Hereditary Disorders of Red Cell Permeability
- Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP; Chief Editor: Max J Coppes, MD, PhD, MBA more...
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. See image below.
Overhydrated hereditary stomatocytosis (OHSt), also called hydrocytosis, was the first of these disorders to be described. 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 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.
CHC has been linked to mutations in the band 3 chloride-bicarbonate exchanger AE1. DHSt and most cases of FP have been mapped to the 16q23-24 genetic locus. OHSt has been linked to mutations in the erythroid ammonia channel Rh-associated glycoprotein (RHAG), the erythroid chloride/bicarbonate exchanger SLC4A1/AE1/band 3, and the erythroid glucose transporter SLC2A1/GLUT1; in Schnauzer dogs, OHSt is asymptomatic and involves none of these genes. Decreases in stromatin, or protein 7.2b, seen in OHSt are thought to be a trafficking alteration.
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 asymmetric 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. Some cases are now linked to mutations of the Rh-associated glycoprotein (RHAG) gene, and decreases in stomatin, or protein 7.2b, are thought to be a trafficking alteration.
In contrast, the primary abnormality in dehydrated hereditary stomatocytosis is a change in the relative membrane permeability to K+. Efflux of K+ is increased 2-fold 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. FP 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] Dehydrated hereditary stomatocytosis and most cases of FP have been mapped to the 16q23-24 genetic locus.
CHC clinically manifests with mild hemolytic anemia and is remarkable for an abnormality of the band 3 chloride-bicarbonate exchanger AE1. At low temperatures, the defective anion channel appears to allow a significant cation leak, and autohemolysis may be seen in vitro at 4ºC. The molecular defects that transform AE1 into a cation channel are currently under investigation.
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. Dehydrated hereditary stomatocytosis (DHSt) is reported in 1 per 50,000 live births. and DHSt kindreds in Ireland and France have been reported.
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. Exchange transfusions are occasionally required. Even simple transfusions carry risks of infection, allergic reactions, and febrile or hemolytic transfusion reactions.
Most patients with hereditary disorders of red cell permeability are of European descent.
These syndromes have no known sex predilection, and clinical manifestations are not affected by sex.
Delaunay J. The molecular basis of hereditary red cell membrane disorders. Blood Rev. 2006 May 25. [Medline].
Lock SP, Smith RS, Hardisty RM. Stomatocytosis: a hereditary red cell anomally associated with haemolytic anaemia. Br J Haematol. 1961 Jul. 7:303-14. [Medline].
Bruce LJ, Robinson HC, 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. Nat Genet. 2005 Nov. 37(11):1258-63. [Medline].
Iolascon A, Stewart GW, Ajetunmobi JF, et al. Familial pseudohyperkalemia maps to the same locus as dehydrated hereditary stomatocytosis (hereditary xerocytosis). Blood. 1999 May 1. 93(9):3120-3. [Medline]. [Full Text].
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 Feb 5. 113(6):1350-7. [Medline].
Shmukler BE, Rivera A, Vandorpe DH, Alves J, Bonfanti U, Paltrinieri S. Cation-leak stomatocytosis in Standard Schnauzers does not cosegregate with coding mutations in the RhAG, SLC4A1, or GLUT1 genes associated with human disease. Blood Cells Mol Dis. 2012 Mar 9. [Medline].
Fricke B, Parsons SF, Knopfle G, et al. Stomatin is mis-trafficked in the erythrocytes of overhydrated hereditary stomatocytosis, and is absent from normal primitive yolk sac-derived erythrocytes. Br J Haematol. 2005 Oct. 131(2):265-77. [Medline].
Stewart GW, Corrall RJ, Fyffe JA, et al. Familial pseudohyperkalaemia. A new syndrome. Lancet. 1979 Jul 28. 2(8135):175-7. [Medline].
Gore DM, Layton M, Sinha AK, et al. Four pedigrees of the cation-leaky hereditary stomatocytosis class presenting with pseudohyperkalaemia. Novel profile of temperature dependence of Na+-K+ leak in a xerocytic form. Br J Haematol. 2004 May. 125(4):521-7. [Medline].
Guizouarn H, Martial S, Gabillat N, Borgese F. Point mutations involved in red cell stomatocytosis convert the electroneutral anion exchanger 1 to a nonselective cation conductance. Blood. 2007 Sep 15. 110(6):2158-65. [Medline].
King MJ, Zanella A. Hereditary red cell membrane disorders and laboratory diagnostic testing. Int J Lab Hematol. 2013 Jun. 35(3):237-43. [Medline].
Stewart GW. Hemolytic disease due to membrane ion channel disorders. Curr Opin Hematol. 2004 Jul. 11(4):244-50. [Medline].
Carella M, Stewart G, Ajetunmobi JF, et al. Genomewide search for dehydrated hereditary stomatocytosis (hereditary xerocytosis): mapping of locus to chromosome 16 (16q23-qter). Am J Hum Genet. 1998 Sep. 63(3):810-6. [Medline].
Beaurain G, Mathieu F, Grootenboer S, Fiquet B, Cynober T, Tchernia G. Dehydrated hereditary stomatocytosis mimicking familial hyperkalaemic hypertension: clinical and genetic investigation. Eur J Haematol. 2007 Mar. 78(3):253-9. [Medline].
Grootenboer-Mignot S, Cretien A, Laurendeau I, et al. Sub-lethal hydrops as a manifestation of dehydrated hereditary stomatocytosis in two consecutive pregnancies. Prenat Diagn. 2003 May. 23(5):380-4. [Medline].
Rees DC, Portmann B, Ball C, et al. Dehydrated hereditary stomatocytosis is associated with neonatal hepatitis. Br J Haematol. 2004 Jul. 126(2):272-6. [Medline].
Syfuss PY, Ciupea A, Brahimi S, et al. Mild dehydrated hereditary stomatocytosis revealed by marked hepatosiderosis. Clin Lab Haematol. 2006 Aug. 28(4):270-4. [Medline].
King MJ, Zanella A. Response to a letter from A. Huisman and R. van Wijk (Ektacytometry and Genetic Testing in Hereditary Red Cell Membrane Disorders). Int J Lab Hematol. 2013 Sep 6. [Medline].
Sanchez M, Palacio M, Borrell A, Carmona F, Cobo T, Coll O. Prenatal diagnosis and management of fetal xerocytosis associated with ascites. Fetal Diagn Ther. 2005 Sep-Oct. 20(5):402-5. [Medline].
Stewart GW, Amess JA, Eber SW, et al. Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol. 1996 May. 93(2):303-10. [Medline].
Perel Y, Dhermy D, Carrere A, et al. Portal vein thrombosis after splenectomy for hereditary stomatocytosis in childhood. Eur J Pediatr. 1999. August:158(8):628-630. [Medline].
Jais X, Till SJ, Cynober T, et al. An extreme consequence of splenectomy in dehydrated hereditary stomatocytosis: gradual thrombo-embolic pulmonary hypertension and lung-heart transplantation. Hemoglobin. 2003 Aug. 27(3):139-47. [Medline].
Mabin DC, Chowdhury V. Aplastic crisis caused by human parvovirus in two patients with hereditary stomatocytosis. Br J Haematol. 1990. Sep;76(1):153-154. [Medline].