Dehydrated Hereditary Stomatocytosis 1 With Or Without Pseudohyperkalemia And/or Perinatal Edema

A number sign (#) is used with this entry because of evidence that dehydrated hereditary stomatocytosis (DHS) is caused by heterozygous or homozygous mutation in the PIEZO1 gene (611184) on chromosome 16q24.

Description

Dehydrated hereditary stomatocytosis (DHS), also known as hereditary xerocytosis, is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. DHS erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. DHS patients typically exhibit mild to moderate compensated hemolytic anemia, with an increased erythrocyte mean corpuscular hemoglobin concentration and a decreased osmotic fragility, both of which reflect cellular dehydration (summary by Zarychanski et al., 2012). Patients may also show perinatal edema and pseudohyperkalemia due to loss of K+ from red cells stored at room temperature. A minor proportion of red cells appear as stomatocytes on blood films. Complications such as splenomegaly and cholelithiasis, resulting from increased red cell trapping in the spleen and elevated bilirubin levels, respectively, may occur. The course of DHS is frequently associated with iron overload, which may lead to hepatosiderosis (summary by Albuisson et al., 2013).

Dehydrated red blood cells, including those from hereditary xerocytosis patients, show delayed infection rates to Plasmodium in vitro, suggesting a potential protective mechanism against malaria (Tiffert et al., 2005). A polymorphism in PIEZO1 that is enriched in populations of African descent and results in xerocytosis conferred resistance to Plasmodium infection in vitro (see 611184.0016).

The 'leaky red blood cells' in familial pseudohyperkalemia show a temperature-dependent loss of potassium when stored at room temperature, manifesting as apparent hyperkalemia. The red blood cells show a reduced life span in vivo, but there is no frank hemolysis. Studies of cation content and transport show a marginal increase in permeability at 37 degrees C and a degree of cellular dehydration, qualitatively similar to the changes seen in dehydrated hereditary stomatocytosis. Physiologic studies show that the passive leak of potassium has an abnormal temperature dependence, such that the leak is less sensitive to temperature than that in normal cells (summary by Iolascon et al., 1999).

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, 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 consistent within affected members of a pedigree.

Genetic Heterogeneity of Hereditary Stomatocytosis

Dehydrated hereditary stomatocytosis-2 (DHS2; 616689) is caused by mutation in the KCNN4 gene (602754) on chromosome 19q13. Another form of stomatocytosis, involving familial pseudohyperkalemia with minimal hematologic abnormalities (PSHK2; 609153), is caused by mutation in the ABCB6 gene (605452) on chromosome 2q35. Cryohydrocytosis (CHC; 185020) is caused by mutation in the SLC4A1 gene (109270) on chromosome 17q21, and stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN; 608885) is caused by mutation in the SLC2A1 gene (138140) on chromosome 1p34. An overhydrated form of hereditary stomatocytosis (OHST; 185000) is caused by mutation in the RHAG gene (180297) on chromosome 6p12.

See 137280 for a discussion of the association of familial stomatocytosis and hypertrophic gastritis in the dog, an autosomal recessive syndrome.

Reviews

Delaunay (2004) reviewed genetic disorders of red cell membrane permeability to monovalent cations, noting 'inevitable' overlap between entities based on clinical phenotype.

Bruce (2009) provided a review of hereditary stomatocytosis and cation-leaky red cells, stating that consistent features include hemolytic anemia, a monovalent cation leak, and changes in red cell morphology that appear to follow a continuum, from normal discocyte to stomatocyte to echinocyte in DHS, and from discocyte to stomatocyte to spherocyte to fragmentation in OHST. Bruce (2009) suggested that the underlying pathologic mechanism might involve misfolded mutant proteins that escape the quality control system of the cell and reach the red cell membrane, where they disrupt the red cell membrane structure and cause a cation leak that alters the hydration of the red cell, thereby changing the morphology and viability of the cell.

