🔗

Mappings

MONDO

MONDO:0019350 hereditary spherocytosis

Orphanet lists MONDO:0019350 as an exact cross-reference for hereditary spherocytosis.

ICD-10-CM

ICD10CM:D58.0 Hereditary spherocytosis

Orphanet lists ICD-10 D58.0 as an exact cross-reference for hereditary spherocytosis.

📘

Definitions

1

Orphanet disease definition

Orphanet defines hereditary spherocytosis as a congenital hemolytic anemia with a wide clinical spectrum characterized by anemia, variable jaundice, splenomegaly and cholelithiasis.

CASE_DEFINITION

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"Hereditary spherocytosis is a congenital hemolytic anemia with a wide clinical spectrum (from symptom-free carriers to severe hemolysis) characterized by anemia, variable jaundice, splenomegaly and cholelithiasis."

Orphanet's definition supports the multisystem hemolytic anemia framing of this entry.

👪

Inheritance

2

Autosomal dominant HP:0000006

Autosomal dominant inheritance

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"Autosomal dominant"

Orphanet records autosomal dominant inheritance for hereditary spherocytosis.

Autosomal recessive HP:0000007

Autosomal recessive inheritance

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"Autosomal recessive"

Orphanet records autosomal recessive inheritance for hereditary spherocytosis.

◆

Subtypes

5

HS Type 1 (ANK1-related)

Most common form, accounting for ~40-65% of cases. Caused by ankyrin deficiency. Autosomal dominant inheritance predominant.

HS Type 2 (SLC4A1/Band 3-related)

Second most common form, ~15-35% of cases. Caused by band 3 (AE1) deficiency. Autosomal dominant.

HS Type 3 (SPTA1-related)

Alpha-spectrin deficiency. Autosomal recessive, typically severe. Less common (~5%).

HS Type 4 (SPTB-related)

Beta-spectrin deficiency. Autosomal dominant. ~15-30% of cases.

HS Type 5 (EPB42-related)

Protein 4.2 deficiency. Autosomal recessive. Most common in Japanese populations.

⚙

Pathophysiology

3

Red Cell Membrane Protein Deficiency

Loss or dysfunction of key membrane skeleton proteins (ankyrin, band 3, spectrin, protein 4.2) that anchor the lipid bilayer to the spectrin-actin cytoskeleton. This weakens the vertical interactions between the membrane skeleton and lipid bilayer, leading to progressive membrane loss.

erythrocyte link

ANK1 link SLC4A1 link SPTA1 link SPTB link EPB42 link

cytoskeleton organization link ⚠ ABNORMAL protein localization to plasma membrane link ⚠ ABNORMAL

cytoskeletal anchor activity link ⚠ ABNORMAL structural constituent of cytoskeleton link ⚠ ABNORMAL spectrin binding link ⚠ ABNORMAL

Downstream

Membrane Surface Area Loss and Spherocyte Formation Loss of vertical membrane-skeleton interactions leads to membrane vesiculation and progressive reduction in surface area-to-volume ratio.

Show evidence (1 reference)

PMID:18940465 SUPPORT Human Clinical

"The primary lesion in hereditary spherocytosis is loss of membrane surface area, leading to reduced deformability due to defects in the membrane proteins ankyrin, band 3, beta spectrin, alpha spectrin, or protein 4.2"

Identifies the five membrane proteins whose defects cause hereditary spherocytosis.

Membrane Surface Area Loss and Spherocyte Formation

Progressive loss of membrane through microvesiculation converts normal biconcave discocytes into spherocytes with reduced surface area-to-volume ratio and decreased deformability. Spherocytes cannot traverse the narrow splenic fenestrations.

erythrocyte link

erythrocyte homeostasis link ⚠ ABNORMAL

Downstream

Splenic Sequestration and Hemolysis Non-deformable spherocytes are trapped in splenic sinusoids and destroyed by splenic macrophages.

Show evidence (1 reference)

PMID:18940465 SUPPORT Human Clinical

"loss of membrane surface area, leading to reduced deformability"

Confirms membrane surface area loss leading to reduced deformability as the key pathogenic step.

Splenic Sequestration and Hemolysis

Rigid spherocytes are trapped and destroyed in the spleen, which is the primary site of hemolysis. The spleen acts as a quality control filter, selectively removing cells with reduced deformability. This extravascular hemolysis is the main cause of anemia.

erythrocyte link macrophage link

erythrocyte homeostasis link ⚠ ABNORMAL

Show evidence (1 reference)

PMID:18940465 SUPPORT Human Clinical

"Abnormal spherocytes are trapped and destroyed in the spleen and this is the main cause of haemolysis in this disorder"

Confirms splenic trapping and destruction of spherocytes as the main cause of hemolysis.

⬡

Pathograph

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

●

Phenotypes

28

Blood 5

Spherocytosis FREQUENT Spherocytosis (HP:0004444)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0004444 | Spherocytosis | Frequent (79-30%)"

Orphanet lists spherocytosis as a frequent phenotype of hereditary spherocytosis.

Hemolytic Anemia VERY_FREQUENT Hemolytic anemia (HP:0001878)

Show evidence (1 reference)

PMID:18940465 SUPPORT Human Clinical

"most patients having a well-compensated haemolytic anaemia"

Confirms hemolytic anemia as the principal feature, well-compensated in most patients.

Anemia FREQUENT Anemia (HP:0001903)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0001903 | Anemia | Frequent (79-30%)"

Orphanet lists anemia as a frequent phenotype of hereditary spherocytosis.

Reticulocytosis FREQUENT Reticulocytosis (HP:0001923)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0001923 | Reticulocytosis | Frequent (79-30%)"

Orphanet lists reticulocytosis as a frequent phenotype of hereditary spherocytosis.

Extramedullary Hematopoiesis OCCASIONAL Extramedullary hematopoiesis (HP:0001978)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0001978 | Extramedullary hematopoiesis | Occasional (29-5%)"

Orphanet lists extramedullary hematopoiesis as an occasional phenotype.

Cardiovascular 1

Splenomegaly FREQUENT Splenomegaly (HP:0001744)

Show evidence (2 references)

PMID:18940465 SUPPORT Human Clinical

"characterised by anaemia, jaundice, and splenomegaly"

Confirms splenomegaly as part of the classic triad.

ORPHA:822 SUPPORT Other

"HP:0001744 | Splenomegaly | Frequent (79-30%)"

Orphanet lists splenomegaly as a frequent phenotype.

Digestive 4

Hepatomegaly FREQUENT Hepatomegaly (HP:0002240)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0002240 | Hepatomegaly | Frequent (79-30%)"

Orphanet lists hepatomegaly as a frequent phenotype.

Cholelithiasis FREQUENT Cholelithiasis (HP:0001081)

Show evidence (2 references)

PMID:18940465 SUPPORT Human Clinical

"Common complications are cholelithiasis, haemolytic episodes, and aplastic crises"

Confirms cholelithiasis as a common complication.

ORPHA:822 SUPPORT Other

"HP:0001081 | Cholelithiasis | Frequent (79-30%)"

Orphanet lists cholelithiasis as a frequent phenotype.

Abdominal Distention VERY_RARE Abdominal distention (HP:0003270)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0003270 | Abdominal distention | Very rare (<4-1%)"

Orphanet lists abdominal distention as a very rare phenotype.

Jaundice FREQUENT Jaundice (HP:0000952)

Show evidence (2 references)

PMID:18940465 SUPPORT Human Clinical

"characterised by anaemia, jaundice, and splenomegaly"

Confirms jaundice as part of the classic triad.

ORPHA:822 SUPPORT Other

"HP:0000952 | Jaundice | Frequent (79-30%)"

Orphanet lists jaundice as a frequent phenotype.

Immune 1

Maculopapular Exanthema OCCASIONAL Maculopapular exanthema (HP:0040186)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0040186 | Maculopapular exanthema | Occasional (29-5%)"

Orphanet lists maculopapular exanthema as an occasional phenotype.

Integument 2

Pallor FREQUENT Pallor (HP:0000980)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0000980 | Pallor | Frequent (79-30%)"

Orphanet lists pallor as a frequent phenotype of hereditary spherocytosis.

Skin Ulcer VERY_RARE Skin ulcer (HP:0200042)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0200042 | Skin ulcer | Very rare (<4-1%)"

Orphanet lists skin ulcer as a very rare phenotype.

Metabolism 1

Fever OCCASIONAL Fever (HP:0001945)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0001945 | Fever | Occasional (29-5%)"

Orphanet lists fever as an occasional phenotype.

Musculoskeletal 2

Gout VERY_RARE Gout (HP:0001997)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0001997 | Gout | Very rare (<4-1%)"

Orphanet lists gout as a very rare phenotype.

Muscle Weakness FREQUENT Muscle weakness (HP:0001324)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0001324 | Muscle weakness | Frequent (79-30%)"

Orphanet lists muscle weakness as a frequent phenotype.

