We aim to inform patients, doctors and researchers about these conditions, in which the membrane surrounding the red blood cell 'leaks' salt and water.
The stomatin protein
The pages come to you from Gordon Stewart at the Department of Medicine, University College London.
Updated, 30 November, 2003.
'Hereditary stomatocytosis' is a term that has come to describe a series of inherited human conditions which affect the red blood cell, in which the membrane or outer coating of the cell 'leaks' the salt atoms sodium and potassium. The original description was by Lock and others (Lock et al 1961). For reviews see Stewart, 1993; Stewart & Turner 1999; Delaunay et al 1999a; Delaunay et al 1999b, Stewart, 2003.
The main task of the red blood cell is to carry oxygen around the body. Because of the internal contents, the cell has a constant tendency to swell and burst, through a process called 'osmosis'. The cell counters this tendency by manipulating the flow of the salt atoms, sodium and potassium. The cell has a 'pump', which forces sodium out of the cell and potassium in, and in normal cells the action of this pump is balanced by a process called 'the passive leak'. Inside the cell, the sodium concentration is held down and the potassium concentration is held up: the cell is robust and lasting. In the hereditary stomatocytoses, the leak is increased, sometimes sixty-fold, the pump cannot cope, the cell becomes swamped with salt and water, and it breaks open in the circulation before its allotted time, a state of affairs known as 'haemolytic anaemia'. For reasons that are not understood, the cells take on an abnormal shape, reminiscent of a mouth or 'stoma', and the conditions go under the name 'hereditary stomatocytosis'. BACK
Haematologists have identified a number of variants on the original theme, reflecting different underlying genetic problems. We can classify the conditions in a rough manner and these are listed below. These are compared in a technical way in Table 1.
This was the original condition (lock et al 1961), and is the most florid and severe. The 'leak' to Na and K is very brisk, the cells look very stomatocytic under the microscope, and the concentrations of sodium and potassium inside the cell are most dramatically abnormal. In addition, the membrane of these cells is deficient in a protein, 'stomatin', but the gene coding for this protein is not abnormal in this condition. Only five families with this condition have been described worldwide, but we know of at least three others not yet reported.
This is a less severe condition but much commoner (about 1 in 10000 kindreds in France and the UK). The sodium /potassium leak is not so severe and the stomatin protein is not missing. This condition is indistinguishable from a condition formerly known as 'hereditary hyperphosphatidylcholine haemolytic anaemia'. Variations are seen between families (see below). In a few families (about 3 or 4 so far), this condition is associated in newborn babies only with an accumulation of fluid in some of the spaces of the body, known as 'perinatal ascites'. This can cause trouble in these infants, but experience shows that with time it spontaneously resolves.
It was Entazami and others (1997) who first noted a link between dehydrated HSt and a syndrome of 'perinatal ascites' (ie accumulation of fluid in the abdominal cavity around the time of birth). This has been seen by others (Grootenboer et al, 2000; Grootenboer-Mignot 2003; Basu, 2003). Although the fluid can cause trouble and much concern, it resolves spontaneously after delivery and carries a good prognosis.
This is as rare as OHSt: about 7 families on the entire planet, four in Britain (Coles et al 1999a; Haines et al 2001b). The cells are leaky at body temperature, but much more strikingly so at refrigerator temperatures, where the cells tend to swell and burst under the strain. With 'pseudohyperkalaemia', this is the other major temperature-based effect seen in these conditions.
A pedigree from Blackburn, Lancashire, shows another variation (Coles et al 1999). This pedigree shows a frank haemolytic state with reticulocytosis and jaundice, and the red cells lose potassium on storage at room temperature, as in cryohydrocytosis, but the way in which the leak depends on temperature is different: the cells are not so leaky at refrigerator temperatures as they are in cryohydrocytosis. We have another case like this, from Norway (Bergheim, 2003).
