Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point of care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

For more information, click below.


Subscribers log in here


Stomatocytosis

INTRODUCTION

Stomatocytosis (also called hydrocytosis) is defined by the appearance on the peripheral smear of erythrocytes with a mouth-shaped area of central pallor (picture 1) [1,2]. Causes of this condition, which can be either congenital or acquired, will be discussed here.

OVERVIEW

Stomatocytes are characterized by a decrease in the ratio of surface area-to-volume that can be induced either by a reduction in surface area or an increase in red cell volume. Almost all cases are due to alteration in permeability, leading to an increase in red cell volume. The reduction in surface area/volume ratio leads to trapping in the microvasculature of the spleen and other organs of the monocyte/macrophage system, producing varying degrees of hemolysis.

The red cell volume is increased in most of these disorders with no parallel increase in membrane surface area. As a result, the biconcave disc becomes a uni-concave cup on electron microscopy (picture 2) and a stomatocyte on dried smear (picture 1). In vitro and perhaps in vivo (see below), one can induce stomatocytosis by incubating normal red cells with amphipathic cations which, according the Sheetz-Singer bilayer couples hypothesis, are supposed to intercalate passively into the relatively negative inner half of the membrane phospholipid bilayer, causing an inner bulging — the beginning of the cup; endocytic vacuoles then form at the advancing mouth causing the loss of surface area that completes the transformation (figure 1) [3,4].

Stomatocytes can be found on the peripheral smear of normal subjects. Since this may be due to drying artifact, it is advisable to evaluate several different areas of the smear before making this diagnosis.

  • The percentage of stomatocytes among the red cells of normal subjects is usually below 3 percent.
  • A higher percentage is seen in the conditions associated with stomatocytosis, eg, up to 40 to 60 percent in patients with hereditary stomatocytosis [5] and 10 percent or more in some patients with acquired disease such as alcoholism [6].

                   