Nervous System 1

Ataxia OCCASIONAL Ataxia (HP:0001251)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0001251 | Ataxia | Occasional (29-5%)"

Orphanet lists ataxia as an occasional phenotype.

Constitutional 3

Abdominal Pain OCCASIONAL Abdominal pain (HP:0002027)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0002027 | Abdominal pain | Occasional (29-5%)"

Orphanet lists abdominal pain as an occasional phenotype.

Chills OCCASIONAL Chills (HP:0025143)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0025143 | Chills | Occasional (29-5%)"

Orphanet lists chills as an occasional phenotype.

Myalgia OCCASIONAL Myalgia (HP:0003326)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0003326 | Myalgia | Occasional (29-5%)"

Orphanet lists myalgia as an occasional phenotype.

Growth 1

Growth Delay VERY_RARE Growth delay (HP:0001510)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0001510 | Growth delay | Very rare (<4-1%)"

Orphanet lists growth delay as a very rare phenotype.

Other 7

Increased Red Cell Osmotic Fragility VERY_FREQUENT Increased red cell osmotic fragility (HP:0005502)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0005502 | Increased red cell osmotic fragility | Very frequent (99-80%)"

Orphanet lists increased red cell osmotic fragility as very frequent in hereditary spherocytosis.

Spontaneous Hemolytic Crises FREQUENT Spontaneous hemolytic crises (HP:0005525)

Show evidence (2 references)

ORPHA:822 SUPPORT Other

"HP:0005525 | Spontaneous hemolytic crises | Frequent (79-30%)"

Orphanet lists spontaneous hemolytic crises as a frequent phenotype.

PMID:18940465 SUPPORT Human Clinical

"Common complications are cholelithiasis, haemolytic episodes, and aplastic crises"

Confirms hemolytic episodes as a common complication.

Increased Mean Corpuscular Hemoglobin Concentration FREQUENT Increased mean corpuscular hemoglobin concentration (HP:0025548)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0025548 | Increased mean corpuscular hemoglobin concentration | Frequent (79-30%)"

Orphanet lists increased MCHC as a frequent phenotype of hereditary spherocytosis.

Hypofibrinogenemia FREQUENT Hypofibrinogenemia (HP:0011900)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0011900 | Hypofibrinogenemia | Frequent (79-30%)"

Orphanet lists hypofibrinogenemia as a frequent phenotype.

Hypercoagulability FREQUENT Hypercoagulability (HP:0100724)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0100724 | Hypercoagulability | Frequent (79-30%)"

Orphanet lists hypercoagulability as a frequent phenotype.

Hyperbilirubinemia FREQUENT Hyperbilirubinemia (HP:0002904)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0002904 | Hyperbilirubinemia | Frequent (79-30%)"

Orphanet lists hyperbilirubinemia as a frequent phenotype.

Restrictive Cardiomyopathy OCCASIONAL Restrictive cardiomyopathy (HP:0001723)

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"HP:0001723 | Restrictive cardiomyopathy | Occasional (29-5%)"

Orphanet lists restrictive cardiomyopathy as an occasional phenotype.

🧬

Genetic Associations

5

ANK1 (Causative)

Autosomal dominant Autosomal recessive

Show evidence (3 references)

ORPHA:822 SUPPORT Other

"ANK1 | ankyrin 1 | hgnc:492 | Disease-causing germline mutation(s) in"

Orphanet lists ANK1 as a disease-causing gene for hereditary spherocytosis.

CGGV:assertion_82460b48-c4a5-4496-92ce-6fbad632d6d7-2021-03-24T160000.000Z SUPPORT Other

ClinGen classifies the autosomal dominant ANK1-hereditary spherocytosis relationship as definitive.

CGGV:assertion_55457b0b-370e-466d-b2da-1cb8d67aecc8-2021-06-23T160000.000Z SUPPORT Other

ClinGen also records a limited autosomal recessive ANK1-hereditary spherocytosis assertion, so the recessive relationship is represented as lower-confidence structured evidence.

SLC4A1 (Causative)

Autosomal dominant

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"SLC4A1 | solute carrier family 4 member 1 (Diego blood group) | hgnc:11027 | Disease-causing germline mutation(s) in"

Orphanet lists SLC4A1 as a disease-causing gene for hereditary spherocytosis.

SPTA1 (Causative)

Autosomal recessive

Show evidence (1 reference)

ORPHA:822 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 spherocytosis.

SPTB (Causative)

Autosomal dominant

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

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

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

EPB42 (Causative)

Autosomal recessive

Show evidence (1 reference)

ORPHA:822 SUPPORT Other

"EPB42 | erythrocyte membrane protein band 4.2 | hgnc:3381 | Disease-causing germline mutation(s) in"

Orphanet lists EPB42 as a disease-causing gene for hereditary spherocytosis.

💊

Treatments

4

Splenectomy

Action: splenectomy MAXO:0001077

Curative treatment that eliminates the site of spherocyte destruction. Should be undertaken only after careful assessment of risks and benefits due to lifelong infection risk.

Show evidence (1 reference)

PMID:18940465 SUPPORT Human Clinical

"Splenectomy is curative but should be undertaken only after careful assessment of the risks and benefits"

Confirms splenectomy as curative with the caveat of careful risk-benefit assessment.

Red Blood Cell Transfusions

Action: blood transfusion MAXO:0000756

For severe anemia, aplastic crises, or hemolytic crises. Most patients with mild to moderate HS do not require regular transfusions.

Folic Acid Supplementation

Action: Pharmacotherapy NCIT:C15986

Recommended to support increased erythropoietic demand from chronic hemolysis.

Genetic Counseling

Action: genetic counseling MAXO:0000079

Family screening and genetic counseling to identify affected relatives and inform reproductive planning.

🔬

Biochemical Markers

4

Hemoglobin (Decreased)

Context: Variable; mild to severe depending on subtype

MCHC (Elevated)

Context: Elevated mean corpuscular hemoglobin concentration is characteristic due to cellular dehydration

Reticulocytes (Elevated)

Context: Elevated from compensatory erythropoiesis

Indirect Bilirubin (Elevated)

