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Hereditary elliptocytosis (HE) is a rare clinically and genetically heterogeneous disorder of the red cell membrane characterized by manifestations ranging from mild to severe transfusion-dependent hemolytic anemia but with the majority of patients being asymptomatic.
ORPHA:288Classification level: Disorder
HE is ubiquitously distributed with an estimated prevalence of 1/1,000-1/4,000 but may be underestimated due to asymptomatic patients. The prevalence may reach up to 1/50 in malaria endemic areas like West and Central Africa. Less than 10% of HE patients manifest with the severe variant of hereditary pyropoikilocytosis (HPP).
HE can present at any age and the clinical picture is heterogeneous. Most have common HE, which is mainly asymptomatic or which can present with mild hemolytic anemia as well as jaundice, splenomegaly and gallstones. Hydrops fetalis (see this term) may be seen in rare cases. A neonatal poikilocytic HE variant may be severe during the first year of life but afterwards (from 4 months-2 years) hemolysis declines and the phenotype becomes that of common HE. Transient poikilocytosis may also occur during infections or pregnancy, leading to hemolytic anemia in previously asymptomatic patients. The HPP variant is characterized by severe, transfusion-dependent hemolytic anemia with onset in infancy and that can also manifest with neonatal jaundice. Complications that can occur due to severe anemia include growth retardation, frontal bossing, marked splenomegaly and early gallbladder disease. Aplastic crisis, brought on by a Parvovirus B19 infection, may occur in some cases.
HE is caused by abnormalities of proteins involved in the red cell membrane horizontal skeletal network including the spectrin dimer-dimer interaction or the spectrin-actin-protein 4.1 junctional complex. The genes involved in HE are: alpha-spectrin erythrocytic 1 (SPTA1) located to 1q21, beta-spectrin erythrocytic (SPTB) located to 14q24.1-q24.2, erythrocyte membrane protein band 4.1 (EPB41) located to 1p33-p32 or glycophorin C (Gerbich blood group) (GYPC) located to 2q14-q21. Heterozygous mutations usually result in common HE. Patients with HPP are either compound heterozygotes or homozygotes for a missense mutation of alpha/beta spectrin. HPP is also due to the presence of one alpha-spectrin mutation in trans to a low-expression alpha-spectrin allele (alpha-LELY).
The laboratory hallmark of HE is the presence of elliptocytes (sometimes also ovalocytes, spherocytes, stomatocytes and fragmented cells) on peripheral blood smears. Osmotic fragility is not informative in common HE, but is usually increased in HPP. SDS-PAGE analysis of red cell membrane proteins may reveal quantitative/qualitative abnormalities of cytoskeletal proteins. The mean corpuscular volume in HPP is of 50-60 fL and marked poikilocytosis and red cell fragmentation is present. Genetic mutation analysis can identify causal mutations, confirming diagnosis.
Differential diagnoses include other acquired causes of elliptocytic or fragmented red cells (i.e. iron, vitamin B12 and folate deficiency, and microangiopathic hemolytic anemia), congenital dyserythropoietic anemia and alpha and beta thalassemia (see these terms).
Since HE is very rarely life threatening, antenatal diagnosis is not necessary, except for HPP cases, where screening for low expression polymorphism (i.e. alpha- LELY) is also needed.
All HE variants, apart from HPP (inherited autosomal recessively), follow an autosomal dominant pattern of inheritance and genetic counseling is possible.
Management and treatment
In most cases treatment is not necessary. In the most severe variants, folic acid, red cell transfusion and splenectomy (after the age of 5) may be required. Patients should be monitored during events known to precipitate hemolysis.
In the majority of cases HE is not life threatening and has no effect on life expectancy.