retinal thinning

The term sickle cell anemia as generally used refers to the disease caused by homozygous mutations in the HBB gene in which both beta chains contain a change in the 6^th position from glutamic acid to valine yielding hemoglobin S.  These cells are susceptible to distortion into a sickle shape under certain conditions such as relative dehydration or anoxia and, as a result, form microthrombi with downstream ischemia.

The term sickle cell disease is commonly used to refer to sickling disorders in which only one beta chain contains the S change and the other chain has another variant such as Hb C (Hb SC disease), beta thalassemia (Hb S beta thalassemia) or some other more rare change in the beta chain.  Symptoms of the variant diseases generally have a later onset and cause a less severe disease.

Hb SS disease accounts for 60-70% of sickle cell disease and often leads to symptoms in the first month of life.  The diagnosis is usually made through newborn screening programs and should be followed by confirmatory testing using genotyping within 6 weeks.

The major early symptom is intermittent pain which can be incapacitating.  This can occur in virtually any organ and results from vascular occlusion, especially in small vessels such as arterioles and capillaries with downstream microinfarctions and hemolysis.  These vasoocclusive episodes can eventually lead to organ failure, especially in adults in which the major causes of death by midlife are pulmonary hypertension, cerebrovascular events, and acute chest syndrome.  Children are more likely to die of infections and organ sequestration.  In particular, the spleen is damaged as early as 3 months of age leaving infants vulnerable to recurrent septicemia and meningitis.  Severe bone pain with osteomyelitis can be debilitating.  Priapism, anemia, and ischemic strokes can occur at any age but are especially worrisome in young children.

Sickle cell disease can damage any part of the body and global evaluations are recommended when the diagnosis is under consideration. 

The primary and most consistent systemic problem is progressive renal disease. Congenital nephrotic syndrome with proteinuria, hypoalbuminemia and hypertension is characteristic.  Renal failure eventually occurs although the rate of progression varies. Most patients require a renal transplant for end-stage kidney disease in the first decade of life.  Kidney histology shows glomerulosclerosis, peritubular scarring, and diffuse mesangial sclerosis.  Hypotonia and muscle weakness are sometimes present and congenital myasthenia has been reported.  Severe global psychomotor retardation is common and many infants never achieve normal milestones.