Hereditary Pulmonary Alveolar Proteinosis

Respiratory Disease MONDO:0012580 Pathograph 13 Pulmonary alveolar proteinosis Hereditary disease

Hereditary pulmonary alveolar proteinosis is a rare autosomal recessive interstitial lung disease caused by biallelic defects in GM-CSF receptor subunits encoded by CSF2RA or CSF2RB. Impaired GM-CSF receptor signaling prevents normal alveolar macrophage maturation and surfactant/cholesterol clearance, allowing periodic acid-Schiff-positive proteinaceous surfactant material and foamy macrophages to accumulate in alveoli while alveolar walls are relatively preserved. Clinical severity ranges from asymptomatic disease to childhood-onset dyspnea, cough, hypoxemia, restrictive ventilatory defect, infections, and respiratory failure requiring assisted ventilation.

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1
Mappings
1
Definitions
1
Inheritance
3
Pathophys.
1
Histopath.
15
Phenotypes
13
Pathograph
2
Genes
3
Treatments
6
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0012580 hereditary pulmonary alveolar proteinosis
skos:exactMatch Orphanet ORPHA:264675
Orphanet ORPHA:264675 lists MONDO:0012580 as an exact cross-reference for hereditary pulmonary alveolar proteinosis.
📘

Definitions

1
Orphanet hereditary PAP definition
A rare genetic interstitial lung disease due to CSF2RA or CSF2RB mutations, with alveolar accumulation of pulmonary surfactant and variable severity from asymptomatic disease to severe respiratory failure.
OTHER
Show evidence (2 references)
ORPHA:264675 SUPPORT Other
"A rare, genetic, interstitial lung disease due to mutations in the CSF2R (colony-stimulating factor 2 receptor) alpha or beta subunits and characterized by alveolar accumulation of pulmonary surfactant"
Orphanet defines hereditary PAP by CSF2R subunit mutations and surfactant accumulation.
PMID:30846703 SUPPORT Human Clinical
"hereditary (due to mutations in CSF2RA or CSF2RB, encoding GM-CSF receptor subunits)"
The disease-primer review confirms the hereditary PAP molecular category.
👪

Inheritance

1
Autosomal recessive HP:0000007
Hereditary PAP due to CSF2RA or CSF2RB follows autosomal recessive inheritance.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:264675 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance.
PMID:21075760 SUPPORT Human Clinical
"the mutant allele may give rise to PAP in an autosomal recessive manner."
The CSF2RB family report supports recessive inheritance.
⚙

Pathophysiology

3
Biallelic GM-CSF receptor subunit dysfunction
Germline pathogenic variants in CSF2RA or CSF2RB disrupt the alpha or beta subunits of the GM-CSF receptor, reducing or abolishing GM-CSF receptor signaling in myeloid cells.
alveolar macrophage link
cytokine-mediated signaling pathway link ↓ DECREASED JAK-STAT signaling downstream of GM-CSF receptor link ↓ DECREASED
alveolus of lung link
Downstream
Defective alveolar macrophage surfactant clearance
Show evidence (2 references)
PMID:20622029 SUPPORT Human Clinical
"Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients."
The CSF2RA cohort directly supports absent or severely reduced GM-CSF signaling.
PMID:21075760 SUPPORT Human Clinical
"Disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signalling causes pulmonary alveolar proteinosis (PAP)."
The CSF2RB report supports GM-CSF signaling disruption as causal for PAP.
Defective alveolar macrophage surfactant clearance
Impaired GM-CSF-dependent macrophage function reduces cholesterol and surfactant clearance from alveoli, producing dysfunctional alveolar macrophages and progressive surfactant retention.
alveolar macrophage link
cholesterol efflux link ↓ DECREASED lipid metabolic process link ↕ DYSREGULATED phagocytosis link ↕ DYSREGULATED
alveolus of lung link
Downstream
Alveolar surfactant and proteinaceous material accumulation
Foam cells
Show evidence (2 references)
PMID:30846703 SUPPORT Human Clinical
"Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages."
The disease-primer review supports surfactant accumulation with alveolar macrophage dysfunction.
PMID:30846703 SUPPORT Human Clinical
"reduced GM-CSF-dependent cholesterol clearance in alveolar macrophages, which impairs alveolar surfactant clearance."
The review directly connects reduced GM-CSF-dependent cholesterol clearance to impaired surfactant clearance.
Alveolar surfactant and proteinaceous material accumulation
Unprocessed surfactant lipids and proteins accumulate in alveolar spaces, creating proteinaceous material, foamy macrophages, crazy-paving HRCT, gas exchange impairment, hypoxemia, and respiratory failure in severe disease.
pulmonary alveolar type 2 cell link alveolar macrophage link
lipid metabolic process link ↕ DYSREGULATED
alveolus of lung link
Downstream
Crazy paving pattern on pulmonary HRCT
Hypoxemia
Respiratory failure requiring assisted ventilation
Show evidence (2 references)
ORPHA:264675 SUPPORT Other
"alveolar accumulation of pulmonary surfactant"
Orphanet supports surfactant accumulation as the defining downstream pathology.
PMID:23001804 SUPPORT Human Clinical
"Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by the accumulation of surfactant lipids and protein in the alveolar spaces, with resultant impairment in gas exchange."
The clinical review supports alveolar surfactant/protein accumulation and impaired gas exchange.
✶

