Diagnostic Criteria

Suggestive Findings Beta-thalassemia (-thalassemia) major should be suspected in an infant or child younger than age two years with the following clinical and laboratory findings. • Clinical findings • Pallor • Poor weight gain • Stunted growth • Mild jaundice • Hepatosplenomegaly • Laboratory findings • Reduced (or absent) hemoglobin A (HbA) on newborn screening (i.e., through hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography [HPLC] on newborn blood spots) • Increased hemoglobin A2 (HbA2) with or without increased hemoglobin F (HbF) on hemoglobin electrophoresis • Absence of iron deficiency • Severe microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear Beta-thalassemia intermedia should be suspected in individuals who present after age two years or with less severe but similar findings to -thalassemia major. Establishing the Diagnosis The diagnosis of -thalassemia is established in a proband older than 12 months by identification of microcytic hypochromic anemia , absence of iron deficiency, anisopoikilocytosis with nucleated red blood cells on peripheral blood smear, and decreased or complete absence of HbA and increased HbA2 with or without increased HbF on hemoglobin analysis . The diagnosis of -thalassemia is established in a proband younger than age 12 months by identification of either: • Complete absence of HbA on newborn screening (diagnostic of 0-thalassemia, in which no beta globin chain is produced; see ); OR • Biallelic pathogenic (or likely pathogenic) variants in HBB on in a proband with suggestive laboratory findings. Note: (1) The reduction of HbA levels in infants with +-thalassemia (in which a reduced amount of beta globin chains are produced; see ) overlaps with the normal range for HbA in healthy infants; therefore, molecular genetic testing is required to diagnose infants younger than age 12 months with +-thalassemia. (2) Per American College of Medical Genetics and Genomics/ Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making . Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (3) Identification of biallelic HBB variants of uncertain significance (or of one known HBB pathogenic variant and one HBB variant of uncertain significance) does not establish or rule out the diagnosis. Hematologic Findings Red blood cell indices show microcytic anemia . Table 1. Red Blood Cell Indices in Beta-Thalassemia

Management Guidelines

Comprehensive reviews of the management of beta-thalassemia (-thalassemia) major and -thalassemia intermedia have been published by the Thalassemia International Federation and are available at the TIF website.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with -thalassemia, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Surveillance Guidelines

Recommendations for clinical and laboratory evaluations for individuals with -thalassemia major have been provided by the Thalassemia International Federation and are available at the TIF website. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations (for -thalassemia major) and (for -thalassemia intermedia) are recommended. Table 5a. Beta-Thalassemia Major: Recommended Surveillance