Hereditary elliptocytosis (HE) is a group of rare conditions caused by abnormalities in the red cell cytoskeleton and marked by the presence on blood smears of numerous elliptical red blood cells, called elliptocytes. These conditions occur in all ethnic groups. They are rare in Europe (2 to 5/10 000 individuals), but their incidence may reach up to 1% of the population in Equatorial Africa (the defect conferring partial protection against malaria). Clinical presentations are highly heterogeneous and vary with age. In older children and adults, most heterozygous forms give few if any symptoms, and are often fortuitously discovered when a blood smear is performed. More severe forms are associated with variable anemia, ranging from moderate to severe and with pyropoikilocytosis including fragmented red cells, microelliptocytes and microspherocytes. In these forms, the red blood cell membrane is much more unstable and very sensitive to heat, breaking up at the temperature of 37°C, hence the name of hereditary pyropoikilocytosis (HPP). Complications can occur, such as gallbladder lithiasis formation and acute erythroblastopenia with rapid loss of circulating red blood cells when erythrovirus B19 is first encountered. Transmission is autosomal dominant. The genetic anomaly is variable. In approximately 70% of the cases, the causative mutation is located on the SPTA1 gene, encoding the spectrin alpha chain. This mutation is responsible for a weakness of the mesh-forming erythrocyte skeleton. In very rare cases, the mutation occurs in the SPTB gene, encoding spectrin beta chain. Other cases (25% to 30%) result from mutations in the EPB41 gene encoding the 4.1R protein, usually linked to the actin and spectrin beta chains. HPP occurs in three settings: 1) during the neonatal period: in the case of simple heterozygotes, the clinical status of the child is severe at birth but progressively improves with a reduction of hemolysis and poïkilocytosis, reaching an asymptomatic HE picture by the second year of life; 2) in forms with homozygous mutations in the spectrin alpha or beta chain or in the protein 4.1R gene; 3) in compound forms, associating a mutation on the spectrin alpha chain causing elliptocytosis with a particular polymorphism referred to as alpha LELY. This alpha LELY allele is frequent in all ethnic groups (20% to 30 %) and leads to the synthesis of half the quantity of alpha chain produced by a normal SPTA1 allele. The presence of an alpha LELY allele is harmless when isolated, but its association in trans with a mutated alpha allele is problematic, as the latter will be predominantly expressed. Diagnosis is established by red blood cell counts and examination of blood smears, revealing a proportion of elliptocytes of between 20% and 100% in simple heterozygotes, or poikilocytosis with varying degrees of cellular fragmentation in expressive forms. When analysing blood samples from simple HE forms, automated hematology analysers do not activate any alarm signal. In HPP cases, automated hematology analysers indicate, beside anemia, the presence of a double erythrocyte population that can be differentiated according to the mean corpuscular volume repartition with a normocytic population and a very microcytic population. In these severe forms, additional investigations should be performed in the index case and in his/her parents (electrophoresis of erythrocyte membrane proteins and a search for alpha LELY polymorphism). The results of these additional texts can be used as predictive elements for the evolution of anemia in the child and allow genetic counselling of the parents. Treatment includes the prescription of folic acid in case of hemolysis, red cell concentrate transfusions in case of poorly tolerated anemia and splenectomy after the age of 5 years in forms that remain severe.
Last update: September 2006