Overview of compound sickle cell syndromes

INTRODUCTION — Compound sickle cell syndromes include any hemoglobinopathy in which the sickle mutation is inherited in combination with another globin gene mutation (affecting alpha globin, beta globin, or gamma globin). These syndromes may have different clinical severity compared with homozygous sickle mutation (HbSS).

This topic presents an overview of the compound sickle cell syndromes and their clinical features.

Related subjects including the diagnosis of sickle syndromes, clinical manifestations, and management, as well as sickle cell trait (generally a benign carrier state) are discussed separately.

●Prenatal testing – (See "Prenatal screening and testing for hemoglobinopathy".)

●Diagnosis – (See "Diagnosis of sickle cell disorders".)

●Further details about laboratory methods – (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

●Clinical manifestations – (See "Overview of the clinical manifestations of sickle cell disease".)

●Sickle cell trait – (See "Sickle cell trait".)

●Management – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Overview of the management and prognosis of sickle cell disease".)

OVERVIEW

Pathophysiology — Vaso-occlusive phenomena and hemolytic anemia are the clinical hallmarks of sickle cell disease (SCD). Vaso-occlusion results in recurrent painful episodes and a variety of serious organ system complications that can lead to life-long disabilities and even death.

Hemoglobin S (HbS) results from the substitution of a valine for glutamic acid as the seventh amino acid of the beta-globin chain, which produces a hemoglobin tetramer (alpha2/betaS2) that is poorly soluble when deoxygenated [1]. The polymerization of deoxy HbS is essential to vaso-occlusive phenomena [1]. The polymer assumes the form of an elongated rope-like fiber which usually aligns with other fibers, resulting in distortion of the affected red blood cell into the classic crescent or sickle shape and a marked decrease in red cell deformability. (See "Pathophysiology of sickle cell disease", section on 'Effects on the RBC'.)

However, polymerization alone does not account for the pathophysiology of SCD. Subsequent changes in red cell membrane structure and function, disordered cell volume control, and increased adherence to vascular endothelium also play an important role [1,2].

The three most common genotypes accounting for SCD are homozygous HbSS and two compound sickle cell syndromes, sickle–beta thalassemia and hemoglobin SC disease.

SCD clinical manifestations are similar in compound heterozygotes as in homozygous HbSS, but they vary in severity (from mild, to as severe as in HbSS). The clinical heterogeneity in different SCD genotypes is accounted for by the hemoglobin variant that accompanies HbS, such as HbD, HbC, or HbE, or a variant causing beta thalassemia. While compound heterozygous genotypes generally have a less severe clinical course than HbSS, there are compound heterozygotes for SCD who have clinical manifestations similar to HbSS; these include HbS-beta⁰ thalassemia, HbSD, and HbS-O Arab. Any individual with a compound heterozygous SCD genotype may have a more severe clinical course than an individual with HbSS. (See 'Sickle-beta thalassemia' below and 'Sickle-HbD disease' below and 'Sickle-HbO Arab disease' below.)

The implications include extending screening, such as transcranial Doppler screening to identify candidates for stroke prevention, in children with most of the compound sickle cell syndromes, with the exception of HbSC disease. The American Society of Hematology (ASH) 2020 guidelines for sickle cell disease recommend that transcranial Doppler (TCD) screening should be performed in children who have compound heterozygous SCD other than HbSC, including HbS-Lepore disease, HbSE disease, HbS-O Arab disease, or HbSD disease phenotypes, and who have evidence of hemolysis in the same range as those with HbSS [3]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".)

In addition, specific complications, such as retinopathy in HbSC, are more frequent in otherwise mild compound sickle cell syndromes. Viral infections, including Dengue and COVID-19, may be more severe in compound heterozygotes, possibly because of their association with fat embolism syndrome [4-9].

Unusual and confusing laboratory presentations for non-sickle cell disorders and suggestive of sickle cell trait

●Occasionally, laboratory testing demonstrates a hemoglobin pattern with HbS <50 percent, HbA2 >3.5 percent, and HbA present. These cases represent sickle cell trait (HbAS, in which one sickle beta globin gene and one normal beta globin gene are present). The SCD phenotype (based on CBC and hemoglobin analysis) as opposed to the SCD genotype (based on beta globin gene sequence) may be confused with sickle cell-beta thalassemia because of an elevated HbA2. However, HbA2 levels are often falsely elevated in the presence of HbS. Any time the proportion of HbS is less than 50 percent, the individual has a sickle trait, regardless of the HbA2 level. Sickle cell trait is discussed separately. (See "Sickle cell trait".)

In a review of newborn screening program results for hemoglobin FSA using protein methods, 30 newborns initially identified as having sickle beta⁺ thalassemia had the diagnosis corrected to sickle cell trait [10]. (See "Diagnosis of sickle cell disorders".)

●Sickle-cell-delta-beta⁺ thalassemia results from heterozygosity for the sickle mutation and heterozygosity for a delta-beta (δβ) fusion gene. This combination is seen in people of Senegalese descent. This is a very mild form of SCD, with patients often asymptomatic. Laboratory testing shows microcytosis, hemoglobin >10 g/dL, elevated HbS >50 percent, and HbA and HbF >12 percent [11].

