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Sickle Cell Anemia - Diagnosis When a newborn’s screening test indicates “sickle cell disease,” it is the primary physician’s responsibility to either establish a definitive diagnosis or to refer the patient to a pediatric hematologist for this purpose. Establishing a definitive diagnosis requires accurate characterization of the hemoglobin phenotype and correlation of the phenotype with the clinical history, blood counts, and red blood cell morphology. Recent advances in molecular biology techniques have identified many variations in the beta globin gene area (beta globin gene haplotype) that may modify the clinical expression of sickle cell disease. Studies of the child’s parents are useful in establishing a definitive diagnosis but must be undertaken with caution as the tests may disclose mistaken paternity. As in all inherited disorders, thorough counseling of the mother is recommended before performing extensive family testing, and family testing should not be performed if the mother objects.Once the definitive diagnosis is established, the parents should be provided with appropriate education and counseling about the specific form of sickle cell disease affecting their child. Providers must explain things carefully, avoiding medical jargon and allowing ample time for questions. Practitioners should not “overload” parents by providing them with too much detail during initial visits. More than one counseling/education session is required to ensure that parents adequately understand the information. A practitioner should not hesitate to refer the patient and family to a specialist for counseling. Many community-based sickle cell organizations are available to help with patient education and the acquisition of social services. The definitive diagnosis should be recorded on the child’s immunization record and in other key medical records. A copy of the diagnostic information also should be given to the parents so that information can be shared with other health professionals involved with the infant’s care.
Newborn screening for sickle cell disease is an effective first step to reduce morbidity and mortality in individuals with the disease. Parents of newborns with a positive screening test result for sickle cell disease must be contacted before the child becomes 2 months of age to confirm the diagnosis. The diagnosis should be confirmed by a laboratory with expertise in analysis of variant hemoglobins. If a child who is presumed to have sickle cell disease through newborn screening is not retested by 4 months of age, he or she should be started on penicillin VK (125 mg given orally twice a day) pending confirmation; the medication can be discontinued in the rare instance that the hemoglobin screening test result was erroneous or is found to represent a benign disorder. Once the disease diagnosis is confirmed, the infant must receive care in an ongoing and comprehensive medical program that includes oral penicillin given twice a day for the prevention of overwhelming Streptococcus pneumoniae infection and parent education about sickle cell disease. The medical program should be staffed by health care professionals who are sensitive to the special needs of infants with sickle cell syndromes and are aware of their propensity to life-threatening infection and death from complications such as acute splenic sequestration and acute chest syndrome. All infants, of every ethnic group, should be tested to ensure the identification of all affected newborns. Where possible, sickle cell disease screening should be coupled with other newborn screening tests performed to detect hypothyroidism and inborn errors of metabolism. Several screening methodologies are acceptable, including hemoglobin electrophoresis on cellulose acetate and citrate agar, isoelectric focusing, and high-pressure liquid chromatography. Because of the high concentration of Hb F in newborns, solubility tests or sickle cell preparations (sodium metabisulfite) should not be used to confirm the presence of Hb S until the infant has reached 12 months of age and should never be used as a sole diagnostic laboratory procedure. States that test for sickle cell disorders as part of their newborn screening procedures usually confirm the original test result by retesting the child and will also request a repeat specimen if the history indicates that the child was transfused before the blood sample was obtained. It must be emphasized that the responsibility for a final and definitive diagnosis rests with the child’s physician. Red cells of normal newborns contain hemoglobins F and A, “FA,” the hemoglobin in highest concentration being listed first. The hemoglobin pattern or phenotype is due to predominance of Hb F at birth. Newborns with sickle cell trait have an “FAS” phenotype, with more Hb A than Hb S. Infants with SC disease have an “FSC” pattern, those with SS disease, Sb o thal, and S HPFH each have an “FS” phenotype on newborn screening. Although infants with Sb + thal will generally have an “FSA” pattern on screening, the percentage of Hb A may be so small that these infants will also have an “FS” phenotype. Definitive diagnosis may require testing both parents or deoxyribonucleic acid (DNA) typing of the infant or retesting the infant after 9 months. It is important to remember that newborns with “FA” patterns are not necessarily hematologically normal—they do not have sickle cell disease but may have thalassemia or another disorder of red blood cells. When definitive diagnostic tests cannot be performed in early infancy, it is best to assume that the infant has SS disease, the most common of the FS disorders. When infants are doubly heterozygous for sickle cell and another abnormal hemoglobin other than C, definitive identification by a knowledgeable hematologist is necessary. In addition to identifying the affected new-born, newborn screening also provides an opportunity to identify couples at risk for having children with sickle cell disorders. Parents of newborns identified with sickle cell trait or hemoglobin C trait should be offered testing for all hemoglobinopathies, including thalassemia, and be appropriately counseled.