This is fairly rare but there are quite a few families about in Europe (Meenaghan et al, 1985; Stewart et al, 1979; Stewart & Ellory 1985; Vantyghen et al, 1991). Strangely, it does not appear to exist in the USA. In the original description and in other families, this condition is very mild haematologically. These patients present with 'pseudohyperkalaemia': that is, falsely high measurements of the plasma potassium, due to leakage of potassium from red cells into the plasma when the blood is taken out of the circulation and (crucially) cooled to room temperature. The red cells are perfectly happy in the circulation&emdash;they do not break down prematurely, there is no 'haemolytic anaemia'&emdash;but the condition causes trouble to the patients, because high potassium levels in the plasma have serious implications for doctors, who can be obliged to act urgently. However, on fresh blood, the potassium levels are normal: this is just a laboratory effect and potassium handling in the body itself is fine. While this condition that we originally described was not associated with frank abnormalities of the red cell, we have now seen families with full scale haemolytic anaemia that also show 'pseudohyperkalaemia' (see below). We have seen three different variants on this theme: Edinburgh (Stewart et al, 1979); Chiswick (Haines et al 2001a), the same as that described by Meenaghan et al 1985; and Cardiff (Gore et al 2002), which is a mild version of cryohydrocytosis. We have reviewed pseudohyperkalaemia (Chetty & Stewart 1999).
There are other families that do not fall neatly into any of these classifications. That described by Oski is one such (Oski et al, 1969). Also, Jarvis et al 2001. Contents
For haematologists, here is a much more technical list:
These families are diagnosed in one of four ways: those with frank haemolysis show Haemoglobin levels of 10-15 g/dl with a reticulocytosis of 5-25% and a macrocytosis of 100-108 fl. The blood film shows some kind of stomatocytosis but unfortunately this sign is not terribly useful. Some families with leaky cells do not show marked stomatocytes; and other patients with stomatocytes do not show ion leaks.
Many patients come to us with pseudohyperkalaemia. Those families with familial pseudohyperkalaemia, where the haematology is virtually normal, will show accumulation of potassium in the plasma if heparinised blood is stored on the bench at 20-25°C for about 6 hours. It is useful to do parallel studies at 37° and 0°C as well. Aliquots can be taken at hourly or two-hourly intervals. Patients with cryohydrocytosis and the Blackburn variant can also present in this way. They are usually previously known to have some form of haemolysis.
In a third presentation, we find cases by virtue of thrombosis after splenectomy (see 'Clinical Problems' below).
Fourthly, a very few patients present with perinatal ascites, an abnormal accumulation of fluid in the compartments and tissues of the body which begins while the baby is within the womb, and happily resolves spontaneously in the months after birth. The fluid may require drainage.
Confirmation of the diagnosis depends on the family variant, but most show some kind of abnormality in the levels of sodium and potassium inside the red cell. These levels are not commonly measured but a few specialist labs will do it (including ours: see list of interested labs). For a method, see this link. Contents
Most hereditary stomatocytoses are quite mild anaemias and the patients can lead a normal life. Gallstones can cause trouble but are usually easy to deal with surgically. Any patient with haemolytic anaemia may be subject to 'crises' in which they become severely, but temporarily, anaemic at times of infection. Transfusion may be required for a few days.
Four special problems affect stomatocytosis patients. First, if the spleen is removed (a procedure which helps a great deal in spherocytosis, from which the stomatocytoses can be difficult to distinguish), then in later life problems with excessive blood clotting may arise (Stewart et al, 1996). This can manifest as abdominal pain, chest pain, breathlessness or episodes of clotting in the superficial veins in the skin. Anticoagulant treatment should be given, often on a long term basis.
Secondly, because the membrane is leaky to sodium and potassium, blood samples which are taken for measurement of the concentration of these substances in the plasma can be misleading (see 'familial pseudohyperkalaemia', above). This effect does not happen in all families.
Thirdly, in some families, (Entazami et al, 1996; Grootenboer et al, 2000) it has been observed that new-born babies can show an excess of fluid in some of the compartments of the body. The cause of this is far from clear, but it seems to simply improve as the infants mature. Presumably the abnormal gene is expressed at this early stage of life and as a result the reabsorption of fluid from the tissues and the ascitic cavity is impaired. The membrane may 'leak' as in the red cell. Adults are normal. We have not seen this in Britain.
