Sickle Cell Disease and Other Hemoglobinopathies Information & Management
The hemoglobinopathies include several disorders that are distinguished by alterations in the normal structure or synthesis of hemoglobin. In the United States, screening for hemoglobinopathies varies from state to state. All 50 states mandate screening for sickle cell disease. Some programs report only sickle cell disease, sickle cell trait, and certain other structural hemoglobin abnormalities. Although some newborn screening methods are capable of identifying potentially clinically significant thalassemia syndromes, states differ in their policies for diagnosing and reporting these results. Thalassemia syndromes will not be considered in this fact sheet. Hemoglobin SS disease (sickle cell anemia; OMIM database No. 603903) 162 is the most common and generally most severe form of sickle cell disease; hemoglobin SC disease and hemoglobin S/ß-thalassemia disease are other clinically important variants.
Incidence
Among newborn infants in the United States, sickle cell disease is 10 times more common than phenylketonuria (PKU). 163 The incidence is relatively high in populations of African (1 in 400), Hispanic (1 in 1000-1400), Mediterranean, and Middle Eastern descent. 163 164 It is much lower in populations of Northern European descent. The incidence of sickle cell trait is 1 in 10 to 12 black individuals. 163 Sickle cell trait is a benign carrier condition; affected individuals are not at increased risk of having sudden death or serious consequences unless they are subjected to conditions of extreme physical stress, dehydration, or hypoxia. 165 166 For other significant hemoglobinopathies, primarily hemoglobin C and E diseases, incidences vary, but they are most prevalent in populations of African and Southeast Asian descent, respectively.
Clinical Manifestations
In most infants with hemoglobinopathies, disease is not clinically apparent at birth. Red blood cells from infants with hemoglobin SS disease generally show no sickling at birth because of the protective effect of fetal hemoglobin (HbF). 167 Although growth usually is normal, infants with sickle cell disease (usually the SS or S/ß0-thalassemia forms) begin to show signs of disease as HbF concentrations decrease and hemoglobin S (HbS) concentrations increase. In older infants, the clinical manifestations of sickle cell disease usually are signs of anemia, severe pain, or severe overwhelming infection. Specifically, the acute manifestations include severe anemia from splenic sequestration or an aplastic crisis, dactylitis (hand-foot syndrome), stroke, acute chest syndrome, or sepsis, usually attributable to Streptococcus pneumoniae. 164 168-170 In early childhood, the spleen usually is enlarged, but progressive splenic fibrosis and atrophy (autosplenectomy) typically occur by 8 years of age. 168 171 Aplastic crises are typically caused by infection with parvovirus B19. As affected children get older, painful vaso-occlusive crises are common.
Some of the structural hemoglobinopathies (eg, hemoglobin E disease) rarely show clinically important symptoms. 172 Compound heterozygous conditions (eg, hemoglobin SC disease and certain hemoglobin E/thalassemia syndromes) may result in severe clinical disease.
Pathophysiology
Hemoglobin consists of 4 globin chains, 2 α and 2 non-α. Normal adult hemoglobin (HbA) has 2 α and 2 ß chains (α2ß2). HbF has 2 α and 2 γ chains (α2γ2). Normal hemoglobin consists of 95% to 98% HbA, 2% to 3% HbA2 (α2δ2), and less than 1% HbF. Normal adult levels of HbA and HbF are reached at approximately 1 year of age.
A structural hemoglobinopathy results from a substitution of 1 or more amino acids in the globin chain. In HbS disease, valine is substituted for glutamic acid at the sixth position of the ß chain. The presence of significant amounts of HbS causes the red blood cell to change shape (ie, sickle) when subjected to a relatively low-oxygen environment. The sickled cells may be trapped in the microvasculature, resulting in tissue hypoxia, ischemia, infarction, and pain. In affected children, the spleen is especially vulnerable to ischemic injury. Destruction of the normal splenic architecture ultimately results in loss of normal reticuloendothelial function and leads to an increased risk of severe, often life-threatening, bacterial infections (usually attributable to encapsulated organisms such as pneumococcus). Trapping of large numbers of red blood cells in the spleen also causes splenic sequestration crises and profound anemia.
Inheritance
Hemoglobin SS disease is an autosomal recessive disorder. To be affected, a child must inherit an abnormal allele from both parents. Hemoglobin SC disease is an example of an autosomal recessively inherited compound heterozygous condition in which the affected child inherits an S allele from one parent and a C allele from the other. Sickle cell trait (AS) is an autosomal recessive carrier state.