King and Zanella (2013) provided an overview of 2 groups of nonimmune hereditary red cell membrane disorders caused by defects in membrane proteins located in distinct layers of the red cell membrane: red cell cytoskeleton disorders, including hereditary spherocytosis (see 182900), hereditary elliptocytosis (see 611804), and hereditary pyropoikilocytosis (266140); and cation permeability disorders of the red cell membrane, or hereditary stomatocytoses, including DHS, OHST, CHC, and PSHK. The authors noted that because there is no specific screening test for the hereditary stomatocytoses, a preliminary diagnosis is based on the presence of a compensated hemolytic anemia, macrocytosis, and a temperature- or time-dependent pseudohyperkalemia in some patients. King et al. (2015) reported the International Council for Standardization in Haematology (ICSH) guidelines for laboratory diagnosis of nonimmune hereditary red cell membrane disorders.

Clinical Features

Miller et al. (1971) described a large kindred of Swiss-German origin with stomatocytosis, in which 3 affected sibs appeared to be homozygous whereas 50 other affected family members were heterozygous. The homozygotes had hemolytic anemia, decreased osmotic fragility, increased intracellular sodium, and marked increase in sodium pump rates. The heterozygotes had no anemia but had cholelithiasis and intermittent jaundice. Decreased fragility distinguished it from other forms of stomatocytosis with hemolytic anemia. Glader et al. (1974) described the disorder as desiccytosis.

In 16 members of 3 generations of a kindred from Edinburgh, Stewart et al. (1979) observed elevated plasma potassium if the red cells were not separated promptly. In vivo plasma potassium concentrations were normal. Affected persons were not anemic. The authors postulated that digoxin, which inhibits the red cell sodium-potassium pump, could exacerbate red cell potassium depletion and lead to frank hemolysis. In the presence of impaired renal or adrenal function, dangerous hyperkalemia might result. Luciani et al. (1980) reported an affected mother and daughter. The family reported by Stewart and Ellory (1985) showed mild hereditary xerocytosis. James and Stansbie (1987) studied the characteristics of potassium loss from red cells.

The red blood cells (RBCs) in DHS have a membrane abnormality with increased permeability to cations with a greater efflux of potassium than of sodium. Consequently these red cells lose potassium in excess of sodium gained with a decrease in total cation content. Osmotically resistant xerocytes result. The disorder was first described as desiccytosis by Glader et al. (1974). Two patients in a family studied by Monzon et al. (1981) showed levels of red cell calmodulin 3 to 4 times normal. Exercise-induced hemolysis occurs with marching, jogging, conga-drumming, karate, and other activities entailing repetitive impact of the hands or feet on an unyielding surface.

Platt et al. (1981) found that episodes of fatigue, jaundice, pallor, and darkened urine associated with periods of training in a 21-year-old world-class competitive freestyle swimmer were the consequence of xerocytosis. Although most persons, given a hard enough surface and long enough run, will develop some hemoglobinuria, the most susceptible persons may have an underlying membrane protein abnormality (Banga et al., 1979). In their swimmer subject, Platt et al. (1981) demonstrated that xerocytes are more susceptible than normal red cells to hemolysis by shear stress. The sensitivity could be partially corrected in vitro by an experimental maneuver that rehydrates xerocytes. Conversely, normal erythrocytes could be rendered shear-sensitive by dehydration. At the other end of the spectrum from xerocytosis is hereditary stomatocytosis (or hydrocytosis; 185000) in which the red cells are overhydrated and sodium-loaded.

Vives Corrons et al. (1991) described xerocytosis and chronic hemolytic anemia related to increased RBC membrane permeability to Na+ and K+. The red cell trait was thought to have been inherited from the father; possible deficiency of factor VII (613878) was inherited from the mother.

Vives Corrons et al. (1995) reported 6 unrelated Spanish families with 11 affected members. They demonstrated unusual heat stability as a feature of this disorder and suggested that, together with increased mean corpuscular hemoglobin concentration and decreased RBC osmotic fragility, the feature is useful for diagnosis of xerocytosis. They commented that affected persons often show normal or near-normal hemoglobin levels, despite clinical and laboratory evidence of mild to moderate hemolysis.