Fourthly, in some families overloading with iron has been found (Stewart et al, 1996). This can cause damage to the liver and heart. Contents
So far, there is no specific treatment for the anaemia itself. Many patients with haemolytic anaemia take folic acid since the greater turnover of cells consumes this vitamin, a member of the B group. Transfusion may be required during crises; anticoagulation may be required if clotting problems occur; treatment for iron overload may also be required (Stewart et al, 1996). Contents
The cause of these conditions is not yet understood. We have identified a region on chromosome 16 where we believe the problem gene for some of the variants within the 'dehydrated HSt' must lie (Carella et al, 1998, Iolascon et al 1999); but exactly what that gene is, we have yet to discover. Other variants map to other chromosomal locations (Carella et al 1999). The other potential clue to the cause of these anaemias is the protein 'stomatin' (Hiebl-Dirschmied 1991 a,b; Stewart et al, 1992), which is missing from the membrane in some forms of the condition (Eber et al, 1989; Lande et al, 1982). In most instances in biology, the identification of a missing protein in cells affected by a disease would lead the investigator to the gene coding for that protein, and there in the gene the investigator would find the genetic fault responsible for the inherited disease. This is not the case with stomatin: as far as we can see, the gene is normal. Contents
These conditions are all inherited as so-called 'autosomal dominants'. That is, both sexes can be affected, and the conditions are passed directly from one generation to the next. Twenty three of the chromosomes (the 'autosomes') are found in pairs in both sexes. One of each pair is inherited from the mother and one from the father. Before the genes are passed on to the child, a certain amount of mixing goes on which determines how much the child gets from the grandparents (see mapping) For each gene on the autosomes, we have two copies. In a 'dominant' condition, if only one of these is abnormal, then the individual is affected by the condition. In a 'recessive', like cystic fibrosis, both genes have to be abnormal for the condition to be present. The implications for the dominantly inherited stomatocytoses are as follows: if an individual is affected, the chances of passing on the condition to his or her children are 1 in 2. If the individual is not affected but has brothers or a parent that are affected, there is no chance that he or she can pass on the condition: these conditions do not 'miss a generation'. Having said all this, Nature has a way of coming up with surprises and each new family tends to be different. Contents
Basu, A., Carey, P., Stewart, G. & Richmond, S. (2003). Dehydrated hereditary stomatocytosis with transient perinatal ascites. Archives of Diseases of Childhood 88:F438-9. PubMed
Bergheim, J., Ernst, P., Brinch, L., Gore, D.M., Chetty, M.C. & Stewart, G.W. (2003). Allogeneic bone marrow transplantation for severe post-splenectomy thrombophilic state in leaky red cell membrane haemolytic anaemia of the stomatocytosis class. British Journal of Haematology 121: 119-22. PubMed
Carella, M., Stewart, G., Ajetunmobi, J., Perrotta, S., Grootenboer, S., Tchernia, G., Delaumay, J., Totaro, A., Zelante, L., Gasparini, P. & Iolacson, A. (1998) Genomewide search for dehydrated hereditary stomatocytosis (hereditary xerocytosis): Mapping of locus to chromosome 16 (q23-qter). American Journal of Human Genetics, 63, 810-816. PubMed
Carella, M., Stewart, G.W., Ajetunmobi, J.F., Schettini, F., Delaunay, J. & Iolascon, A. (1999). Genetic heterogeneity of hereditary stomatocytosis syndromes showing pseudohyperkalaemia. Haematologica 84: 862-863. PubMed.
Chetty, M. & Stewart, G. (2001). Pseudohyperkalaemia and pseudomacrocytosis caused by inherited red cell disorders of the 'hereditary stomatocytosis' group. British Journal of Biomedical Science 58: 48-55. PubMed
Coles, S., Chetty, M., Ho, M., Nicolaou, A., Kearney, J., Wright, S. & Stewart, G. (1999a). Two British families with variants on the 'cryohydrocytosis' form of hereditary stomatocytosis. British Journal of Haematology 105: 1055-1065. PubMed
Coles, S. & Stewart, G. (1999). Temperature effects on cation transport across the red cell membrane in the hereditary stomatocytosis syndromes. International Journal of Experimental Pathology 80: 251-258. PubMed
Coles, S.E., Ho, M.M., Chetty, M.C., Nicolaou, A. & Stewart, G.W. (1999b). A variant of hereditary stomatocytosis with marked pseudohyperkalaemia. British Journal of Haematology 104: 275-283. PubMed
Delaunay, J., Grootenboer, S., Schischmanoff, P., Cynober, T., Tchernia, G., Dommergues, J., Bost, M., Stewart, G., Perrotta, S., Carella, M., Gasparini, P. & Iolascon, A. (1999a). Dehydrated hereditary stomatocytosis revisited. Cellular and Molecular Biology Letters 3: 435-442.