In contrast to sickle-cell-delta beta⁰ thalassemia (see 'Sickle-delta beta(0) thalassemia' below), sickle-cell-delta–beta⁺ thalassemia produces some normal HbA. Overall, the population of individuals with this genotype is likely to have milder disease, but any individual may have more severe disease.

SPECIFIC COMPOUND SICKLE CELL SYNDROMES

HbSC disease

Pathophysiology — The HbC variant in the beta globin locus (HBB p.Glu7Lys) is approximately one-fourth as common among African Americans as the sickle cell variant [12]. Although oxygenated HbC forms crystals, HbC does not participate in polymerization with deoxy HbS [13,14]. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb C'.)

The presence of HbC within the cell leads to enhanced and sustained potassium and chloride cotransport. The loss of K⁺ produces red cell dehydration and an increase in the intraerythrocytic concentration of HbS to levels that may support polymerization, sickling, and clinical symptoms [13,15]. In vitro studies have found that, at the same total Hb concentration, a 50:50 HbS and HbC mixture undergoes polymerization 15 times more rapidly than a 40:60 HbS and HbA mixture; this difference is presumably due to the higher HbS concentration [13]. The net effect is that compound heterozygosity for HbS and C results in a disease (HbSC) that is less severe than sickle cell disease (SCD) but more severe than sickle cell trait [16,17].

Laboratory — Hemoglobin analysis shows approximately equal amounts of HbS and HbC (or slightly more HbS than HbC), with no HbA present. If cellulose acetate electrophoresis is used, HbC may migrate with HbS E, O-Arab, and C-Harlem. Thus, two independent hemoglobin electrophoresis techniques are necessary in order to distinguish HbSC from HbSC Harlem and other compound heterozygotes. The predominant red cell abnormality on the peripheral smear is an abundance of target cells. Sickled cells are relatively uncommon; rare sickled cells may be canoe-shaped (picture 1). Folded (pita bread, clam-shell) cells, irreversibly sickled cells, "billiard ball" cells, and crystal-containing cells also may be seen (picture 1) [18]. (See "Diagnosis of sickle cell disorders".)

Anemia and reticulocytosis are typically mild, with the majority of patients having a milder degree of anemia (hematocrit >28 percent) than is usually seen in SCD. Markers of hemolysis are lower than in HbSS [19]. This difference is due to the longer survival of HbSC compared with HbSS red cells in the circulation (27 versus 17 days) [20,21]. Similarly, markers of inflammation are lower [19]. However, the lipid profiles are higher.

Clinical course — The clinical findings include relatively normal weight, growth, and physical development; splenomegaly is variable. Individuals with HbSC disease are at risk for the same life-threatening complications as HbSS but at a decreased frequency [22].

A small subset of individuals with HbSC have a clinical phenotype similar to HbSS. Overall, the clinical severity of HbSC is milder, as indicated from the Cooperative Study of Sickle Cell Disease, which compared HbSC disease with HbSS. The following have been reported in individuals with HbSC disease:

●A 50 percent lower rate of acute painful episodes (0.4 versus 0.8 per year) [23].

●A lower risk of silent infarcts (3 versus 17 percent) [24] and of having a stroke (2 versus 11 percent incidence of a first stroke by age 20) (figure 1) [25].

●A lower rate of focal segmental glomerulosclerosis (2.4 versus 4.2 percent in one study) with a later onset of progressive renal failure (50 versus 23 years old at diagnosis) [26].

●A lower incidence of fatal bacterial infection in young children [27,28].

●A very low rate of leg ulcers [29].

●Later development of osteonecrosis [30].

●A lesser delay in growth and sexual development [31].

●A two-decade increase in life expectancy (64 versus 45 years) [32]. At two large academic SCD centers, there was no difference in the median survival of individuals with HbSC compared to individuals with HbSS.

●In a prospective cohort study, the incidences of severe acute vaso-occlusive pain requiring hospitalization and pain events were no different in pregnant women with HbSS and HbSC during the third trimester and early postpartum period, the interval with the highest SCD related morbidity [33,34].

●A higher incidence of peripheral retinopathy, thought to be related to the higher hematocrit in this disorder [35].

●Increased risk for systemic and cerebral fat embolism. The overall incidence is unclear and may be higher than thought [36].

Cohort studies in individuals with HbSC disease support the observations of the cooperative study above and highlight specific problems and treatments [37-42].

●A clinical diagnosis is often delayed until a serious event during young adulthood because of the mild anemia and relatively benign clinical course in early pediatrics.

●The rates of maternal-fetal morbidity, retinopathy, avascular necrosis of the hip, and chronic kidney disease are increased. While microalbuminuria is lower in HbSC disease than HbSS, it still occurs in over 23 percent of adults [38]. In addition, thrombosis, silent cerebral infarction, sensorineural hearing loss, and pulmonary hypertension may be higher than previously suspected.