Entezami et al. (1996) described dehydrated hereditary stomatocytosis in association with perinatal edema. Grootenboer et al. (1998) described a pleiotropic, autosomal dominant syndrome consisting of DHS, hereditary pseudohyperkalemia, and severe perinatal edema, including ascites. Edema spontaneously regressed by 8 months of age. In the family reported by Grootenboer et al. (1998), the parents of the proband were said to be unrelated but they were gypsies, raising the possibility of pseudodominant inheritance of an autosomal recessive disorder. The proband was found to have ascites 3 weeks before birth on the basis of a sonogram, and hyperbilirubinemia was found on amniocentesis. Spontaneous delivery occurred after 31 weeks of pregnancy. At birth there was generalized edema, with prevailing ascites, hemolytic anemia, and enlargement of the liver and spleen. Respiratory failure required mechanical ventilation. During the first 10 days of life, an exchange transfusion and 2 transfusions of packed red cells were necessary. There was hyperkalemia in the absence of any abnormality of other plasma cation concentrations and of the ECG. The ascites acquired a chylous character during breastfeeding. The mother of the proband had been taken to hospital at 1 month of age because of ascites and generalized edema since birth. Ascites receded at 3 months of age. The mother had had a previous biamniotic twin pregnancy that ended spontaneously at 27 weeks. One twin had died in utero from generalized edema, including ascites and pleural and pericardial effusions. The other baby died 24 hours after birth from an ill-documented reason but reportedly did not display generalized edema. At the age of 20 years, at the time the proband was hospitalized, the mother was found to have compensated DHS, as well as pseudohyperkalemia. The father was hematologically normal. Grootenboer et al. (1998) suggested that the various manifestations seen in the mother and at least 2 of her children were the result of mutation at a single locus.

Carella et al. (1998) referred to this disorder as dehydrated hereditary stomatocytosis (DHS). It is the most frequent form of the hereditary stomatocytoses in the set of hemolytic anemias, with an abnormal shape of the red blood cells resulting from abnormally high membrane permeability for the monovalent cations Na and K. The clinical presentation is heterogeneous, ranging from mild to moderate hemolytic anemia associated with scleral icterus, splenomegaly, and cholelithiasis. Iron overload may develop later in life. The disorder is transmitted as an autosomal dominant.

Stewart et al. (1996) documented postsplenectomy thrombotic complications in affected individuals from 3 families with DHS, including the Swiss-German kindred originally reported by Miller et al. (1971) and a family previously reported by Lane et al. (1990), as well as in patients from 4 families with OHST. Stewart et al. (1996) stated that because splenectomy is only of limited therapeutic benefit in stomatocytosis, it should not be performed without careful consideration. The authors also noted that a tendency to iron overload is evident in many of these patients, even without hypertransfusion and irrespective of splenectomy.

Perel et al. (1999) reported a 15-year-old boy with a dehydrated hereditary stomatocytosis who underwent splenectomy and developed the rare postoperative complication of partial portal vein thrombosis. With prompt heparin therapy, neither propagation of the thrombus nor further cavernous transformation occurred in the following 6 years. This complication had previously been reported only in adults with hereditary stomatocytosis.

Iolascon et al. (1999) studied the family in which familial pseudohyperkalemia was first described by Stewart et al. (1979) and found that the disorder mapped to the same region of chromosome 16 to which hereditary xerocytosis had been mapped (see MAPPING). This and the fact that the red cells in pseudohyperkalemia show a marginal increase in permeability at 37 degrees C and a degree of cellular dehydration qualitatively similar to the changes seen in dehydrated hereditary stomatocytosis suggested that these disorders are allelic.

Latham et al. (2002) reported a 58-year-old woman, diagnosed with familial pseudohyperkalemia in 1977, who suffered severe recurrent thromboembolic disease despite an intact spleen. Her family had previously been reported by Stewart et al. (1979) and Iolascon et al. (1999). Her red cells showed the classic phenotype of potassium leakage from cells on standing in vitro, but did not have stomatocytic morphology.

