🔗

Mappings

MONDO

MONDO:0017319 hereditary elliptocytosis

Orphanet lists MONDO:0017319 as an exact cross-reference for hereditary elliptocytosis.

ICD-10-CM

ICD10CM:D58.1 Hereditary elliptocytosis

Orphanet lists ICD-10 D58.1 as an exact cross-reference for hereditary elliptocytosis.

📘

Definitions

1

Orphanet disease definition

Orphanet defines hereditary elliptocytosis as a rare heterogeneous red cell membrane disorder with manifestations ranging from mild or asymptomatic disease to severe transfusion-dependent hemolytic anemia.

CASE_DEFINITION

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"Hereditary elliptocytosis (HE) is a rare clinically and genetically heterogeneous disorder of the red cell membrane characterized by manifestations ranging from mild to severe transfusion-dependent hemolytic anemia but with the majority of patients being asymptomatic."

Orphanet's definition supports the disease scope and clinical severity range used in this entry.

👪

Inheritance

2

Autosomal dominant HP:0000006

Autosomal dominant inheritance

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"Autosomal dominant"

Orphanet records autosomal dominant inheritance for hereditary elliptocytosis.

Autosomal recessive HP:0000007

Autosomal recessive inheritance

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"Autosomal recessive"

Orphanet records autosomal recessive inheritance for hereditary elliptocytosis.

◆

Subtypes

5

Elliptocytosis 1 (EPB41-related) MONDO:0012731

EPB41 hgnc:3377

EPB41-related hereditary elliptocytosis, involving quantitative or qualitative defects of erythrocyte protein 4.1R.

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"EPB41 | erythrocyte membrane protein band 4.1 | hgnc:3377 | Disease-causing germline mutation(s) in"

Orphanet lists EPB41 as a disease-causing gene for hereditary elliptocytosis.

Elliptocytosis 2 (SPTA1-related) MONDO:0007533

SPTA1 hgnc:11272

SPTA1-related hereditary elliptocytosis, often involving alpha-spectrin self-association defects and variable severity depending on allele combination.

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"SPTA1 | spectrin alpha, erythrocytic 1 | hgnc:11272 | Disease-causing germline mutation(s) in"

Orphanet lists SPTA1 as a disease-causing gene for hereditary elliptocytosis.

Elliptocytosis 3 MONDO:0054780

OMIM-linked hereditary elliptocytosis subtype described by MONDO as a child of hereditary elliptocytosis.

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"OMIM:617948 | Broader"

Orphanet includes OMIM:617948 among broader cross-references for hereditary elliptocytosis.

Southeast Asian ovalocytosis MONDO:0008165

SLC4A1 hgnc:11027

SLC4A1-related ovalocytic red-cell membrane disorder classified by MONDO as both hereditary elliptocytosis and hereditary stomatocytosis.

Show evidence (1 reference)

PMID:32411010 SUPPORT BACKGROUND Human Clinical

"SAO is caused by the heterozygous deletion of codons 400–408 in SLC4A1."

Names SLC4A1 as the gene and gives the specific heterozygous in-frame deletion that defines this subtype. The quote restates the founding genetic reports rather than this paper's own culture experiments, hence quote_role BACKGROUND.

Hemolytic anemia with thermal sensitivity of red cells MONDO:0009334

OMIM-linked hereditary elliptocytosis subtype characterized by thermally sensitive red cells and hemolytic anemia.

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"OMIM:235370 | Broader"

Orphanet includes OMIM:235370 among broader cross-references for hereditary elliptocytosis.

⚙

Pathophysiology

6

Red Cell Cytoskeleton Protein Defects

Pathogenic variants in erythrocyte membrane-skeleton genes affect spectrin, protein 4.1R, or glycophorin C components that maintain red cell membrane shape and mechanical resilience.

erythrocyte CL:0000232

EPB41 hgnc:3377 GYPC hgnc:4704 SPTA1 hgnc:11272 SPTB hgnc:11274

cortical actin cytoskeleton organization GO:0030866 ⚠ ABNORMAL

structural constituent of cytoskeleton GO:0005200 ⚠ ABNORMAL

Downstream

Weakened Horizontal Cytoskeletal Associations Spectrin, protein 4.1R, and related membrane-skeleton defects weaken the horizontal cytoskeletal network underlying the erythrocyte membrane.

Show evidence (3 references)

ORPHA:288 SUPPORT Other

"SPTA1 | spectrin alpha, erythrocytic 1 | hgnc:11272 | Disease-causing germline mutation(s) in"

Orphanet identifies SPTA1 as a disease-causing hereditary elliptocytosis gene.

ORPHA:288 SUPPORT Other

"SPTB | spectrin beta, erythrocytic | hgnc:11274 | Disease-causing germline mutation(s) in"

Orphanet identifies SPTB as a disease-causing hereditary elliptocytosis gene.

PMID:3748797 SUPPORT Human Clinical

"The major determinant of membrane shape and stability is a proteinaceous meshwork named membrane skeleton, composed mainly of spectrin, actin, protein 4.1 and ankyrin."

This clinical series identifies the membrane skeleton as the determinant of red-cell shape and stability.

Weakened Horizontal Cytoskeletal Associations

Mutations affecting spectrin self-association or protein 4.1R-mediated junctional complexes weaken horizontal links in the erythrocyte cytoskeleton.

erythrocyte CL:0000232

cortical actin cytoskeleton organization GO:0030866 ⚠ ABNORMAL

Downstream

Reduced Erythrocyte Deformability and Stability Horizontal cytoskeletal weakness reduces mechanical stability and red-cell deformability.

Show evidence (3 references)

PMID:27667160 SUPPORT Human Clinical

"The resulting defects alter the horizontal cytoskeletal associations and affect RBC membrane stability and deformability causing shortened RBC survival."

This directly supports horizontal cytoskeletal association defects as the key intermediate mechanism.

PMID:3748797 SUPPORT Human Clinical

"We observed two types of membrane defects in the 38 patients studied: 24 patients (13 kindreds) exhibited spectrin self-association defect (type I HE) and 14 patients (6 kindreds) displayed deficiency in protein 4.1."

This 38-case series supports spectrin self-association and protein 4.1 deficiency as observed membrane defects in hereditary elliptocytosis.

PMID:3692477 SUPPORT Human Clinical

"Our studies revealed a defective ability of spectrin to self-associate"

This family study supports defective spectrin self-association as a shared molecular defect across HE/HPP-spectrum phenotypes.

Reduced Erythrocyte Deformability and Stability

Defective cytoskeletal mechanics decrease erythrocyte deformability and mechanical stability, reducing red-cell survival and producing abnormal osmotic-gradient ektacytometry profiles.

erythrocyte CL:0000232

erythrocyte homeostasis GO:0034101 ⚠ ABNORMAL

Downstream

Elliptocytic and Poikilocytic Red Cell Morphology Reduced membrane stability contributes to elliptocytic and poikilocytic red-cell morphology.

Shortened Red Cell Survival and Hemolysis Decreased deformability and stability shorten erythrocyte survival and produce hemolysis in symptomatic cases.

Show evidence (2 references)

PMID:3748797 SUPPORT Human Clinical

"A study of red cell deformability using an ektacytometer revealed that the cell deformability under isotonic conditions was decreased in all HE patients."

This supports decreased red-cell deformability as a functional consequence in hereditary elliptocytosis.

PMID:27667160 SUPPORT Human Clinical

"The typical HE ektacytometry curve is trapezoidal with decreased RBC deformability"

The ektacytometry finding supports reduced deformability as a characteristic biomechanical abnormality.

SAO Band 3 Over-Association and Increased Membrane Rigidity

The Southeast Asian ovalocytosis arm of this entry does not run through the horizontal membrane-skeleton chain above. The SAO allele of SLC4A1 deletes nine residues at the junction of the cytoplasmic and transmembrane domains of band 3; the mutant protein forms higher-order oligomers and binds the underlying skeleton more tightly than wild-type band 3. The mechanical consequence is an over-stiffened membrane, which is the opposite direction of change from the weakened spectrin and protein 4.1R linkages that produce the other subtypes, even though both routes reduce deformability and both end in an abnormally shaped red cell.

erythrocyte CL:0000232

SLC4A1 hgnc:11027

band 3 homooligomerization GO:0051260 ↑ INCREASED

structural constituent of cytoskeleton GO:0005200 ⚠ ABNORMAL

Downstream

Elliptocytic and Poikilocytic Red Cell Morphology The rigid, over-cross-linked SAO membrane produces the ovalocytic red-cell morphology the subtype is named for.

