Hemoglobin SC, the quieter sickle variant
The second most common form of sickle cell disease in the United States. Generally milder than SS in the early years, with retinopathy, avascular necrosis, and pregnancy complications that catch up over decades.
Sickle cell anemia, the homozygous SS form, is the variant of sickle cell disease that most clinical research has focused on. Hemoglobin SC disease, the compound heterozygous form combining a hemoglobin S allele with a hemoglobin C allele, is the second most common form of sickle cell disease in the United States and accounts for roughly 25 to 30 percent of cases. The clinical phenotype is generally milder than SS, but milder is not the same as benign. SC disease produces vaso-occlusive crises, retinopathy, splenic sequestration in adults, avascular necrosis, and an elevated risk of pregnancy complications. The literature on SC is thinner than the literature on SS, and clinical guidelines have historically been written with SS as the implicit reference.
What hemoglobin SC is
Hemoglobin C is a beta-globin variant produced by the substitution of lysine for glutamic acid at the sixth position of the beta-globin chain (HBB Glu6Lys). Hemoglobin S is the same position with valine substituted for glutamic acid (HBB Glu6Val). A person with one S allele and one C allele has compound heterozygous sickle cell disease, hemoglobin SC.
The molecular biology in SC differs from SS in two ways that matter clinically. First, hemoglobin S polymerizes under deoxygenation, producing the rigid sickled red cells that drive vaso-occlusion in SS. Hemoglobin C does not polymerize. The polymerization in SC red cells is therefore approximately half as concentrated as in SS, and vaso-occlusive crises are typically less frequent. Second, hemoglobin C produces dehydrated red cells with elevated mean corpuscular hemoglobin concentration, and the dehydration enhances S polymerization in mixed cells. The clinical phenotype emerges from the interaction of reduced polymerization driver and increased dehydration enhancer.
The clinical picture in SC includes vaso-occlusive crises (less frequent than SS but still occur, particularly in the bones and joints), proliferative sickle retinopathy (more common in SC than in SS, because the higher hematocrit in SC supports the proliferative response), avascular necrosis of femoral and humeral heads, splenic complications including persistent splenomegaly into adulthood and acute sequestration, and renal complications including hematuria and progressive nephropathy. Pregnancy in women with SC disease carries elevated risk of preterm delivery, preeclampsia, intrauterine growth restriction, and venous thromboembolism, and is managed in centers experienced in hemoglobinopathy obstetrics.
Reported incidence in the United States runs roughly 1 in 800 to 1 in 1,000 Black newborns and substantially lower in other ancestry groups. Geographic origin of the C allele traces to West Africa. Newborn screening for hemoglobinopathies is universal in the United States and detects SC reliably.
Detection
Newborn screening for hemoglobinopathies uses isoelectric focusing, high-performance liquid chromatography, or capillary electrophoresis on the dried blood spot to identify abnormal hemoglobin patterns. Hemoglobin S and hemoglobin C have distinct migration patterns. The presence of S, C, and fetal hemoglobin (without adult A) in a screen-positive sample produces the SC pattern. Confirmation includes hemoglobin electrophoresis or HPLC at age 6 to 12 months when fetal hemoglobin has declined and adult hemoglobin patterns are clearer, and HBB sequencing in equivocal cases.
What management looks like
Standard of care for SC disease has historically been adapted from SS guidelines, with adjustments for the typically milder course. Penicillin prophylaxis in young children, pneumococcal and meningococcal vaccination, and folic acid supplementation are standard. Hydroxyurea, the longstanding disease-modifying therapy for SS, is used in SC disease in selected cases with frequent vaso-occlusive crises or other indicators of high disease burden, although the evidence base for hydroxyurea efficacy in SC is thinner than in SS.
Voxelotor (Oxbryta), a polymerization inhibitor approved by the FDA in 2019, was withdrawn from the market by Pfizer in September 2024 following post-market data showing increased mortality and vaso-occlusive crisis rates in some recipients. Crizanlizumab (Adakveo), a monoclonal antibody against P-selectin, is approved for vaso-occlusive crisis prevention in sickle cell disease aged 16 and older, and is used in selected SC cases.
The 2023 FDA approvals of casgevy (exagamglogene autotemcel, a CRISPR-edited autologous gene therapy) and lyfgenia (lovotibeglogene autotemcel, a lentiviral gene therapy) for sickle cell disease aged 12 and older include hemoglobin SC in the labeled indication. Real-world experience with gene therapy in SC is limited because the SS population has accumulated more clinical experience, and the cost (over two million dollars per patient) and the procedural risk of myeloablative conditioning have constrained uptake across the entire sickle disease population.
Retinal screening from adolescence is part of routine SC management because proliferative retinopathy can develop without symptoms and is more common in SC than in SS. Bone and joint surveillance for avascular necrosis is part of routine adult care. Pregnancy planning, contraception choice (avoiding combined hormonal contraceptives because of thromboembolic risk), and obstetric care at experienced centers are part of reproductive health management.
What this looks like for a family
A baby is born and the heel-prick is sent. The newborn screening report identifies an SC pattern. The family meets the pediatric hematologist. Penicillin prophylaxis begins. Vaccinations follow the immunocompromised schedule. The family learns the early signs of vaso-occlusive crisis, splenic sequestration, and aplastic crisis. The first decade is generally easier than it would be for an SS child: fewer crises, fewer hospitalizations, better growth.
In the second decade, retinopathy surveillance starts. The first vaso-occlusive crisis may come or may not. Avascular necrosis surveillance starts in the third decade. Pregnancy, when planned, is managed at a center with a hemoglobinopathy program.
That is what SC care looks like in practice. Less acute than SS in the early years, with surveillance burden that catches up over decades.