Context: From chronic extravascular hemolysis

{ }

Source YAML

click to show

name: Hereditary Spherocytosis
creation_date: '2026-02-16T18:18:17Z'
updated_date: '2026-05-08T20:54:22Z'
description: >
  Hereditary spherocytosis is a congenital hemolytic anemia with a wide clinical
  spectrum characterized by anemia, variable jaundice, splenomegaly and
  cholelithiasis. It is caused by defects in red cell membrane skeleton proteins
  (ankyrin, band 3, spectrin, protein 4.2) that weaken vertical interactions
  between the membrane and cytoskeleton, leading to progressive membrane loss
  and spherocyte formation.
category: Mendelian
parents:
- Hematological Disease
- Genetic Disease
disease_term:
  preferred_term: hereditary spherocytosis
  term:
    id: MONDO:0019350
    label: hereditary spherocytosis
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:D58.0
      label: Hereditary spherocytosis
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:822
    mapping_justification: Orphanet lists ICD-10 D58.0 as an exact cross-reference for hereditary spherocytosis.
    consistency:
    - reference: ORPHA:822
      consistent: CONSISTENT
      notes: "ICD-10:D58.0 | Exact"
  mondo_mappings:
  - term:
      id: MONDO:0019350
      label: hereditary spherocytosis
    mapping_predicate: skos:exactMatch
    mapping_source: ORPHA:822
    mapping_justification: Orphanet lists MONDO:0019350 as an exact cross-reference for hereditary spherocytosis.
    consistency:
    - reference: ORPHA:822
      consistent: CONSISTENT
      notes: "MONDO:0019350 | Exact"
definitions:
- name: Orphanet disease definition
  definition_type: CASE_DEFINITION
  description: >
    Orphanet defines hereditary spherocytosis as a congenital hemolytic anemia
    with a wide clinical spectrum characterized by anemia, variable jaundice,
    splenomegaly and cholelithiasis.
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hereditary spherocytosis is a congenital hemolytic anemia with a wide clinical spectrum (from symptom-free carriers to severe hemolysis) characterized by anemia, variable jaundice, splenomegaly and cholelithiasis."
    explanation: Orphanet's definition supports the multisystem hemolytic anemia framing of this entry.
external_assertions:
- name: Orphanet hereditary spherocytosis record
  source: Orphanet
  assertion_type: Structured disease record
  external_id: ORPHA:822
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=822
  description: >
    Orphanet structured record for hereditary spherocytosis, including curated
    cross-references to MONDO, ICD-10, OMIM, MeSH, MedDRA, and UMLS identifiers.
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0019350 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:822 to MONDO:0019350.
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-10:D58.0 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:822 to ICD-10 D58.0.
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UMLS:C0037889 | Exact"
    explanation: The Orphanet cross-reference table exactly maps ORPHA:822 to UMLS C0037889.
has_subtypes:
- name: HS Type 1 (ANK1-related)
  description: >
    Most common form, accounting for ~40-65% of cases. Caused by ankyrin
    deficiency. Autosomal dominant inheritance predominant.
- name: HS Type 2 (SLC4A1/Band 3-related)
  description: >
    Second most common form, ~15-35% of cases. Caused by band 3 (AE1)
    deficiency. Autosomal dominant.
- name: HS Type 3 (SPTA1-related)
  description: >
    Alpha-spectrin deficiency. Autosomal recessive, typically severe.
    Less common (~5%).
- name: HS Type 4 (SPTB-related)
  description: >
    Beta-spectrin deficiency. Autosomal dominant. ~15-30% of cases.
- name: HS Type 5 (EPB42-related)
  description: >
    Protein 4.2 deficiency. Autosomal recessive. Most common in
    Japanese populations.
prevalence:
- population: Northern European ancestry
  notes: >
    Most common inherited anemia in individuals of northern European ancestry.
    Prevalence estimated at 1 in 2,000-5,000.
  evidence:
  - reference: PMID:18940465
    reference_title: "Hereditary spherocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is the most common inherited anaemia in individuals of northern European ancestry"
    explanation: Confirms HS as the most common inherited anemia in northern European populations.
- population: Europe (Orphanet point prevalence)
  percentage: 0.01-0.05
  notes: Orphanet reports a European point-prevalence class of 1-5 per 10,000.
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Europe | Point prevalence | EXPERT,PMID:1554800"
    explanation: The Orphanet epidemiology table provides a European point-prevalence class for hereditary spherocytosis.
- population: Germany
  percentage: 0.01-0.05
  notes: Orphanet reports a German point-prevalence class of 1-5 per 10,000 based on osmotic fragility screening.
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Germany | Point prevalence | PMID:1554800"
    explanation: The Orphanet epidemiology table cites PMID:1554800 for German prevalence.
  - reference: PMID:1554800
    reference_title: "Prevalence of increased osmotic fragility of erythrocytes in German blood donors: screening using a modified glycerol lysis test."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of carriers of an erythrocyte membrane defect (possible spherocytosis trait) could be as high as 1.1% in the general population and would distinctly exceed the prevalence of patients with apparent spherocytosis (0.02%)."
    explanation: Reports prevalence of apparent spherocytosis at 0.02% (2 per 10,000) in German blood donors, consistent with the Orphanet 1-5/10,000 class.
- population: United States (Orphanet prevalence at birth)
  percentage: 0.01-0.05
  notes: Orphanet reports a US prevalence-at-birth class of 1-5 per 10,000.
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | United States | Prevalence at birth | PMID:14476391"
    explanation: The Orphanet epidemiology table cites PMID:14476391 for US prevalence at birth.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for hereditary spherocytosis.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for hereditary spherocytosis.
progression:
- phase: Onset
  age_range: All ages
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: All ages"
    explanation: Orphanet records all ages as the age-of-onset category for hereditary spherocytosis.
pathophysiology:
- name: Red Cell Membrane Protein Deficiency
  description: >
    Loss or dysfunction of key membrane skeleton proteins (ankyrin, band 3,
    spectrin, protein 4.2) that anchor the lipid bilayer to the spectrin-actin
    cytoskeleton. This weakens the vertical interactions between the membrane
    skeleton and lipid bilayer, leading to progressive membrane loss.
  genes:
  - preferred_term: ANK1
    term:
      id: hgnc:492
      label: ANK1
  - preferred_term: SLC4A1
    term:
      id: hgnc:11027
      label: SLC4A1
  - preferred_term: SPTA1
    term:
      id: hgnc:11272
      label: SPTA1
  - preferred_term: SPTB
    term:
      id: hgnc:11274
      label: SPTB
  - preferred_term: EPB42
    term:
      id: hgnc:3381
      label: EPB42
  biological_processes:
  - preferred_term: cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0007010
      label: cytoskeleton organization
  - preferred_term: protein localization to plasma membrane
    modifier: ABNORMAL
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
  molecular_functions:
  - preferred_term: cytoskeletal anchor activity
    modifier: ABNORMAL
    term:
      id: GO:0008093
      label: cytoskeletal anchor activity
  - preferred_term: structural constituent of cytoskeleton
    modifier: ABNORMAL
    term:
      id: GO:0005200
      label: structural constituent of cytoskeleton
  - preferred_term: spectrin binding
    modifier: ABNORMAL
    term:
      id: GO:0030507
      label: spectrin binding
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  downstream:
  - target: Membrane Surface Area Loss and Spherocyte Formation
    description: >
      Loss of vertical membrane-skeleton interactions leads to membrane
      vesiculation and progressive reduction in surface area-to-volume ratio.
  evidence:
  - reference: PMID:18940465
    reference_title: "Hereditary spherocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary lesion in hereditary spherocytosis is loss of membrane surface area, leading to reduced deformability due to defects in the membrane proteins ankyrin, band 3, beta spectrin, alpha spectrin, or protein 4.2"
    explanation: Identifies the five membrane proteins whose defects cause hereditary spherocytosis.
- name: Membrane Surface Area Loss and Spherocyte Formation
  description: >
    Progressive loss of membrane through microvesiculation converts
    normal biconcave discocytes into spherocytes with reduced surface
    area-to-volume ratio and decreased deformability. Spherocytes cannot
    traverse the narrow splenic fenestrations.
  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: Splenic Sequestration and Hemolysis
    description: >
      Non-deformable spherocytes are trapped in splenic sinusoids
      and destroyed by splenic macrophages.
  evidence:
  - reference: PMID:18940465
    reference_title: "Hereditary spherocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "loss of membrane surface area, leading to reduced deformability"
    explanation: Confirms membrane surface area loss leading to reduced deformability as the key pathogenic step.
- name: Splenic Sequestration and Hemolysis
  description: >
    Rigid spherocytes are trapped and destroyed in the spleen, which
    is the primary site of hemolysis. The spleen acts as a quality
    control filter, selectively removing cells with reduced deformability.
    This extravascular hemolysis is the main cause of 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
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  evidence:
  - reference: PMID:18940465
    reference_title: "Hereditary spherocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal spherocytes are trapped and destroyed in the spleen and this is the main cause of haemolysis in this disorder"
    explanation: Confirms splenic trapping and destruction of spherocytes as the main cause of hemolysis.
phenotypes:
- category: Hematological
  name: Spherocytosis
  description: >
    Presence of spherocytes on peripheral blood smear. Characteristic finding
    that distinguishes HS from other hemolytic anemias.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: spherocytosis
    term:
      id: HP:0004444
      label: Spherocytosis
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004444 | Spherocytosis | Frequent (79-30%)"
    explanation: Orphanet lists spherocytosis as a frequent phenotype of hereditary spherocytosis.
- category: Hematological
  name: Hemolytic Anemia
  description: >
    Chronic hemolytic anemia of variable severity. Most patients have a
    well-compensated hemolysis with mild to moderate anemia. Some are
    asymptomatic while others have severe transfusion-dependent anemia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: PMID:18940465
    reference_title: "Hereditary spherocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most patients having a well-compensated haemolytic anaemia"
    explanation: Confirms hemolytic anemia as the principal feature, well-compensated in most patients.
- category: Hematological
  name: Anemia
  description: >
    Anemia of variable severity, ranging from well-compensated to severe
    transfusion-dependent forms.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001903 | Anemia | Frequent (79-30%)"
    explanation: Orphanet lists anemia as a frequent phenotype of hereditary spherocytosis.
- category: Hematological
  name: Reticulocytosis
  description: >
    Elevated reticulocyte count reflecting compensatory erythropoietic
    response to chronic hemolysis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: reticulocytosis
    term:
      id: HP:0001923
      label: Reticulocytosis
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001923 | Reticulocytosis | Frequent (79-30%)"
    explanation: Orphanet lists reticulocytosis as a frequent phenotype of hereditary spherocytosis.
- category: Hematological
  name: Increased Red Cell Osmotic Fragility
  description: >
    Increased osmotic fragility of erythrocytes, the hallmark laboratory
    finding in hereditary spherocytosis. Reflects the reduced surface
    area-to-volume ratio of spherocytes.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: increased red cell osmotic fragility
    term:
      id: HP:0005502
      label: Increased red cell osmotic fragility
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005502 | Increased red cell osmotic fragility | Very frequent (99-80%)"
    explanation: Orphanet lists increased red cell osmotic fragility as very frequent in hereditary spherocytosis.
- category: Hematological
  name: Spontaneous Hemolytic Crises
  description: >
    Episodic exacerbation of hemolysis, often triggered by infection.
    May cause acute worsening of anemia.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: spontaneous hemolytic crises
    term:
      id: HP:0005525
      label: Spontaneous hemolytic crises
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005525 | Spontaneous hemolytic crises | Frequent (79-30%)"
    explanation: Orphanet lists spontaneous hemolytic crises as a frequent phenotype.
  - reference: PMID:18940465
    reference_title: "Hereditary spherocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common complications are cholelithiasis, haemolytic episodes, and aplastic crises"
    explanation: Confirms hemolytic episodes as a common complication.
- category: Hematological
  name: Increased Mean Corpuscular Hemoglobin Concentration
  description: >
    Elevated MCHC reflecting cellular dehydration of spherocytes.
    A characteristic laboratory finding that aids diagnosis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: increased mean corpuscular hemoglobin concentration
    term:
      id: HP:0025548
      label: Increased mean corpuscular hemoglobin concentration
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025548 | Increased mean corpuscular hemoglobin concentration | Frequent (79-30%)"
    explanation: Orphanet lists increased MCHC as a frequent phenotype of hereditary spherocytosis.
- category: Hematological
  name: Extramedullary Hematopoiesis
  description: >
    Compensatory hematopoiesis occurring outside the bone marrow,
    typically in severe cases with chronic hemolysis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: extramedullary hematopoiesis
