Dehydrated Hereditary Stomatocytosis 2

A number sign (#) is used with this entry because of evidence that dehydrated hereditary stomatocytosis-2 (DHS2) is caused by heterozygous mutation in the KCNN4 gene (602754) on chromosome 19q13.

Description

In dehydrated hereditary stomatocytosis (DHS), also known as hereditary xerocytosis, red blood cells exhibit altered intracellular cation content and cellular dehydration, resulting in increased erythrocyte mean corpuscular hemoglobin concentration (MCHC) and decreased erythrocyte osmotic fragility. Blood films show various cell shape abnormalities, the most characteristic being the stomatocyte, with a straight or crescent-shaped central pallor (summary by Rapetti-Mauss et al., 2015).

For discussion of clinical and genetic heterogeneity of the stomatocytoses, see DHS1 (194380).

Clinical Features

Glader et al. (1974) reported a mother and son with congenital hemolytic anemia due to a red blood cell permeability defect, which the authors designated 'desiccytosis.' The 21-year-old mother, of French and Irish descent, had a lifelong history of anemia, jaundice, and hepatosplenomegaly. She received multiple blood transfusions in early childhood and underwent splenectomy at age 6 years and cholecystectomy at age 13. She continued to have chronic hemolysis and intermittent episodes of exaggerated icterus, and red cell survival studies showed a half-life of only 8 days. Examination revealed scleral icterus and hepatomegaly. Her 3-year-old son also exhibited jaundice, anemia, and hepatosplenomegaly. Hematologic evaluation showed anemia, reticulocytosis, and increased mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). There were large, dehydrated-appearing red cells in which hemoglobin seemed to be puddled at the cell periphery, as well as fragmented cells and acanthocytes. Osmotic fragility was shifted to the right, with delayed onset and incomplete hemolysis at the most dilute salt concentration, compared to control. Erythrocytes of the proband and her son had increased sodium and decreased potassium content, with an overall reduction in total cation content despite active transport of sodium and potassium that was twice normal; water left the cells due to this decreased solute concentration, resulting in rigid, osmotically resistant, dehydrated erythrocytes that the authors designated 'desiccytes.' Glader et al. (1974) noted that the proband's nonsplenectomized son, with the same degree of anemia, reticulocytosis, hepatosplenomegaly, desiccytes in peripheral smear, and cation abnormality, had not required blood transfusions; thus, splenectomy did not appear to increase red blood cell survival in this disorder.

Fairbanks et al. (1978) studied the membrane defect in red blood cells from a large kindred from Worcester (Massachusetts) consisting of 2 affected sisters and their affected children (8 sons). Affected individuals exhibited mild anemia and red cell dehydration (xerocytosis), associated with net cation deficiency due to excessive passive K+ efflux. The patients' dehydrated cells, or 'xerocytes,' contained depressed levels of 2,3-diphosphoglycerate (DPG) and exhibited left-shifted oxygen dissociation curves. Intracellular pH and other hematologic and metabolic parameters were normal. Fairbanks et al. (1978) analyzed the elevated retention of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in xerocyte membranes and concluded that it is determined by cytoplasmic factors. Snyder et al. (1978) provided additional analysis of red cells from the proband of the Worcester kindred, a 43-year-old woman of Italian, French, and Irish heritage with a lifelong history of anemia, jaundice, and splenomegaly, who underwent cholecystectomy at age 33. She had 4 affected sons, and an affected older sister had 4 sons, all of whom had anemia and jaundice. The authors noted that xerocyte fragments showed the same protein composition as fragments from normal red cells; their findings suggested that ATP depletion plays a role in producing fragmentation and myelin forms. Compared to cells from patients with other forms of hemolytic anemia, such as PNH (see 300818) or G6PD deficiency (300908), xerocytes showed the highest amount of fragmentation in vitro.

In a further study of the Worcester kindred reported by Fairbanks et al. (1978), Fairbanks et al. (1984) noted that all affected individuals exhibited a mild chronic hemolytic anemia with reduced red cell life span (15.5 days) and reticulocyte counts ranging from 4 to 8%. The K+ content of their red cells was reduced but the Na+ content was normal, and dehydration was reflected in decreased osmotic fragility and increased MCHC. Rigorous laboratory evaluation excluded hemoglobinopathy or enzymopathy in the family. Fairbanks et al. (1984) presented evidence that passive K+ permeability in patient red cells was increased. In addition, the authors demonstrated that the chloride-dependent component of passive K+ influx did not exhibit the activation by N-ethylmaleimide (NEM) seen in normal red cells. Fairbanks et al. (1984) reported that the NEM-activated K+ influx in normal human red cells is volume-responsive, and suggested that the insensitivity of xerocytes to the thiol blocking reagent might be related to the osmoregulatory dysfunction.

