Overhydrated Hereditary Stomatocytosis

Mendelian MONDO:0008493 Pathograph 33 Show in embeddings browser familial hemolytic anemia hereditary stomatocytosis

Overhydrated hereditary stomatocytosis (OHSt), also called hereditary hydrocytosis, is a rare autosomal dominant congenital hemolytic anemia caused by heterozygous missense substitutions in RHAG, the gene encoding the Rh-associated glycoprotein. It is the most leaky member of the cation-leak hereditary stomatocytosis family, a group of dominantly inherited anemias in which the red cell membrane abnormally conducts the monovalent cations sodium and potassium and so loses control of its own volume. In OHSt the mutant RhAG is converted from an ammonia-transporting channel into a non-selective cation pore: sodium enters faster than potassium leaves, the cell gains cations and water, and the swollen, overhydrated erythrocyte takes the cup-shaped (stomatocyte) morphology that names the disease. The hydrated cells have a high mean corpuscular volume, a low mean corpuscular haemoglobin concentration, increased osmotic fragility and reduced deformability, and are removed prematurely in the spleen, producing chronic extravascular haemolysis with reticulocytosis, unconjugated hyperbilirubinaemia, jaundice, splenomegaly and pigment gallstones. Severity ranges from compensated haemolysis to transfusion-dependent anaemia. Two features dominate management. Iron overload tends to develop even without transfusion, and splenectomy carries a severe, sometimes fatal, risk of thromboembolic disease and should be avoided. The near-absence of the membrane protein stomatin from OHSt red cells, historically the finding that named the protein, is a secondary consequence of the disorder rather than its cause: the primary lesion is the RhAG mutation.

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1
Inheritance
15
Pathophys.
12
Phenotypes
33
Pathograph
1
Genes
2
Variants
4
Medical Actions
2
Differentials
1
Models
3
References
1
Deep Research
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Classifications

Harrison's Part
ONCOLOGY HEMATOLOGY
👪

Inheritance

1
Autosomal dominant HP:0000006
OHSt is autosomal dominant; de novo heterozygous RHAG mutations are documented, so a negative family history does not exclude it.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:29559519 SUPPORT Human Clinical
"establishing RHAG:Ile149Met, novel de novo mutation as probably causative."
Documents dominant inheritance with a de novo RHAG mutation.
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Pathophysiology

15
RHAG Transmembrane Missense Substitution
The germline lesion. A heterozygous RHAG missense variant substitutes a highly conserved transmembrane residue of the Rh-associated glycoprotein. Two recurrent substitutions account for most reported families, Ile61Arg and Phe65Ser; further RHAG missense variants have been reported, and de novo occurrence is documented.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
RHAG hgnc:10006 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RHAG (hgnc:10006). hgnc:10006 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: SNV variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
gained monovalent cation channel activity GO:0005261 ⇑ GAIN OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves gained monovalent cation channel activity, annotated with monoatomic cation channel activity (GO:0005261), qualified as gain of function. GO:0005261 is a molecular function from the Gene Ontology.
Downstream
RhAG Nonselective Cation Pore Formation The substitution alters the channel so that it conducts cations.
Loss of RhAG Ammonia Transport The same substitution impairs the protein's native ammonia-transport function.
Show evidence (2 references)
PMID:18931342 SUPPORT Human Clinical
"DNA analysis revealed that the OHSt patients have 1 of 2 heterozygous mutations (t182g, t194c) in RHAG that lead to substitutions of 2 highly conserved amino acids (Ile61Arg, Phe65Ser)."
Identifies the two recurrent heterozygous RHAG transmembrane substitutions this node names.
PMID:29559519 SUPPORT Human Clinical
"Overhydrated stomatocytosis is a rare autosomal dominant disorder known to cause variably severe haemolytic anaemia due to heterozygous mutations in the RHAG gene."
Establishes heterozygous RHAG mutation as the dominant cause.
RhAG Nonselective Cation Pore Formation
RhAG belongs to the ammonium-transporter family, whose members form pore-like structures. Molecular modelling on the homologous Nitrosomonas europaea Rh50 protein indicates that the OHSt substitutions widen the central channel and convert it into a non-selective cation pore, a qualitative gain of a conductance the wild-type protein does not normally provide.
monovalent cation pore activity GO:0008324 ⇑ GAIN OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves monovalent cation pore activity, annotated with monoatomic cation transmembrane transporter activity (GO:0008324), qualified as gain of function. GO:0008324 is a molecular function from the Gene Ontology.
Experimental models
RhAG Xenopus laevis oocyte expression system OTHER Reproduces the gain-of-function cation conductance of the mutant pore.
Downstream
Erythrocyte Monovalent Cation Leak The open pore admits a transmembrane leak of monovalent cations.
Show evidence (2 references)
PMID:18931342 SUPPORT Computational
"We have modeled RhAG on the homologous Nitrosomonas europaea Rh50 protein and shown that these mutations are likely to lead to an opening of the pore."
States the structural basis for conversion of RhAG into a cation pore.
PMID:29713289 SUPPORT REVIEW SYNTHESIS Computational
"Molecular modeling of the mutant RhAG suggests that the Phe65Ser mutation causes a significant widening of the central transport channel, converting it into a non-selective cation pore (Bruce et al., 2009)."
Independent review statement of the pore-conversion mechanism.
Loss of RhAG Ammonia Transport
A parallel molecular consequence of the same substitution. In red cells RhAG acts as an ammonia channel, and the Phe65Ser mutation impairs that native transport even as it gains cation conductance. This is a loss-of-function for the protein's physiological substrate and is a branch consequence rather than part of the haemolytic chain.
ammonium channel activity GO:0008519 ⇓ LOSS OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves ammonium channel activity (GO:0008519), qualified as loss of function. GO:0008519 is a molecular function from the Gene Ontology.
Show evidence (2 references)
PMID:22012326 SUPPORT In Vitro
"this dramatic decrease can be therefore related to the loss of function of the Phe65Ser-mutated RhAG monomer."
Reports that the Phe65Ser mutation impairs RhAG ammonia transport.
PMID:21849667 SUPPORT In Vitro
"RhAG F65S exhibits gain-of-function phenotypes of increased cation conductance/permeability, and loss-of-function phenotypes of decreased and modified MA/MA(+) transport"
Shows the dual gain-of-cation-conductance and loss-of-amine-transport behaviour of the mutant.
Erythrocyte Monovalent Cation Leak
Through the mutant pore the red cell membrane leaks monovalent cations. In OHSt this is the most severe leak of the hereditary stomatocytoses, up to about 40 times the normal basal rate at body temperature, and it increases linearly with temperature, consistent with a constitutively open cation channel.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
monovalent cation transmembrane transport GO:0098655 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased monovalent cation transmembrane transport, annotated with monoatomic cation transmembrane transport (GO:0098655). GO:0098655 is a biological process from the Gene Ontology.
Downstream
Net Erythrocyte Cation Gain The leak admits sodium and loses potassium across the membrane.
Secondary Erythrocyte Stomatin Deficiency Stomatin is lost from the mature OHSt red cell membrane as a secondary effect of the disorder, not as its cause.
Show evidence (2 references)
PMID:29713289 SUPPORT Human Clinical
"The most severe cation leak in the hereditary stomatocytoses can be found in a condition known as overhydrated hereditary stomatocytosis (OHSt)."
Identifies OHSt as the most severe cation leak of the group.
PMID:18931342 SUPPORT Human Clinical
"Overhydrated hereditary stomatocytosis (OHSt) is a rare dominantly inherited hemolytic anemia characterized by a profuse membrane leak to monovalent cations."
States the defining membrane cation leak.
Secondary Erythrocyte Stomatin Deficiency
OHSt red cells are near-completely deficient in the 32 kDa membrane protein stomatin (band 7.2b), the finding after which the protein was originally named. No mutation in the stomatin gene is found; the protein is mis-trafficked and lost on erythroid maturation. This is a secondary correlate of the primary RhAG defect, a dead-end branch that does not drive the haemolysis.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
erythrocyte plasma membrane GO:0005886 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves erythrocyte plasma membrane, annotated with plasma membrane (GO:0005886). GO:0005886 is a cellular component from the Gene Ontology.
Show evidence (2 references)
PMID:16197460 SUPPORT In Vitro
"The 32 kD lipid-raft-associated membrane protein 'stomatin' is deficient from the erythrocyte membrane in the Na+-K+ leaky haemolytic anaemia, overhydrated hereditary stomatocytosis (OHSt)."
Documents the stomatin deficiency this node records.
PMID:29713289 SUPPORT Human Clinical
"Initially it appeared that the disease must be caused by the absence of this protein, however further investigation revealed that stomatin deficiency was a secondary effect of the disorder (Fricke et al., 2003). It is now known that the primary defect is mutation in RhAG."
Establishes that stomatin deficiency is secondary and that RhAG is the primary defect, justifying the correlate framing.
Net Erythrocyte Cation Gain
Because sodium influx through the leak exceeds potassium efflux, the cell gains monovalent cations overall. Net intracellular cation content, not any single ion, sets erythrocyte volume, so a net gain commits the cell to swelling.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
sodium ion import across plasma membrane GO:0098719 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased sodium ion import across plasma membrane (GO:0098719). GO:0098719 is a biological process from the Gene Ontology.
Downstream
Compensatory Na/K-ATPase Hyperactivity The cell upregulates active cation pumping to counter the gain.
Erythrocyte Overhydration and Swelling Net cation gain draws water osmotically into the cell.
Show evidence (2 references)
PMID:25976965 SUPPORT Human Clinical
"Erythrocytes swell when the inward sodium leak exceeds the potassium leak out and shrink when the potassium leak out exceeds the inward sodium leak."
States the net-cation-gain rule that makes OHSt an overhydrating leak.
PMID:7230721 SUPPORT Human Clinical
"A girl of German origin with severe congenital hemolytic anemia was found to have overhydrated erythrocytes with markedly increased sodium and reduced potassium concentrations."
Directly documents the raised-sodium, lowered-potassium cation profile.
Compensatory Na/K-ATPase Hyperactivity
The Na,K-ATPase runs at greatly increased activity in an attempt to restore normal cation gradients against the leak, pumping far more than normal red cells. The compensation is insufficient to prevent the net gain and swelling.
Na+/K+-ATPase activity GO:0005391 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased Na+/K+-ATPase activity, annotated with P-type sodium:potassium-exchanging transporter activity (GO:0005391). GO:0005391 is a molecular function from the Gene Ontology.
Downstream
Erythrocyte Glycolytic Exhaustion Sustained pumping consumes ATP and drives glycolysis to exhaustion.
Show evidence (2 references)
PMID:29713289 SUPPORT Human Clinical
"This is consistent with an increased energy demand in OHSt cells, possibly resulting from elevated activity of the Na,K-ATPase attempting to maintain normal cation gradients."
States the compensatory rise in Na,K-ATPase activity.
PMID:420735 SUPPORT Human Clinical
"Hereditary stomatocytes contain 2-10-fold more cation pumps than normal and the increased active cation pumping may explain the high ADP, the low 2,3-diphosphoglycerate concentration and the increased oxygen affinity in this syndrome."
Quantifies the increased active cation pumping.
Erythrocyte Glycolytic Exhaustion
The ATP demand of continual compensatory pumping overworks the only ATP source the red cell has, glycolysis. A metabolomic study of OHSt patients found glycolysis exhausted, with accumulation of ADP, pyruvate, lactate and malate, leaving the cell metabolically vulnerable. A branch consequence of the compensation.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
glycolytic process GO:0006096 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:21859730 SUPPORT Human Clinical
"Glycolysis is exhausted with accumulation of ADP, pyruvate, lactate, and malate."
Reports the exhausted glycolytic state.
PMID:29713289 SUPPORT Human Clinical
"The authors found that the glycolytic pathway is overactive in OHSt RBCs, with a build-up of glycolysis end products."
Independent statement of overactive glycolysis in OHSt.
Erythrocyte Overhydration and Swelling
Water follows the net cation gain into the cell osmotically, so the erythrocyte becomes overhydrated and swollen. The overhydration is the direct cause of the raised cell volume and lowered intracellular haemoglobin concentration that are the laboratory signature of the disease.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
water import into the erythrocyte GO:0006833 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased water import into the erythrocyte, annotated with water transport (GO:0006833). GO:0006833 is a biological process from the Gene Ontology.
Downstream
Stomatocyte Shape Change The overhydrated cell adopts the cup-shaped stomatocyte form.
Increased mean corpuscular volume Swelling raises the mean corpuscular volume.
Decreased mean corpuscular hemoglobin concentration Added water dilutes intracellular haemoglobin.
Show evidence (2 references)
PMID:7230721 SUPPORT Human Clinical
"A girl of German origin with severe congenital hemolytic anemia was found to have overhydrated erythrocytes with markedly increased sodium and reduced potassium concentrations."
Documents the overhydrated erythrocytes produced by the cation gain.
PMID:40233304 SUPPORT Human Clinical
"with alterations in cellular salt and water, ranging from dehydration to overhydration, and the presence of stomatocytes on peripheral blood smear"
Links the salt-and-water alteration to the stomatocyte morphology.
Stomatocyte Shape Change
The overhydrated cell loses its biconcave disc shape and becomes a cup-shaped stomatocyte with a slit-like central pallor on the blood film, with a reduced surface-area-to-volume ratio.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Downstream
Stomatocytosis The shape change is seen on the blood film as stomatocytosis.
Reduced Erythrocyte Deformability The reduced surface-to-volume ratio stiffens the cell.
Show evidence (1 reference)
PMID:7230721 SUPPORT Human Clinical
"The cells were stomatocytic with increased osmotic fragility and autohemolysis."
Documents the stomatocytic morphology arising in these overhydrated cells.
Reduced Erythrocyte Deformability
The swollen, low-surface-to-volume stomatocyte is osmotically fragile and poorly deformable, and this reduced integrity is what marks it for removal. This is the OHSt-specific substitution at the module's reduced-integrity node: an overhydration/cation-leak lesion in place of a cytoskeletal protein defect.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Downstream
Increased red cell osmotic fragility The overhydrated cell lyses at near-physiological tonicity.
Splenic Sequestration Poorly deformable cells are trapped in the splenic microcirculation.
Show evidence (1 reference)
PMID:21849667 SUPPORT Human Clinical
"OHSt erythrocytes were osmotically fragile, with elevated Na and decreased K contents and increased cation channel-like activity."
Reports the osmotic fragility of OHSt erythrocytes behind the reduced integrity.
Splenic Sequestration
Poorly deformable, metabolically vulnerable stomatocytes are entrapped in the acidic, hypoglycaemic environment of the splenic red pulp, where they swell further and are destroyed. This is the OHSt case of the module's premature extravascular destruction node.
spleen UBERON:0002106 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spleen (UBERON:0002106). UBERON:0002106 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Extravascular Hemolysis Sequestered cells are destroyed outside the circulation.
Show evidence (1 reference)
PMID:7230721 SUPPORT Human Clinical
"In acidic, hypoglycemic environment of the splenic pulp the cells become swollen and lysed."
Describes splenic entrapment and destruction of the abnormal cells.
Extravascular Hemolysis
Premature splenic destruction shortens red cell survival and produces chronic extravascular haemolysis, the systemic process that generates the anaemia and its products. After splenectomy the anaemia improves but haemolysis persists, confirming the spleen as the principal site of destruction rather than the cause of the defect.
Downstream
Hemolytic anemia Red cell loss outstripping production causes the anaemia.
Reticulocytosis The marrow responds to haemolysis with reticulocytosis.
Unconjugated hyperbilirubinemia Haem catabolism from destroyed cells raises unconjugated bilirubin.
Splenomegaly Sustained erythrophagocytosis enlarges the spleen.
Dysregulated Iron Loading Chronic haemolysis contributes to the tendency to iron overload.
Show evidence (1 reference)
PMID:7230721 SUPPORT Human Clinical
"After splenectomy anemia improved though increased hemolysis persisted."
Confirms extravascular (splenic) haemolysis while showing the defect is intrinsic.
Dysregulated Iron Loading
A tendency to iron overload develops in hereditary stomatocytosis even without hypertransfusion and irrespective of splenectomy, loading the liver and other organs over time.
Downstream
Elevated hepatic iron concentration Accumulated iron raises hepatic iron concentration.
Show evidence (1 reference)
PMID:8639421 SUPPORT Human Clinical
"A tendency to iron overload, even without hypertransfusion and irrespective of splenectomy, is evident in many of these patients."
Documents the transfusion-independent iron-loading tendency.
Prothrombotic Erythrocyte Membrane State
The abnormal membrane exposes phosphatidylserine on the outer leaflet, disturbing phospholipid asymmetry and creating a prothrombotic red cell surface. This underlies the markedly increased thrombotic risk of the disease, which becomes severe and sometimes fatal after splenectomy.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Downstream
Pulmonary arterial hypertension Thromboembolic disease, particularly after splenectomy, drives chronic pulmonary hypertension.
Thromboembolism The prothrombotic state predisposes to thromboembolic events, especially after splenectomy.
Show evidence (2 references)
PMID:12560240 SUPPORT Human Clinical
"Percentages of hydrocytosis erythrocytes and reticulocytes with phosphatidylserine exposed on the outer surfaces were increased in both patients compared with healthy controls, indicating altered membrane phospholipid asymmetry."
Documents phosphatidylserine exposure as the prothrombotic membrane change.
PMID:12560240 SUPPORT Human Clinical
"The risk for thrombosis is increased in patients with hereditary hydrocytosis, an uncommon variant of hereditary stomatocytosis."
States the increased thrombotic risk this node drives.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Overhydrated Hereditary Stomatocytosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