Show evidence (2 references)

PMID:32411010 SUPPORT BACKGROUND In Vitro

"SAO band 3 is believed to form higher oligomers and associate with the underlying erythrocyte cytoskeleton more readily than wild type band 3, offering an explanation for the observed increase in membrane rigidity in these cells"

States the oligomerization and skeletal over-association that this node asserts, and the increased membrane rigidity that follows from it. The sentence summarises earlier biophysical work on patient red cells rather than this paper's own experiments, hence quote_role BACKGROUND.

PMID:32411010 SUPPORT BACKGROUND In Vitro

"The deletion occurs at the boundary between the cytoplasmic N-terminal domain and the transport-active transmembrane domain. This mutation abolishes the anion exchange activity of band 3"

Locates the deleted residues at the cytoplasmic/transmembrane boundary, as this node's description states, and records that the mutant protein no longer exchanges anions.

Elliptocytic and Poikilocytic Red Cell Morphology

Destabilized red-cell membrane architecture produces elliptical erythrocytes and, in more severe forms, poikilocytosis and red-cell fragmentation on peripheral smear.

erythrocyte CL:0000232

erythrocyte homeostasis GO:0034101 ⚠ ABNORMAL

Downstream

Abnormal Erythrocyte Morphology

Elliptocytosis

Increased Red Cell Osmotic Fragility

Poikilocytosis

Stomatocytosis

Show evidence (1 reference)

PMID:27667160 SUPPORT Human Clinical

"The clinical diagnosis of HE and HPP relies on identifying abnormal RBC morphology on peripheral blood smear (elliptocytes, poikilocytosis and fragmented RBCs)"

This supports abnormal red-cell morphology as a characteristic finding and diagnostic basis.

Shortened Red Cell Survival and Hemolysis

Reduced membrane stability and deformability shorten erythrocyte survival. This drives variable hemolysis, ranging from compensated or asymptomatic disease to severe transfusion-dependent anemia.

erythrocyte CL:0000232

erythrocyte homeostasis GO:0034101 ⚠ ABNORMAL

Downstream

Hemolytic Anemia

Reticulocytosis

Congenital Hemolytic Anemia

Hydrops fetalis

Neonatal Hyperbilirubinemia

Prolonged neonatal jaundice

Hyperbilirubinemia

Jaundice

Splenomegaly

Cholelithiasis

Fatigue

Exercise intolerance

Skin ulcer

Show evidence (2 references)

PMID:27667160 SUPPORT Human Clinical

"The resulting defects alter the horizontal cytoskeletal associations and affect RBC membrane stability and deformability causing shortened RBC survival."

This explicitly links cytoskeletal defects to shortened red-cell survival.

PMID:30504335 SUPPORT Other

"Membrane structural defects lead to hereditary spherocytosis (HS) and hereditary elliptocytosis (HE)"

This review supports classifying hereditary elliptocytosis as a red-cell membrane structural disorder causing inherited hemolytic anemia.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

18

Blood 8

Abnormal Erythrocyte Morphology OBLIGATE HP:0001877

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0001877 | Abnormal erythrocyte morphology | Obligate (100%)"

Orphanet lists abnormal erythrocyte morphology as obligate.

Elliptocytosis FREQUENT HP:0004445

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"HP:0004445 | Elliptocytosis | Frequent (79-30%)"

Orphanet lists elliptocytosis as a frequent phenotype.

PMID:27667160 SUPPORT Human Clinical

"Elliptocytes were noted on blood smear and HE was suspected."

This patient-series statement supports elliptocytes on smear as a diagnostic clue.

Increased Red Cell Osmotic Fragility FREQUENT HP:0005502

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"HP:0005502 | Increased red cell osmotic fragility | Frequent (79-30%)"

Orphanet lists increased red cell osmotic fragility as frequent.

PMID:27667160 SUPPORT Human Clinical

"The resulting ektacytometry curve reflects biomechanical properties of the RBCs including osmotic fragility, surface-to-volume ratio, cytoskeleton flexibility, and cytoplasmic viscosity."

This supports osmotic-gradient ektacytometry as a measure of osmotic fragility and red-cell membrane biomechanics.

Hemolytic Anemia OCCASIONAL HP:0001878

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"HP:0001878 | Hemolytic anemia | Occasional (29-5%)"

Orphanet lists hemolytic anemia as an occasional phenotype.

PMID:27667160 SUPPORT Human Clinical

"Patient # 1 (Figure 2) was a 12-month-old Caucasian boy who had presented with mild hemolytic anemia at 4 months of age"

The patient series documents mild hemolytic anemia in a patient with hereditary elliptocytosis.

Reticulocytosis OCCASIONAL HP:0001923

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0001923 | Reticulocytosis | Occasional (29-5%)"

Orphanet lists reticulocytosis as an occasional phenotype.

Congenital Hemolytic Anemia OCCASIONAL HP:0004804

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"HP:0004804 | Congenital hemolytic anemia | Occasional (29-5%)"

Orphanet lists congenital hemolytic anemia as an occasional phenotype.

PMID:27667160 SUPPORT Human Clinical

"HPP is typically diagnosed in patients with family history of HE but presents with increased severity, frequently with transfusion requirement in infancy or, rarely, long-term transfusion-dependence."

The severe end of the HE/HPP spectrum supports congenital or infancy-onset hemolytic anemia.

Poikilocytosis OCCASIONAL HP:0004447

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"HP:0004447 | Poikilocytosis | Occasional (29-5%)"

Orphanet lists poikilocytosis as an occasional phenotype.

PMID:27667160 SUPPORT Human Clinical

"Peripheral blood smears demonstrate increased poikilocytosis and RBC fragmentation compared to HE."

The HE/HPP case series supports poikilocytosis as a severe-spectrum smear finding.

Stomatocytosis OCCASIONAL HP:0004446

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0004446 | Stomatocytosis | Occasional (29-5%)"

Orphanet lists stomatocytosis as an occasional phenotype.

Cardiovascular 1

Splenomegaly OCCASIONAL HP:0001744

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0001744 | Splenomegaly | Occasional (29-5%)"

Orphanet lists splenomegaly as an occasional phenotype.

Digestive 3

Prolonged neonatal jaundice OCCASIONAL HP:0006579

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0006579 | Prolonged neonatal jaundice | Occasional (29-5%)"

Orphanet lists prolonged neonatal jaundice as an occasional phenotype.

Jaundice OCCASIONAL HP:0000952

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0000952 | Jaundice | Occasional (29-5%)"

Orphanet lists jaundice as an occasional phenotype.

Cholelithiasis VERY_RARE HP:0001081

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0001081 | Cholelithiasis | Very rare (<4-1%)"

Orphanet lists cholelithiasis as a very rare phenotype.

Integument 1

Skin ulcer OCCASIONAL HP:0200042

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0200042 | Skin ulcer | Occasional (29-5%)"

Orphanet lists skin ulcer as an occasional phenotype.

Metabolism 3

Hydrops fetalis VERY_RARE HP:0001789

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0001789 | Hydrops fetalis | Very rare (<4-1%)"

Orphanet lists hydrops fetalis as a very rare phenotype.

Neonatal Hyperbilirubinemia OCCASIONAL HP:0003265

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"HP:0003265 | Neonatal hyperbilirubinemia | Occasional (29-5%)"

Orphanet lists neonatal hyperbilirubinemia as an occasional phenotype.

PMID:27667160 SUPPORT Human Clinical

"Both patients with the missense mutation p.D791E were asymptomatic at baseline but had ektacytometry profile consistent with mild HE; one presented with neonatal hyperbilirubinemia"

The HE/HPP case series documents neonatal hyperbilirubinemia in a mild HE patient.