Rees et al. (2004) noted that 3 families had been reported in which dehydrated hereditary stomatocytosis was associated with a syndrome of self-limiting perinatal ascites (Entezami et al., 1996; Grootenboer et al., 2000; Basu et al., 2003). The authors described a 16-year-old girl who presented neonatally with abnormal liver function tests and ascites. A liver biopsy showed hepatitis and fatty changes. The ascites resolved within 6 months. At the age of 15 years, she developed an episode of acute hemolysis and was reinvestigated; a diagnosis of dehydrated hereditary stomatocytosis was made. Pseudohyperkalemia, due to ex vivo loss of potassium from red cells, was present. The observations confirmed the previously noted association of dehydrated hereditary stomatocytosis, pseudohyperkalemia, and perinatal ascites, and suggested that the ascites is of predominantly hepatic origin.

Syfuss et al. (2006) studied a 65-year-old man who had been diagnosed at 55 years of age with hepatosiderosis that was not fully explained by the heterozygous H63D mutation he carried in the HFE gene (613609.0002); he did not carry the classic HFE mutation C282Y (613609.0001) and no mutation was detected in the ferroportin gene (SLC40A1; 604653). Iron metabolism-related serum parameters were mostly normal, except for an increased transferrin saturation of 60%, and liver iron concentration was 62 micromol/g. After observation of an increased percentage of hyperdense cells and rare stomatocytes or prestomatocytes on blood smear, ektacytometry was performed, which revealed a leftward shift of the osmotic gradient curve, indicating an increase in osmotic resistance and a decrease in cell hydration in a pattern fitting that of DHS. Review of routine plasma potassium measurements over a 7-year period showed values fluctuating between high normal and elevated, consistent with pseudohyperkalemia. Syfuss et al. (2006) noted that although DHS is known to cause significant iron overload, the unusually mild hematologic manifestations of DHS in the patient were overlooked. The authors stated that this patient also had limb-girdle muscular dystrophy (see MFM3, 609200) that was due to mutation in the myotilin gene (MYOT; 604103) and believed to be coincidental.

Beaurain et al. (2007) reported a large 3-generation French kindred exhibiting DHS with pseudohyperkalemia in which 2 branches of the same family were independently ascertained, with 1 branch having been studied by Grootenboer et al. (2000) (family 'VA'). Plasma potassium concentration exceeded 5.0 mmol/L in 8 affected individuals, and was just below this threshold in another 3 patients. Stomatocytes were unusually scarce on blood smears from affected members, and in 1 patient with mild disease, stomatocytes were incompletely formed.

Martinaud et al. (2008) described a woman and her son who both had DHS. The 60-year-old mother had undergone splenectomy at 27 years of age, after diagnosis of chronic hemolytic anemia, and over the following years she suffered at least 5 deep venous thromboses and developed chronic portal vein thrombosis that resulted in esophageal varices requiring annual sclerotherapy and ultimately resection. Blood smears showed 5% stomatocytes, and she displayed a left shift of the osmotic gradient curve on ektacytometry, highly characteristic for DHS. Her 28-year-old son, who was asymptomatic except for jaundice, exhibited blood smears and ektacytometry similar to those of his mother. There was no evidence of pseudohyperkalemia in either patient. Martinaud et al. (2008) noted that antiphospholipid antibodies to IgG were present in both patients, although their association with the disease, if any, was unclear.

Houston et al. (2011) studied 29 affected and 77 unaffected members of a large Canadian kindred segregating an autosomal dominant hemolytic disorder associated with an elevated mean corpuscular hemoglobin concentration (MCHC) and decreased osmotic fragility, a phenotype most consistent with hereditary xerocytosis. A history of transient anemia, jaundice, red or brown urine, red cell transfusion, and either gallstones or cholecystectomy were all significantly more prevalent in affected than in unaffected individuals (p less than 0.01). Despite a mean percent reticulocyte count of 9.7%, affected individuals were not anemic and their hemoglobin concentrations were not statistically different from unaffected individuals. Consistent with hemolysis, affected family members had significantly elevated indirect bilirubin levels and decreased haptoglobin levels; in addition, serum ferritin was elevated in all age groups compared to unaffected individuals, and was greater than 900 micrograms per liter in 7 patients. Osmotic fragility testing in 10 affected individuals showed that affected red blood cells were resistant to lysis in progressively hypotonic saline solutions. Red cell morphology assessments revealed that target cells, schistocytes, and eccentrocytes were increased in affected individuals, with eccentrocytes being the most prominent abnormal red cell phenotype.