Rapetti-Mauss et al. (2015) reported a 4-generation French family with chronic hemolytic anemia. The proband was a boy who received transfusions in utero for severe anemia, which stabilized by 3 months of age on erythropoietin treatment. At age 4.75 years, he exhibited mild anemia and splenomegaly. His mother had chronic moderate hemolytic anemia since childhood, with regular transfusions until adolescence, and had undergone splenectomy at age 25. The mother's sister, their father, a paternal aunt, and the paternal grandmother were also affected, and 3 of them had undergone splenectomy. None of the splenectomized family members had presented thrombotic complications. Rapetti-Mauss et al. (2015) also described a 3-generation family of Polish origin, in which the proband was a 25-year-old woman with chronic moderate hemolytic anemia since childhood and underwent cholecystectomy for biliary lithiasis. The proband's 2-year-old son also had well-tolerated chronic hemolytic anemia, whereas her father was reported to have had severe hemolytic anemia treated by splenectomy and occasional transfusions. Hematologic analysis of affected individuals from both families showed anemia, reticulocytosis, and slightly increased MCHC. Blood smears showed mild anisopoikilocytosis with less than 1% target cells, acanthocytes, polychromatophilic red cells, teardrop cells, elliptocytes, hemighosts, bite cells, knizocytes, schizocytes, and rare stomatocytic red cells.

Andolfo et al. (2015) studied a family from Naples with congenital hemolytic anemia. The 40-year-old mother, who had a history of neonatal jaundice, presented with moderate macrocytic anemia and was found to have high indirect bilirubin and reduced red cell life span. She never required transfusions and underwent splenectomy and cholecystectomy at age 21. A son who was born with jaundice and elevated bilirubin also had chronic hemolytic anemia. Examination at ages 40 years and 10 years, respectively, revealed jaundice and hepatomegaly in both, with splenomegaly and cholelithiasis in the son. Hematology showed moderate macrocytic anemia in the mother and mild normocytic anemia in the son. Blood smears showed anisopoikilocytosis with rare stomatocytes. Ektacytometric analysis in the nonsplenectomized son showed a left-shifted curve, indicating dehydration as usually seen in DHS patients. Andolfo et al. (2015) stated that neither patient exhibited pseudohyperkalemia.

Molecular Genetics

In a 4-generation French family with chronic congenital hemolytic anemia, Rapetti-Mauss et al. (2015) performed whole-exome sequencing and identified a heterozygous missense mutation in the KCNN4 gene (R352H; 602754.0001) that segregated with disease. Direct sequencing of KCNN4 in affected individuals from a 3-generation Polish family revealed heterozygosity for the same R352H mutation. Exome sequencing data excluded mutation in the PIEZO1 gene (611184), which is mutated in DHS1 (194380). Rapetti-Mauss et al. (2015) noted variability in disease severity between the 2 families: affected members of the French family had a rather severe level of anemia, whereas affected members of the Polish family presented either normal or subnormal hemoglobin levels. Functional analysis demonstrated that the mutant channel exhibited a 10-fold increase in activation by calcium compared to wildtype, and also showed delayed inactivation.

By whole-exome sequencing in affected individuals from the previously studied Worcester kindred with chronic anemia (Fairbanks et al. (1978, 1984); Snyder et al., 1978) and the affected mother and son reported by Glader et al. (1974), Glogowska et al. (2015) identified different heterozygous mutations at the same codon in the KCNN4 gene (V282M, 602754.0002; V282E, 602754.0003). No mutations were found in the PIEZO1 gene.

In an Italian mother and son with chronic hemolytic anemia, Andolfo et al. (2015) sequenced the KCNN4 gene and identified heterozygosity for the R352H mutation. They also analyzed KCNN4 in the Worcester kindred and detected the V282M mutation. Each mutation segregated with disease in the respective family, and neither was found in the 1000 Genomes Project database. Andolfo et al. (2015) stated that although the Worcester kindred was 1 of 10 DHS families studied by Grootenboer et al. (2000) with apparent mapping to chromosome 16q23-q24, there were no PIEZO1 mutations cosegregating with disease in the kindred. However, noting the variation in severity of disease among affected individuals carrying the same KCNN4 mutation, Andolfo et al. (2015) suggested that differences in PIEZO1 polymorphisms carried by those individuals might contribute to differences in clinical phenotypes. In addition, the authors noted that although splenectomy in patients with KCNN4-associated DHS did not appear to predispose to thrombotic events as had been observed in patients with PIEZO1-associated DHS, the procedure also did not seem to improve anemia in the KCNN4-mutated patients.