Hyperbilirubinemia OCCASIONAL HP:0002904

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0002904 | Hyperbilirubinemia | Occasional (29-5%)"

Orphanet lists hyperbilirubinemia as an occasional phenotype.

Constitutional 2

Fatigue OCCASIONAL HP:0012378

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0012378 | Fatigue | Occasional (29-5%)"

Orphanet lists fatigue as an occasional phenotype.

Exercise intolerance OCCASIONAL HP:0003546

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0003546 | Exercise intolerance | Occasional (29-5%)"

Orphanet lists exercise intolerance as an occasional phenotype.

🧬

Genetic Associations

5

EPB41 (Causative)

Gene: EPB41 hgnc:3377

Autosomal dominant

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"EPB41 | erythrocyte membrane protein band 4.1 | hgnc:3377 | Disease-causing germline mutation(s) in"

Orphanet lists EPB41 as a disease-causing gene for hereditary elliptocytosis.

PMID:27667160 SUPPORT Human Clinical

"All 15 patients were found to have mutations in SPTA1, SPTB or EPB41"

This patient series found EPB41 among the causative genes in clinically suspected HE/HPP.

GYPC (Causative)

Gene: GYPC hgnc:4704

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"GYPC | glycophorin C (Gerbich blood group) | hgnc:4704 | Disease-causing germline mutation(s) in"

Orphanet lists GYPC as a disease-causing gene for hereditary elliptocytosis.

PMID:9037349 SUPPORT Other

"HE stems from changes in the SPTA1, SPTB, EL1 and (exceptionally) GPYC genes that encode spectrin alpha- and beta- chains, protein 4.1 and glycophorin C/D, respectively."

This review uses older GPYC nomenclature for GYPC and supports glycophorin C/D as a rare HE gene product.

SPTA1 (Causative)

Gene: SPTA1 hgnc:11272 gene page

Autosomal dominant Autosomal recessive

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"SPTA1 | spectrin alpha, erythrocytic 1 | hgnc:11272 | Disease-causing germline mutation(s) in"

Orphanet lists SPTA1 as a disease-causing gene for hereditary elliptocytosis.

PMID:27667160 SUPPORT Human Clinical

"Ten patients had mutations in SPTA1 only"

This patient series supports SPTA1 as a common causative gene in HE/HPP.

SPTB (Causative)

Gene: SPTB hgnc:11274 gene page

Autosomal dominant Autosomal recessive

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"SPTB | spectrin beta, erythrocytic | hgnc:11274 | Disease-causing germline mutation(s) in"

Orphanet lists SPTB as a disease-causing gene for hereditary elliptocytosis.

PMID:27667160 SUPPORT Human Clinical

"one in SPTB, one was compound heterozygous for mutations affecting both α- and β-spectrin and one had a mutation in EPB41."

This series supports SPTB as a causative gene in the HE/HPP spectrum.

SLC4A1 (Causative)

Gene: SLC4A1 hgnc:11027 gene page relationship_type: CAUSATIVE

Autosomal dominant

Show evidence (1 reference)

PMID:32411010 SUPPORT BACKGROUND Human Clinical

"SAO is caused by the heterozygous deletion of codons 400–408 in SLC4A1."

Establishes SLC4A1 as the causative gene of Southeast Asian ovalocytosis and the heterozygous in-frame deletion allele responsible.

🗃️

External Assertions

1

Orphanet hereditary elliptocytosis record

Orphanet Structured disease record ORPHA:288

Orphanet structured record for hereditary elliptocytosis, including curated cross-references to MONDO, ICD-10, ICD-11, OMIM, MeSH, MedDRA, NIH rare-disease, and UMLS identifiers.

Show evidence (3 references)

ORPHA:288 SUPPORT Other

"MONDO:0017319 | Exact"

The Orphanet cross-reference table exactly maps ORPHA:288 to MONDO:0017319.

ORPHA:288 SUPPORT Other

"ICD-10:D58.1 | Exact"

The Orphanet cross-reference table exactly maps ORPHA:288 to ICD-10 D58.1.

ORPHA:288 SUPPORT Other

"UMLS:C0013902 | Exact"

The Orphanet cross-reference table exactly maps ORPHA:288 to UMLS C0013902.

💊

Medical Actions

2

Splenectomy

Action: splenectomy Ontology label: Splenectomy NCIT:C15328

Splenectomy can ameliorate anemia in selected symptomatic patients with red-cell membrane structural disorders by increasing circulating red-cell lifespan; patient selection must consider severity and long-term risks.

Mechanism Target:

MODULATES Shortened Red Cell Survival and Hemolysis — Splenectomy can ameliorate anemia by increasing circulating red-cell life span.

Show evidence (1 reference)

PMID:30504335 SUPPORT Other

"splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span."

This review supports splenectomy as an anemia-ameliorating treatment for HS and HE membrane structural defects.

Red Blood Cell Transfusion

Action: blood transfusion Ontology label: Blood Transfusion NCIT:C15192

Red-cell transfusion is supportive therapy for severe congenital or transfusion-dependent hemolytic anemia in the severe HE/HPP spectrum.

Target Phenotypes: hemolytic anemia HP:0001878

Show evidence (2 references)

ORPHA:288 SUPPORT Other

"manifestations ranging from mild to severe transfusion-dependent hemolytic anemia"

Orphanet's definition supports transfusion-dependent hemolytic anemia as the severe end of the disease spectrum.

PMID:27667160 SUPPORT Human Clinical

"HPP is typically diagnosed in patients with family history of HE but presents with increased severity, frequently with transfusion requirement in infancy or, rarely, long-term transfusion-dependence."

This supports transfusion as supportive management for severe HE/HPP-spectrum presentations.

🔬

Biochemical Markers

3

Red cell osmotic fragility (Increased)

Context: Reflected by abnormal osmotic-gradient ektacytometry and increased red-cell osmotic fragility in affected individuals.

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0005502 | Increased red cell osmotic fragility | Frequent (79-30%)"

Orphanet supports increased osmotic fragility as a frequent laboratory feature.

Red cell deformability (Decreased)

Context: Ektacytometry shows decreased erythrocyte deformability, reflecting impaired membrane-skeleton mechanics.

Show evidence (1 reference)

PMID:3748797 SUPPORT Human Clinical

"A study of red cell deformability using an ektacytometer revealed that the cell deformability under isotonic conditions was decreased in all HE patients."

The clinical series directly reports decreased red-cell deformability in HE.

Bilirubin (Elevated)

Context: Variable; may be elevated in patients with hemolysis.

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"HP:0002904 | Hyperbilirubinemia | Occasional (29-5%)"

Orphanet lists hyperbilirubinemia as an occasional feature.

🔬

Diagnosis

3

Peripheral blood smear morphology

Examination of peripheral blood smear for elliptocytes, poikilocytosis, and red-cell fragmentation supports clinical diagnosis.

clinical assessment NCIT:C124351

Results: Elliptocytes and related abnormal RBC morphology support hereditary elliptocytosis.

Show evidence (1 reference)

PMID:27667160 SUPPORT Human Clinical

"The clinical diagnosis of HE and HPP relies on identifying abnormal RBC morphology on peripheral blood smear (elliptocytes, poikilocytosis and fragmented RBCs)"

This directly supports peripheral-smear morphology as a diagnostic approach.

Osmotic gradient ektacytometry

Osmotic-gradient ektacytometry measures red-cell biomechanical properties and can show the characteristic trapezoidal HE curve with decreased deformability.

clinical assessment NCIT:C124351

Results: A trapezoidal curve with decreased RBC deformability supports hereditary elliptocytosis.

Show evidence (2 references)

PMID:27667160 SUPPORT Human Clinical

"Ektacytometry is an objective reference technique that can aid in the diagnosis of RBC membrane disorders"

This supports ektacytometry as an objective diagnostic technique for red-cell membrane disorders.

PMID:27667160 SUPPORT Human Clinical

"The typical HE ektacytometry curve is trapezoidal with decreased RBC deformability"

This describes the characteristic ektacytometry profile for hereditary elliptocytosis.

Molecular genetic testing

Targeted or next-generation sequencing of red-cell membrane disorder genes can confirm or identify the molecular diagnosis, especially when transfusion obscures the red-cell phenotype.

genetic testing NCIT:C15709

Results: Pathogenic variants in EPB41, GYPC, SPTA1, or SPTB support molecular diagnosis.