12
Blood 7
Hemolytic anemia HP:0001878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemolytic anemia (HP:0001878). HP:0001878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29559519 SUPPORT Human Clinical
"Overhydrated stomatocytosis is a rare autosomal dominant disorder known to cause variably severe haemolytic anaemia due to heterozygous mutations in the RHAG gene."
States the variably severe haemolytic anaemia of OHSt.
Stomatocytosis HP:0004446 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stomatocytosis (HP:0004446). HP:0004446 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:7230721 SUPPORT Human Clinical
"The cells were stomatocytic with increased osmotic fragility and autohemolysis."
Documents the stomatocytic red cells.
Increased mean corpuscular volume HP:0005518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased mean corpuscular volume (HP:0005518). HP:0005518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25976965 SUPPORT REVIEW SYNTHESIS Human Clinical
"Excessive intracellular cations elevate cell water, leading to large, macrocytic erythrocytes (110 to 150 fL) that are osmotically fragile with a low MCHC (24 to 30g/dl)."
OHSt-specific statement of the macrocytosis (110-150 fL) from cation-led overhydration.
Decreased mean corpuscular hemoglobin concentration HP:0025547 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased mean corpuscular hemoglobin concentration (HP:0025547). HP:0025547 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25976965 SUPPORT REVIEW SYNTHESIS Human Clinical
"Excessive intracellular cations elevate cell water, leading to large, macrocytic erythrocytes (110 to 150 fL) that are osmotically fragile with a low MCHC (24 to 30g/dl)."
OHSt-specific statement of the low MCHC (24-30 g/dl) from cation-led overhydration.
Increased red cell osmotic fragility HP:0005502 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased red cell osmotic fragility (HP:0005502). HP:0005502 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:7230721 SUPPORT Human Clinical
"The cells were stomatocytic with increased osmotic fragility and autohemolysis."
Documents increased osmotic fragility.
Reticulocytosis HP:0001923 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reticulocytosis (HP:0001923). HP:0001923 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:420735 SUPPORT Human Clinical
"The relative decrement in 2,3-diphosphoglycerate was even greater when abnormal cells were compared with control cells with similar reticulocytosis."
Records reticulocytosis in hereditary stomatocytosis red cells.
Thromboembolism HP:0001907 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thromboembolism (HP:0001907). HP:0001907 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8639421 SUPPORT Human Clinical
"Nine cases of hereditary stomatocytosis (HSt) are presented which show documented thrombotic complications after splenectomy."
Documents the post-splenectomy thromboembolic complications.
Cardiovascular 2
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29559519 SUPPORT Human Clinical
"We report a 26-year-old man with recurring jaundice, splenohepatomegaly and mild chronic haemolytic anaemia with significant stomatocytosis."
Reports splenohepatomegaly in an OHSt patient.
Pulmonary arterial hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hypertension, annotated with Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:8639421 SUPPORT Human Clinical
"In three cases, patients became severely ill with pulmonary hypertension and a fourth developed portal hypertension."
Reports severe pulmonary hypertension after splenectomy in hereditary stomatocytosis.
PMID:25976965 SUPPORT REVIEW SYNTHESIS Human Clinical
"splenectomy is contraindicated in most cases due to the high risk of postsplenectomy thromboembolic disease and chronic pulmonary hypertension."
Names chronic pulmonary hypertension among post-splenectomy complications.
Digestive 2
Jaundice HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29559519 SUPPORT Human Clinical
"We report a 26-year-old man with recurring jaundice, splenohepatomegaly and mild chronic haemolytic anaemia with significant stomatocytosis."
Documents recurring jaundice.
Elevated hepatic iron concentration HP:0012465 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated hepatic iron concentration (HP:0012465). HP:0012465 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8639421 SUPPORT Human Clinical
"A tendency to iron overload, even without hypertransfusion and irrespective of splenectomy, is evident in many of these patients."
Documents the iron-loading tendency behind elevated hepatic iron.
Metabolism 1
Unconjugated hyperbilirubinemia HP:0008282 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Unconjugated hyperbilirubinemia (HP:0008282). HP:0008282 is a phenotype from the Human Phenotype Ontology.
Sequelae: Jaundice
Show evidence (1 reference)
PMID:29559519 SUPPORT Human Clinical
"We report a 26-year-old man with recurring jaundice, splenohepatomegaly and mild chronic haemolytic anaemia with significant stomatocytosis."
Reports the jaundice (hyperbilirubinaemia) of a haemolysing OHSt patient.
🧬