Subscribers log in here

To continue reading this article you must have access through your hospital or your group practice, log in to your personal subscription, or purchase a personal subscription. For more information, click below.
Literature review current through: Apr 2013. | This topic last updated: Mar 25, 2013.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2013 UpToDate, Inc.
References
Top
  1. Gallagher PG, Lux SE. Disorders of the erythrocyte membrane. In: Hematology of Infancy and Childhood, Nathan DG, Orkin SH, Ginsburg D, Look TA (Eds), WB Saunders, Philadelphia 2003. p.560.
  2. LOCK SP, SMITH RS, HARDISTY RM. Stomatocytosis: a hereditary red cell anomally associated with haemolytic anaemia. Br J Haematol 1961; 7:303.
  3. Deuticke B. Transformation and restoration of biconcave shape of human erythrocytes induced by amphiphilic agents and changes of ionic environment. Biochim Biophys Acta 1968; 163:494.
  4. Sheetz MP, Singer SJ. Biological membranes as bilayer couples. A molecular mechanism of drug-erythrocyte interactions. Proc Natl Acad Sci U S A 1974; 71:4457.
  5. Kanzaki A, Yawata Y. Hereditary stomatocytosis: phenotypical expression of sodium transport and band 7 peptides in 44 cases. Br J Haematol 1992; 82:133.
  6. Wislöff F, Boman D. Acquired stomatocytosis in alcoholic liver disease. Scand J Haematol 1979; 23:43.
  7. Stewart GW. The hereditary stomatocytosis and allied conditions: inherited disorders Na and K transport. In: Red cell membrane transport in health and disease, Bernhardt I, Ellory JC (Eds), Springer Verlag, Berlin 2003. p.511.
  8. Wiley JS, Cooper RA, Adachi K, Asakura T. Hereditary stomatocytosis: association of low 2,3-diphosphoglycerate with increased cation pumping by the red cell. Br J Haematol 1979; 41:133.
  9. Stewart GW. The membrane defect in hereditary stomatocytosis. Baillieres Clin Haematol 1993; 6:371.
  10. Flatt JF, Bruce LJ. The hereditary stomatocytoses. Haematologica 2009; 94:1039.
  11. Mentzer WC, Lubin BH, Emmons S. Correction of the permeability defect in hereditary stomatocytosis by dimethyl adipimidate. N Engl J Med 1976; 294:1200.
  12. Lande WM, Thiemann PV, Mentzer WC Jr. Missing band 7 membrane protein in two patients with high Na, low K erythrocytes. J Clin Invest 1982; 70:1273.
  13. Eber SW, Lande WM, Iarocci TA, et al. Hereditary stomatocytosis: consistent association with an integral membrane protein deficiency. Br J Haematol 1989; 72:452.
  14. Fricke B, Argent AC, Chetty MC, et al. The "stomatin" gene and protein in overhydrated hereditary stomatocytosis. Blood 2003; 102:2268.
  15. Stewart GW, Hepworth-Jones BE, Keen JN, et al. Isolation of cDNA coding for an ubiquitous membrane protein deficient in high Na+, low K+ stomatocytic erythrocytes. Blood 1992; 79:1593.
  16. Stewart GW, Argent AC, Dash BC. Stomatin: a putative cation transport regulator in the red cell membrane. Biochim Biophys Acta 1993; 1225:15.
  17. Salzer U, Prohaska R. Stomatin, flotillin-1, and flotillin-2 are major integral proteins of erythrocyte lipid rafts. Blood 2001; 97:1141.
  18. Turner EJ, Jarvis HG, Chetty MC, et al. ATP-dependent vesiculation in red cell membranes from different hereditary stomatocytosis variants. Br J Haematol 2003; 120:894.
  19. Wang D, Turetsky T, Perrine S, et al. Further studies on RBC membrane protein 7.2B deficiency in hereditary stomatocytosis (abstract). Blood 1992; 80:275a.
  20. Zhu Y, Paszty C, Turetsky T, et al. Stomatocytosis is absent in "stomatin"-deficient murine red blood cells. Blood 1999; 93:2404.
  21. Green JB, Fricke B, Chetty MC, et al. Eukaryotic and prokaryotic stomatins: the proteolytic link. Blood Cells Mol Dis 2004; 32:411.
  22. Fricke B, Parsons SF, Knöpfle 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; 131:265.
  23. Morlé L, Pothier B, Alloisio N, et al. Reduction of membrane band 7 and activation of volume stimulated (K+, Cl-)-cotransport in a case of congenital stomatocytosis. Br J Haematol 1989; 71:141.
  24. Smith BD, Segel GB. Abnormal erythrocyte endothelial adherence in hereditary stomatocytosis. Blood 1997; 89:3451.
  25. Gallagher PG, Chang SH, Rettig MP, et al. Altered erythrocyte endothelial adherence and membrane phospholipid asymmetry in hereditary hydrocytosis. Blood 2003; 101:4625.