●Hydroxyurea therapy is beneficial in decreasing vaso-occlusive events and appears safe. Patients may develop reversible cytopenias and are at risk for hyperviscosity syndrome secondary to an increased hemoglobin, which requires therapeutic phlebotomy [43]. This combination is increasingly being used [44]. Pilot data using therapeutic phlebotomy alone suggest this may also lower the rate of vaso-occlusive events [45,46].

Functional asplenia occurs in many patients with HbSC disease (45 percent in individuals over age 25 in one study) [47]. However, it does not occur prior to age four, and routine administration of prophylactic penicillin may not be necessary in infants and young children. (See "Prevention of infection in patients with impaired splenic function".)

The persistent splenic function means that splenic infarction and splenic sequestration crisis, which primarily occur in young children with SCD, can occur at all ages in HbSC disease [48].

Sickle-beta thalassemia — Thalassemia refers to a spectrum of diseases characterized by reduced or absent production of one or more globin chains. Beta thalassemia is due to impaired production of beta globin chains, which leads to a relative excess of alpha globin chains. These excess alpha globin chains are unstable, incapable of forming soluble tetramers on their own, and precipitate within the cell, leading to a variety of clinical manifestations. (See "Pathophysiology of thalassemia".)

Incidence and classification — The gene frequency of beta thalassemia among African Americans is 0.004, one-tenth that of the sickle cell gene [12]. As a result, the prevalence of compound heterozygous sickle cell-beta thalassemia is one-tenth that of sickle cell anemia (HbSS) in this population. In addition to the African American population, people of Hispanic descent are at risk for sickle-beta thalassemia. In California, 12.5 percent of newborns with sickle-beta thalassemia have Hispanic origin [49].

Sickle cell-beta thalassemia is divided into sickle cell-beta⁰ thalassemia and sickle cell-beta⁺ thalassemia, based upon the complete absence beta globin or the presence of reduced amounts of beta globin, respectively, which in turn determines the level of HbA [50,51]. Most beta thalassemia mutations among African Americans result in beta⁺ thalassemia. The percentage of HbA produced in individuals with beta⁺ thalassemia varies from 5 to 30 percent, depending upon the molecular defect of the mutation [52-54]. As an example, those with a beta thalassemia mutation of -29(A-->G) have a high hemoglobin A level and a mild clinical course.

Eighty percent of African American beta thalassemia mutations are due to promoter region mutations that result in a mild phenotype in which HbA accounts for 18 to 25 percent of total hemoglobin [52,53]. The genotype for sickle-beta thalassemia varies in different regions in the world. Compound heterozygous sickle cell-beta⁰ thalassemia, which results in the production of no normal beta chains and therefore no HbA, occurs infrequently in the African American population, but more commonly in the Greek, Middle Eastern, and Mediterranean regions. The Brazilian REDS 3 NIH study analyzed 167 sickle-beta thalassemia patients and found that beta⁺ and beta⁰ mutations occurred in approximately equal proportions in people with sickle cell beta thalassemia [55]. However, half the sickle beta⁺ variants were severe and clinically similar to sickle cell beta⁰ thalassemia. Some of the variants in this group included IVS-I-110 (G>A), IVS-I-5 (G>C), and IVS-I-5 (G>A).

Diagnosis and misdiagnosis of HbS-beta(0) — The clinical and laboratory phenotype of HbS-beta⁰ thalassemia is similar to that in HbSS. Nearly all the hemoglobin consists of HbS, and there is no HbA present. Microcytosis is a useful indicator of HbS-beta⁰ thalassemia. However, alpha thalassemia trait is a common finding and may cause microcytosis without a beta thalassemia mutation.

Distinguishing HbSS from HbS-beta⁰ thalassemia is challenging, even for hematologists. In a study involving 809 children with a clinical diagnosis of HbSS or HbS-beta⁰ thalassemia based on HLPLC or IEF and laboratory values, phenotypic misclassification occurred in 39 of 53 (74 percent) of those with HbS-beta⁰ thalassemia (they actually had a HbSS genotype) and 6 of 698 (0.9 percent) of those with HbSS (they actually had a HbS-beta⁰ genotype) [56].

Clinical manifestations — The hematologic and clinical severity of sickle cell-beta thalassemia is an inverse function of the quantity of HbA [54,57].

Patients with sickle cell-beta⁰ thalassemia (no HbA production) have a clinical course as severe as homozygous sickle cell disease (SCD; ie, HbSS, sickle cell anemia) [57]. As examples:

●The Cooperative Study of Sickle Cell Disease (over 3000 patients) found that the incidence and severity of painful events and acute chest syndrome were similar between individuals with HbSS and hemoglobin S-beta⁰ disease [23,58].

●A review of 84 patients suggested that pulmonary hypertension is also comparable between sickle beta⁰ thalassemia and HbSS [59].