Delaunay, J., Stewart, G. & Iolascon, A. (1999b). Hereditary dehydrated and overhydrated stomatocytosis: recent advances. Current Opinion in Hematology 6: 110-114. PubMed
Eber, S.W., Lande, W.M., Iarocci, T.A., Mentzer, W.M., Hohn, P., Wiley, J.S. & Schroter, W. (1989) Hereditary stomatocytosis: consistent association with an integral membrane protein deficiency. Br. J. Haematol., 72, 452-455. PubMed
Entezami, M., Becker, R., Mensen, H., Marcinkowki, M. & Versmold, H. (1996) Xerocytosis with concomitant intrauterine ascites: first description and therapeutic approach. Blood, 90, 5392-5393. PubMed
Gore, D., Chetty, M., Fisher, J., Nicolaou, A. & Stewart, G. (2002). Familial pseudohyperkalaemia Cardiff: a mild version of cryohydrocytosis. British Journal of Haematology 117: 212-214. PubMed
Grootenboer, S., Schischmanoff, P.O., Laurendeau, I., Cynober, T., Tchernia, G., Dommergues, J.P., Dhermy, D., Bost, M., Varet, B., Snyder, M., Ballas, S.K., Ducot, B., Babron, M.C., Stewart, G.W., Gasparini, P., Iolascon, A. & Delaunay, J. (2000). Pleiotropic syndrome of dehydrated hereditary stomatocytosis, pseudohyperkalemia, and perinatal edema maps to 16q23-q24. Blood 96(7): 2599-605. PubMed
Haines, P., Crawley, C., Chetty, M., Jarvis, H., Coles, S., Fisher, J., Nicolaou, A. & Stewart, G. (2001a). 'Familial pseudohyperkalaemia Chiswick': a novel congenital thermotropic variant of K and Na transport across the human red cell membrane. British Journal of Haematology 112(2): 469-474. PubMed
Haines, P., Jarvis, H., King, S., Noormohamed, F., Chetty, M., Fisher, J., Hill, P., Nicolaou, A. & Stewart, G. (2001b). Two further British families with the 'cryohydrocytosis' form of hereditary stomatocytosis. British Journal of Haematology 113: 932-937. PubMed
Hiebl-Dirschmied, C.M., Adolf, G.R. & Prohaska, R. (1991a). Isolation and partial characterisation of the human band 7 integral membrane protein. Biochim. Biophys. Acta 1065: 195-202. PubMed
Hiebl-Dirschmied, C.M., Entler, B., Glotzmann, C., Maurer-Fogy, I., Stratowa, C. & Prohaska, R. (1991b). Cloning and nucleotide sequence of cDNA encoding human erythrocyte band 7 integral membrane protein. Biochimica et Biophysica Acta 1090: 123-124.
Iolascon, A., Stewart, G.W., Ajetunmobi, J.F., Perrotta, S., Delaunay, J., Carella, M., Zelante, L. & Gasparini, P. (1999). Familial pseudohyperkalemia maps to the same locus as dehydrated hereditary stomatocytosis (hereditary xerocytosis). Blood 93: 3120-3123. PubMed
Jarvis, H., Chetty, M., Nicolaou, A., Miller, A. & Stewart, G. (2001). A novel stomatocytosis variant showing marked abnormalities in intracellular [Na] and [K] with minimal haemolysis. European Journal of Haematology 66: 412-414. PubMed
Lande, W.M., Thiemann, P.W. & Mentzer, W.M. (1982) Missing band 7 membrane protein in two patients with high Na, low K erythrocytes. J. Clin. Invest., 70, 1273-1280. PubMed
Latham, T., Stewart, G. & Horn, E. (2002). Recurrent thromboembolism in a familial pseudohyperkalaemia patient with an intact spleen. British Journal of Haematology 119: 1141. PubMed
Meenaghan, M., Follett, G.F. & Brophy, P.J. (1985) Temperature sensitivity of potassium flux into red blood cells in the familial pseudohyperkalaemia syndrome. Biochimica et Biophysica Acta, 821, 72-78. PubMed
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Stewart, G.W. & Ellory, J.C. (1985). A family with mild xerocytosis showing increased cation permeability at low temperatures. Clinical Science 69: 309-319. PubMed
Stewart, G.W., Hepworth-Jones, B.E., Keen, J.N., Dash, B.C.J., Argent, A.C. & Casimir, C.M. (1992) Isolation of cDNA coding for a ubiquitous membrane protein deficient in high Na, low K stomatocytic erythrocytes. Blood, 79, 1593-1601. PubMed
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These reviews are not totally reliable on this subject. 'March haemoglobinuria' is not part of these conditions. Nevertheless it is very useful. See this link.