Dehydrated Hereditary Stomatocytosis 1 with or Without Pseudohyperkalemia and/or Perinatal Edema (DHS1)

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Disease Ontology 12 DOID:0111575 DOID:0111576 OMIM 56 194380 KEGG 36 H01978 MeSH 43 C536764 D000745 SNOMED-CT 67 87994004 ICD10 via Orphanet 33 D58.8

UMLS via Orphanet 72 C0272051 Orphanet 58 ORPHA3202 MedGen 41 C0272051 C4551512 SNOMED-CT via HPO 68 109992005 127062003 128241005 13713005 16294009 176271000119108 17920008 18165001 20741006 21522001 263681008 266474003 267038008 281610001 371039008 385472000 38911009 398979000 423666004 42601008 46049004 68600005 79654002 80515008 83414005 more UMLS 71 C0272051

NIH Rare Diseases : ⁵² The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 3202 Definition Dehydrated hereditary stomatocytosis (DHS) is a rare hemolytic anemia characterized by a decreased red cell osmotic fragility due to a defect in cation permeability, resulting in red cell dehydration and mild to moderate compensated hemolysis. Pseudohyperkalemia (loss of potassium ions from red cells on storage at room temperature) is sometimes observed. Epidemiology The prevalence of DHS is unknown but to date, about 20 families with DHS have been described in the literature. Clinical description The clinical presentation of the disease is very heterogeneous. Onset of DHS may occur during the perinatal period with occurrence of edema and ascites (most often not related to an underlying anemia ) that usually resolve spontaneously during the first weeks of life but may rarely lead to hydrops fetalis (see this term). Most adult patients present a mild anemia or a totally compensated hemolysis, with fatigue, icterus, splenomegaly and risks of secondary complications including cholelithiasis. Patients can also be referred for unexplained hemochromatosis, since iron overload is frequently associated with the disease. Thrombotic complications (arterial and venous events, including portal vein thrombosis (see this term) and pulmonary hypertension ) have been described at a high rate after splenectomy. Etiology Most reported DHS cases are caused by gain-of-function mutations in the gene PIEZO1 (16q24.3) which encodes part of a mechanosensitive ion channel. This results in increased red cell membrane permeability for cations that consequently leads to cation depletion, dehydration and shortened red cell survival. Rare atypical forms have been associated with mutations in SLC4A1 (17q21.31), coding for the Band 3 anion transport protein , or KCNN4 (19q13.2) which codes for the putative Gardos channel. Diagnostic methods Diagnosis relies on laboratory findings. The typical presentation includes normal hemoglobin level or mild anemia, normal mean cell volume (MCV) or mild macrocytosis, normal or elevated mean corpuscular hemoglobin concentration (MCHC), elevated reticulocytosis, and a small number of stomatocytes (<10% of red cells). A diagnosis of DHS must be evoked in patients with unexplained iron overload, even if hemoglobin levels are normal, as well as in patients with unexplained hemolysis (before splenectomy) or those presenting with thrombotic events, if already splenectomized. Osmolar gradient ektacytometry is the best phenotypic diagnosis method, showing a leftward shift of the bell-shaped curve with a normal maximum deformability index and a decreased hypo and hyper-osmotic point, reflecting decreased osmotic fragility and cell dehydration, respectively. In some cases, an increased serum potassium level is observed, which results from in vitro leakage and is clinically irrelevant. Measurement of ferritin level and liver magnetic resonance imaging (MRI) are performed to evaluate iron overload. Genetic screening of the causative genes can be performed after phenotypic investigations. Differential diagnosis Differential diagnoses include other causes of hemolysis, including hereditary spherocytosis, overhydrated hereditary stomatocytosis, hemoglobinopathy or red cell enzyme deficiencies such as hemolytic anemia due to red cell pyruvate kinase deficiency (see these terms). Genetic counseling Transmission is autosomal dominant and genetic counseling should be offered to affected families. Management and treatment Treatment is mainly symptomatic. Occurrence of cholelithiasis should be regularly monitored. Folic acid supplementation should be proposed in case of anemia. Pregnancy should be closely monitored. Iron status should be regularly monitored by serum ferritinemia and liver MRI. Iron depletion, most often by phlebotomy, is proposed when ferritinemia reaches the threshold of 1000 ng/ml or when iron liver overload is present. Splenectomy is contraindicated in DHS due to an elevated risk of life threatening arterial and venous thrombotic events. Prognosis Overall prognosis is favorable in well managed patients (not splenectomized and with regular monitoring of their iron status). Splenectomized patients are at risk of early or late thrombotic events. Visit the Orphanet disease page for more resources.

MalaCards based summary : Dehydrated Hereditary Stomatocytosis 1 with or Without Pseudohyperkalemia and/or Perinatal Edema, also known as dehydrated hereditary stomatocytosis, is related to hereditary stomatocytosis and hemolytic anemia. An important gene associated with Dehydrated Hereditary Stomatocytosis 1 with or Without Pseudohyperkalemia and/or Perinatal Edema is PIEZO1 (Piezo Type Mechanosensitive Ion Channel Component 1), and among its related pathways/superpathways is RAB geranylgeranylation. Affiliated tissues include spleen, liver and heart, and related phenotypes are increased red cell osmotic fragility and nonspherocytic hemolytic anemia

Disease Ontology : ¹² A hemolytic anemia characterized by altered intracellular cation content and cellular dehydration of erythocytes resulting in increased mean corpuscular hemoglobin concentrations and altered cell shapes.

OMIM : ⁵⁶ 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. (194380)

KEGG : ³⁶ Dehydrated hereditary stomatocytosis (DHS), also known as hereditary xerocytosis, is an autosomal dominant congenital disorder associated with erythrocyte dehydration clinically manifest as mild to moderate hemolytic anemia. Affected red cells are characterized by a nonspecific cation leak of the red cell membrane, reflected in elevated sodium content, decreased potassium content, elevated mean corpuscular hemoglobin concentration (MCHC) and mean corpuscular volume (MCV), and decreased osmotic fragility. The definitive diagnosis of DHS is made by osmotic gradient ektacytometry, which shows a leftward shift of the bell-shaped curve. In many patients, heterozygous mutations in the mechanosensitive cation channel gene PIEZO1 have been identified. Mutations in the Gardos channel, encoded by the KCNN4 gene, have also been identified.

UniProtKB/Swiss-Prot : ⁷³ Dehydrated hereditary stomatocytosis 1 with or without pseudohyperkalemia and/or perinatal edema: 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. Patients may also show perinatal edema and pseudohyperkalemia due to loss of potassium 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.

Wikipedia : ⁷⁴ Hereditary stomatocytosis describes a number of inherited autosomal dominant human conditions which... more...

Clinical features from OMIM:

194380

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