●Individuals with HbS-beta⁰ thalassemia were found in some studies to have a high rate of ischemic brain injury [25,60]. However, in the absence of genotyping of the beta globin gene, these patients may have been misclassified and may actually have had HbSS [56]. In neurologically asymptomatic individuals with HbS-beta⁰ thalassemia, transcranial Doppler and MRI abnormalities are found [61]. In the SIT trial, children with HbS-beta⁰ thalassemia based on genotyping had significantly lower TCD velocities than children with HbSS, with the same prevalence of silent cerebral infarcts [62].

●Individuals with HbS-beta⁰ thalassemia typically develop functional asplenia in early infancy, have an increased rate of sepsis, and have an associated increased risk of pneumococcal sepsis [63]. Depending on the percentage of hemoglobin A, individuals with HbS-beta⁺ thalassemia do not undergo the rapid splenic infarction seen in HbSS. Individuals with HbS-beta⁺ thalassemia may continue to have splenic enlargement, often into adulthood, and they remain at risk for acute splenic sequestration episodes and hypersplenism.

Higher hemoglobin A levels are generally associated with less severe clinical manifestations (individuals with HbS-beta⁺ thalassemia generally have a more benign clinical course than those with HbS-beta⁰ thalassemia or HbSS). Acute painful events do occur, but are less than half those seen in HbSS [23].

Despite the milder clinical course of individuals with HbS-beta⁺ thalassemia, an individual with HbS-beta⁺ thalassemia may have life-threatening episodes of acute chest syndrome, acute chest syndrome following surgery, complications of acute vaso-occlusive pain, or pregnancy related vaso-occlusive complications.

The lesser severity of HbS-beta⁺ thalassemia was illustrated in the following studies:

●One study compared clinical findings in 27 patients with sickle cell-beta⁺ thalassemia and 28 patients with HbS-beta⁰ thalassemia [64]. Compared with sickle cell-beta⁰ thalassemia, those with HbS-beta⁺ thalassemia had the following findings:

•Threefold higher incidence of incidental diagnosis (26 versus 9 percent)

•Later mean age of presentation (8.2 versus 3.2 years)

•Less frequent leg ulcers (8 versus 23 percent)

•Less frequent episodes of acute chest syndrome (14 versus 24 percent); this approximately 50 percent reduction in painful episodes has been noted in other reports [23]

•Less frequent priapism (0 versus 4 patients)

•Less frequent aplastic crises (0 versus 2 patients)

Splenomegaly occurred in approximately one-third of both groups. There was a higher incidence of proliferative retinopathy in individuals with sickle cell-beta⁺ thalassemia (18 versus 10 percent), consistent with an association of higher hematocrits (and blood viscosity) with ocular complications. Both HbS-beta⁺ thalassemia and HbS-beta⁰ thalassemia have a decreased incidence of stroke compared with HbSS (figure 1) [25]. Some individuals with no history of clinical stroke have demonstrated silent infarction on magnetic resonance imaging as well as abnormal transcranial Doppler studies [61].

●Another series evaluated 2115 patients with HbSS, HbSC disease, HbS-beta⁺ thalassemia, or HbS-beta⁰ thalassemia [31]. The patients with HbSS or HbS-beta⁰ thalassemia were consistently smaller and less sexually developed than those with HbS-beta⁺ thalassemia.

However, the genotype-phenotype correlations in HbS-beta⁺ thalassemia are variable, and a severe clinical course or life-threatening complications can be seen in patients with a milder beta thalassemic mutation. As an example, those with a beta mutation of IVS1-5(G-->C) have a HbA level less than 7 percent and manifestations of similar severity to HbSS [65]. In Brazil, severe HbS-beta⁺ thalassemia accounted for almost half of this beta⁺ group, and the average hemoglobin A was 4.5 percent, in contrast to 26 percent in mild HbS-beta⁺ thalassemia [55].

Splenic dysfunction in HbS-beta⁺ thalassemia is less frequent in childhood but increases with age, resulting in 25 percent of adults having significant functional asplenia [63].

HbS-beta⁺ thalassemia is associated with anemia, microcytosis, and a hemoglobin A fraction that ranges between 5 and 30 percent (table 1). Neonates with sickle beta⁺ thalassemia may have so little hemoglobin A that the diagnosis of sickle beta⁰ thalassemia is given. Family studies and more definitive testing are often indicated.

Sickle-alpha thalassemia — Alpha thalassemia results from impaired production of alpha globin chains, which leads to a relative excess of beta globin chains.

A single alpha globin gene deletion, referred to as alpha thalassemia silent carrier, is present in more than 30 percent of SCD patients of African descent, with an even higher prevalence in some SCD populations in the Middle East and India. The peripheral blood smear contains less polychromasia and fewer sickled cells, and more hypochromia and microcytosis, commensurate with the number of alpha globin genes deleted. HbA2 levels are increased according to the number of alpha globin gene deletions, while HbF levels are not consistently affected [66-69]. The mean corpuscular volume is reduced and the degree of hemolysis and anemia is lessened [70].