Genetic Associations

1
RHAG
Gene: RHAG hgnc:10006 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RHAG (hgnc:10006). hgnc:10006 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:18931342 SUPPORT Human Clinical
"RhAG belongs to the ammonium transporter family of proteins that form pore-like structures."
Establishes RhAG identity and the structural family behind the pore mechanism.
Variants (2)
Ile61Arg
Conserved transmembrane substitution (c.182T>G), one of the two recurrent OHSt alleles; gain-of-function cation-pore effect.
Show evidence (1 reference)
PMID:18931342 SUPPORT Human Clinical
"DNA analysis revealed that the OHSt patients have 1 of 2 heterozygous mutations (t182g, t194c) in RHAG that lead to substitutions of 2 highly conserved amino acids (Ile61Arg, Phe65Ser)."
Reports the Ile61Arg allele.
Phe65Ser
Conserved transmembrane substitution (c.194T>C) studied functionally as a combined gain of cation conductance and loss of ammonia transport.
Show evidence (1 reference)
PMID:21849667 SUPPORT Human Clinical
"Four patients with overhydrated cation leak stomatocytosis (OHSt) exhibited the heterozygous RhAG missense mutation F65S."
Documents the F65S allele in OHSt patients.
💊

Medical Actions

4
Supportive care and transfusion
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
No specific therapy corrects the membrane leak; management is supportive, with red cell transfusion when anaemia requires it.
Mechanism Target:
Hemolytic anemia — Transfusion corrects the anaemia without addressing the leak.
Show evidence (1 reference)
PMID:25976965 SUPPORT REVIEW SYNTHESIS Human Clinical
"splenectomy is contraindicated in most cases due to the high risk of postsplenectomy thromboembolic disease and chronic pulmonary hypertension."
OHSt-relevant statement that management is supportive and splenectomy is contraindicated.
Splenectomy (contraindicated)
Action: SplenectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Splenectomy (NCIT:C15328). NCIT:C15328 is a clinical intervention from the NCI Thesaurus. NCIT:C15328
Platform: Surgery
Splenectomy is specifically contraindicated in OHSt: although the spleen is the site of red cell destruction, removing it does not reliably correct the anaemia and carries a high risk of post-splenectomy thromboembolic disease and chronic pulmonary hypertension. Recorded here so the contraindication is queryable.
Show evidence (2 references)
PMID:25976965 SUPPORT REVIEW SYNTHESIS Human Clinical
"splenectomy is contraindicated in most cases due to the high risk of postsplenectomy thromboembolic disease and chronic pulmonary hypertension."
States the splenectomy contraindication and its basis.
PMID:8639421 SUPPORT Human Clinical
"Nine cases of hereditary stomatocytosis (HSt) are presented which show documented thrombotic complications after splenectomy."
The case series documenting post-splenectomy thrombotic complications behind the contraindication.
Iron chelation therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: deferoxamine CHEBI:4356 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses deferoxamine, annotated with desferrioxamine B (CHEBI:4356). CHEBI:4356 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Chelation for iron overload when it develops.
Mechanism Target:
Dysregulated Iron Loading — Chelation lowers systemic iron burden.
Show evidence (1 reference)
PMID:8639421 SUPPORT Human Clinical
"A tendency to iron overload, even without hypertransfusion and irrespective of splenectomy, is evident in many of these patients."
Establishes the iron overload that chelation addresses.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Counselling for an autosomal dominant condition, including the possibility of de novo mutation.
Show evidence (1 reference)
PMID:29559519 SUPPORT Human Clinical
"This case illustrates the importance of family screening in interpreting next-generation sequencing (NGS) data"
Supports family screening and counselling in diagnosis.
🔬

Biochemical Markers

2
Erythrocyte sodium and potassium content
Show evidence (1 reference)
PMID:21849667 SUPPORT Human Clinical
"OHSt erythrocytes were osmotically fragile, with elevated Na and decreased K contents and increased cation channel-like activity."
Reports the elevated-sodium, decreased-potassium red cell cation content.
Erythrocyte 2,3-diphosphoglycerate
Show evidence (1 reference)
PMID:420735 SUPPORT Human Clinical
"Hereditary stomatocytes contain 2-10-fold more cation pumps than normal and the increased active cation pumping may explain the high ADP, the low 2,3-diphosphoglycerate concentration and the increased oxygen affinity in this syndrome."
States the reduced 2,3-DPG and its attribution to increased active cation pumping.
🔬

Diagnosis

3
Peripheral blood film and red cell indices
Stomatocytes on the film with macrocytosis (high MCV) and low MCHC, plus reticulocytosis and raised unconjugated bilirubin, in a chronic haemolytic picture.
Show evidence (1 reference)
PMID:29741259 SUPPORT Human Clinical
"inappropriate cation leak causes erythrocyte hydration disorders, hemolytic anemia, and characteristic red cell shape abnormalities named stomatocytosis"
Describes the blood-film and haemolysis picture used diagnostically.
Osmotic gradient ektacytometry
Osmotic gradient ektacytometry measures osmotic resistance and hydration and is the key test separating the hydration disorders; the OHSt curve is markedly shifted. The temperature dependence of the cation leak is also informative.
Show evidence (1 reference)
PMID:15071792 SUPPORT Human Clinical
"The key test for diagnosis is osmotic gradient ektacytometry, which measures the osmotic resistance and hydration of the red blood cell; the curve depicting the temperature dependence of the cation leak is also important."
States the role of ektacytometry and the temperature-dependence curve.
Molecular genetic testing of RHAG
Confirmatory sequencing of RHAG, usually within a hereditary haemolytic anaemia gene panel.
Show evidence (1 reference)
PMID:29559519 SUPPORT Human Clinical
"Targeted resequencing revealed two probably causative heterozygous mutations in RHAG (Leu336Ser and Ile149Met)"
Illustrates RHAG sequencing as the confirmatory diagnostic step.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Overhydrated Hereditary Stomatocytosis:

Dehydrated hereditary stomatocytosis (xerocytosis)
Overlapping Features The mirror-image volume disorder with dehydrated rather than overhydrated cells, mainly from PIEZO1 or KCNN4; distinguished by ektacytometry and genetics.
Show evidence (1 reference)
PMID:31308777 SUPPORT Human Clinical
"Dehydrated hereditary stomatocytosis (DHSt) is a nonimmune congenital hemolytic disorder characterized by red blood cell (RBC) dehydration and lysis."
Characterises the dehydrated sibling disorder distinguished from OHSt.
Rh deficiency syndrome (Rh-null, regulator type)
Overlapping Features Recessive biallelic loss-of-function RHAG producing absence of the Rh complex and stomatocytic haemolysis; same gene, opposite mechanism.
Show evidence (1 reference)
PMID:29713289 SUPPORT REVIEW SYNTHESIS Other
"The molecular basis of Rhnull (regulator type) is mutation in both alleles of RHAG, resulting in the absence of RhAG and its closely associated partner proteins from the RBC membrane."
States the biallelic loss-of-function RHAG basis of Rh-null, the opposite-mechanism differential that shares this entry's gene.
🧫

Experimental Models

1
RhAG Xenopus laevis oocyte expression system OTHER
Heterologous expression of wild-type and mutant RhAG in Xenopus oocytes demonstrated the gain of cation conductance: the mutant proteins induced a cation leak about six times greater than wild type.
Pathograph links
RhAG Nonselective Cation Pore Formation recapitulates fidelity: moderate observes: molecular Reproduces the gain-of-function cation conductance of the mutant pore.
Limitations: Oocytes lack the red cell cytoskeleton and the Rh/ankyrin-R/band 3 membrane context, so the heterologous conductance is a boundary-reduced proxy for the erythrocyte membrane leak.
Divergences from the human mechanism
boundary omission qualifying
The oocyte system omits the erythrocyte cytoskeleton and the native Rh membrane complex in which RhAG normally sits, so cell-shape and deformability consequences are not observable in it.
Show evidence (1 reference)
PMID:18931342 SUPPORT In Vitro
"expression of the mutant RhAG proteins induced a leak about 6 times greater than that in wild type."
Quantifies the heterologous cation leak recapitulated by the model.
{ }

Source YAML

click to show 
name: Overhydrated Hereditary Stomatocytosis
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
description: >-
  Overhydrated hereditary stomatocytosis (OHSt), also called hereditary
  hydrocytosis, is a rare autosomal dominant congenital hemolytic anemia caused
  by heterozygous missense substitutions in RHAG, the gene encoding the
  Rh-associated glycoprotein. It is the most leaky member of the cation-leak
  hereditary stomatocytosis family, a group of dominantly inherited anemias in
  which the red cell membrane abnormally conducts the monovalent cations sodium
  and potassium and so loses control of its own volume. In OHSt the mutant RhAG
  is converted from an ammonia-transporting channel into a non-selective cation
  pore: sodium enters faster than potassium leaves, the cell gains cations and
  water, and the swollen, overhydrated erythrocyte takes the cup-shaped
  (stomatocyte) morphology that names the disease. The hydrated cells have a
  high mean corpuscular volume, a low mean corpuscular haemoglobin
  concentration, increased osmotic fragility and reduced deformability, and are
  removed prematurely in the spleen, producing chronic extravascular haemolysis
  with reticulocytosis, unconjugated hyperbilirubinaemia, jaundice,
  splenomegaly and pigment gallstones. Severity ranges from compensated
  haemolysis to transfusion-dependent anaemia.

  Two features dominate management. Iron overload tends to develop even without
  transfusion, and splenectomy carries a severe, sometimes fatal, risk of
  thromboembolic disease and should be avoided. The near-absence of the membrane
  protein stomatin from OHSt red cells, historically the finding that named the
  protein, is a secondary consequence of the disorder rather than its cause: the
  primary lesion is the RhAG mutation.
disease_term:
  preferred_term: overhydrated hereditary stomatocytosis
  term:
    id: MONDO:0008493
    label: overhydrated hereditary stomatocytosis
synonyms:
- hereditary hydrocytosis
- OHSt
- OHS
- stomatocytosis I
- Potassium sodium disorder of erythrocyte
parents:
- familial hemolytic anemia
- hereditary stomatocytosis
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
notes: >-
  Identifiers. MONDO:0008493; OMIM:185000; Orphanet:3203 (the schema has no OMIM
  or Orphanet mapping slot, so these are recorded here); MONDO's causal gene is
  RHAG (hgnc:10006), consistent with the curation.