Prenatal Diagnosis Each year in the United States there are 4,000 to 5,000 pregnancies at risk for sickle cell disease. As with other genetic diseases, advances in technology have provided safe and accurate methods for performing prenatal diagnosis for sickle cell disease as early as the 10th gestational week. Prenatal diagnosis is best accomplished by a reproductive genetics team familiar with sickle cell disease and experienced in the provision of accurate genetic diagnosis of couples at risk after nondirected genetic counseling. The team must be expert in obtaining a fetal sample for analysis and performance of diagnostic laboratory tests and must be prepared to handle consideration of pregnancy termination. A necessary proviso for prenatal diagnosis of sickle cell disease is that diagnostic methodology not be allowed to exceed our ability to predict clinical severity. The degree of control that ethically can be exerted over the biological makeup of unborn children must be weighed.
COUNSELING Couples at risk for conceiving a child with homozygous SS disease, Hb SC disease, or Sb thalassemia should be referred for genetic counseling. This process must be carried out with the realizations that all mothers requesting prenatal diagnosis desire to bear children and that fetal welfare is never enhanced by prenatal diagnosis. Counseling includes an objective description of a patient’s life with a particular form of sickle cell disease. It is important that counseling takes into account the clinical differences among the various types of sickle cell disease and the heterogeneity within genotypes. It is also important that discussions of prenatal diagnosis and pregnancy interruption be conducted in a sensitive nondirected manner. Many patients have relatively benign disease; the ability to predict disease severity would be a valuable asset in counseling and prenatal diagnosis, but this is still lacking. Currently, some centers introduce couples at risk to patients with sickle cell disease to provide a better understanding of the disease and a firmer basis for decisions on prenatal diagnosis and possible interruption of pregnancy. The decision regarding use of the results of prenatal diagnosis should always be left to the parents; informed decisionmaking is their prerogative.Couples who elect to have prenatal diagnosis must be referred to an appropriate center as early in pregnancy as possible because the time-consuming diagnostic processes must be completed before the 24th gestational week, after which pregnancies for genetic diseases are not terminated.
GENETICS Codominant inheritance of the sickle cell gene means that individuals homozygous for the mutation have clinical disease and that heterozygous individuals, although asymptomatic, are detectable. When an individual with sickle cell trait is considering conceiving a child with a mate who is heterozygous for Hb S, Hb C, or b thalassemia, there is a one-in-four chance for each pregnancy that the offspring will inherit a form of sickle cell disease. When one parent has sickle cell anemia and the other is heterozygous for any of these three disorders, there is a one-in-two chance with each pregnancy of conceiving a child with sickle cell disease.FETAL TISSUE SAMPLING Analyses are performed on DNA from fetal cells obtained by chorionic villus sampling (CVS) in the first trimester, perhaps as early as the 10th gestational week. As an alternative approach, amniocentesis can be performed safely in the l6th gestational week, a time when there is sufficient amniotic fluid. These sampling methods result in a far lower rate of fetal demise than the fetal blood sampling method practiced previously, and their use now is nearly universal. It is common practice to initiate tissue culture as a backup source of fetal DNA in case insufficient DNA for analysis is obtained initially. The emphasis on methods of early sampling to safeguard against unacceptable delays in diagnostic testing have encouraged the use of CVS as the method of choice for fetal sampling. However, the use of CVS before 9 weeks’ gestation is associated with increased rates of limb reduction anomalies. Moreover, when CVS is used for sampling, confined placental mosaicism may result in mistaken diagnoses of heterozygosity in homozygous fetuses. CVS is not recommended until after 10 weeks’ gestation, and diagnoses of heterozygosity must be confirmed by amniocentesis later in pregnancy. The use of preimplantation testing and assaying fetal cells in the maternal circulation offer hope for safer sampling in the future.The Hb S and Hb C genes can be detected directly in fetal DNA samples. If the specific mutation responsible for thalassemia in a parent is known, that gene can also be detected. In some laboratories, several relatively common mutations are sought, but a negative result is not helpful. The use of genetic linkage analysis for indirect identification of these genes is no longer necessary. Fetal blood sampling is used only in centers where DNA-based testing is unavailable. DIAGNOSTIC TESTS Tests using polymerase chain reaction (PCR) provide sensitivity, simplicity, and rapidity to DNA-based methods. PCR provides greater amounts of DNA for analysis, often obviates the wait for tissue culture growth, and shortens the time for diagnosis to days rather than weeks. Several molecular diagnostic laboratories are available with expertise in prenatal diagnosis of hemoglobinopathies. |
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