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. Acute chest syndrome 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. Individuals with the highest rates of hemolysis are predisposed to pulmonary artery hypertension, priapism, and leg ulcers but 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 60%-70% of SCD in the United States. Other forms of SCD result from coinheritance of HbS with other abnormal β-globin chain variants, the most common forms being sickle-hemoglobin C disease (Hb S/C) and two types of sickle β-thalassemia (Hb S/β+-thalassemia and Hb S/β°-thalassemia); rarer forms result from coinheritance of other Hb variants such as D-Punjab, O-Arab, and E.
The diagnosis of SCD is established by identification of significant quantities of HbS with or without an additional abnormal β-globin chain variant by hemoglobin assay or by identification of biallelic HBB pathogenic variants where at least one allele is the p.Glu6Val pathogenic variant (e.g., homozygous p.Glu6Val; p.Glu6Val and a second HBB pathogenic variant) on molecular genetic testing.
All states in the US have included newborn screening for SCD since 2005. Newborn screening programs perform isoelectric focusing and/or high-performance liquid chromatography (HPLC) of an eluate of dried blood spots. A few newborn screening programs confirm results with molecular testing.
Management: Treatment of manifestations: Management of pain episodes includes hydration, anti-inflammatory agents, and pain medication. Pain episodes are additionally managed with a multimodel approach (e.g., warmth, massage, distraction, acupuncture, biofeedback, self-hypnosis). Fever and suspected infection is treated with appropriate antibiotics. Life-threatening or severe complications (e.g., severe acute chest syndrome, aplastic crisis, and stroke) are often treated with red blood cell transfusion. Splenectomy may be necessary for splenic sequestration. Severe priapism may require aspiration and irrigation.
Prevention of primary manifestations: Maintain hydration and avoid climate extremes. Chronic red blood cell transfusion in children at risk for stroke and individuals with pulmonary hypertension, chronic renal failure, recurrent acute chest syndrome, and severe end-organ damage. Hydroxyurea can decrease the frequency and severity of vaso-occlusive processes, reduce transfusion needs, and increase life span. Glutamine has received FDA approval for the prevention of acute complications in individuals with SCD age five years and older. Stem cell transplantation may be an option in selected individuals.
Prevention of secondary complications: Aggressive education on the management of fevers; prophylactic antibiotics, including penicillin in children; immunizations; folic acid supplementation; and iron chelation therapy for those with iron overload.
Surveillance: Periodic comprehensive medical and social evaluation, mental health and neurocognitive assessment, and routine dental care. Annual CBC and reticulocyte count, assessment of iron status, liver and renal function tests, urinalysis, LDH, and vitamin D level. Annual transcranial Doppler to determine risk of stroke in all children with Hb S/S and Hb S/β°-thalassemia and ophthalmologic evaluation in all with sickling disorders. There should be a low threshold to evaluate for end-organ damage including chest x-ray, ECG, abdominal ultrasound, and iron overload. Due to the high frequency and severity of cardiopulmonary complications there should be a particularly low threshold to obtain an echocardiogram, pulmonary function tests, and sleep study in individuals of any age with cardiac or pulmonary concerns.
Agents/circumstances to avoid: Dehydration, extremes of temperature, physical exhaustion, extremely high altitude, recreational drugs with vasoconstrictive or cardiac stimulation effects, and meperidine.
Evaluation of relatives at risk: Early diagnosis of at-risk family members allows education and intervention before symptoms or end-organ damage are present.
Pregnancy management: Women with SCD who become pregnant require close follow up and monitoring by a hematologist and obstetrician; an increased risk for preterm labor, thrombosis, infectious complications, and acute painful episodes has been reported during pregnancy; hydroxyurea should be discontinued during pregnancy.
Genetic counseling: SCD is inherited in an autosomal recessive manner. If one parent is a carrier of the HBB HbS pathogenic variant and the other is a carrier of any of the HBB pathogenic variants (e.g., HbS, HbC, β-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 SCD is most commonly accomplished by isoelectric focusing or HPLC. Prenatal and preimplantation genetic testing are possible if the HBB pathogenic variants have been identified in the parents.
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