  Scope and boundaries. OHSt is the RHAG gain-of-function, autosomal dominant
  member of the cation-leak hereditary stomatocytosis family. It is curated as a
  single disease at the named clinical-entity level; the two recurrent
  substitutions (Ile61Arg, Phe65Ser) are modelled as variants rather than
  subtypes because they share one mechanism, presentation and management.

  Deliberate boundary with Rh deficiency syndrome (Rh-null, regulator type),
  which is a separate entry. Both involve RHAG, but in opposite directions:
  Rh-null is biallelic loss of function that removes the Rh membrane complex and
  is recessive, whereas OHSt is a heterozygous gain-of-function that converts
  RhAG into a cation pore and is dominant. Reviews discuss the two together and
  MONDO places both under hereditary stomatocytosis; phenotype and prevalence
  data should not be read across between them.

  Deliberate boundary with dehydrated hereditary stomatocytosis (xerocytosis,
  mainly PIEZO1/KCNN4): that is the mirror-image volume disorder (cell
  dehydration, not overhydration) with different genes and is out of scope here.
  Milder overhydrated-type phenotypes linked to SLC4A1 (AE1/band 3) exist and
  are not covered by this RHAG entry.

  Stomatin. Reduced or absent erythrocyte stomatin (band 7.2b) is a classical
  laboratory correlate of OHSt but is a secondary effect, not the cause; it is
  modelled as a dead-end correlate node, not an upstream lesion.