The effect of alpha thalassemia on the clinical course appears to have positive and negative effects:

●Individuals with sickle cell-alpha thalassemia can have milder anemia, with fewer reticulocytes and sickled cells [66-68,71]. The toxicity of excess normal beta globin chains on the red cell membrane skeleton appears to be less than that of the excess partially oxidized alpha globin chains in beta thalassemia. This may be extrapolated to beta S chains to explain why the clinical manifestations are generally less severe in sickle cell-alpha thalassemia compared with sickle cell-beta thalassemia. (See "Pathophysiology of thalassemia", section on 'Globin chain imbalance'.)

●The higher hemoglobin levels in some individuals with sickle-alpha thalassemia may contribute to hyperviscosity, which can increase symptoms. The higher hematocrit is still associated with HbS-containing red cells, resulting in an overall increase in blood viscosity. This rise in hemoglobin and decreased hemolysis may decrease anemia and hemolysis-related events, while a higher hemoglobin level may increase the risk of some vaso-occlusion complications.

An early report suggested that coinheritance of alpha thalassemia was associated with longevity [72]; this conclusion was controversial [32]. Some studies have shown that the presence of alpha thalassemia and a reduction in intravascular hemolysis is associated with reduced mortality.

In other reports, the simultaneous presence of alpha thalassemia and SCD has been associated with the following effects:

●Reduction in the extent of peripheral retinal vessel closure, without an effect on the frequency of proliferative sickle retinopathy [73]

●Reduction in the incidence of stroke in children [74]

●Protection against high cerebral blood velocities [75,76]

●Reduction in the incidence of leg ulcers [29]

●In some children with high HbF levels, alpha thalassemia appeared to preserve splenic function [77]

●Lower prevalence of glomerulopathy (macroalbuminuria) [78]

●Reduced prevalence of priapism [79]

●Reduced response to treatment with hydroxyurea [80]

However, not all population studies have shown a clinical benefit from the presence of alpha thalassemia. In a study from Jamaica, the absence of alpha thalassemia gene deletions influenced the clinical phenotype [81]. The best data on life expectancy come from the Cooperative Study of Sickle Cell disease, which found an increased mortality rate associated with higher hemoglobin levels after the age of 20 years [23].

These older studies regarding the clinical history of alpha globin gene deletion and its influence on SCD clinical history are quite limited because they do not reflect the influence of improved clinical management including conjugated vaccines, transcranial Doppler screening, and now four FDA-approved therapies.

Perhaps some of the discrepant results of earlier studies are a result of considering only the vaso-occlusive and viscosity-related complications of disease. Other studies suggest that intravascular hemolysis is closely associated with its own constellation of subphenotypes [82].

Studies of the effects of hemolysis on nitric oxide (NO) bioavailability suggest that alpha thalassemia protects against disease complications related to the intensity of hemolysis (eg, priapism, leg ulcers, stroke, and perhaps pulmonary hypertension) while increasing the risk of complications more directly related to blood viscosity (eg, painful episodes, acute chest syndrome, osteonecrosis) [79]. Patients with hyper-hemolysis had higher systolic blood pressure, higher prevalence of leg ulcers, priapism, and pulmonary hypertension, while osteonecrosis and vaso-occlusive pain were less prevalent [83]. Hyper-hemolysis was influenced by HbF levels and the presence of alpha thalassemia, and was a risk factor for earlier death.

Due to the powerful effect of HbS concentration upon HbS polymerization, anemia is significantly milder in individuals with SCD and the deletion of either one (-a/aa) or two (-a/-a) alpha globin genes [66-68,84,85]. In one series, for example, the hemoglobin concentration was 9.8 g/dL in patients with HbSS and the (-a/aa) genotype compared with 7.9 g/dL in those with HbSS without alpha thalassemia [66]. These individuals have reduced hemolysis that is not demonstrable until approximately seven years of age [84,85].

Despite the improvement in anemia, the clinical effects of the interaction between SCD and alpha thalassemia are variable, due in part to the higher hemoglobin concentration and blood viscosity. While the overall clinical phenotype may be improved, there is not a definitive answer to the question of whether alpha thalassemia increases survival in patients with sickle cell anemia [86,87]. This is particularly true in the era of disease-modifying therapies.

This is illustrated by the following observations:

●The incidence of acute chest syndrome was decreased in one study and unchanged in another [67,68]. In a third report from the Cooperative Study of Sickle Cell disease, concurrent alpha thalassemia had no effect on the incidence of acute painful episodes apart from its association with higher hemoglobin concentrations [23].

●There is a reduced incidence of leg ulcers (more in patients with two versus three alpha globin genes) [29,67]; the incidence of osteonecrosis is increased [30,88].

●The frequency of retinal vessel closure is reduced, but the risk of proliferative retinopathy is increased [89].

Sickle-hereditary persistence of fetal hemoglobin — The physiologic switch from the production of fetal hemoglobin (HbF: alpha2/gamma2) to adult hemoglobin (HbA: alpha2/beta2) is usually completed by two years of age, resulting in a normal adult level of HbF of <1 percent. However, increased levels of HbF can ameliorate the clinical course of disorders of beta globin gene expression including sickle cell disease (SCD) and beta thalassemia. (See "Pathophysiology of thalassemia", section on 'Combinations of hemoglobin variants'.)