    term:
      id: HP:0001978
      label: Extramedullary hematopoiesis
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001978 | Extramedullary hematopoiesis | Occasional (29-5%)"
    explanation: Orphanet lists extramedullary hematopoiesis as an occasional phenotype.
- category: Hematological
  name: Hypofibrinogenemia
  description: >
    Reduced fibrinogen levels, potentially related to chronic hemolysis
    and coagulation factor consumption.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: hypofibrinogenemia
    term:
      id: HP:0011900
      label: Hypofibrinogenemia
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011900 | Hypofibrinogenemia | Frequent (79-30%)"
    explanation: Orphanet lists hypofibrinogenemia as a frequent phenotype.
- category: Hematological
  name: Hypercoagulability
  description: >
    Increased tendency toward thrombosis, potentially related to
    membrane vesiculation and phosphatidylserine exposure on
    spherocytes.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: hypercoagulability
    term:
      id: HP:0100724
      label: Hypercoagulability
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100724 | Hypercoagulability | Frequent (79-30%)"
    explanation: Orphanet lists hypercoagulability as a frequent phenotype.
- category: Hematological
  name: Pallor
  description: >
    Pallor from anemia, one of the common presenting signs.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: pallor
    term:
      id: HP:0000980
      label: Pallor
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000980 | Pallor | Frequent (79-30%)"
    explanation: Orphanet lists pallor as a frequent phenotype of hereditary spherocytosis.
- category: Gastrointestinal
  name: Splenomegaly
  description: >
    Splenic enlargement from chronic hemolysis and erythrophagocytosis.
    One of the classic triad features of HS.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:18940465
    reference_title: "Hereditary spherocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterised by anaemia, jaundice, and splenomegaly"
    explanation: Confirms splenomegaly as part of the classic triad.
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001744 | Splenomegaly | Frequent (79-30%)"
    explanation: Orphanet lists splenomegaly as a frequent phenotype.
- category: Gastrointestinal
  name: Hepatomegaly
  description: >
    Liver enlargement, which may occur in the setting of chronic
    hemolysis and extramedullary hematopoiesis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002240 | Hepatomegaly | Frequent (79-30%)"
    explanation: Orphanet lists hepatomegaly as a frequent phenotype.
- category: Gastrointestinal
  name: Cholelithiasis
  description: >
    Pigment gallstones from chronic bilirubin overproduction.
    Common complication, may occur in childhood.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: cholelithiasis
    term:
      id: HP:0001081
      label: Cholelithiasis
  evidence:
  - reference: PMID:18940465
    reference_title: "Hereditary spherocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common complications are cholelithiasis, haemolytic episodes, and aplastic crises"
    explanation: Confirms cholelithiasis as a common complication.
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001081 | Cholelithiasis | Frequent (79-30%)"
    explanation: Orphanet lists cholelithiasis as a frequent phenotype.
- category: Gastrointestinal
  name: Abdominal Pain
  description: >
    Abdominal pain, which may be related to splenomegaly, cholelithiasis,
    or hemolytic crises.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002027 | Abdominal pain | Occasional (29-5%)"
    explanation: Orphanet lists abdominal pain as an occasional phenotype.
- category: Gastrointestinal
  name: Abdominal Distention
  description: >
    Abdominal distention, which may occur with significant splenomegaly
    or hepatomegaly.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: abdominal distention
    term:
      id: HP:0003270
      label: Abdominal distention
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003270 | Abdominal distention | Very rare (<4-1%)"
    explanation: Orphanet lists abdominal distention as a very rare phenotype.
- category: Metabolic
  name: Jaundice
  description: >
    Unconjugated hyperbilirubinemia from chronic hemolysis. Part of the
    classic triad. May present as neonatal jaundice.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:18940465
    reference_title: "Hereditary spherocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterised by anaemia, jaundice, and splenomegaly"
    explanation: Confirms jaundice as part of the classic triad.
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000952 | Jaundice | Frequent (79-30%)"
    explanation: Orphanet lists jaundice as a frequent phenotype.
- category: Metabolic
  name: Hyperbilirubinemia
  description: >
    Elevated unconjugated bilirubin from chronic extravascular hemolysis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: hyperbilirubinemia
    term:
      id: HP:0002904
      label: Hyperbilirubinemia
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002904 | Hyperbilirubinemia | Frequent (79-30%)"
    explanation: Orphanet lists hyperbilirubinemia as a frequent phenotype.
- category: Metabolic
  name: Gout
  description: >
    Gout from increased purine turnover due to chronic hemolysis
    and elevated uric acid levels.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: gout
    term:
      id: HP:0001997
      label: Gout
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001997 | Gout | Very rare (<4-1%)"
    explanation: Orphanet lists gout as a very rare phenotype.
- category: Constitutional
  name: Fever
  description: >
    Fever, which may accompany hemolytic crises or aplastic crises.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001945 | Fever | Occasional (29-5%)"
    explanation: Orphanet lists fever as an occasional phenotype.
- category: Constitutional
  name: Chills
  description: >
    Chills, which may accompany hemolytic crises.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: chills
    term:
      id: HP:0025143
      label: Chills
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025143 | Chills | Occasional (29-5%)"
    explanation: Orphanet lists chills as an occasional phenotype.
- category: Cardiovascular
  name: Restrictive Cardiomyopathy
  description: >
    Restrictive cardiomyopathy, a rare cardiac complication that may
    occur in severe cases with chronic anemia or iron overload.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001723 | Restrictive cardiomyopathy | Occasional (29-5%)"
    explanation: Orphanet lists restrictive cardiomyopathy as an occasional phenotype.
- category: Musculoskeletal
  name: Muscle Weakness
  description: >
    Muscle weakness, likely related to chronic anemia and reduced
    oxygen delivery to tissues.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001324 | Muscle weakness | Frequent (79-30%)"
    explanation: Orphanet lists muscle weakness as a frequent phenotype.
- category: Musculoskeletal
  name: Myalgia
  description: >
    Muscle pain, which may occur during hemolytic crises.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003326 | Myalgia | Occasional (29-5%)"
    explanation: Orphanet lists myalgia as an occasional phenotype.
- category: Growth
  name: Growth Delay
  description: >
    Growth delay, which may occur in severe forms with chronic
    anemia and increased metabolic demand.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001510 | Growth delay | Very rare (<4-1%)"
    explanation: Orphanet lists growth delay as a very rare phenotype.
- category: Neurological
  name: Ataxia
  description: >
    Ataxia, a rare neurological finding that may occur in severe cases.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001251 | Ataxia | Occasional (29-5%)"
    explanation: Orphanet lists ataxia as an occasional phenotype.
- category: Dermatological
  name: Maculopapular Exanthema
  description: >
    Maculopapular skin rash, an occasional dermatological manifestation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: maculopapular exanthema
    term:
      id: HP:0040186
      label: Maculopapular exanthema
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0040186 | Maculopapular exanthema | Occasional (29-5%)"
    explanation: Orphanet lists maculopapular exanthema as an occasional phenotype.
- category: Dermatological
  name: Skin Ulcer
  description: >
    Skin ulceration, a very rare complication that may occur in
    severe forms, typically leg ulcers.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0200042 | Skin ulcer | Very rare (<4-1%)"
    explanation: Orphanet lists skin ulcer as a very rare phenotype.
biochemical:
- name: Hemoglobin
  presence: Decreased
  context: Variable; mild to severe depending on subtype
- name: MCHC
  presence: Elevated
  context: Elevated mean corpuscular hemoglobin concentration is characteristic due to cellular dehydration
- name: Reticulocytes
  presence: Elevated
  context: Elevated from compensatory erythropoiesis
- name: Indirect Bilirubin
  presence: Elevated
  context: From chronic extravascular hemolysis
genetic:
- name: ANK1
  association: Causative
  gene_term:
    preferred_term: ANK1
    term:
      id: hgnc:492
      label: ANK1
  inheritance:
  - name: Autosomal dominant
  - name: Autosomal recessive
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANK1 | ankyrin 1 | hgnc:492 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists ANK1 as a disease-causing gene for hereditary spherocytosis.
  - reference: CGGV:assertion_82460b48-c4a5-4496-92ce-6fbad632d6d7-2021-03-24T160000.000Z
    reference_title: "ANK1 / hereditary spherocytosis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANK1 | HGNC:492 | hereditary spherocytosis | MONDO:0019350 | AD | Definitive"
    explanation: ClinGen classifies the autosomal dominant ANK1-hereditary spherocytosis relationship as definitive.
  - reference: CGGV:assertion_55457b0b-370e-466d-b2da-1cb8d67aecc8-2021-06-23T160000.000Z
    reference_title: "ANK1 / hereditary spherocytosis (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANK1 | HGNC:492 | hereditary spherocytosis | MONDO:0019350 | AR | Limited"
    explanation: ClinGen also records a limited autosomal recessive ANK1-hereditary spherocytosis assertion, so the recessive relationship is represented as lower-confidence structured evidence.
- name: SLC4A1
  association: Causative
  gene_term:
    preferred_term: SLC4A1
    term:
      id: hgnc:11027
      label: SLC4A1
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC4A1 | solute carrier family 4 member 1 (Diego blood group) | hgnc:11027 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SLC4A1 as a disease-causing gene for hereditary spherocytosis.
- name: SPTA1
  association: Causative
  gene_term:
    preferred_term: SPTA1
    term:
      id: hgnc:11272
      label: SPTA1
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    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 spherocytosis.
- name: SPTB
  association: Causative
  gene_term:
    preferred_term: SPTB
    term:
      id: hgnc:11274
      label: SPTB
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    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 spherocytosis.
- name: EPB42
  association: Causative
  gene_term:
    preferred_term: EPB42
    term:
      id: hgnc:3381
      label: EPB42
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: ORPHA:822
    reference_title: "Hereditary spherocytosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EPB42 | erythrocyte membrane protein band 4.2 | hgnc:3381 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists EPB42 as a disease-causing gene for hereditary spherocytosis.
treatments:
- name: Splenectomy
  description: >
    Curative treatment that eliminates the site of spherocyte destruction.
    Should be undertaken only after careful assessment of risks and benefits
    due to lifelong infection risk.
  treatment_term:
    preferred_term: splenectomy
    term:
      id: MAXO:0001077
      label: splenectomy
  evidence:
  - reference: PMID:18940465
    reference_title: "Hereditary spherocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Splenectomy is curative but should be undertaken only after careful assessment of the risks and benefits"
    explanation: Confirms splenectomy as curative with the caveat of careful risk-benefit assessment.
- name: Red Blood Cell Transfusions
  description: >
    For severe anemia, aplastic crises, or hemolytic crises.
    Most patients with mild to moderate HS do not require regular transfusions.
  treatment_term:
    preferred_term: blood transfusion
    term:
      id: MAXO:0000756
      label: blood transfusion
- name: Folic Acid Supplementation
  description: >
    Recommended to support increased erythropoietic demand from chronic hemolysis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Genetic Counseling
  description: >
    Family screening and genetic counseling to identify affected relatives
    and inform reproductive planning.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
datasets:
references:
- reference: DOI:10.1038/s41598-024-78622-w
  title: Identification and functional analysis of novel SPTB and ANK1 mutations in hereditary spherocytosis patients
  findings: []
- reference: DOI:10.1111/bjh.19692
  title: 'Intragenic deletions in <i>SPTB</i> are associated with hereditary spherocytosis: Series of 12 cases'
  findings: []
- reference: DOI:10.1186/s12864-023-09364-8
  title: Genotype-degree of hemolysis correlation in hereditary spherocytosis
  findings: []
- reference: DOI:10.3389/fped.2023.1269645
  title: 'Hematological characteristics and hepatobiliary complications of hereditary spherocytosis in a tertiary care pediatric center: optimizing diagnosis and care through local and international networks'
  findings: []
- reference: DOI:10.3390/biomedicines12071607
  title: Flow Cytometry as a New Accessible Method to Evaluate Diagnostic Osmotic Changes in Patients with Red Blood Cell Membrane Defects
  findings: []
- reference: DOI:10.3390/ijms242317021
  title: 'Hereditary Spherocytosis: Can Next-Generation Sequencing of the Five Most Frequently Affected Genes Replace Time-Consuming Functional Investigations?'
  findings: []
- reference: DOI:10.3390/ijms27020721
  title: 'Hereditary Spherocytosis: Linking Ion Transport Defects to Osmotic Gradient Ektacytometry Profiles—A Review'
  findings: []