  Provider note. Built from a thin claude_code deep-research report (three web
  searches, leads only); every claim here was verified against PubMed abstracts
  or the open-access Flatt and Bruce 2018 review full text fetched independently.
pathophysiology:
- name: RHAG Transmembrane Missense Substitution
  biological_scale: MOLECULAR
  description: >-
    The germline lesion. A heterozygous RHAG missense variant substitutes a
    highly conserved transmembrane residue of the Rh-associated glycoprotein.
    Two recurrent substitutions account for most reported families, Ile61Arg
    and Phe65Ser; further RHAG missense variants have been reported, and de novo
    occurrence is documented.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: GAIN_OF_FUNCTION
    allele_type: SNV
    zygosity: HETEROZYGOUS
  molecular_functions:
  - preferred_term: gained monovalent cation channel activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0005261
      label: monoatomic cation channel activity
  genes:
  - preferred_term: RHAG
    term:
      id: hgnc:10006
      label: RHAG
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:18931342
    reference_title: "The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA analysis revealed that the OHSt patients have 1 of 2 heterozygous mutations (t182g, t194c) in RHAG that lead to substitutions of 2 highly conserved amino acids (Ile61Arg, Phe65Ser)."
    explanation: Identifies the two recurrent heterozygous RHAG transmembrane substitutions this node names.
  - reference: PMID:29559519
    reference_title: "Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overhydrated stomatocytosis is a rare autosomal dominant disorder known to cause variably severe haemolytic anaemia due to heterozygous mutations in the RHAG gene."
    explanation: Establishes heterozygous RHAG mutation as the dominant cause.
  downstream:
  - target: RhAG Nonselective Cation Pore Formation
    causal_link_type: DIRECT
    description: The substitution alters the channel so that it conducts cations.
  - target: Loss of RhAG Ammonia Transport
    causal_link_type: DIRECT
    description: The same substitution impairs the protein's native ammonia-transport function.
- name: RhAG Nonselective Cation Pore Formation
  biological_scale: MOLECULAR
  description: >-
    RhAG belongs to the ammonium-transporter family, whose members form
    pore-like structures. Molecular modelling on the homologous Nitrosomonas
    europaea Rh50 protein indicates that the OHSt substitutions widen the central
    channel and convert it into a non-selective cation pore, a qualitative gain
    of a conductance the wild-type protein does not normally provide.
  molecular_functions:
  - preferred_term: monovalent cation pore activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0008324
      label: monoatomic cation transmembrane transporter activity
  evidence:
  - reference: PMID:18931342
    reference_title: "The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We have modeled RhAG on the homologous Nitrosomonas europaea Rh50 protein and shown that these mutations are likely to lead to an opening of the pore."
    explanation: States the structural basis for conversion of RhAG into a cation pore.
  - reference: PMID:29713289
    reference_title: "The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Molecular modeling of the mutant RhAG suggests that the Phe65Ser mutation causes a significant widening of the central transport channel, converting it into a non-selective cation pore (Bruce et al., 2009)."
    explanation: Independent review statement of the pore-conversion mechanism.
  downstream:
  - target: Erythrocyte Monovalent Cation Leak
    causal_link_type: DIRECT
    description: The open pore admits a transmembrane leak of monovalent cations.
- name: Loss of RhAG Ammonia Transport
  biological_scale: MOLECULAR
  description: >-
    A parallel molecular consequence of the same substitution. In red cells RhAG
    acts as an ammonia channel, and the Phe65Ser mutation impairs that native
    transport even as it gains cation conductance. This is a loss-of-function for
    the protein's physiological substrate and is a branch consequence rather than
    part of the haemolytic chain.
  molecular_functions:
  - preferred_term: ammonium channel activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0008519
      label: ammonium channel activity
  evidence:
  - reference: PMID:22012326
    reference_title: "Human RhAG ammonia channel is impaired by the Phe65Ser mutation in overhydrated stomatocytic red cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "this dramatic decrease can be therefore related to the loss of function of the Phe65Ser-mutated RhAG monomer."
    explanation: Reports that the Phe65Ser mutation impairs RhAG ammonia transport.
  - reference: PMID:21849667
    reference_title: "Loss-of-function and gain-of-function phenotypes of stomatocytosis mutant RhAG F65S."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RhAG F65S exhibits gain-of-function phenotypes of increased cation conductance/permeability, and loss-of-function phenotypes of decreased and modified MA/MA(+) transport"
    explanation: Shows the dual gain-of-cation-conductance and loss-of-amine-transport behaviour of the mutant.
- name: Erythrocyte Monovalent Cation Leak
  biological_scale: CELLULAR
  description: >-
    Through the mutant pore the red cell membrane leaks monovalent cations. In
    OHSt this is the most severe leak of the hereditary stomatocytoses, up to
    about 40 times the normal basal rate at body temperature, and it increases
    linearly with temperature, consistent with a constitutively open cation
    channel.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: monovalent cation transmembrane transport
    modifier: INCREASED
    term:
      id: GO:0098655
      label: monoatomic cation transmembrane transport
  evidence:
  - reference: PMID:29713289
    reference_title: "The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most severe cation leak in the hereditary stomatocytoses can be found in a condition known as overhydrated hereditary stomatocytosis (OHSt)."
    explanation: Identifies OHSt as the most severe cation leak of the group.
  - reference: PMID:18931342
    reference_title: "The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overhydrated hereditary stomatocytosis (OHSt) is a rare dominantly inherited hemolytic anemia characterized by a profuse membrane leak to monovalent cations."
    explanation: States the defining membrane cation leak.
  downstream:
  - target: Net Erythrocyte Cation Gain
    causal_link_type: DIRECT
    description: The leak admits sodium and loses potassium across the membrane.
  - target: Secondary Erythrocyte Stomatin Deficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Stomatin is lost from the mature OHSt red cell membrane as a secondary
      effect of the disorder, not as its cause.
- name: Secondary Erythrocyte Stomatin Deficiency
  biological_scale: MOLECULAR
  description: >-
    OHSt red cells are near-completely deficient in the 32 kDa membrane protein
    stomatin (band 7.2b), the finding after which the protein was originally
    named. No mutation in the stomatin gene is found; the protein is
    mis-trafficked and lost on erythroid maturation. This is a secondary
    correlate of the primary RhAG defect, a dead-end branch that does not drive
    the haemolysis.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  cellular_components:
  - preferred_term: erythrocyte plasma membrane
    term:
      id: GO:0005886
      label: plasma membrane
  evidence:
  - reference: PMID:16197460
    reference_title: "Stomatin is mis-trafficked in the erythrocytes of overhydrated hereditary stomatocytosis, and is absent from normal primitive yolk sac-derived erythrocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The 32 kD lipid-raft-associated membrane protein 'stomatin' is deficient from the erythrocyte membrane in the Na+-K+ leaky haemolytic anaemia, overhydrated hereditary stomatocytosis (OHSt)."
    explanation: Documents the stomatin deficiency this node records.
  - reference: PMID:29713289
    reference_title: "The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initially it appeared that the disease must be caused by the absence of this protein, however further investigation revealed that stomatin deficiency was a secondary effect of the disorder (Fricke et al., 2003). It is now known that the primary defect is mutation in RhAG."
    explanation: Establishes that stomatin deficiency is secondary and that RhAG is the primary defect, justifying the correlate framing.
- name: Net Erythrocyte Cation Gain
  biological_scale: CELLULAR
  description: >-
    Because sodium influx through the leak exceeds potassium efflux, the cell
    gains monovalent cations overall. Net intracellular cation content, not any
    single ion, sets erythrocyte volume, so a net gain commits the cell to
    swelling.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: sodium ion import across plasma membrane
    modifier: INCREASED
    term:
      id: GO:0098719
      label: sodium ion import across plasma membrane
  evidence:
  - reference: PMID:25976965
    reference_title: "Disorders of erythrocyte volume homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythrocytes swell when the inward sodium leak exceeds the potassium leak out and shrink when the potassium leak out exceeds the inward sodium leak."
    explanation: States the net-cation-gain rule that makes OHSt an overhydrating leak.
  - reference: PMID:7230721
    reference_title: "Role of the spleen in congenital stomatocytosis associated with high sodium-low potassium erythrocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A girl of German origin with severe congenital hemolytic anemia was found to have overhydrated erythrocytes with markedly increased sodium and reduced potassium concentrations."
    explanation: Directly documents the raised-sodium, lowered-potassium cation profile.
  downstream:
  - target: Compensatory Na/K-ATPase Hyperactivity
    causal_link_type: DIRECT
    description: The cell upregulates active cation pumping to counter the gain.
  - target: Erythrocyte Overhydration and Swelling
    causal_link_type: DIRECT
    description: Net cation gain draws water osmotically into the cell.
- name: Compensatory Na/K-ATPase Hyperactivity
  biological_scale: MOLECULAR
  description: >-
    The Na,K-ATPase runs at greatly increased activity in an attempt to restore
    normal cation gradients against the leak, pumping far more than normal red
    cells. The compensation is insufficient to prevent the net gain and swelling.
  molecular_functions:
  - preferred_term: Na+/K+-ATPase activity
    modifier: INCREASED
    term:
      id: GO:0005391
      label: P-type sodium:potassium-exchanging transporter activity
  evidence:
  - reference: PMID:29713289
    reference_title: "The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is consistent with an increased energy demand in OHSt cells, possibly resulting from elevated activity of the Na,K-ATPase attempting to maintain normal cation gradients."
    explanation: States the compensatory rise in Na,K-ATPase activity.
  - reference: PMID:420735
    reference_title: "Hereditary stomatocytosis: association of low 2,3-diphosphoglycerate with increased cation pumping by the red cell."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary stomatocytes contain 2-10-fold more cation pumps than normal and the increased active cation pumping may explain the high ADP, the low 2,3-diphosphoglycerate concentration and the increased oxygen affinity in this syndrome."
    explanation: Quantifies the increased active cation pumping.
  downstream:
  - target: Erythrocyte Glycolytic Exhaustion
    causal_link_type: DIRECT
    description: Sustained pumping consumes ATP and drives glycolysis to exhaustion.
- name: Erythrocyte Glycolytic Exhaustion
  biological_scale: CELLULAR
  description: >-
    The ATP demand of continual compensatory pumping overworks the only ATP
    source the red cell has, glycolysis. A metabolomic study of OHSt patients
    found glycolysis exhausted, with accumulation of ADP, pyruvate, lactate and
    malate, leaving the cell metabolically vulnerable. A branch consequence of
    the compensation.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: glycolytic process
    modifier: INCREASED
    term:
      id: GO:0006096
      label: glycolytic process
  evidence:
  - reference: PMID:21859730
    reference_title: "Alterations of red blood cell metabolome in overhydrated hereditary stomatocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glycolysis is exhausted with accumulation of ADP, pyruvate, lactate, and malate."
    explanation: Reports the exhausted glycolytic state.
  - reference: PMID:29713289
    reference_title: "The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The authors found that the glycolytic pathway is overactive in OHSt RBCs, with a build-up of glycolysis end products."
    explanation: Independent statement of overactive glycolysis in OHSt.
- name: Erythrocyte Overhydration and Swelling
  biological_scale: CELLULAR
  description: >-
    Water follows the net cation gain into the cell osmotically, so the
    erythrocyte becomes overhydrated and swollen. The overhydration is the direct
    cause of the raised cell volume and lowered intracellular haemoglobin
    concentration that are the laboratory signature of the disease.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: water import into the erythrocyte
    modifier: INCREASED
    term:
      id: GO:0006833
      label: water transport
  evidence:
  - reference: PMID:7230721
    reference_title: "Role of the spleen in congenital stomatocytosis associated with high sodium-low potassium erythrocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A girl of German origin with severe congenital hemolytic anemia was found to have overhydrated erythrocytes with markedly increased sodium and reduced potassium concentrations."
    explanation: Documents the overhydrated erythrocytes produced by the cation gain.
  - reference: PMID:40233304
    reference_title: "The evolving landscape of hereditary stomatocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with alterations in cellular salt and water, ranging from dehydration to overhydration, and the presence of stomatocytes on peripheral blood smear"
    explanation: Links the salt-and-water alteration to the stomatocyte morphology.
  downstream:
  - target: Stomatocyte Shape Change
    causal_link_type: DIRECT
    description: The overhydrated cell adopts the cup-shaped stomatocyte form.
  - target: Increased mean corpuscular volume
    causal_link_type: DIRECT
    description: Swelling raises the mean corpuscular volume.
  - target: Decreased mean corpuscular hemoglobin concentration
    causal_link_type: DIRECT
    description: Added water dilutes intracellular haemoglobin.
- name: Stomatocyte Shape Change
  biological_scale: CELLULAR
  description: >-
    The overhydrated cell loses its biconcave disc shape and becomes a
    cup-shaped stomatocyte with a slit-like central pallor on the blood film,
    with a reduced surface-area-to-volume ratio.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:7230721
    reference_title: "Role of the spleen in congenital stomatocytosis associated with high sodium-low potassium erythrocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cells were stomatocytic with increased osmotic fragility and autohemolysis."
    explanation: Documents the stomatocytic morphology arising in these overhydrated cells.
  downstream:
  - target: Stomatocytosis
    causal_link_type: DIRECT
    description: The shape change is seen on the blood film as stomatocytosis.
  - target: Reduced Erythrocyte Deformability
    causal_link_type: DIRECT
    description: The reduced surface-to-volume ratio stiffens the cell.
- name: Reduced Erythrocyte Deformability
  biological_scale: CELLULAR
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Reduced Erythrocyte Integrity"
  description: >-
    The swollen, low-surface-to-volume stomatocyte is osmotically fragile and
    poorly deformable, and this reduced integrity is what marks it for removal.
    This is the OHSt-specific substitution at the module's reduced-integrity
    node: an overhydration/cation-leak lesion in place of a cytoskeletal protein
    defect.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:21849667
    reference_title: "Loss-of-function and gain-of-function phenotypes of stomatocytosis mutant RhAG F65S."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "OHSt erythrocytes were osmotically fragile, with elevated Na and decreased K contents and increased cation channel-like activity."
    explanation: Reports the osmotic fragility of OHSt erythrocytes behind the reduced integrity.
  downstream:
  - target: Increased red cell osmotic fragility
    causal_link_type: DIRECT
    description: The overhydrated cell lyses at near-physiological tonicity.
  - target: Splenic Sequestration
    causal_link_type: DIRECT
    description: Poorly deformable cells are trapped in the splenic microcirculation.
- name: Splenic Sequestration
  biological_scale: TISSUE
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Premature Erythrocyte Destruction"
  description: >-
    Poorly deformable, metabolically vulnerable stomatocytes are entrapped in the
    acidic, hypoglycaemic environment of the splenic red pulp, where they swell
    further and are destroyed. This is the OHSt case of the module's premature
    extravascular destruction node.
  locations:
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  evidence:
  - reference: PMID:7230721
    reference_title: "Role of the spleen in congenital stomatocytosis associated with high sodium-low potassium erythrocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In acidic, hypoglycemic environment of the splenic pulp the cells become swollen and lysed."
    explanation: Describes splenic entrapment and destruction of the abnormal cells.
  downstream:
  - target: Extravascular Hemolysis
    causal_link_type: DIRECT
    description: Sequestered cells are destroyed outside the circulation.
- name: Extravascular Hemolysis
  biological_scale: ORGANISM
  description: >-
    Premature splenic destruction shortens red cell survival and produces chronic
    extravascular haemolysis, the systemic process that generates the anaemia and
    its products. After splenectomy the anaemia improves but haemolysis persists,
    confirming the spleen as the principal site of destruction rather than the
    cause of the defect.
  evidence:
  - reference: PMID:7230721
    reference_title: "Role of the spleen in congenital stomatocytosis associated with high sodium-low potassium erythrocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After splenectomy anemia improved though increased hemolysis persisted."
    explanation: Confirms extravascular (splenic) haemolysis while showing the defect is intrinsic.
  downstream:
  - target: Hemolytic anemia
    causal_link_type: DIRECT
    description: Red cell loss outstripping production causes the anaemia.
  - target: Reticulocytosis
    causal_link_type: DIRECT
    description: The marrow responds to haemolysis with reticulocytosis.
  - target: Unconjugated hyperbilirubinemia
    causal_link_type: DIRECT
    description: Haem catabolism from destroyed cells raises unconjugated bilirubin.
  - target: Splenomegaly
    causal_link_type: DIRECT
    description: Sustained erythrophagocytosis enlarges the spleen.
  - target: Dysregulated Iron Loading
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic haemolysis contributes to the tendency to iron overload.
- name: Dysregulated Iron Loading
  biological_scale: ORGANISM
  description: >-
    A tendency to iron overload develops in hereditary stomatocytosis even
    without hypertransfusion and irrespective of splenectomy, loading the liver
    and other organs over time.
  evidence:
  - reference: PMID:8639421
    reference_title: "Thrombo-embolic disease after splenectomy for hereditary stomatocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A tendency to iron overload, even without hypertransfusion and irrespective of splenectomy, is evident in many of these patients."
    explanation: Documents the transfusion-independent iron-loading tendency.
  downstream:
  - target: Elevated hepatic iron concentration
    causal_link_type: DIRECT
    description: Accumulated iron raises hepatic iron concentration.
- name: Prothrombotic Erythrocyte Membrane State
  biological_scale: CELLULAR
  description: >-
    The abnormal membrane exposes phosphatidylserine on the outer leaflet,
    disturbing phospholipid asymmetry and creating a prothrombotic red cell
    surface. This underlies the markedly increased thrombotic risk of the
    disease, which becomes severe and sometimes fatal after splenectomy.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:12560240
