Hereditary elliptocytosis and hereditary pyropoikilocytosis

Deficiency of spectrin tetramers, the horizontal links of the cytoskeleton, produces a wide spectrum of disease from fully compensated haemolysis with mildly elliptocytic red cells to severe and life-threatening anaemia with grossly distorted cells. When the morphological characteristic is a relatively uniform elliptical shape, the condition is referred to as hereditary ellip-tocytosis (HE). Haemolytic anaemia associated with the more distorted forms, which are also heat labile, is called hereditary pyropoikilocytosis (HPP). Within a family, HE and HPP may both be present, the more severely affected individuals having both a total spectrin deficiency as well as a relative deficiency of spectrin tetramers. This may be caused by co-inheritance of a low-expression allele for a-spectrin, compound heterozygosity for two HE alleles or HE homozygosity. A number of families have been described in which mutations involving the initiation codon of the protein 4.1 gene result in failure to produce the protein. In heterozygotes with this variant, elliptocytosis occurs without haemolysis; in homozygotes, there is a severe haemolysis with pyropoikilocytosis.

Clinical features

As mentioned above, the HE/HPP group of haemolytic anaemias has a heterogeneous clinical presentation and molecular basis. Heterogeneity is amplified by the not uncommon co-inheritance of a mutated gene in trans (see below) with the HE gene, usually resulting in more marked heterotetramer deficiency.

Figure 8.6 Hereditary elliptocytosis, peripheral blood. Characteristic elliptocytes of mild common HE.

Mild common hereditary elliptocytosis

Frequently, HE is discovered by chance from a blood film (Figure 8.6) or the presence of marginally raised bilirubin. Some affected people have no evidence of shortened red cell survival, whereas others have a well-compensated haemolytic anaemia. No treatment is required, although the blood film of partners should be examined if there is consanguinity, making homozy-gosity in offspring possible. For patients with mild haemolysis, anaemia may increase during infections, in pregnancy, with folate deficiency or with other conditions that are likely to enhance anaemia.

Silent carriers: low-expression genes

Mutations that produce low expression (LE) of a-spectrin, may lead to no haematological abnormality because of the normal overexpression of a-spectrin in red cells when compared with P-spectrin. However, when these defects are inherited in trans, on the other allele from an HE gene, HPP may result. Several mutations have been described, particularly commonly in codon 28, which produces LE genes. A common polymorphism, intron 45 C ^ T, is spectrin aLELY, standing for 'low-expression allele Lyon'.

Hereditary elliptocytosis and poikilocytosis in the neonate

In the neonate, the manifestations of HE may be a more marked pyropoikilocytosis resembling HPP, with more fragmented red

Figure 8.7 Hereditary pyropoikiloctosis, peripheral blood. Marked anisocytosis and poikilocytosis in the film from a child with homozygous hereditary elliptocytosis.

cells. These red cells are susceptible to fragmentation above 40°C, whereas normal cells only fragment above 50°C. The morphological changes and haemolysis gradually decrease over the first year until the typical picture of mild HE remains. Treatment of neonatal pyropoikilocytosis is required only if the anaemia is such as to warrant transfusion.

Spherocytic hereditary elliptocytosis

In rare Caucasian families with HE, haemolysis with modest splenomegaly is found with a blood film that has a low proportion of abnormally shaped cells, ranging from spherocytes to elliptocytes. Splenectomy is not usually indicated.

Hereditary pyropoikilocytosis

The characteristics of hereditary pyropoikilocytosis (HPP) are densely contracted and fragmented cells (Figure 8.7), moderate to severe haemolysis and heterogeneity of manifestations within a family. In general, patients with HPP have spectrin deficiency in addition to the abnormalities of spectrin-spectrin contacts that produce the heterotetramer deficiency of HE. One parent of an HE propositus may have normal haematology but carry a mutation in trans, which leads to spectrin deficiency. The affected cells show thermal lability and fragmentation at lower temperatures than normal. HPP is more common in black people.

Hereditary elliptocytosis in Africa

In some parts of West Africa, a high incidence (up to 1.6% of the population) of HE has been found. Interestingly, there is a considerable molecular heterogeneity for the basis of the condition in this area. In vitro, Plasmodium falciparum is less able to parasitize HE cells that have mutations in a-spectrin, glycophorin C or protein 4.1. Invasion is reduced in red cells from homozygous patients, and intracellular multiplication reduced, particularly in homozygous 4.1(-) red cells. It seems possible that the varieties of HE offer some protection against the clinical manifestations of falciparum malaria.

Laboratory investigation

The standard approach to the diagnosis of HE/HPP is the identification of haemolysis, coupled to a careful examination of the blood film of the patient and as many first-degree relatives as possible. Examples of blood films are shown in Figures 8.6 and 8.7. Other acquired causes of elliptocytic or fragmented red cells need to be excluded, including iron, folate or vitamin B12 deficiency, and the microangiopathic haemolytic anaemias. Congenital dyserythropoietic anaemia and thalassaemia intermedia also need to be excluded.

As with the investigation of HS, SDS-PAGE may reveal protein abnormalities, although more specific identification requires a sophisticated approach beyond the abilities of most haemato-logy laboratories.

Hereditary Elliptocytosis
Figure 8.8 Hereditary stomatocytosis, peripheral blood.

Treatment

Patients with chronic haemolysis should be given folate supplements. Splenectomy is indicated for severe haemolytic anaemia in patients with HPP or homozygous HE. Response in HPP may not be complete, but the anaemia is usually markedly alleviated. There may be a theoretical risk of increased thrombotic tendency due to remaining high platelet count, but the risk is small. The precautions against OPSI are the same as for HS.

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