Show evidence (1 reference)

PMID:27667160 SUPPORT Human Clinical

"Targeted sequencing using a Next-Generation sequencing platform is an efficient approach to identify or confirm the diagnosis of HE and HPP"

This supports genetic testing as a diagnostic confirmation method.

📈

Progression

1

Onset

Age: All ages

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"Age of onset: All ages"

Orphanet records all ages as the age-of-onset category for hereditary elliptocytosis.

📊

Prevalence

1

Worldwide

Point Prevalence 10.0–50.0 per 100,000 1–9 per 10,000

Orphanet reports a worldwide point-prevalence class of 1-5 per 10,000.

Show evidence (1 reference)

ORPHA:288 SUPPORT Other

"1-5 / 10 000 | Worldwide | Point prevalence | EXPERT"

The Orphanet epidemiology table provides the worldwide point-prevalence class.

{ }

Source YAML

click to show

name: Hereditary Elliptocytosis
creation_date: "2026-05-09T11:51:13Z"
description: >
  Hereditary elliptocytosis is a clinically and genetically heterogeneous
  red-cell membrane disorder in which defects in erythrocyte cytoskeleton
  proteins weaken horizontal membrane-skeleton interactions. Most affected
  individuals are asymptomatic or mildly affected, but severe forms can cause
  congenital or transfusion-dependent hemolytic anemia.
category: Mendelian
parents:
- Hematological Disease
- Genetic Disease
disease_term:
  preferred_term: hereditary elliptocytosis
  term:
    id: MONDO:0017319
    label: hereditary elliptocytosis
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:D58.1
      label: Hereditary elliptocytosis
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:288
    mapping_justification: Orphanet lists ICD-10 D58.1 as an exact cross-reference for hereditary elliptocytosis.
    consistency:
    - reference: ORPHA:288
      consistent: CONSISTENT
      notes: "ICD-10:D58.1 | Exact"
  mondo_mappings:
  - term:
      id: MONDO:0017319
      label: hereditary elliptocytosis
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:288
    mapping_justification: Orphanet lists MONDO:0017319 as an exact cross-reference for hereditary elliptocytosis.
    consistency:
    - reference: ORPHA:288
      consistent: CONSISTENT
      notes: "MONDO:0017319 | Exact"
definitions:
- name: Orphanet disease definition
  definition_type: CASE_DEFINITION
  description: >
    Orphanet defines hereditary elliptocytosis as a rare heterogeneous red cell
    membrane disorder with manifestations ranging from mild or asymptomatic
    disease to severe transfusion-dependent hemolytic anemia.
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hereditary elliptocytosis (HE) is a rare clinically and genetically heterogeneous disorder of the red cell membrane characterized by manifestations ranging from mild to severe transfusion-dependent hemolytic anemia but with the majority of patients being asymptomatic."
    explanation: Orphanet's definition supports the disease scope and clinical severity range used in this entry.
external_assertions:
- name: Orphanet hereditary elliptocytosis record
  source: Orphanet
  assertion_type: Structured disease record
  external_id: ORPHA:288
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=288
  description: >
    Orphanet structured record for hereditary elliptocytosis, including curated
    cross-references to MONDO, ICD-10, ICD-11, OMIM, MeSH, MedDRA, NIH rare-disease, and
    UMLS identifiers.
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0017319 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:288 to MONDO:0017319.
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-10:D58.1 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:288 to ICD-10 D58.1.
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UMLS:C0013902 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:288 to UMLS C0013902.
has_subtypes:
- name: EL1
  display_name: Elliptocytosis 1 (EPB41-related)
  subtype_term:
    preferred_term: elliptocytosis 1
    term:
      id: MONDO:0012731
      label: elliptocytosis 1
  description: >
    EPB41-related hereditary elliptocytosis, involving quantitative or
    qualitative defects of erythrocyte protein 4.1R.
  genes:
  - preferred_term: EPB41
    term:
      id: hgnc:3377
      label: EPB41
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EPB41 | erythrocyte membrane protein band 4.1 | hgnc:3377 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists EPB41 as a disease-causing gene for hereditary elliptocytosis.
- name: EL2
  display_name: Elliptocytosis 2 (SPTA1-related)
  subtype_term:
    preferred_term: elliptocytosis 2
    term:
      id: MONDO:0007533
      label: elliptocytosis 2
  description: >
    SPTA1-related hereditary elliptocytosis, often involving alpha-spectrin
    self-association defects and variable severity depending on allele
    combination.
  genes:
  - preferred_term: SPTA1
    term:
      id: hgnc:11272
      label: SPTA1
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPTA1 | spectrin alpha, erythrocytic 1 | hgnc:11272 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SPTA1 as a disease-causing gene for hereditary elliptocytosis.
- name: EL3
  display_name: Elliptocytosis 3
  subtype_term:
    preferred_term: elliptocytosis 3
    term:
      id: MONDO:0054780
      label: elliptocytosis 3
  description: >
    OMIM-linked hereditary elliptocytosis subtype described by MONDO as a child
    of hereditary elliptocytosis.
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:617948 | Broader"
    explanation: Orphanet includes OMIM:617948 among broader cross-references for hereditary elliptocytosis.
- name: SAO
  display_name: Southeast Asian ovalocytosis
  subtype_term:
    preferred_term: southeast Asian ovalocytosis
    term:
      id: MONDO:0008165
      label: southeast Asian ovalocytosis
  description: >
    SLC4A1-related ovalocytic red-cell membrane disorder classified by MONDO
    as both hereditary elliptocytosis and hereditary stomatocytosis.
  genes:
  - preferred_term: SLC4A1
    term:
      id: hgnc:11027
      label: SLC4A1
  evidence:
  - reference: PMID:32411010
    reference_title: "Expression of South East Asian Ovalocytic Band 3 Disrupts Erythroblast Cytokinesis and Reticulocyte Maturation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "SAO is caused by the heterozygous deletion of codons 400–408 in SLC4A1."
    explanation: >-
      Names SLC4A1 as the gene and gives the specific heterozygous in-frame
      deletion that defines this subtype. The quote restates the founding
      genetic reports rather than this paper's own culture experiments, hence
      quote_role BACKGROUND.
- name: Thermal-sensitive HE
  display_name: Hemolytic anemia with thermal sensitivity of red cells
  subtype_term:
    preferred_term: hemolytic anemia with thermal sensitivity of red cells
    term:
      id: MONDO:0009334
      label: hemolytic anemia with thermal sensitivity of red cells
  description: >
    OMIM-linked hereditary elliptocytosis subtype characterized by thermally
    sensitive red cells and hemolytic anemia.
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:235370 | Broader"
    explanation: Orphanet includes OMIM:235370 among broader cross-references for hereditary elliptocytosis.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 10.0
  rate_high: 50.0
  percentage: 0.01-0.05
  notes: Orphanet reports a worldwide point-prevalence class of 1-5 per 10,000.
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Worldwide | Point prevalence | EXPERT"
    explanation: The Orphanet epidemiology table provides the worldwide point-prevalence class.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for hereditary elliptocytosis.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for hereditary elliptocytosis.
progression:
- phase: Onset
  age_range: All ages
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: All ages"
    explanation: Orphanet records all ages as the age-of-onset category for hereditary elliptocytosis.
pathophysiology:
- name: Red Cell Cytoskeleton Protein Defects
  description: >
    Pathogenic variants in erythrocyte membrane-skeleton genes affect
    spectrin, protein 4.1R, or glycophorin C components that maintain red cell
    membrane shape and mechanical resilience.
  genes:
  - preferred_term: EPB41
    term:
      id: hgnc:3377
      label: EPB41
  - preferred_term: GYPC
    term:
      id: hgnc:4704
      label: GYPC
  - preferred_term: SPTA1
    term:
      id: hgnc:11272
      label: SPTA1
  - preferred_term: SPTB
    term:
      id: hgnc:11274
      label: SPTB
  biological_processes:
  - preferred_term: cortical actin cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0030866
      label: cortical actin cytoskeleton organization
  molecular_functions:
  - preferred_term: structural constituent of cytoskeleton
    modifier: ABNORMAL
    term:
      id: GO:0005200
      label: structural constituent of cytoskeleton
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  downstream:
  - target: Weakened Horizontal Cytoskeletal Associations
    description: >
      Spectrin, protein 4.1R, and related membrane-skeleton defects weaken the
      horizontal cytoskeletal network underlying the erythrocyte membrane.
    causal_link_type: DIRECT
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPTA1 | spectrin alpha, erythrocytic 1 | hgnc:11272 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies SPTA1 as a disease-causing hereditary elliptocytosis gene.
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPTB | spectrin beta, erythrocytic | hgnc:11274 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies SPTB as a disease-causing hereditary elliptocytosis gene.
  - reference: PMID:3748797
    reference_title: "Hereditary elliptocytosis: clinical, morphological and biochemical studies of 38 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The major determinant of membrane shape and stability is a proteinaceous meshwork named membrane skeleton, composed mainly of spectrin, actin, protein 4.1 and ankyrin."
    explanation: This clinical series identifies the membrane skeleton as the determinant of red-cell shape and stability.
- name: Weakened Horizontal Cytoskeletal Associations
  description: >
    Mutations affecting spectrin self-association or protein 4.1R-mediated
    junctional complexes weaken horizontal links in the erythrocyte
    cytoskeleton.
  biological_processes:
  - preferred_term: cortical actin cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0030866
      label: cortical actin cytoskeleton organization
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  downstream:
  - target: Reduced Erythrocyte Deformability and Stability
    description: >
