Do hemoglobin S levels always correlate with SCD phenotype?

The severity of sickle cell disease (SCD) is usually associated with the level of hemoglobin S (HbS). For example, HbSS and HbSB0 thalassemia, which generally have higher HbS levels, are usually more severe than HbSC and HbSB+ thalassemia. While patients with HbSC and HbSB+ thalassemia typically have "milder" clinical phenotypes, some may have clinically "severe" disease, much as is observed in many individuals with HbSS/HbSB0 thalassemia. The corollary is also true for HbSS/HbSB0 thalassemia. However, disease severity is not only related to HbS level. 

It is well recognized that SCD severity is modulated by several genetic and environmental factors within (and between) disease genotypes. Fetal hemoglobin (HbF) and presence of co-existing alpha thalassemia are the best described genetic modifiers of SCD severity. Individuals with high levels of HbF have fewer episodes of vaso-occlusive crisis, acute chest syndrome, and decreased mortality vs. those with low levels. Alpha thalassemia decreases the level of HbS and results in lower rates of hemolysis and increased hemoglobin concentrations, although it also appears to increase the rates of vaso-occlusive crises. There is a lot of ongoing work to identify other genetic modulators of SCD severity. For example, it is recognized that high risk APOL1 variants are associated with the development and progression of chronic kidney disease in SCD. 

Finally, there is evidence that environmental factors, including psychosocial stress, cold temperature, wind speed, etc., can also affect disease severity. 

I wonder what Sickle cell experts think about this:
SC and SBeta plus have a different natural history than SS and SBeta zero, and calling them less severe may be a misnomer. They wouldn’t have a typical “sickle cell crisis” as often, but in adulthood, they often suffer from Severe DJD and disabling AVNs requiring multiple joint replacements or triggering frequent admissions for pain, retinopathy, even stroke. So we could say they progress to severe disease over time, but with a different presentation and phenotype. They may have a quiet childhood, but severe consequences of Recurrent Chronic Vesoocclusive events quietly in the background result in a very difficult adulthood. 

I agree with Dr. @Dr. First Last. His observation is clear and correct. The clinical and hematological features of patients with SS are variable. The same observation applies to patients with SBo Thalassem. I learned something important during my 37 years of providing care to patients with sickle cell disease, which is the importance of early diagnosis, education, comprehensive health maintenance care, smooth transition from pediatric to adult care. Those are key factors in the clinical course and prognosis of sickle cell disease. 

Agree, SS and SB0 generally have severe phenotype compared to SC and SB+ thal. However, this is not always true as there are several other factors (as mentioned above) that play a role in the pathophysiology. Knowing why some patients with SS have minimal symptoms will help develop therapeutics and lots of work is being done from genetics to adhesion studies.