  26. 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; 63:810.
  27. Iolascon A, Stewart GW, Ajetunmobi JF, et al. Familial pseudohyperkalemia maps to the same locus as dehydrated hereditary stomatocytosis (hereditary xerocytosis). Blood 1999; 93:3120.
  28. Houston BL, Zelinski T, Israels SJ, et al. Refinement of the hereditary xerocytosis locus on chromosome 16q in a large Canadian kindred. Blood Cells Mol Dis 2011; 47:226.
  29. Zarychanski R, Schulz VP, Houston BL, et al. Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis. Blood 2012; 120:1908.
  30. Andolfo I, Alper SL, De Franceschi L, et al. Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1. Blood 2013.
  31. Bae C, Gnanasambandam R, Nicolai C, et al. Xerocytosis is caused by mutations that alter the kinetics of the mechanosensitive channel PIEZO1. Proc Natl Acad Sci U S A 2013; 110:E1162.
  32. Grootenboer S, Schischmanoff PO, Laurendeau I, et al. Pleiotropic syndrome of dehydrated hereditary stomatocytosis, pseudohyperkalemia, and perinatal edema maps to 16q23-q24. Blood 2000; 96:2599.
  33. 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.
  34. Goossens D, Trinh-Trang-Tan MM, Debbia M, et al. Generation and characterisation of Rhd and Rhag null mice. Br J Haematol 2010; 148:161.
  35. Stewart AK, Shmukler BE, Vandorpe DH, et al. Loss-of-function and gain-of-function phenotypes of stomatocytosis mutant RhAG F65S. Am J Physiol Cell Physiol 2011; 301:C1325.
  36. 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; 37:1258.
  37. Iolascon A, De Falco L, Borgese F, et al. A novel erythroid anion exchange variant (Gly796Arg) of hereditary stomatocytosis associated with dyserythropoiesis. Haematologica 2009; 94:1049.
  38. Stewart AK, Kedar PS, Shmukler BE, et al. Functional characterization and modified rescue of novel AE1 mutation R730C associated with overhydrated cation leak stomatocytosis. Am J Physiol Cell Physiol 2011; 300:C1034.
  39. 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; 110:2158.
  40. Stewart AK, Vandorpe DH, Heneghan JF, et al. The GPA-dependent, spherostomatocytosis mutant AE1 E758K induces GPA-independent, endogenous cation transport in amphibian oocytes. Am J Physiol Cell Physiol 2010; 298:C283.
  41. Kodippili GC, Spector J, Sullivan C, et al. Imaging of the diffusion of single band 3 molecules on normal and mutant erythrocytes. Blood 2009; 113:6237.
  42. Bruce LJ. Hereditary stomatocytosis and cation-leaky red cells--recent developments. Blood Cells Mol Dis 2009; 42:216.
  43. Darghouth D, Koehl B, Heilier JF, et al. Alterations of red blood cell metabolome in overhydrated hereditary stomatocytosis. Haematologica 2011; 96:1861.
  44. Rees DC, 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.
  45. Neff AT. Sitosterolemia's stomatocytosis and macrothrombocytopenia. Blood 2012; 120:4283.
  46. Grootenboer-Mignot S, Crétien A, Laurendeau I, et al. Sub-lethal hydrops as a manifestation of dehydrated hereditary stomatocytosis in two consecutive pregnancies. Prenat Diagn 2003; 23:380.
  47. Fricke B, Jarvis HG, Reid CD, et al. Four new cases of stomatin-deficient hereditary stomatocytosis syndrome: association of the stomatin-deficient cryohydrocytosis variant with neurological dysfunction. Br J Haematol 2004; 125:796.
  48. Stewart GW, Amess JA, Eber SW, et al. Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol 1996; 93:303.
  49. Yoshimoto A, Fujimura M, Nakao S. Pulmonary hypertension after splenectomy in hereditary stomatocytosis. Am J Med Sci 2005; 330:195.
  50. MILLER G, TOWNES PL, MACWHINNEY JB. A NEW CONGENITAL HEMOLYTIC ANEMIA WITH DEFORMED ERYTHROCYTES ("STOMATOCYTES") AND REMARKABLE SUSCEPTIBILITY OF ERYTHROCYTES TO COLD HEMOLYSIS IN VITRO. I. CLINICAL AND HEMATOLOGIC STUDIES. Pediatrics 1965; 35:906.
  51. Haines PG, Jarvis HG, King S, et al. Two further British families with the 'cryohydrocytosis' form of hereditary stomatocytosis. Br J Haematol 2001; 113:932.
  52. Bruce L. Mutations in band 3 and cation leaky red cells. Blood Cells Mol Dis 2006; 36:331.
  53. Guizouarn H, Borgese F, Gabillat N, et al. South-east Asian ovalocytosis and the cryohydrocytosis form of hereditary stomatocytosis show virtually indistinguishable cation permeability defects. Br J Haematol 2011; 152:655.