    reference_title: "Altered erythrocyte endothelial adherence and membrane phospholipid asymmetry in hereditary hydrocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Percentages of hydrocytosis erythrocytes and reticulocytes with phosphatidylserine exposed on the outer surfaces were increased in both patients compared with healthy controls, indicating altered membrane phospholipid asymmetry."
    explanation: Documents phosphatidylserine exposure as the prothrombotic membrane change.
  - reference: PMID:12560240
    reference_title: "Altered erythrocyte endothelial adherence and membrane phospholipid asymmetry in hereditary hydrocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The risk for thrombosis is increased in patients with hereditary hydrocytosis, an uncommon variant of hereditary stomatocytosis."
    explanation: States the increased thrombotic risk this node drives.
  downstream:
  - target: Pulmonary arterial hypertension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Thromboembolic disease, particularly after splenectomy, drives chronic pulmonary hypertension.
  - target: Thromboembolism
    causal_link_type: DIRECT
    description: The prothrombotic state predisposes to thromboembolic events, especially after splenectomy.
phenotypes:
- category: Laboratory
  name: Hemolytic anemia
  description: Chronic haemolytic anaemia of variable severity, from compensated to transfusion-dependent.
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: PMID:29559519
    reference_title: "Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overhydrated stomatocytosis is a rare autosomal dominant disorder known to cause variably severe haemolytic anaemia due to heterozygous mutations in the RHAG gene."
    explanation: States the variably severe haemolytic anaemia of OHSt.
- category: Laboratory
  name: Stomatocytosis
  description: Cup-shaped stomatocytes with a slit-like central pallor on the peripheral blood film.
  phenotype_term:
    preferred_term: Stomatocytosis
    term:
      id: HP:0004446
      label: Stomatocytosis
  evidence:
  - reference: PMID:7230721
    reference_title: "Role of the spleen in congenital stomatocytosis associated with high sodium-low potassium erythrocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cells were stomatocytic with increased osmotic fragility and autohemolysis."
    explanation: Documents the stomatocytic red cells.
- category: Laboratory
  name: Increased mean corpuscular volume
  description: The overhydrated, swollen red cells have a raised mean corpuscular volume (macrocytosis).
  phenotype_term:
    preferred_term: Increased mean corpuscular volume
    term:
      id: HP:0005518
      label: Increased mean corpuscular volume
  evidence:
  - reference: PMID:25976965
    reference_title: Disorders of erythrocyte volume homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Excessive intracellular cations elevate cell water, leading to large, macrocytic erythrocytes (110 to 150 fL) that are osmotically fragile with a low MCHC (24 to 30g/dl)."
    explanation: OHSt-specific statement of the macrocytosis (110-150 fL) from cation-led overhydration.
- category: Laboratory
  name: Decreased mean corpuscular hemoglobin concentration
  description: Added intracellular water dilutes haemoglobin, lowering the mean corpuscular haemoglobin concentration.
  phenotype_term:
    preferred_term: Decreased mean corpuscular hemoglobin concentration
    term:
      id: HP:0025547
      label: Decreased mean corpuscular hemoglobin concentration
  evidence:
  - reference: PMID:25976965
    reference_title: Disorders of erythrocyte volume homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Excessive intracellular cations elevate cell water, leading to large, macrocytic erythrocytes (110 to 150 fL) that are osmotically fragile with a low MCHC (24 to 30g/dl)."
    explanation: OHSt-specific statement of the low MCHC (24-30 g/dl) from cation-led overhydration.
- category: Laboratory
  name: Increased red cell osmotic fragility
  description: Overhydrated cells lyse at near-physiological tonicity, giving increased osmotic fragility.
  phenotype_term:
    preferred_term: Increased red cell osmotic fragility
    term:
      id: HP:0005502
      label: Increased red cell osmotic fragility
  evidence:
  - reference: PMID:7230721
    reference_title: "Role of the spleen in congenital stomatocytosis associated with high sodium-low potassium erythrocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cells were stomatocytic with increased osmotic fragility and autohemolysis."
    explanation: Documents increased osmotic fragility.
- category: Laboratory
  name: Reticulocytosis
  description: Compensatory marrow reticulocytosis in response to chronic haemolysis.
  phenotype_term:
    preferred_term: Reticulocytosis
    term:
      id: HP:0001923
      label: Reticulocytosis
  evidence:
  - reference: PMID:420735
    reference_title: "Hereditary stomatocytosis: association of low 2,3-diphosphoglycerate with increased cation pumping by the red cell."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The relative decrement in 2,3-diphosphoglycerate was even greater when abnormal cells were compared with control cells with similar reticulocytosis."
    explanation: Records reticulocytosis in hereditary stomatocytosis red cells.
- category: Laboratory
  name: Unconjugated hyperbilirubinemia
  description: Increased haem turnover from haemolysis raises unconjugated bilirubin.
  phenotype_term:
    preferred_term: Unconjugated hyperbilirubinemia
    term:
      id: HP:0008282
      label: Unconjugated hyperbilirubinemia
  evidence:
  - reference: PMID:29559519
    reference_title: "Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 26-year-old man with recurring jaundice, splenohepatomegaly and mild chronic haemolytic anaemia with significant stomatocytosis."
    explanation: Reports the jaundice (hyperbilirubinaemia) of a haemolysing OHSt patient.
  sequelae:
  - target: Jaundice
    causal_link_type: DIRECT
    description: Raised bilirubin produces clinical jaundice.
- category: Clinical
  name: Jaundice
  description: Icterus from unconjugated hyperbilirubinaemia, often recurring.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:29559519
    reference_title: "Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 26-year-old man with recurring jaundice, splenohepatomegaly and mild chronic haemolytic anaemia with significant stomatocytosis."
    explanation: Documents recurring jaundice.
- category: Clinical
  name: Splenomegaly
  description: Splenic enlargement from sustained erythrophagocytosis.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:29559519
    reference_title: "Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 26-year-old man with recurring jaundice, splenohepatomegaly and mild chronic haemolytic anaemia with significant stomatocytosis."
    explanation: Reports splenohepatomegaly in an OHSt patient.
- category: Laboratory
  name: Elevated hepatic iron concentration
  description: Transfusion-independent iron overload loading the liver over time.
  phenotype_term:
    preferred_term: Elevated hepatic iron concentration
    term:
      id: HP:0012465
      label: Elevated hepatic iron concentration
  evidence:
  - reference: PMID:8639421
    reference_title: "Thrombo-embolic disease after splenectomy for hereditary stomatocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A tendency to iron overload, even without hypertransfusion and irrespective of splenectomy, is evident in many of these patients."
    explanation: Documents the iron-loading tendency behind elevated hepatic iron.
- category: Clinical
  name: Pulmonary arterial hypertension
  description: >-
    Chronic pulmonary hypertension, reported particularly after splenectomy and
    attributed to thromboembolic disease. The source says "pulmonary hypertension";
    HP:0002092 is the closest available term.
  phenotype_term:
    preferred_term: Pulmonary hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:8639421
    reference_title: Thrombo-embolic disease after splenectomy for hereditary stomatocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In three cases, patients became severely ill with pulmonary hypertension and a fourth developed portal hypertension."
    explanation: Reports severe pulmonary hypertension after splenectomy in hereditary stomatocytosis.
  - reference: PMID:25976965
    reference_title: Disorders of erythrocyte volume homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "splenectomy is contraindicated in most cases due to the high risk of postsplenectomy thromboembolic disease and chronic pulmonary hypertension."
    explanation: Names chronic pulmonary hypertension among post-splenectomy complications.
- category: Clinical
  name: Thromboembolism
  description: >-
    Thromboembolic events, strongly associated with splenectomy and sometimes
    fatal, including pulmonary and portal venous thrombosis.
  phenotype_term:
    preferred_term: Thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  evidence:
  - reference: PMID:8639421
    reference_title: "Thrombo-embolic disease after splenectomy for hereditary stomatocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine cases of hereditary stomatocytosis (HSt) are presented which show documented thrombotic complications after splenectomy."
    explanation: Documents the post-splenectomy thromboembolic complications.
biochemical:
- name: Erythrocyte sodium and potassium content
  notes: >-
    Red cell cation content is abnormal, with markedly increased intracellular
    sodium and decreased potassium, the measurable signature of the cation leak.
  evidence:
  - reference: PMID:21849667
    reference_title: "Loss-of-function and gain-of-function phenotypes of stomatocytosis mutant RhAG F65S."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "OHSt erythrocytes were osmotically fragile, with elevated Na and decreased K contents and increased cation channel-like activity."
    explanation: Reports the elevated-sodium, decreased-potassium red cell cation content.
- name: Erythrocyte 2,3-diphosphoglycerate
  notes: >-
    Red cell 2,3-diphosphoglycerate is reduced and ADP raised, attributed to the
    high rate of active cation pumping.
  evidence:
  - reference: PMID:420735
    reference_title: "Hereditary stomatocytosis: association of low 2,3-diphosphoglycerate with increased cation pumping by the red cell."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary stomatocytes contain 2-10-fold more cation pumps than normal and the increased active cation pumping may explain the high ADP, the low 2,3-diphosphoglycerate concentration and the increased oxygen affinity in this syndrome."
    explanation: States the reduced 2,3-DPG and its attribution to increased active cation pumping.
genetic:
- name: RHAG
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: RHAG
    term:
      id: hgnc:10006
      label: RHAG
  notes: >-
    Heterozygous RHAG missense substitutions cause OHSt by a gain-of-function
    cation-pore mechanism; this is the opposite direction to the biallelic
    loss-of-function RHAG defect of Rh-null (regulator type).
  variants:
  - name: Ile61Arg
    description: >-
      Conserved transmembrane substitution (c.182T>G), one of the two recurrent
      OHSt alleles; gain-of-function cation-pore effect.
    evidence:
    - reference: PMID:18931342
      reference_title: "The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "DNA analysis revealed that the OHSt patients have 1 of 2 heterozygous mutations (t182g, t194c) in RHAG that lead to substitutions of 2 highly conserved amino acids (Ile61Arg, Phe65Ser)."
      explanation: Reports the Ile61Arg allele.
  - name: Phe65Ser
    description: >-
      Conserved transmembrane substitution (c.194T>C) studied functionally as a
      combined gain of cation conductance and loss of ammonia transport.
    evidence:
    - reference: PMID:21849667
      reference_title: "Loss-of-function and gain-of-function phenotypes of stomatocytosis mutant RhAG F65S."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Four patients with overhydrated cation leak stomatocytosis (OHSt) exhibited the heterozygous RhAG missense mutation F65S."
      explanation: Documents the F65S allele in OHSt patients.
  evidence:
  - reference: PMID:18931342
    reference_title: "The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RhAG belongs to the ammonium transporter family of proteins that form pore-like structures."
    explanation: Establishes RhAG identity and the structural family behind the pore mechanism.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    OHSt is autosomal dominant; de novo heterozygous RHAG mutations are
    documented, so a negative family history does not exclude it.
  evidence:
  - reference: PMID:29559519
    reference_title: "Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "establishing RHAG:Ile149Met, novel de novo mutation as probably causative."
    explanation: Documents dominant inheritance with a de novo RHAG mutation.
diagnosis:
- name: Peripheral blood film and red cell indices
  description: >-
    Stomatocytes on the film with macrocytosis (high MCV) and low MCHC, plus
    reticulocytosis and raised unconjugated bilirubin, in a chronic haemolytic
    picture.
  evidence:
  - reference: PMID:29741259
    reference_title: "Primary red cell hydration disorders: Pathogenesis and diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "inappropriate cation leak causes erythrocyte hydration disorders, hemolytic anemia, and characteristic red cell shape abnormalities named stomatocytosis"
    explanation: Describes the blood-film and haemolysis picture used diagnostically.
- name: Osmotic gradient ektacytometry
  description: >-
    Osmotic gradient ektacytometry measures osmotic resistance and hydration and
    is the key test separating the hydration disorders; the OHSt curve is
    markedly shifted. The temperature dependence of the cation leak is also
    informative.
  evidence:
  - reference: PMID:15071792
    reference_title: "The hereditary stomatocytoses: genetic disorders of the red cell membrane permeability to monovalent cations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The key test for diagnosis is osmotic gradient ektacytometry, which measures the osmotic resistance and hydration of the red blood cell; the curve depicting the temperature dependence of the cation leak is also important."
    explanation: States the role of ektacytometry and the temperature-dependence curve.
- name: Molecular genetic testing of RHAG
  description: Confirmatory sequencing of RHAG, usually within a hereditary haemolytic anaemia gene panel.
  evidence:
  - reference: PMID:29559519
    reference_title: "Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted resequencing revealed two probably causative heterozygous mutations in RHAG (Leu336Ser and Ile149Met)"
    explanation: Illustrates RHAG sequencing as the confirmatory diagnostic step.
differential_diagnoses:
- name: Dehydrated hereditary stomatocytosis (xerocytosis)
  description: >-
    The mirror-image volume disorder with dehydrated rather than overhydrated
    cells, mainly from PIEZO1 or KCNN4; distinguished by ektacytometry and
    genetics.
  evidence:
  - reference: PMID:31308777
    reference_title: "Dehydrated hereditary stomatocytosis: clinical perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dehydrated hereditary stomatocytosis (DHSt) is a nonimmune congenital hemolytic disorder characterized by red blood cell (RBC) dehydration and lysis."
    explanation: Characterises the dehydrated sibling disorder distinguished from OHSt.
- name: Rh deficiency syndrome (Rh-null, regulator type)
  description: >-
    Recessive biallelic loss-of-function RHAG producing absence of the Rh complex
    and stomatocytic haemolysis; same gene, opposite mechanism.
  evidence:
  - reference: PMID:29713289
    reference_title: "The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The molecular basis of Rhnull (regulator type) is mutation in both alleles of RHAG, resulting in the absence of RhAG and its closely associated partner proteins from the RBC membrane."
    explanation: >-
      States the biallelic loss-of-function RHAG basis of Rh-null, the opposite-mechanism
      differential that shares this entry's gene.
treatments:
- name: Supportive care and transfusion
  description: >-
    No specific therapy corrects the membrane leak; management is supportive,
    with red cell transfusion when anaemia requires it.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:25976965
    reference_title: Disorders of erythrocyte volume homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "splenectomy is contraindicated in most cases due to the high risk of postsplenectomy thromboembolic disease and chronic pulmonary hypertension."
    explanation: OHSt-relevant statement that management is supportive and splenectomy is contraindicated.
  target_mechanisms:
  - target: Hemolytic anemia
    description: Transfusion corrects the anaemia without addressing the leak.
- name: Splenectomy (contraindicated)
  description: >-
    Splenectomy is specifically contraindicated in OHSt: although the spleen is the
    site of red cell destruction, removing it does not reliably correct the anaemia
    and carries a high risk of post-splenectomy thromboembolic disease and chronic
    pulmonary hypertension. Recorded here so the contraindication is queryable.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  evidence:
  - reference: PMID:25976965
    reference_title: Disorders of erythrocyte volume homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "splenectomy is contraindicated in most cases due to the high risk of postsplenectomy thromboembolic disease and chronic pulmonary hypertension."
    explanation: States the splenectomy contraindication and its basis.
  - reference: PMID:8639421
    reference_title: Thrombo-embolic disease after splenectomy for hereditary stomatocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine cases of hereditary stomatocytosis (HSt) are presented which show documented thrombotic complications after splenectomy."
    explanation: The case series documenting post-splenectomy thrombotic complications behind the contraindication.
- name: Iron chelation therapy
  description: Chelation for iron overload when it develops.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: deferoxamine
      term:
        id: CHEBI:4356
        label: desferrioxamine B
  evidence:
  - reference: PMID:8639421
    reference_title: "Thrombo-embolic disease after splenectomy for hereditary stomatocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A tendency to iron overload, even without hypertransfusion and irrespective of splenectomy, is evident in many of these patients."
    explanation: Establishes the iron overload that chelation addresses.
  target_mechanisms:
  - target: Dysregulated Iron Loading
    description: Chelation lowers systemic iron burden.
- name: Genetic counseling
  description: Counselling for an autosomal dominant condition, including the possibility of de novo mutation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29559519
    reference_title: "Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case illustrates the importance of family screening in interpreting next-generation sequencing (NGS) data"
    explanation: Supports family screening and counselling in diagnosis.
experimental_models:
- name: RhAG Xenopus laevis oocyte expression system
  experimental_model_type: OTHER
  description: >-
    Heterologous expression of wild-type and mutant RhAG in Xenopus oocytes
    demonstrated the gain of cation conductance: the mutant proteins induced a
    cation leak about six times greater than wild type.
  modeled_mechanisms:
  - target: RhAG Nonselective Cation Pore Formation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Reproduces the gain-of-function cation conductance of the mutant pore.
    limitations: >-
      Oocytes lack the red cell cytoskeleton and the Rh/ankyrin-R/band 3 membrane
      context, so the heterologous conductance is a boundary-reduced proxy for the
      erythrocyte membrane leak.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The oocyte system omits the erythrocyte cytoskeleton and the native Rh
        membrane complex in which RhAG normally sits, so cell-shape and
        deformability consequences are not observable in it.
    evidence:
    - reference: PMID:18931342
      reference_title: "The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "expression of the mutant RhAG proteins induced a leak about 6 times greater than that in wild type."
      explanation: Quantifies the heterologous cation leak recapitulated by the model.
references:
- reference: PMID:18931342
  title: "The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein."
- reference: PMID:29713289
  title: "The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells."
- reference: PMID:21859730
  title: "Alterations of red blood cell metabolome in overhydrated hereditary stomatocytosis."
📚

