Hereditary Xerocytosis

December 31, 2014

Synonyms

Overview

Hereditary stomatocytosis and hereditary xerocytosis are rare, genetically distinct, autosomal dominant diseases of red blood cell sodium and potassium permeability. Hereditary cryohydrocytosis is a subtype of hereditary stomatocytosis. All three present with hemolysis and anemia, which can vary from mild to severe. The key signs and symptoms are those of all hemolytic anemias: jaundice, pallor, fatigue, splenomegaly, gallbladder disease, and susceptibility to an aplastic crisis following infection with parvovirus B19. The diseases begin at birth, but especially in the case of hereditary xerocytosis and hereditary cryohydrocytosis, may be mild enough to go undiscovered for years.

Symptoms

The key signs and symptoms are those of all hemolytic anemias: jaundice, pallor, fatigue, splenomegaly, gallbladder disease, and susceptibility to an aplastic crisis following infection with parvovirus B19. The diseases begin at birth, but especially in the case of hereditary xerocytosis and hereditary cryohydrocytosis, may be mild enough to go undiscovered for years.

Causes

Physiologically, the major red cell abnormality is a change in the relative permeability of the membrane to potassium. Efflux of K+ is increased two to four fold and approximates or slightly exceeds Na+ influx. Na+, K+ pump activity is increased appropriately for the slightly elevated Na+ content, but the pump cannot compensate for K+ losses in excess of Na+ gain, because the pump expels three Na+ ions for every two K+ ions it returns, which is the normal ratio of the Na+ in and K+ out leaks. As a consequence, the K+ permeability defect, though modest, causes HX red cells to gradually become cation depleted and dehydrated.

The defective gene has been traced to a relatively small segment on the long arm of chromosome 16 (q24.2-qter), and was recently pinpointed to a protein called Piezo1 (gene name FAM38A) in multiple HX kindreds. Missense mutations near the center or tail end of this very large protein have been found in all families studied to date.

Diagnosis

A careful family history should be taken, looking for anemia, splenectomy, jaundice, early gallbladder disease, transfusion, neonatal jaundice or edema, hyperkalemia, iron overload, iron chelation therapy, or thromboembolic disease. The red cell membrane permeability diseases are transmitted from generation to generation with no gender preference (autosomal dominant pattern). As with most dominant diseases, symptoms may vary among affected family members. A careful family history should always be taken; however, the lack of a positive family history is not critical, as many patients have new mutations.

The diagnostic features observed in commonly available laboratory tests include, unique red cell morphology (5 to 40% stomatocytes, with or without spherocytes) (see Figure 1), moderate to severe hemolysis and anemia, macrocytosis (high mean corpuscular volume [MCV], that is, 95 to 150fL), low MCHC (24 to 30%), and a positive osmotic fragility test (osmotically fragile cells, curve shifted toward high ionic strengths). The combination of macrocytosis and a low MCHC is virtually diagnostic of hereditary stomatocytosis, especially when stomatocytes are present on the peripheral blood smear and the osmotic fragility test is positive.

Once the diagnosis of hemolytic anemia is established, the key readily available diagnostic tests to distinguish hereditary stomatocytosis, hereditary cryohydrocytosis, and hereditary xerocytosis are:

MCV and MCHC
Blood smear for erythrocyte morphology
Osmotic fragility test (unincubated)

Prognosis

The natural histories of hereditary stomatocytosis and hereditary xerocytosis are not well understood. There are no systematic studies of the lifespan of patients who have not been splenectomized or about late complications of the diseases. As noted earlier, it is clear that splenectomy poses a high risk of thromboembolic complications and there seems to be a higher than expected risk of iron accumulation, which may require intervention. Also, these patients, like all patients with hemolytic anemias, are at relatively high risk for developing bilirubin gallstones and cholecystitis or biliary obstruction.

Overall, however, the red cell membrane permeability diseases are often relatively well tolerated, and most patients live reasonably normal lives.

Treatment

Physicians who care for patients with either HSt or HX agree that there is a high risk of thromboembolic complications following splenectomy. So much so, that the operation is contraindicated in these diseases in all but extreme situations. Unfortunately, the data backing up this prohibition are not very extensive. The recommendation flows primarily from a single study, a retrospective compilation of case reports of nine splenectomized adults collected by Stewart and his colleagues in 1996.

All patients with moderate to severe hemolytic anemias should probably receive supplemental folic acid (1mg/d PO) to be sure that deficiency of this cheap and harmless water-soluble vitamin does not limit erythropoiesis.

For unknown reasons, patients with hereditary stomatocytosis and xerocytosis are susceptible to iron overload, even if they have not been transfused. This seems to be true in most patients, suggesting it is not due to co-inheritance of a gene for hemochromatosis, though if that occurs, it increases the risk even more.

In some patients. the problem is severe and tissue iron deposition is great enough to damage the liver and other organs. For this reason, all patients with hereditary stomatocytosis or xerocytosis should have laboratory studies to assess iron status, with follow-up studies as indicated. If necessary, they should be treated with Exjade or other iron chelators. The diagnosis and treatment of iron overload is discussed in more detail elsewhere.