  54. Coles SE, Chetty MC, Ho MM, et al. Two British families with variants of the 'cryohydrocytosis' form of hereditary stomatocytosis. Br J Haematol 1999; 105:1055.
  55. Gore DM, Chetty MC, Fisher J, et al. Familial pseudohyperkalaemia Cardiff: a mild version of cryohydrocytosis. Br J Haematol 2002; 117:212.
  56. Flatt JF, Guizouarn H, Burton NM, et al. Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome. Blood 2011; 118:5267.
  57. Weber YG, Storch A, Wuttke TV, et al. GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest 2008; 118:2157.
  58. Bawazir WM, Gevers EF, Flatt JF, et al. An infant with pseudohyperkalemia, hemolysis, and seizures: cation-leaky GLUT1-deficiency syndrome due to a SLC2A1 mutation. J Clin Endocrinol Metab 2012; 97:E987.
  59. Bogdanova A, Goede JS, Weiss E, et al. Cryohydrocytosis: increased activity of cation carriers in red cells from a patient with a band 3 mutation. Haematologica 2010; 95:189.
  60. Jarvis HG, Gore DM, Briggs C, et al. Cold storage of 'cryohydrocytosis' red cells: the osmotic susceptibility of the cold-stored erythrocyte. Br J Haematol 2003; 122:859.
  61. Stewart GW, Corrall RJ, Fyffe JA, et al. Familial pseudohyperkalaemia. A new syndrome. Lancet 1979; 2:175.
  62. Alani FS, Dyer T, Hindle E, et al. Pseudohyperkalaemia associated with hereditary spherocytosis in four members of a family. Postgrad Med J 1994; 70:749.
  63. Stewart GW, Ellory JC. A family with mild hereditary xerocytosis showing high membrane cation permeability at low temperatures. Clin Sci (Lond) 1985; 69:309.
  64. James DR, Stansbie D. Familial pseudohyperkalaemia: inhibition of erythrocyte K+ efflux at 4 degrees C by quinine. Clin Sci (Lond) 1987; 73:557.
  65. Haines PG, Crawley C, Chetty MC, et al. Familial pseudohyperkalaemia Chiswick: a novel congenital thermotropic variant of K and Na transport across the human red cell membrane. Br J Haematol 2001; 112:469.
  66. Coles SE, Ho MM, Chetty MC, et al. A variant of hereditary stomatocytosis with marked pseudohyperkalaemia. Br J Haematol 1999; 104:275.
  67. 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; 125:521.
  68. Carella M, d'Adamo AP, Grootenboer-Mignot S, et al. A second locus mapping to 2q35-36 for familial pseudohyperkalaemia. Eur J Hum Genet 2004; 12:1073.
  69. Andolfo I, Alper SL, Delaunay J, et al. Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia. Am J Hematol 2013; 88:66.
  70. Helias V, Saison C, Ballif BA, et al. ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis. Nat Genet 2012; 44:170.
  71. Beaurain G, Mathieu F, Grootenboer S, et al. Dehydrated hereditary stomatocytosis mimicking familial hyperkalaemic hypertension: clinical and genetic investigation. Eur J Haematol 2007; 78:253.
  72. Marcello AP, Vercellati C, Fermo E, et al. Coexistence of congenital red cell pyruvate kinase deficiency and hereditary stomatocytosis (abstract). Blood 2007; 110:1738a.
  73. Bailly P, Cartron JP, Wang D, Johnson RM. Hereditary stomatocytosis and Rh-deficient patients exhibit distinct molecular defects. Blood 1992; 80:1624.
  74. Ballas SK, Clark MR, Mohandas N, et al. Red cell membrane and cation deficiency in Rh null syndrome. Blood 1984; 63:1046.
  75. Remaley AT, Schumacher UK, Stonik JA, et al. Decreased reverse cholesterol transport from Tangier disease fibroblasts. Acceptor specificity and effect of brefeldin on lipid efflux. Arterioscler Thromb Vasc Biol 1997; 17:1813.
  76. Reinhart WH, Gössi U, Bütikofer P, et al. Haemolytic anaemia in analpha-lipoproteinaemia (Tangier disease): morphological, biochemical, and biophysical properties of the red blood cell. Br J Haematol 1989; 72:272.
  77. Davidson RJ, How J, Lessels S. Acquired stomatocytosis: its prevalence of significance in routine haematology. Scand J Haematol 1977; 19:47.
  78. Ohsaka A, Kano Y, Sakamoto S, et al. A transient hemolytic reaction and stomatocytosis following vinca alkaloid administration. Nihon Ketsueki Gakkai Zasshi 1989; 52:7.
  79. Schrier SL, Zachowski A, Devaux PF. Mechanisms of amphipath-induced stomatocytosis in human erythrocytes. Blood 1992; 79:782.
  80. Douglass CC, Twomey JJ. Transient stomatocytosis with hemolysis: a previously unrecognized complication of alcoholism. Ann Intern Med 1970; 72:159.