📚

References & Deep Research

References

7

DOI:10.1038/s41598-024-78622-w

Identification and functional analysis of novel SPTB and ANK1 mutations in hereditary spherocytosis patients

No top-level findings curated for this source.

DOI:10.1111/bjh.19692

Intragenic deletions in <i>SPTB</i> are associated with hereditary spherocytosis: Series of 12 cases

No top-level findings curated for this source.

DOI:10.1186/s12864-023-09364-8

Genotype-degree of hemolysis correlation in hereditary spherocytosis

No top-level findings curated for this source.

DOI:10.3389/fped.2023.1269645

Hematological characteristics and hepatobiliary complications of hereditary spherocytosis in a tertiary care pediatric center: optimizing diagnosis and care through local and international networks

No top-level findings curated for this source.

DOI:10.3390/biomedicines12071607

Flow Cytometry as a New Accessible Method to Evaluate Diagnostic Osmotic Changes in Patients with Red Blood Cell Membrane Defects

No top-level findings curated for this source.

DOI:10.3390/ijms242317021

Hereditary Spherocytosis: Can Next-Generation Sequencing of the Five Most Frequently Affected Genes Replace Time-Consuming Functional Investigations?

No top-level findings curated for this source.

DOI:10.3390/ijms27020721

Hereditary Spherocytosis: Linking Ion Transport Defects to Osmotic Gradient Ektacytometry Profiles—A Review

No top-level findings curated for this source.

Deep Research

2

Disorder ▸

Disorder

Name: Hereditary Spherocytosis
Category: Mendelian
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 16

Key Pathophysiology Nodes

Red Cell Membrane Protein Deficiency
Membrane Surface Area Loss and Spherocyte Formation
Splenic Sequestration and Hemolysis
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1038/s41598-024-78622-w
DOI:10.1111/bjh.19692
DOI:10.1186/s12864-023-09364-8
DOI:10.3389/fped.2023.1269645
DOI:10.3390/biomedicines12071607
DOI:10.3390/ijms242317021
DOI:10.3390/ijms27020721

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 28 citations 2026-02-15T22:01:54.835374

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Hereditary Spherocytosis
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Hereditary Spherocytosis. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Comprehensive research report: Hereditary spherocytosis (HS) pathophysiology (Mendelian)

Disease identifiers

Hereditary spherocytosis is represented in Open Targets as MONDO:0019350 (“hereditary spherocytosis”). (boesveld2023genotypetophenotypecorrelationsin pages 6-9)

1) Key concepts and definitions (current understanding)

Definition

HS is an inherited red blood cell (RBC) membrane disorder characterized by decreased RBC deformability and formation of spherocytes that are preferentially cleared in the spleen, producing chronic extravascular hemolysis. HS is described as “a disorder of reduced RBC deformability” due to pathogenic variants in membrane-skeleton and anchoring-complex genes. (boesveld2023genotypetophenotypecorrelationsin pages 6-9)

Core mechanical concept: surface area loss → spherical shape → splenic clearance

Multiple contemporary sources converge on a “vertical linkage” failure model in which weakened connections between the lipid bilayer and cytoskeleton cause microvesiculation and loss of membrane surface area, reducing the surface-area-to-volume ratio, creating rigid spherocytes that cannot traverse splenic microcirculation efficiently. HS membrane instability is described as producing “a decreased surface/volume ratio, a decreased deformability and in fine in RBC sequestration in the splenic cords of the red pulp.” (evrard2024intragenicdeletionsin pages 1-3)

Panarach et al. similarly describe that deficiency/dysfunction of cytoskeleton proteins “disrupt[s] the linkage between the phospholipid bilayer and cytoskeleton, altering the red blood cells’ surface area-to-volume ratio,” yielding “decreased membrane mechanical stability and cellular deformability,” with selective trapping and destruction “by splenic macrophages.” (panarach2024identificationandfunctional pages 1-2)

Extravascular hemolysis and macrophage-mediated clearance

A recent genotype–phenotype review describes the downstream mechanism as “extravascular haemolysis due to entrapment in the spleen and phagocytosis by resident macrophages.” (boesveld2023genotypetophenotypecorrelationsin pages 6-9)