      Horizontal cytoskeletal weakness reduces mechanical stability and red-cell
      deformability.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The resulting defects alter the horizontal cytoskeletal associations and affect RBC membrane stability and deformability causing shortened RBC survival."
    explanation: This directly supports horizontal cytoskeletal association defects as the key intermediate mechanism.
  - reference: PMID:3748797
    reference_title: "Hereditary elliptocytosis: clinical, morphological and biochemical studies of 38 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed two types of membrane defects in the 38 patients studied: 24 patients (13 kindreds) exhibited spectrin self-association defect (type I HE) and 14 patients (6 kindreds) displayed deficiency in protein 4.1."
    explanation: This 38-case series supports spectrin self-association and protein 4.1 deficiency as observed membrane defects in hereditary elliptocytosis.
  - reference: PMID:3692477
    reference_title: Hereditary pyropoikilocytosis and elliptocytosis in a Caucasian family. Transmission of the same molecular defect in spectrin through three generations with different clinical expression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our studies revealed a defective ability of spectrin to self-associate"
    explanation: This family study supports defective spectrin self-association as a shared molecular defect across HE/HPP-spectrum phenotypes.
- name: Reduced Erythrocyte Deformability and Stability
  description: >
    Defective cytoskeletal mechanics decrease erythrocyte deformability and
    mechanical stability, reducing red-cell survival and producing abnormal
    osmotic-gradient ektacytometry profiles.
  biological_processes:
  - preferred_term: erythrocyte homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  downstream:
  - target: Elliptocytic and Poikilocytic Red Cell Morphology
    description: Reduced membrane stability contributes to elliptocytic and poikilocytic red-cell morphology.
    causal_link_type: DIRECT
  - target: Shortened Red Cell Survival and Hemolysis
    description: Decreased deformability and stability shorten erythrocyte survival and produce hemolysis in symptomatic cases.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:3748797
    reference_title: "Hereditary elliptocytosis: clinical, morphological and biochemical studies of 38 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A study of red cell deformability using an ektacytometer revealed that the cell deformability under isotonic conditions was decreased in all HE patients."
    explanation: This supports decreased red-cell deformability as a functional consequence in hereditary elliptocytosis.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The typical HE ektacytometry curve is trapezoidal with decreased RBC deformability"
    explanation: The ektacytometry finding supports reduced deformability as a characteristic biomechanical abnormality.
- name: SAO Band 3 Over-Association and Increased Membrane Rigidity
  description: >-
    The Southeast Asian ovalocytosis arm of this entry does not run through the
    horizontal membrane-skeleton chain above. The SAO allele of SLC4A1 deletes
    nine residues at the junction of the cytoplasmic and transmembrane domains
    of band 3; the mutant protein forms higher-order oligomers and binds the
    underlying skeleton more tightly than wild-type band 3. The mechanical
    consequence is an over-stiffened membrane, which is the opposite direction
    of change from the weakened spectrin and protein 4.1R linkages that produce
    the other subtypes, even though both routes reduce deformability and both
    end in an abnormally shaped red cell.
  genes:
  - preferred_term: SLC4A1
    term:
      id: hgnc:11027
      label: SLC4A1
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: band 3 homooligomerization
    modifier: INCREASED
    term:
      id: GO:0051260
      label: protein homooligomerization
  molecular_functions:
  - preferred_term: structural constituent of cytoskeleton
    modifier: ABNORMAL
    term:
      id: GO:0005200
      label: structural constituent of cytoskeleton
  evidence:
  - reference: PMID:32411010
    reference_title: "Expression of South East Asian Ovalocytic Band 3 Disrupts Erythroblast Cytokinesis and Reticulocyte Maturation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "SAO band 3 is believed to form higher oligomers and associate with the underlying erythrocyte cytoskeleton more readily than wild type band 3, offering an explanation for the observed increase in membrane rigidity in these cells"
    explanation: >-
      States the oligomerization and skeletal over-association that this node
      asserts, and the increased membrane rigidity that follows from it. The
      sentence summarises earlier biophysical work on patient red cells rather
      than this paper's own experiments, hence quote_role BACKGROUND.
  - reference: PMID:32411010
    reference_title: "Expression of South East Asian Ovalocytic Band 3 Disrupts Erythroblast Cytokinesis and Reticulocyte Maturation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "The deletion occurs at the boundary between the cytoplasmic N-terminal domain and the transport-active transmembrane domain. This mutation abolishes the anion exchange activity of band 3"
    explanation: >-
      Locates the deleted residues at the cytoplasmic/transmembrane boundary, as
      this node's description states, and records that the mutant protein no
      longer exchanges anions.
  downstream:
  - target: Elliptocytic and Poikilocytic Red Cell Morphology
    description: >-
      The rigid, over-cross-linked SAO membrane produces the ovalocytic red-cell
      morphology the subtype is named for.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32411010
      reference_title: "Expression of South East Asian Ovalocytic Band 3 Disrupts Erythroblast Cytokinesis and Reticulocyte Maturation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Southeast Asian Ovalocytosis results from a heterozygous deletion of 9 amino acids in the erythrocyte anion exchange protein AE1 (band 3)."
      explanation: >-
        Links the band 3 lesion directly to the ovalocytic phenotype that names
        the subtype.
- name: Elliptocytic and Poikilocytic Red Cell Morphology
  description: >
    Destabilized red-cell membrane architecture produces elliptical erythrocytes
    and, in more severe forms, poikilocytosis and red-cell fragmentation on
    peripheral smear.
  biological_processes:
  - preferred_term: erythrocyte homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical diagnosis of HE and HPP relies on identifying abnormal RBC morphology on peripheral blood smear (elliptocytes, poikilocytosis and fragmented RBCs)"
    explanation: This supports abnormal red-cell morphology as a characteristic finding and diagnostic basis.
  downstream:
  - target: Abnormal Erythrocyte Morphology
    causal_link_type: DIRECT
  - target: Elliptocytosis
    causal_link_type: DIRECT
  - target: Increased Red Cell Osmotic Fragility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Poikilocytosis
    causal_link_type: DIRECT
  - target: Stomatocytosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Shortened Red Cell Survival and Hemolysis
  description: >
    Reduced membrane stability and deformability shorten erythrocyte survival.
    This drives variable hemolysis, ranging from compensated or asymptomatic
    disease to severe transfusion-dependent anemia.
  biological_processes:
  - preferred_term: erythrocyte homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  evidence:
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The resulting defects alter the horizontal cytoskeletal associations and affect RBC membrane stability and deformability causing shortened RBC survival."
    explanation: This explicitly links cytoskeletal defects to shortened red-cell survival.
  - reference: PMID:30504335
    reference_title: "Inherited hemolytic anemia: a possessive beginner's guide."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Membrane structural defects lead to hereditary spherocytosis (HS) and hereditary elliptocytosis (HE)"
    explanation: This review supports classifying hereditary elliptocytosis as a red-cell membrane structural disorder causing inherited hemolytic anemia.
  downstream:
  - target: Hemolytic Anemia
    causal_link_type: DIRECT
  - target: Reticulocytosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Congenital Hemolytic Anemia
    causal_link_type: DIRECT
  - target: Hydrops fetalis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Neonatal Hyperbilirubinemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Prolonged neonatal jaundice
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hyperbilirubinemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Jaundice
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Splenomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cholelithiasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Fatigue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Exercise intolerance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Skin ulcer
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Hematological
  name: Abnormal Erythrocyte Morphology
  description: >
    Structural erythrocyte abnormalities are an obligate feature of the
    disorder, with elliptocytes and other abnormal forms detected on blood
    smear or related laboratory assessment.
  frequency: OBLIGATE
  diagnostic: true
  phenotype_term:
    preferred_term: abnormal erythrocyte morphology
    term:
      id: HP:0001877
      label: Abnormal erythrocyte morphology
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001877 | Abnormal erythrocyte morphology | Obligate (100%)"
    explanation: Orphanet lists abnormal erythrocyte morphology as obligate.
- category: Hematological
  name: Elliptocytosis
  description: >
    Elliptical or oval erythrocytes on peripheral smear, the defining red-cell
    morphology for hereditary elliptocytosis.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: elliptocytosis
    term:
      id: HP:0004445
      label: Elliptocytosis
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004445 | Elliptocytosis | Frequent (79-30%)"
    explanation: Orphanet lists elliptocytosis as a frequent phenotype.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elliptocytes were noted on blood smear and HE was suspected."
    explanation: This patient-series statement supports elliptocytes on smear as a diagnostic clue.
- category: Hematological
  name: Increased Red Cell Osmotic Fragility
  description: >