In individuals with HbSS, a HbF level of 10 to 20 percent has been suggested as a threshold for diminished clinical severity [90], although some studies have suggested that any increment in HbF may be clinically important [32]. HbF in HbSS usually consists of 4 percent to 10 percent of total hemoglobin.

In a group of disorders called hereditary persistence of fetal hemoglobin (HPFH), expression of the gamma globin gene persists at high levels in almost all of the adult red cells, referred to as pancellular HbF distribution, with normal red blood cell indices and morphology. The gene frequency of the deletional HPFH locus is 0.0005 among African Americans, resulting in a calculated incidence of compound heterozygous sickle cell-deletional HPFH that is 1 percent that of SCD [91]. Sickle-HPFH may be more frequent than previously estimated [92].

Individuals with compound heterozygosity for HbS and HPFH have high concentrations of HbS and 20 to 30 percent HbF evenly distributed among red cells, are not anemic, and do not experience vaso-occlusive complications or other major complications of SCD [93,94].

In individuals with HbS-HPFH, hemoglobin analysis reveals only HbS, HbF, and HbA2, which resembles sickle cell anemia, sickle cell-beta⁰ thalassemia, and sickle cell-delta beta⁰ thalassemia. Notable differences, however, are the markedly increased percentage of HbF (10 to 40 percent) and HbA2 levels <2.5 percent (in contrast to the elevated levels in beta thalassemia) [95,96]. To avoid unnecessary over-treatment of this benign condition, genotypes should be determined in parents and especially in all children with high HbF levels.

Sickle cell-deletional HPFH provided the first evidence that HbF was a potent inhibitor of HbS polymerization. Genetic modulation of the sickle cell anemia phenotype by HbF as a strategy for cure is discussed separately. (See "Investigational therapies for sickle cell disease", section on 'Gene therapy and gene editing' and "Fetal hemoglobin (hemoglobin F) in health and disease".)

In contrast, individuals with HbSS and heterocellular HbF distribution may have HbF levels as high as 25 percent but may still have a clinical course similar to individuals with HbSS who have lower HbF levels, particularly as they become older [97,98]. Multiple genetic etiologies for elevated HbF have been discussed, including beta-globin gene deletions or point mutations in the promoters of the gamma globin gene (HBG1). Unusually high HbF can also be associated with variants of the major repressors of gamma globin expression, BCL11A and MYB. Perhaps most often, an explanation for very high HbF levels in SCD is lacking. These conditions are discussed in detail separately. (See "Fetal hemoglobin (hemoglobin F) in health and disease", section on 'Increased HbF in adults'.)

Sickle-delta beta(0) thalassemia — The delta-beta (δβ) thalassemia variants usually are large deletions of the delta and beta globin genes. Unlike HPFH, these variants fail to block the switch from fetal to adult hemoglobin production. This allows an attempted switch from the expression of gamma globin to that of the deleted delta and beta genes. The uncommon compound heterozygous condition of HbS delta-beta⁰ thalassemia results in the presence of HbS, HbF, and HbA2. The 15 to 25 percent HbF is distributed in a heterocellular fashion. Anemia and reticulocytosis are mild, and clinical complications are infrequent [99]. Compound heterozygosity for delta-beta⁺ thalassemia and the sickle mutation produces an even milder phenotype. (See 'Unusual and confusing laboratory presentations for non-sickle cell disorders and suggestive of sickle cell trait' above.)

Sickle-Hb Lepore disease — The Hb Lepore gene is a crossover fusion product of the delta and beta globin genes, the product of which, in the case of Hb Lepore Boston, has the same alkaline electrophoretic mobility as HbS [100]. Because of the thalassemic expression of the fusion gene, individuals with simple heterozygosity for Hb Lepore Boston resemble sickle cell trait on hemoglobin electrophoresis, with only 12 percent of the mutant hemoglobin being present. (See "Molecular genetics of the thalassemia syndromes", section on 'Hb Lepore'.)

The doubly heterozygous condition of sickle cell-Hb Lepore (HbS-Lepore) is rare [101]. The peripheral smear shows microcytosis, hypochromia, and irreversibly sickled cells. Vaso-occlusive complications occur and splenomegaly is common [102].

Patients with this disorder resemble those with HbSS or sickle cell-beta⁰ thalassemia electrophoretically, but have less severe anemia similar to sickle cell-beta⁺ thalassemia. The combination of predominantly HbS with microcytosis suggests sickle cell-beta thalassemia, but the diagnosis of HbS Lepore is suggested by the low to low normal HbA2 levels that result from the incapacitation of one delta globin gene by the crossover. HbF levels vary.

Sickle-HbD disease — The most common hemoglobin D variant, HbD Los Angeles (HBB p.Glu121Gln, also called HbD Punjab), is caused by a glutamic acid to glutamine substitution at codon 121 of the beta globin gene [103]. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb D'.)

