Hereditary Disorders of Red Cell Permeability

Abnormalities of red cell membrane cation permeability are seen in several hereditary disorders. These dominantly inherited conditions are collectively called the hereditary stomatocytoses and allied disorders. This class of hemolytic anemias is clinically diverse.[1] See image below.

Overhydrated hereditary stomatocytosis (OHSt), also called hydrocytosis, was the first of these disorders to be described.[2] An abnormally increased cation influx results in swollen erythrocytes, hemolysis, and stomatocytes. At the other end of the spectrum, net loss of cations and water results in the more common dehydrated hereditary stomatocytosis (DHSt), also called xerocytosis.

Intermediate syndromes that are asymptomatic or have mixed features, such as cryohydrocytosis (CHC) and familial pseudohyperkalemia (FP), have also been described.

OHSt has been linked to mutations in the erythroid ammonia channel Rh-associated glycoprotein (RhAG),[3, 4]  as well as, occasionally, to mutations in the band 3 chloride-bicarbonate exchanger AE1, regulated by SLC4A1. Decreases in stomatin are seen in OHSt.[5] The causative gene for DHSt was mapped to 16q23-24 and was identified with genome-wide sequencing as PIEZO1, with a few patients linked to KCCN4.[6] CHC has been linked to mutations in SLC4A1.[7] The causative gene for FP, mapped to 2q35-36, was identified as ABCB6.

Syndromic forms of hereditary stomatocytosis are rare but increasingly recognized and have improved our understanding of genetic mechanisms. Described syndromes including the following:

• CHC with mental retardation, seizures, and hepatosplenomegaly (stomatin deficiency linked to SLC4A1)
• Nonleaky stomatocytosis with hypercholesterolemia, xanthomas, splenomegaly, and macrothrombocytopenia (severe phytosterolemia linked to ABCG5 or ABCG8)
• DHSt with transient perinatal edema, including neonatal ascites (linked to PIEZO1)

Erythrocytes have intracellular hemoglobin, 2-3,diphosphoglycerate (2,3-DPG), and ATP, which all exert osmotic pressure across the semipermeable cell membrane. By transporting Na+ and K+ ions across the cell membrane, red cells can adjust the intracellular concentration of these cations and regulate intracellular hydration. Any disturbances in membrane cation permeability alter cellular hydration and can cause numerous effects, including hemolysis.

In overhydrated hereditary stomatocytosis, the major defect is a marked asymmetrical increase in passive Na+ and K+ permeability. The influx of Na+ exceeds the loss of K+, causing a net influx of water, overhydration, and swelling. The resulting hydrocytosis leads to increased osmotic fragility and decreased deformability, with consequent hemolysis. This is primarily due to mutations of the Rh-associated glycoprotein gene (RHAG),[3] with decreases in stomatin, or protein 7.2b, due to a trafficking alteration.[5]

In contrast, the primary abnormality in DHSt is a change in the relative membrane permeability to K+. Efflux of K+ is increased 2- to 4-fold and results in cation depletion, with decreased intracellular osmolality and water loss. The xerocytes formed are shear-sensitive and prone to membrane fragmentation in response to metabolic stress, with subsequent hemolysis. DHSt has been mapped to gain-of-function mutations in PIEZO1 and KCCN4, with the latter affecting the Gardos channel.[6] FP has been linked to mutations in the ABCB6 gene and is usually asymptomatic or (rarely) shows mild macrocytosis. When erythrocytes are cooled to room temperature or lower (eg, after phlebotomy), the net K+ leak is greater than expected and results in factitious hyperkalemia.[8, 9]

CHC clinically manifests with mild hemolytic anemia and is remarkable for an abnormality of the band 3 chloride-bicarbonate exchanger AE1.[7] At low temperatures, the defective anion channel appears to allow a significant cation leak, and autohemolysis may be seen in vitro at 4ºC. The protein defect results from missense mutations in the SLC4A1 gene.[10]

Frequency

International

These hereditary syndromes are extremely rare, and accurate data concerning their prevalence are lacking; however, overall they are thought to be 40-50 times less common than hereditary spherocytosis.[11] DHSt is reported in 1 per 50,000 live births.[12] and DHSt kindreds in Ireland[13] and France[14] have been reported.

