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.
Management: Treatment of manifestations: Education of parents, caregivers, and affected individuals on health maintenance, prophylactic medications such as hydroxyurea, early interventions, warning signs of acute illness, pain management options, and urgent care plan; antibiotic prophylaxis for Streptococcus pneumoniæ; immunizations including those for asplenic individuals; folic acid supplementation; red blood cell (RBC) transfusion therapy and treatment for iron overload. Management of pain episodes includes reversal of inciting triggers, hydration, anti-inflammatory agents, and pain medication. Pain episodes are additionally managed with a multimodal approach (e.g., warmth, massage, distraction, acupuncture, biofeedback, self-hypnosis). RBC transfusion as needed for splenic sequestration; splenectomy may be necessary. Fever and suspected infection are treated with appropriate antibiotics. Life-threatening or severe complications (e.g., severe ACS, stroke, aplastic crisis, chronic kidney failure) are often treated with RBC transfusion or RBC exchange. Treatment of pulmonary hypertension generally includes treating inciting factors and optimizing SCD therapy to stop progression; severe priapism may require aspiration and irrigation. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for those with kidney disease with kidney transplant for end-stage kidney disease; mental health therapy and community resources.
Prevention of primary manifestations: Education on ways to avoid potential triggers of vaso-occlusion is essential. Maintaining hydration, avoiding climate extremes, overexertion, and, when possible, trauma and infection. Hydroxyurea is the standard of care to decrease the frequency and severity of vaso-occlusive processes, reduce transfusion needs, and increase life span. L-glutamine, voxelotor, and crizanlizumab have received FDA approval for the prevention of acute complications and/or anemia in individuals with SCD as young as age four years. Chronic RBC transfusion to reduce risk of pain, stroke, ACS, and severe end-organ damage; stem cell transplantation may be an option in selected individuals and trials involving gene therapy are ongoing.
Surveillance: Periodic comprehensive medical and social evaluation, mental health and neurocognitive assessment, and routine dental care. Annual complete blood count with differential and reticulocyte count; annual transcranial Doppler to determine risk of stroke in all children with Hb S/S and Hb S/β0-thalassemia; annual developmental assessment throughout childhood; neurocognitive assessment prior to school entry and as needed; brain MRI in childhood when examination can be tolerated without anesthesia and repeated as needed; annual assessment of vitamin D level and renal function (blood urea nitrogen, serum creatinine, urinalysis, and urine microalbumin or urine protein-to-creatinine ratio); ophthalmologic evaluation annually beginning at age ten years. Because of the high frequency and severity of cardiopulmonary complications there should be a particularly low threshold to obtain an echocardiogram, pulmonary function tests, six-minute walk test, N-terminal pro-brain natriuretic peptide (NT-proBNP), and sleep study in individuals of any age with cardiac or pulmonary concerns; EKG in those on medications that may alter corrected QT interval; growth assessments throughout childhood; annual assessment of iron status and liver function; MRI as needed to evaluate for iron overload; assessment of mental health and social needs at least annually.
Agents/circumstances to avoid: Dehydration, extremes of temperature, physical exhaustion, extremely high altitude, trauma, infection, recreational drugs with vasoconstrictive or cardiac stimulation effects, and meperidine.
Evaluation of relatives at risk: Early diagnosis of at-risk family members allows for genetic counseling as well as 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. Increased risk for preterm labor, thrombosis, preeclampsia, infectious complications, ACS, and acute painful episodes have been reported during pregnancy. Hydroxyurea should be discontinued during pregnancy.
Genetic counseling: SCD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a HBB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic beta globin chain variants and being affected, a 50% chance of inheriting one beta globin chain variant and being heterozygous, and a 25% chance of inheriting neither of the familial beta globin chain variants. If the SCD-related HBB pathogenic variants in a family are known, molecular genetic testing can be used to identify which at-risk family members are heterozygous; if only one (or neither) SCD-related HBB pathogenic variant in a family is known, HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). Molecular genetic prenatal testing and preimplantation genetic testing for SCD are possible when both HBB pathogenic variants have been identified in an affected family member and the genetic status of the parents is known.
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