    Abnormal osmotic fragility or osmotic-gradient ektacytometry reflects
    impaired red-cell membrane biomechanical properties.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: increased red cell osmotic fragility
    term:
      id: HP:0005502
      label: Increased red cell osmotic fragility
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005502 | Increased red cell osmotic fragility | Frequent (79-30%)"
    explanation: Orphanet lists increased red cell osmotic fragility as frequent.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The resulting ektacytometry curve reflects biomechanical properties of the RBCs including osmotic fragility, surface-to-volume ratio, cytoskeleton flexibility, and cytoplasmic viscosity."
    explanation: This supports osmotic-gradient ektacytometry as a measure of osmotic fragility and red-cell membrane biomechanics.
- category: Hematological
  name: Hemolytic Anemia
  description: >
    Variable hemolytic anemia may occur, from mild compensated hemolysis to
    severe transfusion-dependent disease in severe or biallelic presentations.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001878 | Hemolytic anemia | Occasional (29-5%)"
    explanation: Orphanet lists hemolytic anemia as an occasional phenotype.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient # 1 (Figure 2) was a 12-month-old Caucasian boy who had presented with mild hemolytic anemia at 4 months of age"
    explanation: The patient series documents mild hemolytic anemia in a patient with hereditary elliptocytosis.
- category: Hematological
  name: Reticulocytosis
  description: >
    Increased reticulocytes can accompany compensated hemolysis as marrow output
    rises to replace shortened-survival erythrocytes.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: reticulocytosis
    term:
      id: HP:0001923
      label: Reticulocytosis
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001923 | Reticulocytosis | Occasional (29-5%)"
    explanation: Orphanet lists reticulocytosis as an occasional phenotype.
- category: Hematological
  name: Congenital Hemolytic Anemia
  description: >
    Severe forms can present in infancy or the neonatal period with congenital
    hemolysis, particularly when biallelic or modifying alleles produce
    hereditary pyropoikilocytosis-like severity.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: congenital hemolytic anemia
    term:
      id: HP:0004804
      label: Congenital hemolytic anemia
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004804 | Congenital hemolytic anemia | Occasional (29-5%)"
    explanation: Orphanet lists congenital hemolytic anemia as an occasional phenotype.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HPP is typically diagnosed in patients with family history of HE but presents with increased severity, frequently with transfusion requirement in infancy or, rarely, long-term transfusion-dependence."
    explanation: The severe end of the HE/HPP spectrum supports congenital or infancy-onset hemolytic anemia.
- category: Prenatal
  name: Hydrops fetalis
  description: >
    Severe fetal or neonatal hereditary elliptocytosis-spectrum presentations can
    rarely include hydrops fetalis.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001789 | Hydrops fetalis | Very rare (<4-1%)"
    explanation: Orphanet lists hydrops fetalis as a very rare phenotype.
- category: Hematological
  name: Poikilocytosis
  description: >
    Abnormally shaped erythrocytes beyond elliptocytes can occur, especially in
    severe hereditary pyropoikilocytosis-spectrum presentations.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: poikilocytosis
    term:
      id: HP:0004447
      label: Poikilocytosis
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004447 | Poikilocytosis | Occasional (29-5%)"
    explanation: Orphanet lists poikilocytosis as an occasional phenotype.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripheral blood smears demonstrate increased poikilocytosis and RBC fragmentation compared to HE."
    explanation: The HE/HPP case series supports poikilocytosis as a severe-spectrum smear finding.
- category: Hematological
  name: Stomatocytosis
  description: >
    Stomatocytic red cells can be present in a subset, especially overlapping
    ovalocytosis or stomatocytic elliptocytosis presentations.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: stomatocytosis
    term:
      id: HP:0004446
      label: Stomatocytosis
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004446 | Stomatocytosis | Occasional (29-5%)"
    explanation: Orphanet lists stomatocytosis as an occasional phenotype.
- category: Hematological
  name: Neonatal Hyperbilirubinemia
  description: >
    Neonatal hyperbilirubinemia can occur in infants with hereditary
    elliptocytosis or more severe HE/HPP-spectrum disease.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: neonatal hyperbilirubinemia
    term:
      id: HP:0003265
      label: Neonatal hyperbilirubinemia
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003265 | Neonatal hyperbilirubinemia | Occasional (29-5%)"
    explanation: Orphanet lists neonatal hyperbilirubinemia as an occasional phenotype.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients with the missense mutation p.D791E were asymptomatic at baseline but had ektacytometry profile consistent with mild HE; one presented with neonatal hyperbilirubinemia"
    explanation: The HE/HPP case series documents neonatal hyperbilirubinemia in a mild HE patient.
- category: Gastrointestinal
  name: Prolonged neonatal jaundice
  description: >
    Prolonged neonatal jaundice can occur in infants with hereditary
    elliptocytosis-spectrum hemolysis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Prolonged neonatal jaundice
    term:
      id: HP:0006579
      label: Prolonged neonatal jaundice
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006579 | Prolonged neonatal jaundice | Occasional (29-5%)"
    explanation: Orphanet lists prolonged neonatal jaundice as an occasional phenotype.
- category: Gastrointestinal
  name: Hyperbilirubinemia
  description: >
    Hemolysis can elevate bilirubin outside the neonatal period, contributing
    to jaundice and gallstone risk.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: hyperbilirubinemia
    term:
      id: HP:0002904
      label: Hyperbilirubinemia
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002904 | Hyperbilirubinemia | Occasional (29-5%)"
    explanation: Orphanet lists hyperbilirubinemia as an occasional phenotype.
- category: Gastrointestinal
  name: Jaundice
  description: >
    Jaundice can accompany bilirubin elevation from hemolysis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000952 | Jaundice | Occasional (29-5%)"
    explanation: Orphanet lists jaundice as an occasional phenotype.
- category: Gastrointestinal
  name: Splenomegaly
  description: >
    Splenic enlargement can occur with chronic hemolysis and erythrocyte
    clearance in symptomatic patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001744 | Splenomegaly | Occasional (29-5%)"
    explanation: Orphanet lists splenomegaly as an occasional phenotype.
- category: Gastrointestinal
  name: Cholelithiasis
  description: >
    Pigment gallstones may occur as a rare complication of chronic hemolysis and
    bilirubin turnover.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: cholelithiasis
    term:
      id: HP:0001081
      label: Cholelithiasis
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001081 | Cholelithiasis | Very rare (<4-1%)"
    explanation: Orphanet lists cholelithiasis as a very rare phenotype.
- category: Constitutional
  name: Fatigue
  description: >
    Fatigue can occur in symptomatic individuals with anemia or compensated
    hemolysis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012378 | Fatigue | Occasional (29-5%)"
    explanation: Orphanet lists fatigue as an occasional phenotype.
- category: Constitutional
  name: Exercise intolerance
  description: >
    Exercise intolerance is an occasional symptom in hereditary elliptocytosis,
    likely reflecting reduced oxygen delivery during symptomatic anemia or
    hemolysis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003546 | Exercise intolerance | Occasional (29-5%)"
    explanation: Orphanet lists exercise intolerance as an occasional phenotype.
- category: Dermatologic
  name: Skin ulcer
  description: >
    Skin ulceration is an occasional complication reported in the Orphanet
    phenotype record for hereditary elliptocytosis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0200042 | Skin ulcer | Occasional (29-5%)"
    explanation: Orphanet lists skin ulcer as an occasional phenotype.
biochemical:
- name: Red cell osmotic fragility
  presence: Increased
  context: >
    Reflected by abnormal osmotic-gradient ektacytometry and increased red-cell
    osmotic fragility in affected individuals.
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005502 | Increased red cell osmotic fragility | Frequent (79-30%)"
    explanation: Orphanet supports increased osmotic fragility as a frequent laboratory feature.
- name: Red cell deformability
  presence: Decreased
  context: >
    Ektacytometry shows decreased erythrocyte deformability, reflecting
    impaired membrane-skeleton mechanics.
  evidence:
  - reference: PMID:3748797
    reference_title: "Hereditary elliptocytosis: clinical, morphological and biochemical studies of 38 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A study of red cell deformability using an ektacytometer revealed that the cell deformability under isotonic conditions was decreased in all HE patients."
    explanation: The clinical series directly reports decreased red-cell deformability in HE.
- name: Bilirubin
  presence: Elevated
  context: Variable; may be elevated in patients with hemolysis.
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002904 | Hyperbilirubinemia | Occasional (29-5%)"
    explanation: Orphanet lists hyperbilirubinemia as an occasional feature.
genetic:
- name: EPB41
  association: Causative
  gene_term:
    preferred_term: EPB41
    term:
      id: hgnc:3377
      label: EPB41
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EPB41 | erythrocyte membrane protein band 4.1 | hgnc:3377 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists EPB41 as a disease-causing gene for hereditary elliptocytosis.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 15 patients were found to have mutations in SPTA1, SPTB or EPB41"
    explanation: This patient series found EPB41 among the causative genes in clinically suspected HE/HPP.
- name: GYPC
  association: Causative
  gene_term:
    preferred_term: GYPC
    term:
