Sickle Cell Disease

Bender MA, Carlberg K. Sickle Cell Disease. 2003 Sep 15 [updated 2023 Dec 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301551.

Clinical characteristics
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 system, including the bones, spleen, liver, brain, lungs, kidneys, and joints. Dactylitis (pain and/or swelling of the hands or feet) is often the earliest manifestation of SCD. In children, the spleen can become engorged with blood cells in a “splenic sequestration.” The spleen is particularly vulnerable to infarction and the majority of individuals with SCD who are not on hydroxyurea or transfusion therapy become functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections, primarily encapsulated organisms. Acute chest syndrome (ACS) is a major cause of mortality in SCD. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation as well as activating pathways that contribute to the pathophysiology directly. Individuals with the highest rates of hemolysis are at higher risk for pulmonary artery hypertension, priapism, and leg ulcers and may be relatively protected from vaso-occlusive pain.

Diagnosis/testing
SCD encompasses a group of disorders characterized by the presence of at least one hemoglobin S allele (HbS; p.Glu6Val in HBB) and a second HBB pathogenic variant resulting in abnormal hemoglobin polymerization. Hb S/S (homozygous p.Glu6Val in HBB) accounts for the majority of SCD. Other forms of SCD result from compound heterozygosity for HbS with other specific pathogenic beta globin chain variants (e.g., sickle-hemoglobin C disease [Hb S/C], sickle beta-thalassemia [Hb S/β+-thalassemia and Hb S/β0-thalassemia], Hb S/D, Hb S/OArab, Hb S/E).

The diagnosis of SCD is established by identification of significant quantities of HbS with or without an additional abnormal beta globin chain variant by hemoglobin assay or by identification of biallelic HBB pathogenic variants including at least one p.Glu6Val allele (e.g., homozygous p.Glu6Val; p.Glu6Val and a second HBB pathogenic variant) on molecular genetic testing.

Newborn screening for SCD began in the United States in 1975 in New York and expanded to include all 50 states by 2006. Newborn screening programs perform isoelectric focusing and/or high-performance liquid chromatography (HPLC) of an eluate of dried blood spots. Some newborn screening programs confirm results with molecular testing.

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