2) Core pathophysiology (molecular pathways, cellular processes)

2.1 Primary pathophysiological mechanisms

(A) Membrane–cytoskeleton uncoupling and instability HS is predominantly caused by mutations affecting RBC cytoskeleton proteins and anchoring complexes, destabilizing vertical linkages and leading to progressive membrane surface loss and reduced deformability. (boesveld2023genotypetophenotypecorrelationsin pages 6-9, panarach2024identificationandfunctional pages 1-2, evrard2024intragenicdeletionsin pages 1-3)

(B) Microparticle (microvesicle) release Weakened vertical linkages “may contribute to the release of microparticles (MPs)” in HS, consistent with vesiculation-mediated surface loss. (panarach2024identificationandfunctional pages 1-2)

(C) Splenic filtration as a central amplifier of disease Splenic cords and macrophages create a mechanical/immune clearance bottleneck; poorly deformable spherocytes undergo trapping and phagocytosis, driving anemia and hyperbilirubinemia. (boesveld2023genotypetophenotypecorrelationsin pages 6-9, evrard2024intragenicdeletionsin pages 1-3)

2.2 Ion transport and hydration as contributors/modifiers

While the canonical model is structural, modern work emphasizes additional ion-homeostasis perturbations in many HS patients. A recent mechanistic synthesis reports HS RBCs show “increased passive Na+ and K+ permeability” with compensatory Na+/K+ ATPase activity, but still “undergo net Na+ gain and K+ loss, leading to cellular dehydration and the characteristically elevated MCHC,” contributing to reduced deformability and hemolysis; abnormal permeability is estimated in ~40–70% of patients in cited literature. (vivescorrons2026hereditaryspherocytosislinking pages 3-4)

Mechanosensitive and Ca2+-activated potassium channels are implicated as phenotype modifiers: PIEZO1 and KCNN4 (Gardos channel) gain-of-function variants can shift patients toward dehydrated phenotypes and complicate differential diagnosis with xerocytosis-like profiles on osmotic gradient ektacytometry. (vivescorrons2026hereditaryspherocytosislinking pages 8-9, vivescorrons2026hereditaryspherocytosislinking pages 11-12)

3) Key molecular players (genes/proteins, chemicals, cells, anatomy)

3.1 Causal genes/proteins (core HS genes)

Recent literature and cohort studies consistently identify five principal HS genes: - ANK1 (ankyrin-1) (boesveld2023genotypetophenotypecorrelationsin pages 6-9, panarach2024identificationandfunctional pages 1-2) - SPTB (β-spectrin) (boesveld2023genotypetophenotypecorrelationsin pages 6-9, evrard2024intragenicdeletionsin pages 1-3) - SPTA1 (α-spectrin) (boesveld2023genotypetophenotypecorrelationsin pages 6-9) - SLC4A1 (band 3 / AE1) (boesveld2023genotypetophenotypecorrelationsin pages 6-9) - EPB42 (protein 4.2) (boesveld2023genotypetophenotypecorrelationsin pages 6-9)

These proteins organize the RBC membrane-skeleton and anchoring complexes; disruption destabilizes membrane cohesion and deformability. (boesveld2023genotypetophenotypecorrelationsin pages 6-9, panarach2024identificationandfunctional pages 1-2)

Notable recent molecular genetics development (2024): Evrard et al. (British Journal of Haematology, Aug 2024, https://doi.org/10.1111/bjh.19692) highlight that intragenic deletions in SPTB can be a substantial subset of SPTB molecular defects (“up to 20%” in their series), emphasizing the need for CNV-aware molecular pipelines. (evrard2024intragenicdeletionsin pages 1-3)

3.2 Modifiers / related channel genes affecting hydration and deformability

PIEZO1 (mechanosensitive cation channel; modifier) (vivescorrons2026hereditaryspherocytosislinking pages 8-9, vivescorrons2026hereditaryspherocytosislinking pages 11-12)
KCNN4 (Gardos channel; modifier) (vivescorrons2026hereditaryspherocytosislinking pages 8-9, vivescorrons2026hereditaryspherocytosislinking pages 11-12)

3.3 Cell types (Cell Ontology, CL)

Primary affected cell type: erythrocyte (RBC) (CL term suggestion: erythrocyte) (boesveld2023genotypetophenotypecorrelationsin pages 6-9, panarach2024identificationandfunctional pages 1-2)
Key effector immune cell: splenic macrophage (CL term suggestion: macrophage) driving phagocytosis in extravascular hemolysis (boesveld2023genotypetophenotypecorrelationsin pages 6-9, panarach2024identificationandfunctional pages 1-2)

3.4 Anatomical locations (UBERON)

Spleen red pulp / splenic cords are central to sequestration and clearance (UBERON term suggestions: spleen, red pulp of spleen) (evrard2024intragenicdeletionsin pages 1-3)
Gallbladder is involved in pigment gallstone complications in chronic hemolysis (UBERON term suggestion: gallbladder) (boaro2023hematologicalcharacteristicsand pages 1-2)

3.5 Chemical entities (CHEBI) relevant to diagnosis/management

Eosin-5’-maleimide (EMA) dye used in flow cytometry EMA binding test (CHEBI term suggestion: eosin-5-maleimide) (boaro2023hematologicalcharacteristicsand pages 2-3, beltran2024flowcytometryas pages 2-4)
Sodium chloride (NaCl) in osmotic fragility testing and osmotic-gradient protocols (CHEBI: sodium chloride) (hauser2023hereditaryspherocytosiscan pages 5-7)

4) Biological processes (GO) and cellular components (GO-CC) disrupted

4.1 Biological processes (GO) disrupted (ontology-ready suggestions)

Based on the extracted mechanisms, HS disrupts: - Erythrocyte morphology and deformability regulation (spherocyte formation due to reduced S/V ratio) (boesveld2023genotypetophenotypecorrelationsin pages 6-9, evrard2024intragenicdeletionsin pages 1-3) - Membrane organization / vesicle-mediated membrane remodeling (microvesiculation / microparticle release) (panarach2024identificationandfunctional pages 1-2) - Macrophage-mediated phagocytosis of erythrocytes / extravascular hemolysis (boesveld2023genotypetophenotypecorrelationsin pages 6-9) - Ion transport / cellular potassium ion homeostasis / sodium ion homeostasis contributing to dehydration and high MCHC (vivescorrons2026hereditaryspherocytosislinking pages 3-4)

4.2 Cellular components (GO-CC) (ontology-ready suggestions)

Key processes occur at: - Plasma membrane and membrane skeleton (submembranous cytoskeleton) (vertical linkage between phospholipid bilayer and cytoskeleton) (panarach2024identificationandfunctional pages 1-2) - Spectrin-based membrane skeleton / anchoring complexes involving ankyrin, band 3, spectrins (boesveld2023genotypetophenotypecorrelationsin pages 6-9)

5) Disease progression (sequence of events)

Germline pathogenic variant in a membrane-skeleton gene (e.g., ANK1, SPTB, SLC4A1, SPTA1, EPB42) alters abundance/structure of key components. (boesveld2023genotypetophenotypecorrelationsin pages 6-9, panarach2024identificationandfunctional pages 1-2)
Vertical linkage weakening between lipid bilayer and cytoskeleton reduces membrane mechanical stability. (panarach2024identificationandfunctional pages 1-2)
Microvesiculation / microparticle release causes membrane surface loss, lowering surface-area-to-volume ratio and producing rigid spherocytes. (panarach2024identificationandfunctional pages 1-2, evrard2024intragenicdeletionsin pages 1-3)
Reduced deformability leads to poor passage through splenic microarchitecture, causing sequestration in splenic cords/red pulp. (evrard2024intragenicdeletionsin pages 1-3)
Extravascular hemolysis: spherocytes undergo “phagocytosis by resident macrophages,” producing chronic hemolytic anemia and downstream bilirubin burden. (boesveld2023genotypetophenotypecorrelationsin pages 6-9)
Complications over time: pigment gallstones and hemolytic/aplastic crises can occur; clinical severity varies widely by genotype and modifiers (including ion-transport effects). (evrard2024intragenicdeletionsin pages 1-3, boaro2023hematologicalcharacteristicsand pages 1-2)

6) Phenotypic manifestations (HP) and mechanistic links

Ontology-ready phenotype suggestions (Human Phenotype Ontology, HP) consistent with the evidence: - Spherocytosis (HP: Spherocytosis) due to reduced S/V ratio and cytoskeletal instability (panarach2024identificationandfunctional pages 1-2, evrard2024intragenicdeletionsin pages 1-3) - Hemolytic anemia (HP: Hemolytic anemia) due to splenic trapping and macrophage clearance (boesveld2023genotypetophenotypecorrelationsin pages 6-9, panarach2024identificationandfunctional pages 1-2) - Jaundice (HP: Jaundice) and splenomegaly (HP: Splenomegaly) reported as common clinical features in genetic series (evrard2024intragenicdeletionsin pages 1-3) - Cholelithiasis / gallstones (HP: Cholelithiasis) as a common complication in pediatric cohorts (boaro2023hematologicalcharacteristicsand pages 1-2) - Aplastic crisis (HP: Aplastic crisis) noted as a complication in molecular diagnostic series and review discussions (hauser2023hereditaryspherocytosiscan pages 5-7)