Andolfo et al. (2013) described a 38-year-old female triathlete who was first diagnosed with hemolytic anemia at 14 years of age, after a 1-month duration of weakness. A similar episode of weakness recurred in her 20s, and again at age 32; both episodes resolved spontaneously. The patient reported chronic yellowing of her eyes without changes in color of urine or stool and without fever or gastrointestinal symptoms. The patient's brother was also diagnosed with hemolytic anemia, accompanied by 50% deficiency of pyruvate kinase (see 266200), and her father was reported to have mild anemia of unclear etiology. On physical examination, the patient had mild scleral icterus and hepatomegaly; peripheral blood smear showed spherocytes, macrocytes, rare stomatocytes, and tear drop-shaped red cells. Osmotic fragility testing demonstrated osmotic resistance, and ektacytometry revealed decreased RBC deformability in hypertonic solutions, supporting the clinical diagnosis of dehydrated stomatocytosis.

Diagnosis

Albuisson et al. (2013) noted that DHS is a difficult diagnosis to make because of highly variable clinical expression, ranging from the absence of clinical features to lethal perinatal edema. Although features of DHS can include severe iron overload leading to hepatic transplantation or life-threatening thromboembolic disease after splenectomy, the most frequent DHS condition is moderately symptomatic hemolysis. In addition, the only laboratory test for DHS is ektacytometry, which is available in a limited number of laboratories. The disease may be overlooked for years or decades, and it is sometimes confused with spherocytosis (see 182900).

Inheritance

One instance of male-to-male transmission occurred in the family with DHS reported by Stewart et al. (1979), consistent with autosomal dominant inheritance.

The transmission pattern of DHS in a large Irish family reported by Carella et al. (1998) was consistent with autosomal dominant inheritance.

Mapping

Carella et al. (1998) studied a large 3-generation Irish family in which 14 members had dehydrated hereditary stomatocytosis. Two additional small families were also included in the study. Linkage of DHS was found to microsatellite markers on the long arm of chromosome 16 (16q23-q24). A maximum 2-point lod score of 6.62 at recombination fraction 0.00 was obtained at marker D16S520.

Iolascon et al. (1999) studied the original Edinburgh family in which familial pseudohyperkalemia was first described by Stewart et al. (1979) and found that the disorder mapped to the same locus (16q23-qter) that Carella et al. (1998) had identified for dehydrated hereditary stomatocytosis.

Grootenboer et al. (2000) studied 10 kindreds, including 8 French and 2 American. Four families had dehydrated hereditary stomatocytosis alone; 3 had DHS and pseudohyperkalemia; 2 had DHS and perinatal edema; and 1 family, which was originally reported by Grootenboer et al. (1998), exhibited all 3 manifestations. Grootenboer et al. (2000) presented evidence that DHS with pseudohyperkalemia and perinatal edema is a pleiotropic syndrome in which some features may be missing. Specifically, they found linkage to 16q23-q24 in all kindreds with no evidence of heterogeneity.

In a large 3-generation French family with DHS and pseudohyperkalemia, 1 branch of which had been studied by Grootenboer et al. (2000) (family 'VA'), Beaurain et al. (2007) analyzed 19 microsatellite markers at chromosome 16q24.1-qter, obtaining 2-point lod scores greater than 3.5 for 8 of the 12 telomeric markers. Multipoint linkage analysis yielded a maximum lod score of 4.7 for the marker at the start of the telomeric region, D16S539. Recombination events reduced the disease haplotype to an 11.45-cM (5.17-Mb) interval from D16S3037 to the 16q telomere.

In a large Canadian kindred segregating autosomal dominant xerocytosis, Houston et al. (2011) performed linkage analysis using 6 microsatellite markers within the 16q22.2-q24.3 interval and obtained lod scores greater than 3.0 at D16S3074, D16S2621, and D16S3026. Recombination events placed the centromeric boundary between D16S2621 and D16S3026, thus narrowing the disease interval to 16q24.2-qter and strongly suggesting that the causative gene was not located between 16q23-q24 as previously reported.

