Hemoglobin SC Disease · Hb SC

Description

Hemoglobin SC disease is a form of sickle cell disease produced by compound heterozygosity for two HBB variants. One allele carries the sickle variant, HbS, a glutamic acid to valine substitution at codon 6. The other allele carries HbC, a glutamic acid to lysine substitution at the same codon. People with HbSC make no normal adult hemoglobin. HbS polymerizes under deoxygenation, and HbC raises red cell density and dehydration, which together produce a sickling phenotype that is generally less severe than homozygous HbSS.

Clinical features include chronic hemolytic anemia that is usually milder than in HbSS, vaso-occlusive crises, and splenic complications including persistent splenomegaly into adulthood. Two complications are particularly associated with HbSC: proliferative sickle retinopathy, which can progress to vision loss, and avascular necrosis of the femoral and humeral heads. Acute chest syndrome, stroke, and kidney disease occur at lower rates than in HbSS but remain meaningful risks across a lifetime.

HbSC accounts for roughly a quarter to a third of sickle cell disease cases in the United States. Detection is by newborn screening using isoelectric focusing or high-performance liquid chromatography, which resolve the FSC pattern, followed by a confirmatory second method and HBB sequencing where the screening pattern is ambiguous. Annual dilated retinal examinations beginning in adolescence are part of standard follow-up because retinopathy can be asymptomatic until it threatens vision.

Treatments to date

The therapeutic landscape for HbSC overlaps with HbSS, but indication coverage on individual FDA labels varies, and the evidence base in HbSC alone is thinner. Hydroxyurea is used in HbSC for frequent vaso-occlusive crises and is included in NHLBI guidance for severe disease. Droxia, the adult hydroxyurea formulation, was approved by the FDA in March 1998. Siklos was approved in December 2017 for children ages 2 and older. The FDA-approved pediatric label centers on HbSS but clinicians use hydroxyurea in HbSC when symptom burden is high.

L-glutamine oral powder, marketed as Endari, was approved by the FDA in July 2017 for sickle cell disease ages 5 and older to reduce acute complications, an indication that includes HbSC. Crizanlizumab, marketed as Adakveo, was approved by the FDA in November 2019 to reduce vaso-occlusive crisis frequency in patients 16 and older with sickle cell disease. Voxelotor, marketed as Oxbryta, was approved by the FDA in November 2019. Pfizer voluntarily withdrew Oxbryta from worldwide markets in September 2024 after post-marketing data raised concerns about excess vaso-occlusive crises and deaths.

The two cell and gene therapies approved by the FDA in December 2023 for sickle cell disease, Casgevy and Lyfgenia, are indicated in patients 12 and older with a history of recurrent vaso-occlusive crises. Trial enrollment was almost entirely HbSS, and uptake in HbSC is low because most people with HbSC do not meet the recurrent-crisis threshold. Allogeneic hematopoietic stem cell transplant remains an option for severe disease.

Surveillance is the load of disease management for many adults with HbSC. Annual dilated eye examination, hip and shoulder imaging when symptoms develop, transcranial Doppler in childhood, and standard sickle cell pneumococcal prophylaxis through age 5 are routine. Vaso-occlusive crises are managed with hydration, oxygen as indicated, and analgesia.