      id: hgnc:4704
      label: GYPC
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GYPC | glycophorin C (Gerbich blood group) | hgnc:4704 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists GYPC as a disease-causing gene for hereditary elliptocytosis.
  - reference: PMID:9037349
    reference_title: Molecular genetics of hereditary elliptocytosis and hereditary spherocytosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HE stems from changes in the SPTA1, SPTB, EL1 and (exceptionally) GPYC genes that encode spectrin alpha- and beta- chains, protein 4.1 and glycophorin C/D, respectively."
    explanation: This review uses older GPYC nomenclature for GYPC and supports glycophorin C/D as a rare HE gene product.
- name: SPTA1
  association: Causative
  gene_term:
    preferred_term: SPTA1
    term:
      id: hgnc:11272
      label: SPTA1
  inheritance:
  - name: Autosomal dominant
  - name: Autosomal recessive
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPTA1 | spectrin alpha, erythrocytic 1 | hgnc:11272 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SPTA1 as a disease-causing gene for hereditary elliptocytosis.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten patients had mutations in SPTA1 only"
    explanation: This patient series supports SPTA1 as a common causative gene in HE/HPP.
- name: SPTB
  association: Causative
  gene_term:
    preferred_term: SPTB
    term:
      id: hgnc:11274
      label: SPTB
  inheritance:
  - name: Autosomal dominant
  - name: Autosomal recessive
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPTB | spectrin beta, erythrocytic | hgnc:11274 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SPTB as a disease-causing gene for hereditary elliptocytosis.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one in SPTB, one was compound heterozygous for mutations affecting both α- and β-spectrin and one had a mutation in EPB41."
    explanation: This series supports SPTB as a causative gene in the HE/HPP spectrum.
- name: SLC4A1
  association: Causative
  relationship_type: CAUSATIVE
  subtype: SAO
  gene_term:
    preferred_term: SLC4A1
    term:
      id: hgnc:11027
      label: SLC4A1
  inheritance:
  - name: Autosomal dominant
  notes: >-
    SLC4A1 encodes band 3 (anion exchanger 1), a transmembrane protein, and is
    the gene of the Southeast Asian ovalocytosis subtype only. It is scoped to
    that subtype rather than listed alongside the other four genes because its
    lesion is not of the horizontal membrane-skeleton kind those genes share:
    the SAO allele is a single defined in-frame deletion whose product
    over-associates with the skeleton and stiffens the membrane, which is why
    this entry models it on its own pathophysiology node. The same gene appears
    under Hereditary_Spherocytosis for a different, band 3 deficiency route.
  evidence:
  - reference: PMID:32411010
    reference_title: "Expression of South East Asian Ovalocytic Band 3 Disrupts Erythroblast Cytokinesis and Reticulocyte Maturation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "SAO is caused by the heterozygous deletion of codons 400–408 in SLC4A1."
    explanation: >-
      Establishes SLC4A1 as the causative gene of Southeast Asian ovalocytosis
      and the heterozygous in-frame deletion allele responsible.
diagnosis:
- name: Peripheral blood smear morphology
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  description: >
    Examination of peripheral blood smear for elliptocytes, poikilocytosis, and
    red-cell fragmentation supports clinical diagnosis.
  results: Elliptocytes and related abnormal RBC morphology support hereditary elliptocytosis.
  evidence:
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical diagnosis of HE and HPP relies on identifying abnormal RBC morphology on peripheral blood smear (elliptocytes, poikilocytosis and fragmented RBCs)"
    explanation: This directly supports peripheral-smear morphology as a diagnostic approach.
- name: Osmotic gradient ektacytometry
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  description: >
    Osmotic-gradient ektacytometry measures red-cell biomechanical properties
    and can show the characteristic trapezoidal HE curve with decreased
    deformability.
  results: A trapezoidal curve with decreased RBC deformability supports hereditary elliptocytosis.
  evidence:
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ektacytometry is an objective reference technique that can aid in the diagnosis of RBC membrane disorders"
    explanation: This supports ektacytometry as an objective diagnostic technique for red-cell membrane disorders.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The typical HE ektacytometry curve is trapezoidal with decreased RBC deformability"
    explanation: This describes the characteristic ektacytometry profile for hereditary elliptocytosis.
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >
    Targeted or next-generation sequencing of red-cell membrane disorder genes
    can confirm or identify the molecular diagnosis, especially when transfusion
    obscures the red-cell phenotype.
  results: Pathogenic variants in EPB41, GYPC, SPTA1, or SPTB support molecular diagnosis.
  evidence:
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted sequencing using a Next-Generation sequencing platform is an efficient approach to identify or confirm the diagnosis of HE and HPP"
    explanation: This supports genetic testing as a diagnostic confirmation method.
treatments:
- name: Splenectomy
  description: >
    Splenectomy can ameliorate anemia in selected symptomatic patients with
    red-cell membrane structural disorders by increasing circulating red-cell
    lifespan; patient selection must consider severity and long-term risks.
  treatment_term:
    preferred_term: splenectomy
    term:
      id: NCIT:C15328
      label: Splenectomy
  target_mechanisms:
  - target: Shortened Red Cell Survival and Hemolysis
    treatment_effect: MODULATES
    description: Splenectomy can ameliorate anemia by increasing circulating red-cell life span.
  evidence:
  - reference: PMID:30504335
    reference_title: "Inherited hemolytic anemia: a possessive beginner's guide."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span."
    explanation: This review supports splenectomy as an anemia-ameliorating treatment for HS and HE membrane structural defects.
- name: Red Blood Cell Transfusion
  description: >
    Red-cell transfusion is supportive therapy for severe congenital or
    transfusion-dependent hemolytic anemia in the severe HE/HPP spectrum.
  treatment_term:
    preferred_term: blood transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_phenotypes:
  - preferred_term: hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: ORPHA:288
    reference_title: "Hereditary elliptocytosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "manifestations ranging from mild to severe transfusion-dependent hemolytic anemia"
    explanation: Orphanet's definition supports transfusion-dependent hemolytic anemia as the severe end of the disease spectrum.
  - reference: PMID:27667160
    reference_title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HPP is typically diagnosed in patients with family history of HE but presents with increased severity, frequently with transfusion requirement in infancy or, rarely, long-term transfusion-dependence."
    explanation: This supports transfusion as supportive management for severe HE/HPP-spectrum presentations.
notes: "The MONDO record currently includes an unrelated NORD-derived exact synonym, Hashimoto Encephalopathy, for MONDO:0017319; it is intentionally not represented as a synonym in this curation."
references:
- reference: ORPHA:288
  title: Hereditary elliptocytosis
  findings:
  - statement: Orphanet structured record for hereditary elliptocytosis disease definition, inheritance, prevalence, genes, phenotypes, and cross-references.
    supporting_text: "Hereditary elliptocytosis (HE) is a rare clinically and genetically heterogeneous disorder of the red cell membrane characterized by manifestations ranging from mild to severe transfusion-dependent hemolytic anemia but with the majority of patients being asymptomatic."
- reference: PMID:27667160
  title: Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.
  findings:
  - statement: HE/HPP result from SPTA1, SPTB, and EPB41 mutations that weaken horizontal cytoskeletal associations and reduce RBC stability and deformability.
    supporting_text: "The resulting defects alter the horizontal cytoskeletal associations and affect RBC membrane stability and deformability causing shortened RBC survival."
  - statement: Peripheral smear morphology, osmotic gradient ektacytometry, and next-generation sequencing support diagnosis.
    supporting_text: "Targeted sequencing using a Next-Generation sequencing platform is an efficient approach to identify or confirm the diagnosis of HE and HPP"
- reference: PMID:3748797
  title: "Hereditary elliptocytosis: clinical, morphological and biochemical studies of 38 cases."
  findings:
  - statement: A 38-case clinical series reported spectrin self-association defects, protein 4.1 deficiency, and decreased red-cell deformability.
    supporting_text: "A study of red cell deformability using an ektacytometer revealed that the cell deformability under isotonic conditions was decreased in all HE patients."
- reference: PMID:9037349
  title: Molecular genetics of hereditary elliptocytosis and hereditary spherocytosis.
  findings:
  - statement: A genetics review identifies SPTA1, SPTB, EPB41/EL1, and rare GYPC/GPYC changes in hereditary elliptocytosis.
    supporting_text: "HE stems from changes in the SPTA1, SPTB, EL1 and (exceptionally) GPYC genes that encode spectrin alpha- and beta- chains, protein 4.1 and glycophorin C/D, respectively."
- reference: PMID:30504335
  title: "Inherited hemolytic anemia: a possessive beginner's guide."
  findings:
  - statement: Hereditary elliptocytosis is a membrane structural defect disorder and splenectomy can ameliorate anemia in HS and HE.
    supporting_text: "splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span."
- reference: PMID:3692477
  title: Hereditary pyropoikilocytosis and elliptocytosis in a Caucasian family. Transmission of the same molecular defect in spectrin through three generations with different clinical expression.
  findings:
  - statement: Hereditary pyropoikilocytosis and mild HE can share a spectrin self-association defect with variable clinical expression.
    supporting_text: "The co-transmission of HPP and HE phenotypes in the same lineage might suggest variability in the clinical expression of the same molecular defect"