Although asymptomatic in the heterozygous form, inheritance together with an HbS allele (HbSD disease) can result in a severe disease with clinical manifestations similar to homozygous SCD [104]. The glutamic acid to glutamine substitution appears to support the polymerization of HbS [105].

HbD Los Angeles has an electrophoretic mobility that is similar to HbS under alkaline conditions. For this reason, HbSD disease was first reported as an unusual case of sickle cell anemia [106]. HbD can be distinguished from HbS by acid electrophoresis or isoelectric focusing. There is moderately severe hemolytic anemia and the peripheral smear shows marked anisocytosis and poikilocytosis, target cells, and irreversibly sickled cells. Some children have severe disease similar to that of sickle cell anemia [107,108]. However, persistent splenomegaly is more common.

Sickle-HbO Arab disease — Hemoglobin O-Arab is another hemoglobinopathy due to a variant beta globin chain (HBB p.Glu121Lys). It was first described in an Israeli Arab family but its distribution is widespread [109]. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb O-Arab'.)

Sickle cell-HbO-Arab resembles HbSC on alkaline electrophoresis, but HbO-Arab can be distinguished from HbC by either acid electrophoresis or isoelectric focusing. HbO-Arab may be confused with HbC-Harlem when HbS is also present. The syndrome is characterized by moderately severe hemolytic anemia, and the peripheral smear shows anisocytosis, poikilocytosis and irreversibly sickled cells [110,111]. Oxygen affinity is reduced in sickle cell-HbO-Arab compared with sickle cell anemia.

The clinical manifestations are severe and resemble those of homozygous sickle cell anemia. In one study of 13 patients, for example, all patients had significant sickling events including acute chest syndrome (11), recurrent painful episodes (10), nephropathy (four), aplastic crises (two), avascular necrosis (two), leg ulcers (two), and stroke (one) [111].

Sickle-HbE disease — HbE (HBB p.glu26Lys) is a beta thalassemic hemoglobinopathy found predominantly in Southeast Asia. The mutant hemoglobin has an electrophoretic mobility similar to HbC under alkaline conditions but can be resolved by acid electrophoresis or isoelectric focusing [112]. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb E'.)

The variant in codon 26 activates a cryptic splice site within the first intron of the beta globin gene, causing alternate splicing and decreased expression of the structural mutant [113]. As a result, HbE comprises only 30 percent of the total hemoglobin in patients with compound heterozygosity for the HbS and HbE variants.

Heterozygotes and homozygotes for HbE are asymptomatic with minimal anemia and microcytosis [114]. HbSE disease may cause only mild hemolysis, no vaso-occlusive complications, and no remarkable abnormality of red blood cell morphology in those ≤18 years [115]. However, there are several case reports of more severe manifestations, such as the following:

●Hematuria

●Splenic infarct during air travel [116]

●Acute chest syndrome

●Reversible bone marrow necrosis associated with parvovirus B19 infection [117]

●Exercise-related death syndrome [118]

In one family, three siblings had moderately severe hemolysis, jaundice, bone pain, splenic infarction, recurrent pneumonia, and irreversibly sickled cells on the blood smear [119]. It has been suggested that patients with HbSE disease be followed and managed in a similar fashion as those with HbS beta⁺ thalassemia and treated appropriately when they develop sickling-related symptoms and complications [115].

SICKLE CELL SYNDROMES THAT APPEAR TO BE SICKLE CELL TRAIT ON HEMOGLOBIN ANALYSIS — Depending on the geographic location, the prevalence of sickle cell trait (HbAS) in newborns can be approximately 0.07 percent in the general United States population and 9 percent of African American births [120]. The prevalence is 30 percent of the births in West Africa [121]. (See "Sickle cell trait", section on 'Genetics and epidemiology'.)

In individuals suspected of having sickle cell trait, the hemoglobin and red blood cell (RBC) parameters are expected to be normal, and these individuals are expected to have a normal life-expectancy, with rare clinical events only seen in extreme physical conditions [120]. There is also a high relative risk (but low absolute risk) of renal cell carcinoma (RCC). (See "Sickle cell trait", section on 'Urologic and kidney disease'.)

However, a very small subset of individuals with a HbAS pattern will have clinical symptoms typically associated with sickle cell disease (SCD). These individuals should be evaluated for rare syndromes that have a clinical phenotype associated with SCD. At least 14 different clinically relevant sickling Hb variants other than HbS have been described [122]. Two examples are HbS-Jamaica Plain and HbS with pyruvate kinase deficiency. (See 'HbS-Jamaica plain' below and 'HbS plus pyruvate kinase deficiency' below.)

These rare SCD syndromes are difficult to diagnosis and are often missed because high-performance liquid chromatography (HPLC) reveals a majority of hemoglobin A. The total hemoglobin levels are low but often not low enough to prompt an extensive evaluation. These compound heterozygotes are heterozygous for both the sickle cell variant and a second beta globin variant. The clinical manifestations can vary considerably, including clinical phenotypes that mimic SCD, such as HbS-Oman, HbS-Antilles, HbS-Jamaica Plain, and HbS-São Paulo [123].