Benefits of Newborn Screening
The primary benefit of newborn screening for sickle cell disease is a reduction in mortality in the first few years of life. 163 173 By initiating prophylactic administration of penicillin by 2 months of age, the incidence of severe pneumococcal sepsis is reduced dramatically. 170 173 In addition, education of parents of affected children about the signs and symptoms of complications of sickle cell disease and when to seek medical evaluation has decreased morbidity and mortality from acute sequelae of the disease. 164 168 174
Screening
Several accurate, highly sensitive, and specific screening tests exist for hemoglobinopathies. The initial method for almost all screening programs is isoelectric focusing or high-performance liquid chromatography. Some screening programs use a second method to verify abnormal results. To provide valid results, both methods of analysis require specimens obtained either by heel prick or from cord blood. Most false-negative screening results are attributable to clerical error, extreme prematurity, or prior blood transfusion.
State newborn screening programs should report both disease and trait conditions to the physician of record. Results generally are reported in decreasing order of the amount of hemoglobin present. A normal newborn screening test result is reported as FA, indicating that HbF and HbA are present and that there is more HbF than HbA. The presence of significant amounts of HbS without HbA (eg, FS) generally is indicative of hemoglobin SS disease or hemoglobin S/ß0-thalassemia disease. The presence of HbF, HbS, and HbC (FSC) is indicative of hemoglobin SC disease. In addition to sickle cell disease and sickle cell trait (FAS), screening tests may detect other structural variants (eg, HbC, HbE) and various types of thalassemia. It may be necessary for the primary care physician to contact the newborn screening program to ascertain whether the presence of these latter disorders is determined by the specific screening protocol in that state.
Follow-up and Diagnostic Testing
Whenever a positive screening result for sickle cell disease is obtained, definitive diagnosis requires confirmatory testing. Such testing generally involves quantitative hemoglobin electrophoresis. These results require careful interpretation to distinguish the various forms of sickle cell disease and other hemoglobinopathies. Molecular genetic testing is rarely required.
It also is important to provide follow-up evaluation and genetic counseling to the families of all infants who have sickle cell trait (eg, FAS) or another abnormal hemoglobin trait. It has been estimated that almost 50% of couples at risk of having a child with sickle cell disease can be identified through newborn screening for variant hemoglobin traits.
Brief Overview of Disease Management
All infants who have a hemoglobinopathy require care in a medical home by an experienced primary care physician in consultation with a pediatric hematologist. 164 168 Care of children with sickle cell disease includes routine general pediatric management, daily administration of prophylactic penicillin, provision of appropriate immunizations including the 23-valent pneumococcal vaccine, and prompt evaluation of all febrile episodes or signs of acute illness. 164 173 174 Parent education regarding the manifestations of splenic sequestration, signs of infection, and importance of compliance with the prescribed medical regimen is essential. Transcranial Doppler ultrasonography, a noninvasive predictor of impending stroke in children with sickle cell disease, enables early intervention to prevent stroke. 175 Children with hemoglobinopathies may present special challenges during surgical procedures and require attentive perioperative care. 164
Children with more severe symptoms of sickle cell disease may benefit from specific therapies. For example, some children will require chronic transfusion therapy to prevent recurrent stroke. The complications of continuous transfusion therapy, such as iron overload, require careful long-term management. Recent evidence indicates that treatment with hydroxyurea increases concentrations of HbF, resulting in significant clinical improvement for some patients with severe sickle cell disease. 176 177 Cure of sickle cell disease has resulted from bone marrow transplantation.
Current Controversies
Although it is clear that early diagnosis and institution of prophylactic measures reduces morbidity and mortality from sickle cell disease, 163 173 many parents of children who test positive do not seem to understand the implications of a positive screening result. Furthermore, in many instances, prophylactic penicillin therapy is not started by 2 months of age, or parents discontinue the drug prematurely. These issues underscore the need for early and repeated counseling for families of an affected child.
Because there also are substantial psychosocial issues raised when carrier testing is performed, the communication of carrier status and provision of genetic counseling to the family is an important component of appropriate follow-up. 163 The resources required to provide comprehensive genetic counseling are not uniformly available in all state screening programs, and pediatricians may face significant challenges in meeting this need.