Histopathology

1
PAS-positive proteinaceous alveolar material with foamy macrophages
Characteristic biopsy or lavage findings include PAS-positive granular eosinophilic material, enlarged foamy alveolar macrophages, and relatively preserved alveolar walls.
Show evidence (2 references)
ORPHA:264675 SUPPORT Other
"Characteristic lung biopsy findings include periodic acid-Schiff-positive, granular eosinophilic material, enlarged foamy alveolar macrophages, and well-preserved alveolar walls."
Orphanet describes the characteristic histopathology of hereditary PAP.
PMID:23001804 SUPPORT Human Clinical
"periodic acid-Schiff (PAS)-positive material on bronchoalveolar lavage and transbronchial biopsies is usually sufficient."
The clinical review supports PAS-positive material in BAL or biopsy as diagnostic.
⬡

Pathograph

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

Phenotypes

15
Cardiovascular 1
Tachycardia OCCASIONAL Tachycardia (HP:0001649)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0001649 | Tachycardia | Occasional (29-5%)"
Orphanet records tachycardia as occasional.
Respiratory 5
Restrictive ventilatory defect FREQUENT Restrictive ventilatory defect (HP:0002091)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0002091 | Restrictive ventilatory defect | Frequent (79-30%)"
Orphanet records restrictive ventilatory defect as frequent.
Respiratory distress FREQUENT Respiratory distress (HP:0002098)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0002098 | Respiratory distress | Frequent (79-30%)"
Orphanet records respiratory distress as frequent.
Tachypnea OCCASIONAL Tachypnea (HP:0002789)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0002789 | Tachypnea | Occasional (29-5%)"
Orphanet records tachypnea as occasional.
Hypoxemia FREQUENT Hypoxemia (HP:0012418)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0012418 | Hypoxemia | Frequent (79-30%)"
Orphanet records hypoxemia as frequent.
Cough OCCASIONAL Cough (HP:0012735)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0012735 | Cough | Occasional (29-5%)"
Orphanet records cough as occasional.
Other 9
Failure to thrive in infancy FREQUENT Failure to thrive in infancy (HP:0001531)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0001531 | Failure to thrive in infancy | Frequent (79-30%)"
Orphanet records failure to thrive in infancy as frequent.
Foam cells OCCASIONAL Foam cells (HP:0003651)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0003651 | Foam cells | Occasional (29-5%)"
Orphanet records foam cells as occasional.
Respiratory failure requiring assisted ventilation FREQUENT Respiratory failure requiring assisted ventilation (HP:0004887)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0004887 | Respiratory failure requiring assisted ventilation | Frequent (79-30%)"
Orphanet records respiratory failure requiring assisted ventilation as frequent.
Abnormal circulating protein level VERY_FREQUENT Abnormal circulating protein concentration (HP:0010876)
Show evidence (2 references)
ORPHA:264675 SUPPORT Other
"HP:0010876 | Abnormal circulating protein level | Very frequent (99-80%)"
Orphanet records abnormal circulating protein level as very frequent.
PMID:20622029 SUPPORT Human Clinical
"Increased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction."
The cohort supports increased serum GM-CSF as a circulating biomarker of GM-CSF receptor dysfunction.
Acute infectious pneumonia OCCASIONAL Acute infectious pneumonia (HP:0011949)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0011949 | Acute infectious pneumonia | Occasional (29-5%)"
Orphanet records acute infectious pneumonia as occasional.
Crazy paving pattern on pulmonary HRCT FREQUENT Crazy paving pattern (HP:0025391)
Show evidence (2 references)
ORPHA:264675 SUPPORT Other
"HP:0025391 | Crazy paving pattern on pulmonary HRCT | Frequent (79-30%)"
Orphanet records crazy paving pattern on pulmonary HRCT as frequent.
PMID:23001804 SUPPORT Human Clinical
"high-resolution computed tomography reveals diffuse ground-glass opacities and airspace consolidation with interlobular septal thickening in a characteristic "crazy paving" pattern."
The clinical review supports the HRCT pattern.
Autoimmune antibody positivity OCCASIONAL Autoimmune antibody positivity (HP:0030057)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0030057 | Autoimmune antibody positivity | Occasional (29-5%)"
Orphanet records autoimmune antibody positivity as occasional.
Crackles OCCASIONAL Crackles (HP:0030830)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0030830 | Crackles | Occasional (29-5%)"
Orphanet records crackles as occasional.
Elevated circulating CEA concentration OCCASIONAL Elevated circulating CEA concentration (HP:0031029)
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"HP:0031029 | Elevated carcinoembryonic antigen level | Occasional (29-5%)"
Orphanet records elevated carcinoembryonic antigen level as occasional.
🧬