Molecular Genetics

Using high-resolution SNP typing in a presumed homozygote from a family of Swiss-German origin segregating autosomal dominant stomatocytosis, originally reported by Miller et al. (1971), Zarychanski et al. (2012) identified a large region of homozygosity within the 16q24.2-qter interval. Whole-exome sequencing in the Swiss-German family and in a Canadian DHS kindred previously studied by Houston et al. (2011) revealed 2 heterozygous missense mutations in the PIEZO1 gene (M2225R, 611184.0001 and R2456H, 611184.0002) that segregated with disease in each family, respectively.

In a large 4-generation French pedigree with DHS mapping to 16q24.1-qter, previously studied by Grootenboer et al. (2000) (family 'VA') and Beaurain et al. (2007), Albuisson et al. (2013) performed whole-exome sequencing and identified a heterozygous missense mutation in the PIEZO1 gene (A2020T; 611184.0003) that segregated with disease. Screening of the entire coding sequence of PIEZO1 in 2 more DHS kindreds, previously reported by Grootenboer et al. (2000) (family 'VE') and Martinaud et al. (2008), respectively, and in 11 unrelated DHS cases, 1 of which was previously reported by Syfuss et al. (2006), revealed 3 additional heterozygous mutations in 10 probands, including 2 missense mutations (R1358P, 611184.0004; T2127M, 611184.0005) and a recurrent 6-bp duplication (611184.0006) that was present in 8 unrelated index cases. Functional analysis demonstrated that all 6 PIEZO1 mutations identified in DHS patients to date could be defined as gain-of-function mutations, leading to increased channel activity in response to a given stimulus.

In an Edinburgh family with DHS and pseudohyperkalemia, originally reported by Stewart et al. (1979), Andolfo et al. (2013) performed whole-exome sequencing and identified a missense mutation in the PIEZO1 gene (T2127M; 611184.0005) that segregated with disease and was not found in 38 unrelated control exomes. Sequencing of PIEZO1 in an additional 6 families, including 3 French families previously studied by Grootenboer et al. (2000) (families 'AR,' 'DA,' and 'TR'), a French Gypsy family originally reported by Grootenboer et al. (1998) and studied by Grootenboer et al. (2000) as family 'BI,' and an Irish mother and son previously reported by Carella et al. (1998), revealed heterozygous mutations in all of them (see, e.g., 611184.0002, 611184.0007, and 611184.0008). In 3 of those families, multiple in cis missense mutations in PIEZO1 were found (see, e.g., 611184.0007 and 611184.0008); Andolfo et al. (2013) noted that because the linked variants at sites of lesser evolutionary conservation were not present among normal alleles or SNP databases, the contribution of each individual mutation to its linked phenotype could not yet be assigned.

Malaria Resistance

Ma et al. (2018) identified a novel PIEZO1 allele, E756del (611184.0016), present in one-third of populations of African descent. Among blood samples from 25 healthy African American blood donors, Ma et al. (2018) found that 9 (36%) were heterozygous for this allele. Scanning electron microscopy of 3 of these 9 samples showed that all had RBCs with echinocyte and stomatocyte morphologies. It was not known whether carriers of this allele had anemia or splenomegaly. RBCs from all 9 E756del carriers were dehydrated as assayed by osmotic fragility testing. Ma et al. (2018) infected RBCs from E756del carriers and controls with P. falciparum in vitro and found that parasitemia was significantly lower for E756del carriers. These and other analyses led Ma et al. (2018) to conclude that E756del is a common PIEZO1 gain-of-function mutation in African populations that causes RBC dehydration and is likely under positive selection due to its ability to confer reduced susceptibility of RBCs to P. falciparum infection (see 611162).

Exclusion Studies

In a large 4-generation French family with DHS and pseudohyperkalemia mapping to 16q24.1-qter, Beaurain et al. (2007) sequenced the positional candidate TUBB3 gene but found no mutations. Southern blot showed no evidence of deletion or gene rearrangement.