📚

References & Deep Research

References

6

ORPHA:288

Hereditary elliptocytosis

1 finding

Orphanet structured record for hereditary elliptocytosis disease definition, inheritance, prevalence, genes, phenotypes, and cross-references.

"Hereditary elliptocytosis (HE) is a rare clinically and genetically heterogeneous disorder of the red cell membrane characterized by manifestations ranging from mild to severe transfusion-dependent hemolytic anemia but with the majority of patients being asymptomatic."

PMID:27667160

Genotype-phenotype correlations in hereditary elliptocytosis and hereditary pyropoikilocytosis.

2 findings

HE/HPP result from SPTA1, SPTB, and EPB41 mutations that weaken horizontal cytoskeletal associations and reduce RBC stability and deformability.

"The resulting defects alter the horizontal cytoskeletal associations and affect RBC membrane stability and deformability causing shortened RBC survival."

Peripheral smear morphology, osmotic gradient ektacytometry, and next-generation sequencing support diagnosis.

"Targeted sequencing using a Next-Generation sequencing platform is an efficient approach to identify or confirm the diagnosis of HE and HPP"

PMID:3748797

Hereditary elliptocytosis: clinical, morphological and biochemical studies of 38 cases.

1 finding

A 38-case clinical series reported spectrin self-association defects, protein 4.1 deficiency, and decreased red-cell deformability.

"A study of red cell deformability using an ektacytometer revealed that the cell deformability under isotonic conditions was decreased in all HE patients."

PMID:9037349

Molecular genetics of hereditary elliptocytosis and hereditary spherocytosis.

1 finding

A genetics review identifies SPTA1, SPTB, EPB41/EL1, and rare GYPC/GPYC changes in hereditary elliptocytosis.

"HE stems from changes in the SPTA1, SPTB, EL1 and (exceptionally) GPYC genes that encode spectrin alpha- and beta- chains, protein 4.1 and glycophorin C/D, respectively."

PMID:30504335

Inherited hemolytic anemia: a possessive beginner's guide.

1 finding

Hereditary elliptocytosis is a membrane structural defect disorder and splenectomy can ameliorate anemia in HS and HE.

"splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span."

PMID:3692477

Hereditary pyropoikilocytosis and elliptocytosis in a Caucasian family. Transmission of the same molecular defect in spectrin through three generations with different clinical expression.

1 finding

Hereditary pyropoikilocytosis and mild HE can share a spectrin self-association defect with variable clinical expression.

"The co-transmission of HPP and HE phenotypes in the same lineage might suggest variability in the clinical expression of the same molecular defect"

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.

Hereditary Elliptocytosis Research Fallback ▸

Hereditary Elliptocytosis Research Fallback

Provider Attempt

timeout 180s just research-disorder falcon Hereditary_Elliptocytosis
Result: terminated by timeout (signal 15, exit 124) without producing a research artifact.

Manual Evidence Scope

Primary curation used the structured Orphanet record and cached PubMed sources:

ORPHA:288 for disease definition, inheritance, prevalence class, gene assertions, HPO phenotype frequencies, and cross-references.
PMID:27667160 for HE/HPP genotype-phenotype correlation, horizontal cytoskeletal association defects, RBC deformability/stability, peripheral smear, ektacytometry, sequencing, and severe transfusion-dependent presentations.
PMID:3748797 for a 38-case clinical/morphologic/biochemical HE series showing spectrin self-association defects, protein 4.1 deficiency, and decreased red-cell deformability.
PMID:9037349 for molecular-genetic review evidence on SPTA1, SPTB, EPB41/EL1, and rare GYPC/GPYC involvement.
PMID:30504335 for inherited red-cell membrane disorder management and splenectomy rationale in HS/HE.
PMID:3692477 for family evidence linking HE/HPP-spectrum variable expression to a shared spectrin self-association defect.

The resulting curation intentionally emphasizes direct disease-level evidence and avoids extrapolating unrelated hereditary spherocytosis or stomatocytosis management beyond the shared red-cell membrane structural-defect context explicitly stated in the cited sources.

Hereditary Elliptocytosis

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References & Deep Research

References

Deep Research

Hereditary Elliptocytosis Research Fallback

Provider Attempt

Manual Evidence Scope