Mortality/Morbidity

Morbidity in these disorders depends on the severity of the hemolytic anemia. The risks for neonatal hyperbilirubinemia with kernicterus are similar to those of other hemolytic anemias. Exchange transfusion is occasionally required. Aplastic crises associated with parvovirus infection occur, although they are infrequent. Both OHSt and DHSt are associated with a significant risk of serious thrombosis after splenectomy, although the reason for this is unknown.

Most patients with overhydrated hereditary stomatocytosis have chronic low-grade anemia punctuated by recurrent episodes of more severe anemia and jaundice. Other patients have a much milder disease. Iron overload, regardless of transfusion status, is now well recognized.

Most patients with dehydrated hereditary stomatocytosis are asymptomatic but experience mild-to-moderate hemolytic anemia, which is generally well compensated. Hydrops fetalis and neonatal ascites have been reported in a few kindreds.[15] Exchange transfusions are occasionally required. Even simple transfusions carry risks of infection, allergic reactions, and febrile or hemolytic transfusion reactions.

Race

Most patients with hereditary disorders of red cell permeability are of European descent.

Sex

These syndromes have no known sex predilection, and clinical manifestations are not affected by sex.

The hereditary stomatocytosis syndromes and allied disorders are usually transmitted in an autosomal dominant pattern, although sporadic cases have been reported. Penetrance varies, with significant disparity in clinical symptoms between affected individuals in the same kindred.

Many patients present with hemolytic anemia in the neonatal period, but others are asymptomatic throughout their lifetime. Aplastic crises associated with parvovirus and other infections have been reported. An unusual characteristic of the stomatocytosis syndromes is a predisposition to severe life-threatening thrombosis after splenectomy.

A number of acquired conditions are associated with stomatocytes in the blood, although these patients do not usually have hematologic symptoms. Stomatocytosis may also be observed with inherited conditions such as Mediterranean stomatocytosis, which does not affect erythrocyte permeability and has an accompanying thrombocytopenia.

It is now recognized that stomatocytosis may occur in association with syndromes, including the following:

• CHC with mental retardation, seizures, and hepatosplenomegaly
• Nonleaky stomatocytosis with hypercholesterolemia, xanthomas, splenomegaly, and macrothrombocytopenia
• DHSt with transient perinatal edema

Overhydrated hereditary stomatocytosis (OHSt)

The degree of hemolysis and anemia varies. Moderate-to-severe lifelong hemolytic anemia is most typical. A few reports described patients who experienced symptoms of vaso-occlusion, such as dyspnea, chest pain, and abdominal pain, particularly after splenectomy.

Anemia is generally not present at birth, but neonatal jaundice is relatively common and is occasionally serious enough to warrant exchange transfusion. Patients with severe disease are usually younger than 6 months at presentation.

Dehydrated hereditary stomatocytosis (DHSt)

This is the most common form of the hereditary stomatocytosis syndromes. Patients typically present with mild-to-moderate hemolytic anemia. Periodic episodes of jaundice are common. Most patients are asymptomatic, although easy fatigability is a common symptom.[16]

A few case reports have documented DHSt in association with recurrent fetal loss or with hydrops fetalis (which, as previously mentioned, is a feature of the syndromic form of DHSt). The presence of perinatal effusions may require ascitic taps but is not a predictor of the severity of anemia later in life, and usually resolves in infancy.[17] The mechanism for this is uncertain but may involve hepatic dysfunction.[18]

Iron overload is common, and adults may be diagnosed with hemochromatosis. The mechanism for this is unknown.[19]

Intermediate syndromes

Patients with intermediate syndromes do not have consistent hemolytic anemia.

Cryohydrocytosis (CHC) is an intermediate syndrome in which erythrocytes undergo spontaneous in vitro hemolysis after storage at 4°C.

Familial pseudohyperkalemia (FP) manifests with factitious hyperkalemia. Red cell macrocytosis is rare.

