Student Education in Pediatrics, Hemophilia and Thrombosis Research Society, American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Vikramjit S Kanwar, MBBS, MBA, MRCP(UK) Professor Emeritus of Pediatrics, Albany Medical College; Chief of Pediatric Oncology, Homi Bhabha Cancer Hospital, Varanasi, India

Vikramjit S Kanwar, MBBS, MBA, MRCP(UK) is a member of the following medical societies: Children's Oncology Group, Indian Academy of Pediatrics, International Society of Pediatric Oncology

Disclosure: Nothing to disclose.

Additional Contributors

J Martin Johnston, MD Associate Professor of Pediatrics, Mercer University School of Medicine; Director of Hematology/Oncology, The Children's Hospital at Memorial University Medical Center; Consulting Oncologist/Hematologist, St Damien's Pediatric Hospital

J Martin Johnston, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, International Society of Paediatric Oncology

Disclosure: Nothing to disclose.