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Hereditary spherocytosis is a congenital hemolytic anemia with a wide clinical spectrum (from symptom-free carriers to severe hemolysis) characterized by anemia, variable jaundice, splenomegaly and cholelithiasis.
ORPHA:822Classification level: Disorder
HS is the most common cause of inherited chronic hemolysis in North America with a prevalence of 1/5,000 births. However, osmotic fragility studies suggest the existence of extremely mild or subclinical forms, raising the prevalence to 1/2,000 in Northern Europe.
Jaundice is usually the first clinical manifestation in newborns (50% of cases) with anemia developing a few days after birth and requiring exchange transfusion (~10%) and transfusion support (~35%). Splenomegaly is frequently observed. Age of onset and severity vary considerably depending on the degree of anemia and hemolysis. Four HS categories have been identified: trait (normal hemoglobin (Hb), reticulocytes < 3%, bilirubin < 17micromoles/L), mild (Hb 11-15 g/dL, reticulocytes 3-6%, bilirubin 17-34 micromoles/L), moderate (Hb 8-12 g/dL, reticulocytes > 6%, bilirubin > 34 micromoles/L), and severe (Hb < 8 g/dL, reticulocytes > 10%, bilirubin > 51 micromoles/L). Aplastic crisis, often associated with viral infections, is observed in 10-15% of cases, particularly pediatric. Rare complications include poor growth, skin ulceration, chronic dermatitis, high output heart failure, and secondary iron overload.
HS is caused by mutations in one of the following genes: SPTA1 (1q21), SPTB (14q23.3), ANK1 (8p11.21), SLC4A1 ( 17q21.31) and EPB42 (15q15-q21), that encode the red blood cell (RBC) membrane proteins erythrocytic 1 spectrin alpha chain, erythrocytic 1 spectrin beta chain, ankyrin-1, band 3 anion transport protein, and erythrocyte membrane protein band 4.2, respectively. Defects in these proteins lead to a loss in RBC membrane cohesion and membrane surface area, resulting in erythrocyte sphering, decreased deformability and premature destruction in the spleen.
Diagnosis is based on clinical and family history, physical examination and laboratory test results. Red cell morphology, osmotic resistance, hypertonic cryohemolysis test, eosin-5-maleimide binding in flow cytometry, sodium dodecyl sulfate-poly acrylamide gel electrophoresis and ektacytometry are all used to diagnose HS. Mean cellular Hb concentration is usually above normal range (~35 g/dl), reticulocyte count normal or increased, and indirect bilirubin moderately increased. Molecular genetic testing is not routinely used to confirm diagnosis.
Differential diagnoses include hereditary elliptocytosis, hereditary stomatocytosis, Southeast Asian ovalocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, autoimmune hemolytic anemia, and alpha-thalassemia (see these terms).
Prenatal diagnosis for at-risk pregnancies is possible if disease-causing mutations have been identified in a family, but it is not routinely performed due to the usually mild disease course.
HS is inherited autosomal dominantly in 75% of cases. Autosomal recessive inheritance and de novo mutations have also been reported, but are less common. Genetic counseling is recommended in families with a history of HS.
Management and treatment
Treatment involves management of jaundice (phototherapy and even exchange blood transfusion to prevent hyperbilirubinemic encephalopathy) and RBC transfusions in case of severe, symptomatic anemia. Splenectomy usually results in disappearance of anemia and clear amelioration of hemolytic markers. It is not indicated in patients with HS trait, whereas it is usually necessary in severe cases, albeit delayed if possible until the age of 6 years. For intermediate categories the indication is less clear, being useful in moderate cases before puberty. Laparoscopic splenectomy is preferred if performed by experienced surgeons. A combined splenectomy and cholecystectomy may be beneficial in patients with gallstones. Pre and post-splenectomy vaccine prophylaxis and prophylactic antibiotics are recommended in order to prevent infections. Folate supplement is recommended particularly after infectious events. Serum ferritin levels should be checked annually.
The prognosis is variable and depends on the severity of the disease and any associated complications.