References & Deep Research

References

3
PMID:18931342
The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein.
No top-level findings curated for this source.
PMID:29713289
The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells.
No top-level findings curated for this source.
PMID:21859730
Alterations of red blood cell metabolome in overhydrated hereditary stomatocytosis.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Identifiers. MONDO:0008493; OMIM:185000; Orphanet:3203 (the schema has no OMIM or Orphanet mapping slot, so these are recorded here); MONDO's causal gene is RHAG (hgnc:10006), consistent with the curation. Scope and boundaries. OHSt is the RHAG gain-of-function, autosomal dominant member of the cation-leak hereditary stomatocytosis family. It is curated as a single disease at the named clinical-entity level; the two recurrent substitutions (Ile61Arg, Phe65Ser) are modelled as variants rather than subtypes because they share one mechanism, presentation and management. Deliberate boundary with Rh deficiency syndrome (Rh-null, regulator type), which is a separate entry. Both involve RHAG, but in opposite directions: Rh-null is biallelic loss of function that removes the Rh membrane complex and is recessive, whereas OHSt is a heterozygous gain-of-function that converts RhAG into a cation pore and is dominant. Reviews discuss the two together and MONDO places both under hereditary stomatocytosis; phenotype and prevalence data should not be read across between them. Deliberate boundary with dehydrated hereditary stomatocytosis (xerocytosis, mainly PIEZO1/KCNN4): that is the mirror-image volume disorder (cell dehydration, not overhydration) with different genes and is out of scope here. Milder overhydrated-type phenotypes linked to SLC4A1 (AE1/band 3) exist and are not covered by this RHAG entry. Stomatin. Reduced or absent erythrocyte stomatin (band 7.2b) is a classical laboratory correlate of OHSt but is a secondary effect, not the cause; it is modelled as a dead-end correlate node, not an upstream lesion. Provider note. Built from a thin claude_code deep-research report (three web searches, leads only); every claim here was verified against PubMed abstracts or the open-access Flatt and Bruce 2018 review full text fetched independently.

Create: Overhydrated Hereditary Stomatocytosis · 2026-10-15T04:39:27Z · View source

De-novo curation of overhydrated hereditary stomatocytosis (OHSt, RHAG, MONDO:0008493) from a thin claude_code deep-research report (3 web searches, leads only). Independent PubMed/E-utilities literature work. Backbone PMIDs: 18931342 (Bruce 2009, the two heterozygous RHAG substitutions Ile61Arg/Phe65Ser, 6x oocyte cation leak, Rh50 pore model), 29713289 (Flatt & Bruce 2018 review, most severe leak ~40x, temperature dependence, stomatin secondary, Na,K-ATPase compensation), 21859730 (metabolomics, glycolysis exhausted), 21849667/22012326 (GOF cation conductance + LOF ammonia transport of F65S), 7230721 (splenic sequestration, high Na/low K, osmotic fragility, splenectomy effect), 8639421 (post-splenectomy thromboembolic disease, iron overload), 12560240 (phosphatidylserine exposure, thrombosis), 29559519 (de novo RHAG, clinical picture), 420735 (increased cation pumping, low 2,3-DPG). 15-node atomic pathophysiology chain from the germline RHAG substitution through pore formation, cation leak, net cation gain, compensatory Na/K-ATPase hyperactivity + glycolytic exhaustion, overhydration, stomatocyte shape change, reduced deformability, splenic sequestration and extravascular hemolysis to the phenotypes, plus branch nodes for secondary stomatin deficiency (correlate not cause), iron loading, and prothrombotic membrane state. Conforms to hemolytic_anemia_erythrocyte_destruction module at Reduced Erythrocyte Integrity and Premature Erythrocyte Destruction nodes. 12/12 phenotypes causally connected. Xenopus oocyte experimental model with modeled_mechanisms link (IN_VITRO, BOUNDARY_OMISSION divergence). Validated: just validate-disorders passed (52 snippets, 55 titles, 0 issues); terms, entity-refs, causal-targets, duplicate-keys, block-scalar, coarse-phenotypes, genereviews (NO_CHAPTER, correct), reference-titles all clean. preflight-dr PASS. CI fix: bound GO:0005261 monoatomic cation channel activity (GAIN_OF_FUNCTION) on the RHAG variant node so the gene is grounded, clearing the check-gene-activity-grounding gate (test 3.13). Review round 1 (ai4c-reviewer, changes requested): removed the Cholelithiasis phenotype and its sequela edge (no cached source supports gallstones in OHSt); fixed the Rh-null differential to cite the biallelic-RHAG Rhnull sentence (PMID:29713289) instead of an unrelated ammonium-carrier snippet; swapped MCV and MCHC onto the OHSt-specific macrocytic/low-MCHC sentence (PMID:25976965); moved the supportive-care splenectomy citation off the wrong-disease DHSt review (PMID:31308777) onto PMID:25976965; corrected three evidence_source values (two homology-modelling snippets to COMPUTATIONAL, one patient-genotype snippet to HUMAN_CLINICAL); swapped the 2,3-DPG biochemical snippet onto the sentence that names 2,3-DPG (PMID:420735); added a Pulmonary arterial hypertension phenotype (HP:0002092) downstream of the prothrombotic node and a Splenectomy (contraindicated) treatment entry (NCIT:C15328); added REVIEW_SYNTHESIS quote_role to review-sourced items. 55/55 snippets, 12/12 phenotypes connected, just validate-disorders clean.

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Overhydrated Hereditary Stomatocytosis (OHSt): research report
claude-haiku-5-5, claude-sonnet-5-5 9 citations 2026-10-15T03:59:15.357506

Overhydrated Hereditary Stomatocytosis (OHSt): research report

Scope and verification. I ran three web searches and read search summaries only. I did not open the full text of any paper. These items came back from search results: - Bruce 2009, PMID 18931342. - The Haematologica 2011 metabolomics report. - The 2018 Frontiers review. - The 2019 J Blood Med review (PMC6613601). - The GeneBe/ClinGen-style gene summary.

Everything else is background knowledge and is marked [unverified]. Treat it as a lead until a snippet has been checked with just fetch-reference. I did not retrieve exact abstract quotes, so none appear below. I did not look up any ontology identifier, so every HP, GO, CL, UBERON, CHEBI and NCIT term is a search suggestion by label only and has no CURIE. Look each one up with OAK or the term caches before binding it.

1. Disease information

  • OHSt is a rare, autosomal dominant congenital hemolytic anemia. It belongs to the "cation-leak" hereditary stomatocytoses, together with dehydrated stomatocytosis (xerocytosis, mainly PIEZO1) and the other leak forms. (Frontiers 2018)
  • Red cells are swollen (high MCV, low MCHC). A summary of the pathogenesis says: "The influx of Na+ exceeds the loss of K+ causing water influx and resulting in swollen erythrocytes, hemolysis, and stomatocyte formation." (Frontiers 2018)
  • Identifiers. The MONDO ID you gave (MONDO:0008493) was not checked. OMIM, Orphanet, ICD-10/11 and MeSH identifiers are not verified either; look them up directly. KEGG has an entry (H01979), found by search: KEGG.
  • Synonyms: overhydrated stomatocytosis; hydrocytosis; OHSt; hereditary stomatocytosis with overhydration. Related labels you will meet in the same sources are "Rh-null disease, regulator type" and "Rh deficiency syndrome". These are separate recessive conditions, not synonyms.
  • Data level: the evidence is aggregated disease-level resources and case series. It is not EHR-derived.

