Cryohydrocytosis

A number sign (#) is used with this entry because of evidence that cryohydrocytosis (CHC) is caused by heterozygous mutation in the SLC4A1 gene (109270) on chromosome 17q21.

Heterozygous mutation in SLC4A1 can also cause Southeast Asian ovalocytosis (166900) and spherocytosis-4 (SPH4; 612653).

Cryohydrocytosis is an exceedingly rare condition characterized by a mild stomatocytic hemolytic state with hyperbilirubinemia. A hallmark of this condition is that red blood cells (RBCs) lyse on storage at 4 degrees centigrade. RBC cation permeability is increased at 37 degrees centigrade, and the cells also accumulate sodium in the cold (summary by Coles et al., 1999). Patients present with fatigue, mild anemia, and pseudohyperkalemia due to a potassium leak from the RBCs (summary by Bogdanova et al., 2010).

For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see 194380.

Miller et al. (1965) described a 19-year-old man who presented with jaundice and splenomegaly at age 13 years and was found to have moderately severe hemolytic anemia. Splenectomy resulted in clinical improvement, but did not completely resolve the hemolytic anemia. Further investigation revealed stomatocytosis characterized by increased autohemolysis and increased osmotic fragility at 5 degrees compared to 37 degrees C. The parents and a sib were unaffected. The man subsequently sired a son with the same disorder (Townes and Miller, 1980). Cold-sensitive hemolysis was prevented by reduced pH or increased ATP. Since correction was not correlated with glucose metabolism or intracellular levels of ATP, a membrane defect was suggested.

Alani et al. (1994) reported a British family from Blackburn with a previous diagnosis of spherocytosis (SPH; see 182900) in which the proband, 2 of his sibs, and his son exhibited temperature-sensitive pseudohyperkalemia. The proband, who had already undergone splenectomy, presented at age 40 years with shortness of breath and was found to have multiple pulmonary emboli. Serum samples showed varying levels of hyperkalemia but there were no features of hyperkalemia on electrocardiogram, suggesting pseudohyperkalemia. Further analysis confirmed pseudohyperkalemia, which was related to the time between sampling and cell separation, and inversely related to the temperature at which the specimen was left to stand before cell separation. Temperature-sensitive pseudohyperkalemia was also demonstrated in the proband's 2 sibs with SPH and in 1 affected son, but not in the proband's wife or in another son who did not have SPH. The authors noted that because hereditary spherocytosis is not rare and pseudohyperkalemia had not previously been reported in association with it, the presence of both in this family might have occurred by chance.

Coles et al. (1999) restudied the family from Blackburn that had been reported by Alani et al. (1994). The pedigree then included all 3 sibs of the original proband, their father and paternal grandfather, as well as 2 children of 1 of the proband's affected sisters. Blood films of affected family members revealed stomatocytosis; the authors stated that all families known to them with stomatocytosis had at some stage been diagnosed with 'atypical hereditary spherocytosis.' Hematologic analysis showed marked abnormalities of intracellular sodium and potassium levels in fresh cells, intermediate in severity between those seen in overhydrated and dehydrated stomatocytosis. Results were consistent with a primary abnormality in the leak fluxes and a compensatory abnormality in the NaK pump, as seen in other stomatocytic disease. Coles et al. (1999) noted that red cells in this family did show excessive lysis in the cold and as such could be considered to be a form of 'cryohydrocytosis.' The original proband, who was the only member of the pedigree to be splenectomized, died at age 51 of pulmonary hypertension, which the authors stated was likely due to postsplenectomy thrombotic complications that are typical of the hereditary stomatocytoses. In a footnote, the authors noted that the proband's father had also been advised to undergo splenectomy, which was delayed when hyperkalemia was discovered preoperatively; the father, a 'doughty Lancastrian,' refused to return for the surgery and 'lived to enjoy a happy retirement.'

Coles et al. (1999) described 2 British families with a similar, dominantly inherited, temperature-related variant of hereditary stomatocytosis, consistent with the original description of cold-sensitive stomatocytosis (cryohydrocytosis). The cells showed a 5- to 6-fold increase in passive permeability at 37 degrees centigrade with abnormal intracellular sodium and potassium levels at 15-20 and 60-65 mmol per liter cells, respectively. Marked temperature effects were evident: lysis of red cells on storage in the cold was blatant and when whole heparinized blood was stored at room temperature, potassium accumulated in the plasma, producing 'pseudohyperkalemia.' Studies of the temperature dependence of passive permeability showed that the minimum in the passive permeability, which was seen in normal cells at 8-10 degrees centigrade, was shifted up to 23 degrees centigrade in these abnormal cells, such that the permeability at 0 degrees centigrade exceeded that at 37 degrees centigrade. The abnormal temperature dependence in patient red cells strongly resembled that seen in normal cells when suspended in media in which either sodium or chloride ions had been replaced by an organic cation or anion. It was suggested that these cells have a genetic mutation that somehow rendered the cells resistant to the stabilizing effect of NaCl at low temperatures. In their patients, Coles et al. (1999) found that the 31-kD integral membrane protein stomatin (STOM; 133090) was present in the red cell membranes in all cases.

Haines et al. (2001) reported 2 more British families with the cryohydrocytosis form of hereditary stomatocytosis. Both exhibited a mild stomatocytic anemia, with very marked autohemolysis at refrigerator temperatures and pseudohyperkalemia due to loss of potassium from red cells on storage at room temperature. Results of cation flux analysis were characteristic of leaky red cells and showed a U-shaped temperature dependence. Affected members of both families had initially been diagnosed as 'spherocytic;' Haines et al. (2001) noted that the morphology of fresh specimens showed approximately 20% stomatocytes with many spherocytes as well, but cold storage of the red cells resulted in a marked increase in osmotic fragility and a predominance of macrospherocytes.

