Key Points
Disease summary:
Sickle cell anemia (HbSS) is caused by homozygosity for a point mutation in the β-globin gene (HBB) that leads to replacement of glutamic acid by valine at position six of the β-globin chain of hemoglobin (β6 Glu>Val) leading to the synthesis of abnormal β-globin chains. The HbS β-globin chain pairs with normal a-globin chains to produce sickle hemoglobin or HbS (a2βS2).
Clinical presentation of HbSS is heterogeneous among patients even though all cases have the identical HbS mutation suggesting modification of the disease phenotype by other genes and the environment.
Complications can be related to sickle vaso-occlusion, for example, acute painful episodes, osteonecrosis, and acute chest syndrome and also be associated with the degree of hemolysis, for example, gallbladder disease, stroke, priapism, leg ulcers, and pulmonary hypertension.
The major treatment modalities include blood transfusion for severe anemia, stem cell transplantation for selected cases and administration of hydroxyurea (hydroxycarbamide) to stimulate the production of fetal hemoglobin (HbF) that by virtue of its effects on HbS polymerization, can decrease most complications of disease and extend lifespan.
Hereditary basis:
HbSS is inherited in an autosomal recessive fashion. If both parents are carriers, each child has a 25% risk of inheriting the disease.
HbSS can be seen in successive generations given the high carrier rates in some populations.
Differential diagnosis:
It is important to distinguish HbSS from other forms of sickle cell disease that are shown in Table 31-1, especially in genetic counseling.
| Hemoglobin HPLC | |||||||
|---|---|---|---|---|---|---|---|
| Type | HbA | HbA2 | HbF | HbS | Other | Severity | |
| HbSS (sickle cell anemia) | 0 | <3.6 | <10 | 90-95 | Severe | ||
| HbSS-α thalassemia | 0 | <3.6 | <10 | 90-95 | Low MCV | Severe | |
| HbS-β0 thalassemia | 0 | ≥3.6 | <10 | 90-95 | Severe | ||
| HbS-β+ thalassemia | 5-30 | ≥3.6 | <10 | 60-90 | Moderate | ||
| HbSC disease | 0 | <3.6 | <3 | 45-50 | HbC 45-50 | Moderate | |
| HbS-OArab | 0 | <3.6 | <3 | 45-50 | Hb OArab 45-50 | Severe | |
| HbS-HPFH | 0 | <3.6 | 20-40 | 60-80 | Mild | ||
Diagnostic Criteria and Clinical Characteristics
HbSS is a monogenic disease caused by homozygosity for a point mutation in the HBB that leads to replacement of glutamic acid by valine at position six of β-globin (β6 Glu>Val). Diagnosis of HbSS can be established based on family studies, history and physical examination, hematologic studies and by separating the hemoglobin fractions present in red blood cells by high-performance liquid chromatography (HPLC) or some other similarly sensitive and rapid method (Table 31-1). The definitive method of ascertaining the presence of HbS and/or identifying homozygosity or heterozygosity for the HbS (βs) mutation is based on DNA testing. The term sickle cell disease includes HbSS and other genotypes as shown in Table 31-1. The large range of HbF levels reflects different haplotypes of the HbS-globin gene.
Clinical presentation of HbSS is widely heterogeneous among patients and the severity and extent of HbSS-related complications are difficult to predict in any individual patient. HbSS-related complications include acute painful episodes, osteonecrosis, acute chest syndrome, gallbladder disease, splenic dysfunction, splenic sequestration, stroke, priapism, leg ulcers, pulmonary hypertension, renal failure, proliferative retinopathy, and predisposition to infections, for example, osteomyelitis. The rate of complications in HbSC disease and HbS-β+
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