Sickle Cell Disease (SCD) Differential Diagnoses

Updated: Oct 25, 2022
  • Author: Joseph E Maakaron, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Diagnostic Considerations

SCD is suggested by the typical clinical picture of chronic hemolytic anemia and vaso-occlusive crisis. The diagnosis is confirmed when electrophoresis demonstrates the presence of homozygous HbS. In addition to HbSS, this test may also document other hemoglobinopathies (eg, HbSC, HbS-beta+ thalassemia).

Sickling variants and sickle trait must be distinguished from HbS disease. HbS exists in combination with other hemoglobins in a double heterozygous state. The clinically important diseases involved, observed in patients in the United States, are HbSC and Hb-beta thalassemia.

HbSC disease is a milder sickling disorder. It is present in 1 in 1100 African Americans. In the HbC mutation, lysine replaces glutamic acid in position 6 on the beta chain. HbA is not present. The RBCs contain 50% HbS and 50% HbC. Anemia is much milder, with Hb levels of 11 g/dL or higher.

Symptoms of HbSC disease are similar to SCD but less frequent and less severe. Splenomegaly often persists well into adult life. Aseptic necrosis of the femoral head is not more common than in SCD. A proliferative retinopathy may lead to progressive loss of vision.

The diagnosis of HbSC disease is made with Hb electrophoresis. The peripheral blood smear may have some sickled cells and a high proportion of target cells. In addition, microcytic, dehydrated, dense RBCs are seen. These may contain crystal-like condensations. Treatment and management strategies are similar to those employed in Hb S disease.

In HbS–beta 0 thalassemia, only HbS is found on electrophoresis. HbA2 is elevated and splenomegaly usually is present. The clinical picture is similar to SCD but is slightly less severe. Management is similar to that for SCD. In HbS–beta+ thalassemia, Hb A is present, usually between 10% and 30%. The spleen is usually enlarged. This disease is otherwise similar to SCD but is milder.

Sickle cell trait is the heterozygous carrier state of HbS. These individuals have approximately 40% HbS and 60% HbA, less so with coexisting alpha-thalassemia trait.

People with sickle trait generally are well and have the following characteristics:

  • Normal life expectancy

  • Not at excessive risk for infection

  • Not subject to painful crisis under normal circumstances

  • No anemia

Nevertheless, providing genetic counseling to prospective parents with sickle cell trait is important. Reports exist of excessive deaths under extreme conditions, such as military basic training involving strenuous exertion; however, this is very uncommon. Similarly, isolated reports exist of organ infarction and crisis under unusual circumstances. Many of these patients lose urine-concentrating capacity. Painless hematuria may be present.

HbS variants may occur as double heterozygotes with other Hb variants. These include HbD, HbE, and HbO Arab. These are observed very infrequently in the United States, and information about them can be found in hematology texts.

Other problems to be considered

Gaucher disease also expands the marrow cavity and causes bone marrow infarction. Unlike sickle cell disease, which causes splenic infarction, Gaucher disease causes splenomegaly.

Depending on the clinical presentation, the differential diagnosis may also include the following:

  • Valvular heart disease

  • Septic arthritis

  • Sepsis

  • Upper respiratory tract infection

  • Aortic arch syndrome

  • Facioscapulohumeral muscular dystrophy

  • Incontinentia pigmenti

  • Familial exudative vitreoretinopathy

  • Lupus erythematosus

  • Macroglobulinemia

  • Polycythemia vera

  • Talc and cornstarch emboli

  • Uveitis, including pars planitis

Differential Diagnoses