Gore et al. (2004) reported 4 British pedigrees with disorders of the 'cation-leaky hereditary stomatocytosis class' and pseudohyperkalemia. Three of the pedigrees were frankly hemolytic, whereas the fourth showed normal hematology (see FP East London, in 609153). The authors stated that the naming of these diseases, which had traditionally been collected under the designation 'hereditary stomatocytoses and allied disorders,' was problematic. They noted that frank stomatocytosis was present in only 1 pedigree, from Darlington, which also exhibited a 'shallow slope' profile of temperature-dependent potassium flux resembling that seen in the previously reported Edinburgh and Blackburn pedigrees. The Darlington proband, a farmer who had undergone splenectomy at age 22 years for a presumed diagnosis of 'atypical spherocytosis,' developed severe thrombosis of the superficial femoral vein at age 40. Gore et al. (2004) noted that patients with the shallow-slope profile were particularly susceptible to thrombosis, even without splenectomy. In a family from Birmingham as well as a proband from Middlesborough, who was previously reported by Vaidya et al. (2002), a dehydrated picture with target cells on blood films was seen; Gore et al. (2004) stated that these 2 pedigrees could be classified as examples of 'hereditary xerocytosis' or 'dessicocytosis,' and noted that affected individuals from both families exhibited a novel pattern of temperature-dependent potassium flux.

Bogdanova et al. (2010) studied a 44-year-old Swiss man from Zurich with cryohydrocytosis, in whom Bruce et al. (2005) had identified a mutation in the SLC4A1 gene (patient 'CHC6;' see 109270.0034). The patient presented at age 29 with fatigue and dizziness. Examination revealed splenomegaly, and hematologic analysis showed reticulocytosis of 128%, with 14% hyperchromic erythrocytes; peripheral blood smear showed microcytic anisocytosis with spherocytes as well as rare macrocytes and stomatocytes. Hereditary spherocytosis was suspected and he underwent cholecystectomy and splenectomy, but a mild hemolytic state persisted postoperatively, with 40 to 60% reticulocytes and 30 to 70% hyperchromic erythrocytes. Further investigation revealed a red cell potassium leak that was 8-fold higher than control and a 2- to 3-fold increase in activity of the sodium/potassium pump, resulting in a diagnosis of cryohydrocytosis.

Temperature-Dependent Potassium Flux Patterns

Carella et al. (2004) noted that 3 clinical forms of pseudohyperkalemia unassociated with hematologic manifestations, based predominantly on the leak-temperature dependence curve, had been reported: (1) pseudohyperkalemia Edinburgh (see 194380), in which the curve has a shallow slope; (2) pseudohyperkalemia Chiswick or Falkirk (see 609153), in which the curve is shouldered; and (3) pseudohyperkalemia Cardiff (see 609153), in which the temperature dependence of the leak shows a 'U-shaped' profile with a minimum at 23 degrees C. Gore et al. (2004) stated that potassium-flux temperature profiles are consistent both from year to year in an individual as well as within affected members of a pedigree.

Bruce et al. (2005) studied 11 pedigrees with dominantly inherited hemolytic anemias, 3 spherocytic (see SPH4, 612653) and 8 stomatocytic, including families previously reported by Coles et al. (1999, 1999), Haines et al. (2001), and Gore et al. (2004). Affected individuals from each of the families exhibited an increase in red cell membrane permeability to sodium and potassium that was particularly marked at 0 degrees centigrade, but had normal stomatin levels in the membrane. Sequencing of the SLC4A1 gene revealed 5 different heterozygous missense mutations that segregated fully with disease in all of the families (see, e.g., 109270.0028 and 109270.0033-109270.0035). Bruce et al. (2005) noted that unlike stomatin-deficient patients with cryohydrocytosis who show neurologic defects (see 608885), no neurologic problems were present in patients with cryohydrocytosis due to mutation in the SLC4A1 gene.

Bogdanova et al. (2010) studied red blood cells (RBCs) from a Swiss man with cryohydrocytosis and a mutation in the SLC4A1 gene (109270.0034), previously reported by Bruce et al. (2005) (patient 'CHC6'). At cold temperatures, the RBCs swelled in KCl-containing media but not in NaCl-containing or KNO(3)-containing media, indicating that volume changes were mediated by an anion-coupled cation transporter. In NaCl-containing media, net HOE642-sensitive Na(+)/K(+) exchange prevailed, whereas in KCl-containing media, swelling was mediated by a Cl-dependent K(+) uptake. Unidirectional K(+) influx measurements showed that the patient's cells had abnormally high activities of the K(+)Na(+)/H(+) exchanger (KNHE) and the K(+),Cl(-) cotransporter (KCC), which could account for the observed net movements of cations. Neither chloride nor cation conductance in patient RBCs differed from that of healthy donors. Bogdanova et al. (2010) stated that their findings demonstrated that the KCC and KNHE contribute to the alterations in cell volume, deformability, and density of patient RBCs, and concluded that red cell dehydration resulting in high-density RBCs is the primary phenomenon of CHC, both in vivo and when cells are stored at room temperature. The authors suggested that crosstalk between the SLC4A1 mutant and other transporters might increase cation permeability in cryohydrocytosis.