Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Vaso-occlusive events result in tissue ischemia leading to acute and chronic pain as well as organ damage that can affect any organ in the body, including the bones, lungs, liver, kidneys, brain, eyes, and joints. Dactylitis (pain and/or swelling of the hands or feet) in infants and young children is often the earliest manifestation of sickle cell disease. In children the spleen can become engorged with blood cells in a splenic sequestration crisis. The spleen is also particularly subject to infarction and the majority of individuals with SCD are functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation. Individuals with the highest rates of hemolysis are predisposed to pulmonary artery hypertension, priapism, and leg ulcers.
The term sickle cell disease encompasses a group of symptomatic disorders associated with mutations in the HBB gene and defined by the presence of hemoglobin S (Hb S). Normal human hemoglobin is a heterotetramer composed of two alpha-hemoglobin chains and two beta-hemoglobin chains. Hemoglobin S results from a point mutation in the HBB gene, changing the sixth amino acid in the beta-hemoglobin chain from glutamic acid to valine (Glu6Val). Sickle cell anemia (homozygous Hb SS) accounts for 60%-70% of sickle cell disease in the US. Other forms of sickle cell disease result from coinheritance of Hb S with other abnormal beta-globin chain variants, the most common forms being sickle-hemoglobin C disease (Hb SC) and two types of sickle -thalassemia (Hb S +-thalassemia and Hb S -thalassemia); rarer forms result from coinheritance of other Hb variants such as D-Punjab and O-Arab. The diagnosis of sickle cell disease is established by demonstrating the presence of significant quantities of Hb S by isoelectric focusing (IEF), cellulose acetate electrophoresis, high-performance liquid chromatography (HPLC), or, less commonly, DNA analysis. Targeted mutation analysis is used to identify the common mutations of HBB associated with hemoglobin S, hemoglobin C, and additional rarer mutations. HBB sequence analysis may be used to detect mutations associated with -thalassemia hemoglobin variants. Gel electrophoresis or HPLC can differentiate these disorders from heterozygous carriers of the Hb S mutation (Hb AS). In the US, mandatory newborn screening establishes the diagnosis of sickle cell disease in neonates, usually prior to the onset of symptoms.
Sickle cell disease is inherited in an autosomal recessive manner. If one parent is a carrier of the HBB Hb S mutation and the other is a carrier of an HBB mutation (e.g., Hb S, Hb C, -thalassemia), each child has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection for common forms of sickle cell disease is most commonly accomplished by HPLC. Prenatal diagnosis for pregnancies at increased risk for sickle cell disease is possible by molecular genetic testing if the HBB mutations have been identified in the parents.