Focus the physical examination on organ systems affected by hemolytic anemia. Pallor, jaundice, hepatosplenomegaly, and signs of gallstone disease are the most likely physical findings. The presence of xanthomas, splenomegaly, bleeding tendency, seizure disorder, or mental retardation would suggest syndromic stomatocytosis. Evaluate signs of cardiovascular compromise in patients who are ill. Monitor growth parameters yearly in children. Monitor ferritin levels for iron overload.

Peripheral blood smear

As many as 3% of RBCs may be stomatocytes in a normal smear. Stomatocytes have a mouth-shaped (stoma) area of central pallor, and the cells are large and osmotically fragile. In overhydrated hereditary stomatocytosis (OHSt), this amount rises to 5-50%.

In dehydrated hereditary stomatocytosis (DHSt), target cells and echinocytes may be observed, as well as dense erythrocytes that have hemoglobin puddled at the periphery. Stomatocytes are usually not seen, and most RBCs have normal morphology.

CBC count

A CBC count reveals the degree of anemia, if present. In OHSt, there is usually macrocytosis with a mean cell volume (MCV; mean corpuscular volume) of 110-150 fL and a decreased mean cell hemoglobin concentration (MCHC; mean corpuscular hemoglobin concentration). In DHSt, macrocytosis is also seen (>100 fL), but the MCHC is elevated and this is often diagnostic.

The WBC and platelet counts are typically normal.

Reticulocyte count

The reticulocyte count is usually elevated, and in OHSt can be as high as 50% during active hemolysis, and in DHSt higher than expected for the degree of anemia (3-30%).

Osmotic fragility tests

The stomatocytes or hydrocytes of OHSt are osmotically fragile, whereas xerocytes in dehydrated hereditary stomatocytosis are resistant to osmotic lysis.

Although osmotic fragility tests are not required to establish the diagnosis, in patients in whom the peripheral blood smear has not been reviewed carefully, OHSt may be misdiagnosed as hereditary spherocytosis.

Miscellaneous tests

The eosin-5′-maleimide (EMA)–binding test detects the band 3 complex in red blood cells, which is normal or increased in OHSt and DHSt, but decreased in hereditary spherocytosis.[11]

RBC sodium, potassium, and 2,3-DPG levels are useful but not always available in clinical laboratories. In OHSt, the intracellular sodium concentration and total cation content is high, but potassium and 2,3-DPG levels can be low. In DHSt, the intracellular potassium and the total cation content are low.

Although ektacytometry detects characteristic red blood cell deformability profiles in stomatocytosis syndromes, access to this technique remains limited, reducing its utility.[20]

Genetic mutations can be detected in kindreds with familial pseudohyperkalemia (FP), cryohydrocytosis (CHC), and DHSt. Unfortunately, the wide variety of mutations has precluded genetic screening thus far.

Perform abdominal ultrasonography in symptomatic patients to assess for pigment gallstones.

Monitor patients with hemolytic anemia for complications of hemolysis, such as cholelithiasis. Acute infections may cause decreased erythropoiesis (eg, parvovirus) or episodes of hyperhemolysis; in either case, an exacerbation of anemia may result. These patients should also receive folate supplementation if they have significant ongoing hemolysis.

Neonates with overhydrated hereditary stomatocytosis (OHSt) or dehydrated hereditary stomatocytosis (DHSt) may require phototherapy, simple blood transfusions, and, occasionally, exchange transfusions for treatment of anemia and hyperbilirubinemia. Prenatal diagnosis with cordocentesis is feasible if a severe variant is suspected, although this is generally useful only if fetal complications are evident.[21]

Patients with hereditary stomatocytosis syndromes do not require splenectomy. The results of splenectomy vary, and the benefits are unpredictable. Patients with these disorders are at an increased risk of life-threatening thrombosis after splenectomy. Venous thromboemboli predominate, sometimes with complicating pulmonary or portal hypertension.[22, 23] The complication may occur some time after surgery, and a patient who eventually needed a heart and lung transplant has been described.[24] Postoperative anticoagulation has not overcome this problem.

