Hereditary Stomatocytosis

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Chapter 454 Hereditary Stomatocytosis

George B. Segel, Lisa R. Hackney

Hereditary stomatocytosis includes a rare group of dominantly inherited hemolytic anemias in which there are characteristic morphologic changes in the RBCs and increased red cell cation permeability. The RBCs are cup shaped, creating a mouth-shaped area (stoma) of central pallor instead of the usual circular area of central pallor. Hereditary stomatocytosis is classified by the RBC hydration status. The two major varieties are either overhydrated (hydrocytosis) or dehydrated (xerocytosis).

Hydrocytosis

Pathophysiology

Stomatocytes of the hydrocytic variant have excess intracellular sodium and water content and decreased intracellular potassium content. The principal defect in this variant is an increase in Na⁺ and K⁺ permeability, caused by mutations in Rhesus-associated glycoprotein (RHAG). However, the amount of Na⁺ influx exceeds the K⁺ efflux, and the cells subsequently develop increased cation content and water, and thus swell. These hydrocytic cells have increased osmotic fragility. Additionally, the integral membrane protein, stomatin or band 7.2 b, is decreased or absent from the erythrocyte membrane. The function of stomatin is not fully understood, although it might act as a switch that influences the function of GLUT1, the glucose transporter. It has been found that stomatin in the hydrocytic variant is synthesized early in RBC development but is lost as the cell matures. The mechanism for this loss of stomatin is not yet determined. It also is unclear how the loss of stomatin expression contributes to the cation leak, which is characteristic of this variant.

Clinical Features

The hydrocytic variant is the most severe form of hereditary stomatocytosis and is characterized by moderate to severe hemolysis, macrocytosis, and large numbers of stomatocytes on the blood smear. Patients commonly develop jaundice, splenomegaly, and cholelithiasis.

Xerocytosis

Pathophysiology

The xerocytic variant is the more common form of hereditary stomatocytosis and usually results in a milder anemia in affected patients. The underlying cation defect is a net loss of RBC potassium that is not accompanied by an increase in sodium. Subsequently, the erythrocyte develops decreased intracellular water content and becomes dehydrated. It may be associated with a syndrome of perinatal edema and ascites. These findings are transient and remain unexplained.

Clinical Features

Patients affected by the xerocytic variant have a mild compensated macrocytic hemolytic anemia, variable numbers of stomatocytes and/or target cells on peripheral smear, increased mean corpuscular hemoglobin concentration (MCHC) due to the cellular dehydration, and typically jaundice and splenomegaly.

Intermediate Syndromes

The Rh deficiency syndrome is characterized by an absence or profound decrease in the Rh antigen on the RBC membrane. Affected RBCs in this disorder are dehydrated and have decreased cell cation and water content. This decreased cell cation content may be due to increased potassium leak in spite of increased Na⁺-K⁺ pump activity. This syndrome is associated with mild to moderate hemolytic anemia, reticulocytosis, and stomatocytes and spherocytes on the blood smear.

Cryohydrocystosis is a mild form of stomatocytosis, typically caused by mutations in SLC4A1 coding for the band 3 anion exchanger, in which the RBCs lyse on cooling in vitro and may be associated with “pseudohyperkalemia.”

Absence of high-density lipoproteins (an-α-liproteinemia or Tangier disease) can lead to hematologic manifestations such as a moderate hemolytic anemia, stomatocytosis, and thrombocytopenia. Affected patients can also have large orange tonsils, hepatosplenomegaly, lymphadenopathy, cloudy corneas, and peripheral neuropathy.

One of the most flagrant forms of stomatocytosis is seen in phytosterolaemia, another metabolic disorder, in which the absorption of sterols, both cholesterol and its plant-derived relatives (e.g., sitosterol), is unlimited and unselective. The cells are not leaky to cations; there is macrothrombocytopenia and a degree of short stature. The plasma cholesterol may or may not be abnormal, but mass spectrography always shows a massive increase in plant sterol levels.

Other Disorders Associated with Stomatocytosis

Acquired stomatocytosis may be seen with liver disease but also in alcoholism, malignancy, and cardiovascular disease. Stomatocytes can be seen on the blood smears of normal patients due to drying artifact.

Treatment

For severe hemolysis, patients might require RBC transfusion. Splenectomy is not recommended as a treatment for cation-leaky hereditary stomatocytosis. It is not effective and predisposes patients to in situ thrombosis after splenectomy. The thrombosis appears related to abnormal adherence of stomatocytic erythrocytes to the vascular endothelium.

Bruce LJ, Guizouarn H, Burton NM, et al. The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein. Blood. 2009;113:1350-1357.

Bruce LJ, Robinson H, Guizouarn H, et al. Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1. Nature Genetics. 2005;37:1258-1263.

Delaunay J, Stewart GW. Disorders of the red cell membrane. In: Runge MS, Paterson C, Thein SL, editors. Principles of molecular medicine. Totowa, NJ: Humana, 2005.

Montel-Hagen A, Kinet S, Manel N, et al. Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C. Cell. 2008;132:1039-1048.

Rees D, Iolascon A, Carella M, et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol. 2005;130:297-309.

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