encompass a heterogeneous group of red blood cell disorders caused by mutations in the alpha globin (HBA) or beta-globin (HBB) genes. The clinical disorders that arise from these mutations are classified based on a structural change (Hb variant) or a reduction in the synthesis (thalassemia) of one or more globin chains comprising the hemoglobin molecule.

The common Hb variants, Hb S and Hb C, are responsible for the majority of sickle cell disorders. 

Beta thalassemias are typically caused by point mutations that disrupt regulatory elements of gene expression. The majority of alpha thalassemias are caused by large deletions of one or both alpha globin genes (HBA1 and HBA2).  Decreased production of the affected globin chains leads to an imbalance in the α to β globin chain ratio.  Excess globin chains form non-functional aggregates that precipitate within the red blood cells lead to premature destruction in the bone marrow (beta thalassemia) or in the peripheral circulation (alpha thalassemia).

Sickle Cell Disease 

Sickle cell disease refers to individuals who are homozygous for the sickle cell mutation (Hb SS), or compound heterozygous for the sickle cell mutation and other hemoglobin variants such as Hb C, Hb D-LA, Hb O-Arab, or beta thalassemia mutations (Hb S beta thalassemia).  The pathophysiology of sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia.  One of the earliest manifestations of SCD in young children is dactylitis, or  “hand-foot syndrome.”   Common problems in children include intermittent vaso-occlusive pain episodes, febrile events, acute chest syndrome, splenic sequestration and aplastic episodes due to infection with parvovirus.  Cerebrovascular disease is one of the most serious complications of SCD, manifested as overt stroke or silent cerebral infarcts.  Ongoing hemolysis and vaso-occlusion affects virtually every organ system and may manifest in older patients as a chronic pain syndrome, cholelithiasis, osteonecrosis, retinopathy, renal disease, priapism, chronic lung disease and pulmonary hypertension.


Beta thalassemia major refers to individuals who are homozygous or compound heterozygous for beta thalassemia mutations and are transfusion dependent as a result of both ineffective erythropoiesis and hemolytic anemia. Without aggressive chelation therapy, transfusion-associated hemosiderosis eventually leads to endocrine, hepatic and cardiac dysfunction.  Hb E beta thalassemia presents in infancy as a variably severe anemia with a clinical phenotype ranging from a complete lack of symptoms to transfusion dependence. Osteoporosis, iron overload, growth failure, and pulmonary hypertension are commonly reported complications in both transfused and nontransfused patients.  More than 200 beta thalassemia mutations have been described.  In many cases, the genotype may not explain the observed clinical phenotype, reflecting the complex genetic interactions between the globin genes, expression controlling regions, and a growing list of other potential genetic modifiers.  Alpha thalassemias represent a group of conditions resulting from a reduced rate of alpha globin synthesis. Hb H disease results from deletion or dysfunction of three of the four alpha globin genes.  The most common genotype leading to Hb H disease is a single alpha gene deletion coinherited with a two alpha gene deletion, e.g. - -SEA/- a4.2 in the Southeast Asian population.  Compound heterozygosity for a two alpha gene deletion and a non-deletional alpha thalassemia mutation, e.g. Hb H Constant Spring may also cause Hb H disease. Individuals with Hb H disease present with cholelithiasis, exacerbations of severe anemia, or splenomegaly arise. Intermittent transfusions are required in up to 50% of patients with Hb H disease and as early as infancy in the majority of those with the more severe HbH Constant Spring phenotype. 

Accurate diagnosis based on identification of hemoglobin variants or thalassemia mutations is essential for optimal management of hemoglobin disorders.  In California, newborns are screened for sickle cell disease, HbH disease and beta thalassemia.  Serving as the reference laboratory for the California State Newborn Screening Program,  the laboratory confirms all screen-positive results on a second sample collected from the newborn.  Most of the common Hb variants, such as Hb S, Hb C, and Hb E can be identified using a combination of chromatographic and electrophoretic methods.   Automated cation exchange high performance liquid chromatography (HPLC) is a rapid and sensitive technique for the presumptive identification of many hemoglobin variants and for quantification of HbA2 and Hb F.  Various complementary techniques including cellulose acetate and citrate electrophoresis, isoelectric focusing and capillary electrophoresis (CE) are used to detect and resolve Hb variants.  Definitive diagnosis of a thalassemia, requires molecular testing by DNA sequencing, gap PCR or MLPA. 

For more information, visit thalassemia.com and the UCSF Center of Excellence in Sickle Cell Care.

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