Because of the high risk of serious postsplenectomy thrombosis, the standard infection risks of splenectomy, and uncertain benefits, this procedure should be strongly discouraged in patients with hereditary stomatocytosis syndromes.[1, 25]

Cholecystectomy may be considered in patients with symptomatic cholelithiasis. The level of thrombotic risk is less certain but not trivial.

Because of the rarity of these disorders, consult a pediatric hematologist if questions arise regarding the diagnosis and for further management.

The only medication used in hereditary stomatocytosis syndromes is folic acid for patients with significant hemolysis. Iron chelation with deferoxamine may be needed for patients with significant iron overload.

Class Summary

These are essential for normal DNA synthesis. The only medication used to treat stomatocytosis syndromes is folic acid, which is used in patients with hemolytic anemia.

Folic acid (Folvite)

Important cofactor for enzymes required for nucleic acid synthesis and normal erythropoiesis.

Class Summary

Iron overload may occur in adults with overhydrated hereditary stomatocytosis (OHSt) and dehydrated hereditary stomatocytosis (DHSt); the mechanism is unknown.

Deferoxamine mesylate (Desferal)

Usually administered as slow SC infusion through portable pump. Freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. Promotes renal and hepatic excretion in urine and bile in feces. Gives urine a red discoloration. Readily chelates iron from ferritin and hemosiderin but not transferrin. Does not affect iron in cytochromes or hemoglobin. Most effective when provided to the circulation continuously by infusion. Helps prevent damage to liver and bone marrow from iron deposition. May be administered either by IM injection or by slow IV infusion. Does not effectively chelate other trace metals of nutritional importance. Provided in vials containing 500 mg of lyophilized sterile drug. 2 mL of sterile water for injection should be added to each vial, bringing the concentration to 250 mg/mL. For IV use, this may be diluted in 0.9% sterile saline, 5% dextrose solution, or Ringer solution.

IM is preferred route of administration, except in hypotension and cardiovascular collapse, in which the IV route should be considered.

Monitor patients for complications of hemolysis, such as cholelithiasis and parvovirus infection, as well as iron overload in older patients.

Follow-up care every 1-2 years with CBC count, physical examination, and as-needed visits for illness is usually sufficient.

Inpatient care is generally required only in the newborn period if significant anemia or hyperbilirubinemia is present. In older patients, hospitalization may be needed if aplastic crisis or serious infection occurs.

Patients with significant hemolysis should receive 1 mg of folic acid daily. Patients with hyperferritinemia (usually adults) should be considered for chelation therapy with deferoxamine.

Offer genetic counseling to all patients with a hereditary stomatocytosis syndrome; autosomal dominant inheritance is generally observed.

Hemolytic anemia is the primary complication of the stomatocytosis syndromes. Severity widely varies, although most patients have some degree of hemolysis. Cholelithiasis may occur in patients with significant hemolysis.

Iron overload may occur, even in patients who have not been transfused. Transfusion-related problems may occur.

Hypercoagulability with devastating venous thrombosis is a complication in patients with these disorders who have undergone splenectomy. Thrombotic complications have affected peripheral and pulmonary arteries, as well as superficial, deep, and portal veins. Intracardiac mural thrombi have also been reported. Heparinization followed by long-term warfarin (Coumadin) use has not been effective in preventing recurrent thrombosis.

Parvovirus and other severe infections can induce aplasia in patients with hereditary stomatocytosis syndromes. A significant drop in hemoglobin can result because of decreased erythrocyte half-life.[26]

The prognosis for patients with stomatocytosis disorders is generally good.

Patients and their parents should be educated about the genetics of the disease, signs and symptoms of hemolysis and anemia, and when to call their physician.

Patients considering splenectomy should be educated about the reasons why this procedure should be avoided.

Patients should know the signs and symptoms of gallstones and understand that they are at increased risk if they have significant hemolysis.

Patients with dehydrated hereditary stomatocytosis (DHSt) and overhydrated hereditary stomatocytosis (OHSt) should be aware of the risk of iron overload over time, even in the absence of red cell transfusions.