HbS-Jamaica plain — In HbS-Jamaica Plain, the proband has HbAS on HPLC and is heterozygous for the sickle cell variant. They also have a second, charge-neutral beta globin variant, Leu68Phe. This hemoglobin was studied and noted to have severely reduced oxygen affinity, and structural modeling suggested destabilization of the oxy conformation as a molecular mechanism for sickling in a heterozygote at normal oxygen pressure [124]. Following splenectomy, laboratory values included a hemoglobin of 8.0 g/dL and a mean corpuscular volume (MCV) of 80.4 fL. HPLC showed HbA >60 percent, with 25 to 40 percent HbS, 2.1 to 3.1 percent HbA2, and 2.7 to 13 percent HbF.

HbS plus pyruvate kinase deficiency — The SCD phenotype has also be seen in a compound heterozygote for the sickle cell variant and a variant that causes pyruvate kinase (PK) deficiency. A case report described a female who had recurrent acute vaso-occlusive pain episodes and leg ulcers, clinical features typically associated with SCD [125]. The authors postulated that decreased oxygen affinity associated with PK deficiency caused clinical features of SCD. Her baseline laboratory parameters revealed Hb 9.8 g/dL, and MCV 88.7 fL. Her blood smear revealed a few sickle cells. HPLC showed 62 percent HbA, 35 percent HbS, 2 to 3 percent HbA2, and 0.4 percent HbF.

Two variants on one beta globin gene — Another example of SCD in heterozygotes occurs when there are two separate variants affecting the same beta globin chain. (See "Sickle cell trait", section on 'Symptoms of sickle cell disease'.)

The two most common types of variants are HbS-Antilles and HbS-Oman. Heterozygotes for HbS-Antilles have a mild hemolytic anemia with sickle cells on the blood smear. These individuals may also develop painful episodes and other symptoms [126]. On hemoglobin electrophoresis, these conditions may appear as sickle trait. Additional molecular and DNA techniques are required to make these diagnoses. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

SUMMARY

●Definitions – There are a variety of sickle cell disease (SCD) syndromes that result from inheritance of the sickle cell variant in compound heterozygosity with other beta globin gene variants (table 1). Sickle cell trait is not a sickle cell disease syndrome. (See 'Overview' above.)

●Hemoglobin SC disease (HbSC) – Individuals with HbSC disease are at risk for the same complications as those with HbSS disease but at a decreased frequency. Anemia is mild, and splenomegaly may be the only finding on physical examination. The blood smear shows target cells, folded cells, occasional irreversibly sickled cells, and occasional cells containing hemoglobin crystals. HbS and HbC are seen in equal amounts on electrophoresis. (See 'HbSC disease' above.)

●HbS-beta⁰ thalassemia – Individuals with HbS-beta⁰ thalassemia have severe disease that may be somewhat less severe than HbSS disease. This variant is more common in the Greek and Mediterranean regions than in the African American population. No HbA is present on electrophoresis. It is distinguished from HbSS disease by the presence of hypochromic, microcytic red cells and increased levels of HbA2. Management is similar to individuals with homozygous SCD (HbSS). (See 'Sickle-beta thalassemia' above.)

●HbS-beta⁺ thalassemia – Individuals with HbS-beta⁺ thalassemia have a form of SCD that is less severe than HbSS disease. Disease severity is inversely related to the amount of HbA present, which varies from 5 to 30 percent. The peripheral smear shows the presence of hypochromic, microcytic red cells, and levels of HbA2 are increased. Management is individualized depending on the patient's clinical course. (See 'Sickle-beta thalassemia' above.)

●HbSS with alpha thalassemia – The clinical manifestations and degree of anemia in HbSS with alpha thalassemia are generally less severe than those seen in HbS-beta⁰ thalassemia. HbA2 levels are increased according to the number of alpha globin gene deletions. Clinically, a distinction between HbSS with alpha thalassemia and without alpha thalassemia is not required. (See 'Sickle-alpha thalassemia' above.)

●Sickle hereditary persistence of fetal hemoglobin (sickle HPFH) – Individuals with pancellular sickle HPFH are not anemic, do not experience vaso-occlusive episodes, and may have HbF levels as high as 35 percent. (See 'Sickle-hereditary persistence of fetal hemoglobin' above.)

●Other variants – Other sickle cell syndrome variants such as sickle-delta beta⁰ thalassemia, HbS-Lepore, HbSD, HbS-O Arab, HbSE, and variants that cause SCD in heterozygotes are less common and are discussed in the text above. (See 'Sickle-Hb Lepore disease' above and 'Sickle-HbD disease' above and 'Sickle-HbO Arab disease' above and 'Sickle-HbE disease' above and 'Sickle cell syndromes that appear to be sickle cell trait on hemoglobin analysis' above.)

●Diagnosis and management – The diagnosis, clinical manifestations, and management of sickle cell trait and SCD are presented in detail separately. (See "Sickle cell trait" and "Diagnosis of sickle cell disorders" and "Overview of the clinical manifestations of sickle cell disease" and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Overview of the management and prognosis of sickle cell disease".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.