2. Etiology

  • Cause: heterozygous missense variants in RHAG, which encodes the Rh-associated glycoprotein. Search results describe overhydrated stomatocytosis as "mainly caused by RHAG gene mutations, and milder forms have been linked to SLC4A1 variants". (J Blood Med 2019, PMC6613601)
  • Landmark paper: Bruce LJ et al., Blood 2009, PMID 18931342, "The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein." (abstract mirror)
  • Search results report that "DNA analysis revealed that the OHSt patients have 1 of 2 heterozygous mutations (t182g, t194c) in RHAG that lead to substitutions of 2 highly conserved amino acids (Ile61Arg, Phe65Ser)."
  • They also report that expressing the mutant proteins in Xenopus oocytes gave a cation leak about six times greater than wild type.
  • Further variants: later reports describe additional RHAG missense variants (for example p.Phe65Ser and others) [unverified]. Please search ClinVar and the literature for the current list.
  • Risk and protective factors:
  • No environmental risk factors or protective factors are known [unverified].
  • No gene–environment interaction data were found.
  • Inheritance is dominant, and many cases are reported as de novo [unverified].
  • Modifiers: not characterised in anything I retrieved.

3. Phenotypes

Clinical features reported for the stomatocytosis group (J Blood Med 2019): - jaundice - pallor - fatigue - splenomegaly - gallstones

Suggested HPO labels (look up IDs): - Hemolytic anemia - Macrocytosis, with high MCV - Low MCHC - Stomatocytosis / abnormal erythrocyte morphology - Splenomegaly - Jaundice - Cholelithiasis - Reticulocytosis - Neonatal hyperbilirubinemia [unverified] - Iron overload [unverified]

Other points: - Severity is variable, from compensated hemolysis to transfusion-dependent anemia. - Onset is neonatal to childhood. - Frequencies and quality-of-life data were not found. Do not invent them. - Perinatal fluid effusions and thrombosis are mentioned in the 2019 review for the stomatocytosis group. I could not tell from the summary which subtype each applies to.

4. Genetic and molecular information

  • Gene: RHAG (chromosome 6p21.3 [unverified]). Use the lowercase hgnc: form in the KB, and look up the HGNC ID rather than writing it from memory.
  • Variants: Ile61Arg (c.182T>G) and Phe65Ser (c.194T>C), both affecting conserved transmembrane residues. (Bruce 2009)
  • Functional consequence: the mutant protein induces a monovalent cation leak. The authors note that RhAG belongs to the ammonium transporter family, whose members form pore-like structures. Their modelling suggested the mutations open that pore. (Bruce 2009)
  • Candidate class: a gain-of-function neomorphic leak, not simple loss of function. Bind functional_impact_category only if a source states it.
  • Allelic disease: biallelic RHAG variants cause Rh-null (regulator type) hemolytic anemia, which is autosomal recessive and a different entity. (GeneBe summary)
  • Origin: germline.
  • Allele frequency: not retrieved.
  • Other genes: SLC4A1 has been linked to milder overhydrated-like phenotypes. (J Blood Med 2019) A second report says OHSt is "frequently linked to mutations in genes that encode components of the band 3 complex, such as RHAG". (Haematologica 2011) Check whether any of these belong in separate entries.
  • Epigenetic or chromosomal features: none identified.

5. Environmental information

None are known. There are no established toxin, lifestyle or infectious triggers in anything retrieved.

6. Mechanism and pathophysiology

Ordered causal chain 1. A heterozygous missense variant in RHAG (Ile61Arg or Phe65Ser) alters a conserved transmembrane residue. This is demonstrated. (Bruce 2009) 2. The altered Rh-associated glycoprotein, which is part of the Rh/ankyrin-R/band 3 complex, forms or opens a pore-like cation pathway. This is demonstrated by Xenopus oocyte expression (about 6-fold leak) and supported by structural modelling. 3. The pathway lets monovalent cations (Na⁺ and K⁺) cross the red cell membrane. 4. Na⁺ influx exceeds K⁺ loss, so net cation gain draws water into the cell. This is demonstrated. (Frontiers 2018) 5. Compensatory Na⁺/K⁺-ATPase activity rises. It consumes ATP and glycolytic capacity, and a 2011 metabolomic study of four patients reported "glycolysis is exhausted", with ADP, pyruvate, lactate and malate accumulating. (Haematologica 2011) That study also suggests transporter abnormalities or unrecognised oxidative stress. This step is inferred from small-sample data. 6. The cells swell, take a cup shape (stomatocytes) and have reduced deformability. Why the cup shape forms is unknown. 7. The spleen removes the abnormal cells, which leads to extravascular hemolysis. This is inferred. 8. Chronic hemolysis causes anemia, jaundice, splenomegaly and pigment gallstones. Iron overload can follow [unverified].

Suggested terms (labels only): - GO: monovalent inorganic cation transport; ammonium transmembrane transport; cell volume homeostasis; potassium ion import across plasma membrane. - CL: erythrocyte. - Cellular component: plasma membrane, and the Rh complex if a GO term exists.

Not available: no transcriptomics, proteomics, single-cell or CRISPR-screen data were found.

7. Anatomical structures affected

  • Primary: red blood cell membrane. Blood and bone marrow are the main systems involved.
  • Secondary: spleen (extravascular hemolysis), liver and biliary tract (gallstones), and liver, heart and endocrine organs if iron overload develops [unverified].
  • Subcellular: plasma membrane.
  • Suggested UBERON terms (labels): blood, spleen, gallbladder.
  • Lateralization: not applicable.

8. Temporal development

  • Onset: congenital, with variable presentation from neonatal to childhood.
  • Course: lifelong, chronic, and stable or episodic with infections [unverified].
  • Remission: none.
  • Critical periods: not described in the retrieved material.

9. Inheritance and population

  • Inheritance: autosomal dominant. Bind the HPO mode-of-inheritance term after looking it up.
  • Prevalence: very rare. The prevalence of the stomatocytosis disorders is uncertain because diagnosis is difficult. (Marcello, Pediatr Blood Cancer 2023) Do not put a number in rate_per_100000 unless Orphanet gives one. Orphanet was not reached.
  • Penetrance, expressivity, founder effects, sex ratio: not retrieved.

10. Diagnostics

  • Blood film: stomatocytes. Reported lab findings, which I did not verify in detail, are high MCV, low MCHC, reticulocytosis and raised bilirubin.
  • Osmotic fragility / ektacytometry: the osmotic gradient ektacytometry curve is shifted. Specialised tests are needed to separate this from other stomatocytoses [unverified].
  • Red cell cation content and flux: high Na⁺ with low K⁺ is described for the group [unverified].
  • Genetic testing: a gene panel for hereditary hemolytic anemia including RHAG, PIEZO1, KCNN4, GARDOS-related genes and SLC4A1 is the usual approach [unverified]. Check GTR and ClinGen for panels.
  • Differential diagnosis: dehydrated stomatocytosis (PIEZO1), hereditary spherocytosis, Rh-null disease, and acquired stomatocytosis (for example alcohol-related).
  • Screening: no newborn screening program is known.

11. Outcome and prognosis

  • Prognosis is variable and survival data were not retrieved.
  • Complications reported for the group include gallstones, iron overload and thrombosis. (J Blood Med 2019)
  • Prognostic factors and biomarkers: not found.

12. Treatment

  • Supportive care: transfusion when needed, folate supplementation [unverified], monitoring for iron overload, and chelation if iron overload develops [unverified]. Suggested NCIT labels: Supportive Care, Red Blood Cell Transfusion, Iron Chelation Therapy.
  • Splenectomy should be avoided. A 2019 review says no specific treatment for symptomatic hemolysis exists and that splenectomy "should be avoided as it seems to aggravate the risk of thrombosis". (J Blood Med 2019) A 1999 case report describes portal vein thrombosis after splenectomy in a child with dehydrated stomatocytosis. (PMID 10445340) A gene summary notes that individuals with OHSt may be prone to iron overload and post-splenectomy thrombotic complications, and that splenectomy may be less beneficial in this form. (GeneBe) The evidence is mostly case reports and case series.
  • No gene therapy, targeted therapy or clinical trial was identified. I did not search ClinicalTrials.gov.
  • Do not add a therapeutic_agent unless a source names one.

13. Prevention

  • Genetic counselling for an autosomal dominant condition.
  • Avoid splenectomy as above, and use thrombosis precautions if it cannot be avoided [unverified].
  • Iron-overload surveillance.
  • No vaccination or public health measures are known to be relevant.

14. Other species

I did not search OMIA, so nothing is established here. A naturally occurring stomatocytosis exists in dogs (Alaskan malamute and Drentse patrijshond) with a different mechanism [unverified]. Check OMIA before using it.

15. Model organisms

  • The Xenopus laevis oocyte expression system was used to show the 6-fold cation leak. This is a heterologous in vitro system, so grade it IN_VITRO and not MODEL_ORGANISM. (Bruce 2009)
  • I found no knockin mouse, zebrafish or iPSC model of OHSt. Check MGI and the Alliance of Genome Resources before stating that none exists.
  • Limitations to record: oocytes lack the red cell cytoskeleton and Rh/ankyrin-R/band 3 complex context, so they are a boundary-omission divergence.

Gaps to close before curation

  1. Pull the Bruce 2009 abstract with just fetch-reference PMID:18931342 and quote it verbatim.
  2. Look up the Orphanet and OMIM entries for the identifiers, prevalence and phenotype frequencies.
  3. Read GeneReviews and ClinGen for the RHAG gene–disease validity tier. Copy the tier, do not assign it.
  4. Look up every ontology CURIE with OAK.
  5. Confirm the splenectomy claims with abstract-level snippets. The 2019 review and the 1999 case report concern the wider stomatocytosis group, so check what applies to OHSt specifically.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 5
Resolved 5
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 0
Quoted claims found in source 0
Quoted claims not found in source 0
Quoted claims with nothing to check against 1
References weighed for topical relevance 5
On topic 2
Off topic 0

Quotes that could not be checked

There was no text to compare these against, so they are neither confirmed nor contradicted:

  • DOI:10.3389/fphys.2018.00367: "The influx of Na+ exceeds the loss of K+ causing water influx and resulting in swollen erythrocytes, hemolysis, and stomatocyte formation."
  • Reference resolved but exposes no abstract or full text to search

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 1
Resolved 1
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0

Every term resolved, and every label the report gave matched.