Mechanistic coupling: decreased deformability and splenic clearance explain anemia/splenomegaly, while chronic hemolysis increases bilirubin turnover, predisposing to pigment gallstones. (boesveld2023genotypetophenotypecorrelationsin pages 6-9, boaro2023hematologicalcharacteristicsand pages 1-2)

7) Recent developments and latest research (prioritize 2023–2024)

7.1 Quantifying hemolysis using RBC lifespan (2023)

Shi et al. (BMC Genomics, Jun 2023, https://doi.org/10.1186/s12864-023-09364-8) combined NGS with Levitt’s CO breath test in 23 HS patients, reporting median RBC lifespan 14 (8–48) days and providing gene distribution (8 ANK1, 9 SPTB, 5 SLC4A1, 1 SPTA1). They found no statistically significant correlation between genotype class and RBC lifespan in this small cohort. (shi2023genotypedegreeofhemolysis pages 1-2)

7.2 Molecular diagnostics: five-gene NGS panel performance (2023)

Häuser et al. (International Journal of Molecular Sciences, Nov 2023, https://doi.org/10.3390/ijms242317021) evaluated whether a 5-gene NGS approach could replace functional testing; among genetically tested suspected HS patients (n=17), they report 100% sensitivity (95% CI 81.5–100.0%), and conclude that “the combination of medical history, basic laboratory parameters, and an NGS panel with five genes is sufficient for diagnosis in most cases.” (hauser2023hereditaryspherocytosiscan pages 1-2)

7.3 Hepatobiliary complications and care pathways in pediatrics (2023)

Boaro et al. (Frontiers in Pediatrics, Oct 2023, https://doi.org/10.3389/fped.2023.1269645) report gallstones in 16/40 (40%) children undergoing ultrasound surveillance, with higher hemolytic crises and parvovirus infections among those with stones (53.6% vs 26.1% and 63.6% vs 28.6%). (boaro2023hematologicalcharacteristicsand pages 1-2)

7.4 CNVs in SPTB as an under-recognized mechanism (2024)

Evrard et al. (British Journal of Haematology, Aug 2024, https://doi.org/10.1111/bjh.19692) describe intragenic deletions in SPTB associated with HS and report that such deletions represented “up to 20% of molecular defects found in the SPTB gene” in their series, reinforcing the need for CNV-sensitive molecular methods. (evrard2024intragenicdeletionsin pages 1-3)

7.5 Expanding access to functional diagnostics (2024)

Beltrán et al. (Biomedicines, Jul 2024, https://doi.org/10.3390/biomedicines12071607) address limited access to osmotic gradient ektacytometry by developing a flow-cytometry-based osmotic method. In the pediatric group, they report AUC 1.0 (100% sensitivity, 93.3% specificity), and in adults AUC 0.98 (80% sensitivity, 90.9% specificity) for discriminating HS patients from controls using an iso-osmolar assessment point. (vivescorrons2026hereditaryspherocytosislinking pages 1-3)

8) Current applications and real-world implementations

8.1 Diagnostic testing in practice

A real-world pediatric center experience shows reliance on confirmatory tests such as osmotic fragility testing (OFT) and EMA binding. In Boaro et al., OFT was performed in 32 patients (26 positive) and EMA binding in 28 (27 positive). (boaro2023hematologicalcharacteristicsand pages 3-5)

Ektacytometry is described as a “gold standard” deformability test but is often not widely available, motivating alternative implementations such as flow-cytometric osmotic profiling and more NGS-first workflows. (boaro2023hematologicalcharacteristicsand pages 2-3, beltran2024flowcytometryas pages 2-4)

8.2 Molecular diagnosis workflows

NGS panels targeting the five main HS genes (ANK1, EPB42, SLC4A1, SPTA1, SPTB) can have high diagnostic sensitivity in selected cohorts and are particularly practical in pediatrics due to low blood volume requirements and sample stability. (hauser2023hereditaryspherocytosiscan pages 1-2)

8.3 Management and monitoring implementations

Boaro et al. recommend longitudinal follow-up including labs and ultrasound surveillance, with cholecystectomy for symptomatic gallstones and careful consideration of splenectomy; they note annual ultrasound after age 5 years in their institutional practice. (boaro2023hematologicalcharacteristicsand pages 2-3)

9) Expert opinion and analysis (authoritative synthesis)

Conceptual consensus: Contemporary reviews emphasize HS as primarily a membrane-skeleton disorder with splenic clearance as the proximate cause of anemia, but they increasingly highlight integrated molecular-functional diagnostics (NGS + functional deformability assays) to address heterogeneity and overlap with related membranopathies. (boesveld2023genotypetophenotypecorrelationsin pages 6-9, vivescorrons2026hereditaryspherocytosislinking pages 11-12)

Precision hematology direction: The ion-transport synthesis argues HS is multifactorial in many individuals, where ion homeostasis defects (including PIEZO1/KCNN4-driven dehydration) can modulate deformability and may influence management decisions (e.g., avoiding splenectomy in dehydrating channelopathies). (vivescorrons2026hereditaryspherocytosislinking pages 11-12)

10) Evidence items (mechanistic + numeric), with publication dates and URLs

Boaro et al. Frontiers in Pediatrics. 2023-10. “Hematological characteristics and hepatobiliary complications of hereditary spherocytosis…” https://doi.org/10.3389/fped.2023.1269645 — Gallstones 16/40 (40%); OFT/EMA real-world testing uptake and outcomes. (boaro2023hematologicalcharacteristicsand pages 1-2, boaro2023hematologicalcharacteristicsand pages 3-5)
Shi et al. BMC Genomics. 2023-06. “Genotype-degree of hemolysis correlation in hereditary spherocytosis.” https://doi.org/10.1186/s12864-023-09364-8 — RBC lifespan median 14 (8–48) days; gene distribution in n=23. (shi2023genotypedegreeofhemolysis pages 1-2)
Häuser et al. Int J Mol Sci. 2023-11. “Hereditary Spherocytosis: Can NGS… replace functional investigations?” https://doi.org/10.3390/ijms242317021 — 5-gene NGS sensitivity 100% (95% CI 81.5–100.0%); de novo example. (hauser2023hereditaryspherocytosiscan pages 1-2, hauser2023hereditaryspherocytosiscan pages 5-7)
Panarach et al. Scientific Reports. 2024-11. “Identification and functional analysis of novel SPTB and ANK1 mutations…” https://doi.org/10.1038/s41598-024-78622-w — Structural linkage disruption, decreased S/V ratio, splenic macrophage clearance; microparticles. (panarach2024identificationandfunctional pages 1-2)
Evrard et al. British Journal of Haematology. 2024-08. “Intragenic deletions in SPTB…” https://doi.org/10.1111/bjh.19692 — Mechanism to splenic sequestration; CNV contribution up to 20% of SPTB molecular defects in series. (evrard2024intragenicdeletionsin pages 1-3)
Beltrán et al. Biomedicines. 2024-07. “Flow cytometry as a new accessible method…” https://doi.org/10.3390/biomedicines12071607 — Alternative diagnostic osmotic profiling; sensitivity/specificity/AUC in small cohort. (beltran2024flowcytometryas pages 2-4)

Limitations of this extraction

The provided full-text slices did not include PubMed identifiers (PMIDs) directly. Therefore, evidence is linked using DOIs and URLs available in the extracted text, which are sufficient for unambiguous retrieval. (shi2023genotypedegreeofhemolysis pages 1-2, hauser2023hereditaryspherocytosiscan pages 1-2, boaro2023hematologicalcharacteristicsand pages 1-2)

References

(boesveld2023genotypetophenotypecorrelationsin pages 6-9): M Boesveld. Genotype-to-phenotype correlations in hereditary spherocytosis. Unknown journal, 2023.
(evrard2024intragenicdeletionsin pages 1-3): Ophélie Evrard, Alexis Billes, Catherine Badens, Estelle Cadet, Lamisse Mansour‐Hendili, Kahia Messaoudi, Valérie Li Thiao Te, Philippe Joly, Caroline Favennec, Guillaume Jedraszak, Céline Renoux, and Loïc Garçon. Intragenic deletions in sptb are associated with hereditary spherocytosis: series of 12 cases. British Journal of Haematology, Aug 2024. URL: https://doi.org/10.1111/bjh.19692, doi:10.1111/bjh.19692. This article has 2 citations and is from a domain leading peer-reviewed journal.
(panarach2024identificationandfunctional pages 1-2): Charuwan Panarach, Chaiwat Netsawang, Issarang Nuchprayoon, and Kamonlak Leecharoenkiat. Identification and functional analysis of novel sptb and ank1 mutations in hereditary spherocytosis patients. Scientific Reports, Nov 2024. URL: https://doi.org/10.1038/s41598-024-78622-w, doi:10.1038/s41598-024-78622-w. This article has 5 citations and is from a peer-reviewed journal.
(vivescorrons2026hereditaryspherocytosislinking pages 3-4): Joan Lluís Vives-Corrons and Elena Krishnevskaya. Hereditary spherocytosis: linking ion transport defects to osmotic gradient ektacytometry profiles—a review. International Journal of Molecular Sciences, 27:721, Jan 2026. URL: https://doi.org/10.3390/ijms27020721, doi:10.3390/ijms27020721. This article has 0 citations.
(vivescorrons2026hereditaryspherocytosislinking pages 8-9): Joan Lluís Vives-Corrons and Elena Krishnevskaya. Hereditary spherocytosis: linking ion transport defects to osmotic gradient ektacytometry profiles—a review. International Journal of Molecular Sciences, 27:721, Jan 2026. URL: https://doi.org/10.3390/ijms27020721, doi:10.3390/ijms27020721. This article has 0 citations.
(vivescorrons2026hereditaryspherocytosislinking pages 11-12): Joan Lluís Vives-Corrons and Elena Krishnevskaya. Hereditary spherocytosis: linking ion transport defects to osmotic gradient ektacytometry profiles—a review. International Journal of Molecular Sciences, 27:721, Jan 2026. URL: https://doi.org/10.3390/ijms27020721, doi:10.3390/ijms27020721. This article has 0 citations.
(boaro2023hematologicalcharacteristicsand pages 1-2): Maria Paola Boaro, Giulia Reggiani, Mirco D’Agnolo, Vania Munaretto, Francesco Pozzebon, Roberta Trapanese, Maddalena Martella, and Raffaella Colombatti. Hematological characteristics and hepatobiliary complications of hereditary spherocytosis in a tertiary care pediatric center: optimizing diagnosis and care through local and international networks. Frontiers in Pediatrics, Oct 2023. URL: https://doi.org/10.3389/fped.2023.1269645, doi:10.3389/fped.2023.1269645. This article has 3 citations.
(boaro2023hematologicalcharacteristicsand pages 2-3): Maria Paola Boaro, Giulia Reggiani, Mirco D’Agnolo, Vania Munaretto, Francesco Pozzebon, Roberta Trapanese, Maddalena Martella, and Raffaella Colombatti. Hematological characteristics and hepatobiliary complications of hereditary spherocytosis in a tertiary care pediatric center: optimizing diagnosis and care through local and international networks. Frontiers in Pediatrics, Oct 2023. URL: https://doi.org/10.3389/fped.2023.1269645, doi:10.3389/fped.2023.1269645. This article has 3 citations.
(beltran2024flowcytometryas pages 2-4): Asunción Beltrán, María Sánchez-Villalobos, Eduardo Salido, Carmen Algueró, Eulalia Campos, Ana Belén Pérez-Oliva, Miguel Blanquer, and José M. Moraleda. Flow cytometry as a new accessible method to evaluate diagnostic osmotic changes in patients with red blood cell membrane defects. Biomedicines, 12:1607, Jul 2024. URL: https://doi.org/10.3390/biomedicines12071607, doi:10.3390/biomedicines12071607. This article has 4 citations.
(hauser2023hereditaryspherocytosiscan pages 5-7): Friederike Häuser, Heidi Rossmann, Anke Adenaeuer, Annette Shrestha, Dana Marandiuc, Claudia Paret, Jörg Faber, Karl J. Lackner, Bernhard Lämmle, and Olaf Beck. Hereditary spherocytosis: can next-generation sequencing of the five most frequently affected genes replace time-consuming functional investigations? International Journal of Molecular Sciences, 24:17021, Nov 2023. URL: https://doi.org/10.3390/ijms242317021, doi:10.3390/ijms242317021. This article has 10 citations.
(shi2023genotypedegreeofhemolysis pages 1-2): Yimeng Shi, Yuan Li, Xiawan Yang, Xiaoxia Li, Guangxin Peng, Xin Zhao, Xu Liu, Yufei Zhao, Jing Hu, Xiangrong Hu, Baohang Zhang, Kang Zhou, Yang Yang, Youzhen Xiong, Jianping Li, Huihui Fan, Wenrui Yang, Lei Ye, Liping Jing, Li Zhang, and Fengkui Zhang. Genotype-degree of hemolysis correlation in hereditary spherocytosis. BMC Genomics, Jun 2023. URL: https://doi.org/10.1186/s12864-023-09364-8, doi:10.1186/s12864-023-09364-8. This article has 7 citations and is from a peer-reviewed journal.
(hauser2023hereditaryspherocytosiscan pages 1-2): Friederike Häuser, Heidi Rossmann, Anke Adenaeuer, Annette Shrestha, Dana Marandiuc, Claudia Paret, Jörg Faber, Karl J. Lackner, Bernhard Lämmle, and Olaf Beck. Hereditary spherocytosis: can next-generation sequencing of the five most frequently affected genes replace time-consuming functional investigations? International Journal of Molecular Sciences, 24:17021, Nov 2023. URL: https://doi.org/10.3390/ijms242317021, doi:10.3390/ijms242317021. This article has 10 citations.
(vivescorrons2026hereditaryspherocytosislinking pages 1-3): Joan Lluís Vives-Corrons and Elena Krishnevskaya. Hereditary spherocytosis: linking ion transport defects to osmotic gradient ektacytometry profiles—a review. International Journal of Molecular Sciences, 27:721, Jan 2026. URL: https://doi.org/10.3390/ijms27020721, doi:10.3390/ijms27020721. This article has 0 citations.
(boaro2023hematologicalcharacteristicsand pages 3-5): Maria Paola Boaro, Giulia Reggiani, Mirco D’Agnolo, Vania Munaretto, Francesco Pozzebon, Roberta Trapanese, Maddalena Martella, and Raffaella Colombatti. Hematological characteristics and hepatobiliary complications of hereditary spherocytosis in a tertiary care pediatric center: optimizing diagnosis and care through local and international networks. Frontiers in Pediatrics, Oct 2023. URL: https://doi.org/10.3389/fped.2023.1269645, doi:10.3389/fped.2023.1269645. This article has 3 citations.

Ask OpenScientist

OpenScientist Report

Mappings

Definitions

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Source YAML

References & Deep Research

References

Deep Research

Disorder

Key Pathophysiology Nodes

Citation Inventory (for evidence mapping)

Disease Pathophysiology Research Template

Target Disease

Research Objectives

Required Information

1. Core Pathophysiology

2. Key Molecular Players

3. Biological Processes (for GO annotation)

4. Cellular Components

5. Disease Progression

6. Phenotypic Manifestations

Citation Requirements

Output Format

Comprehensive research report: Hereditary spherocytosis (HS) pathophysiology (Mendelian)

Disease identifiers

1) Key concepts and definitions (current understanding)

Definition

Core mechanical concept: surface area loss → spherical shape → splenic clearance

Extravascular hemolysis and macrophage-mediated clearance

2) Core pathophysiology (molecular pathways, cellular processes)

2.1 Primary pathophysiological mechanisms

2.2 Ion transport and hydration as contributors/modifiers

3) Key molecular players (genes/proteins, chemicals, cells, anatomy)

3.1 Causal genes/proteins (core HS genes)

3.2 Modifiers / related channel genes affecting hydration and deformability

3.3 Cell types (Cell Ontology, CL)

3.4 Anatomical locations (UBERON)

3.5 Chemical entities (CHEBI) relevant to diagnosis/management

4) Biological processes (GO) and cellular components (GO-CC) disrupted

4.1 Biological processes (GO) disrupted (ontology-ready suggestions)

4.2 Cellular components (GO-CC) (ontology-ready suggestions)

5) Disease progression (sequence of events)

6) Phenotypic manifestations (HP) and mechanistic links

7) Recent developments and latest research (prioritize 2023–2024)

7.1 Quantifying hemolysis using RBC lifespan (2023)

7.2 Molecular diagnostics: five-gene NGS panel performance (2023)

7.3 Hepatobiliary complications and care pathways in pediatrics (2023)

7.4 CNVs in SPTB as an under-recognized mechanism (2024)

7.5 Expanding access to functional diagnostics (2024)

8) Current applications and real-world implementations

8.1 Diagnostic testing in practice

8.2 Molecular diagnosis workflows

8.3 Management and monitoring implementations

9) Expert opinion and analysis (authoritative synthesis)

10) Evidence items (mechanistic + numeric), with publication dates and URLs

Limitations of this extraction