Genetic Associations

2
CSF2RA pathogenic variants
Autosomal recessive
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"CSF2RA | colony stimulating factor 2 receptor subunit alpha | hgnc:2435 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline CSF2RA mutations.
CSF2RB pathogenic variants
Autosomal recessive
Show evidence (1 reference)
ORPHA:264675 SUPPORT Other
"CSF2RB | colony stimulating factor 2 receptor subunit beta | hgnc:2436 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline CSF2RB mutations.
💊

Treatments

3
Whole-lung lavage
Action: therapeutic irrigation MAXO:0000460
Whole-lung lavage mechanically removes excess surfactant and proteinaceous material from the alveoli and remains a main symptomatic treatment for PAP, including CSF2RA-associated hereditary PAP.
Mechanism Target:
INHIBITS Alveolar surfactant and proteinaceous material accumulation — Whole-lung lavage removes accumulated surfactant from alveolar spaces.
Show evidence (1 reference)
PMID:30846703 SUPPORT Human Clinical
"whole-lung lavage effectively removes excessive surfactant."
The disease-primer review supports lavage removal of accumulated surfactant.
Show evidence (2 references)
PMID:20622029 SUPPORT Human Clinical
"All symptomatic patients responded well to whole-lung lavage therapy."
The CSF2RA cohort supports whole-lung lavage response in symptomatic hereditary PAP.
PMID:23001804 SUPPORT Human Clinical
"The standard of care for treatment of PAP remains whole lung lavage"
The clinical review supports whole-lung lavage as the standard PAP treatment.
Supportive respiratory care
Action: supportive care MAXO:0000950
Oxygen, assisted ventilation, infection treatment, and general supportive care are used for hypoxemia, respiratory distress, infection, or respiratory failure while disease-specific management is pursued.
Show evidence (2 references)
ORPHA:264675 SUPPORT Other
"severe respiratory failure"
Orphanet records severe respiratory failure as part of the disease spectrum, supporting respiratory support as clinically relevant.
ORPHA:264675 SUPPORT Other
"HP:0004887 | Respiratory failure requiring assisted ventilation | Frequent (79-30%)"
Orphanet records assisted ventilation-requiring respiratory failure as frequent.
Experimental pulmonary macrophage transplantation
Action: cellular therapy MAXO:0000016
Pulmonary macrophage transplantation or gene-corrected macrophage approaches are experimental strategies intended to replace defective alveolar macrophage function in hereditary PAP.
Mechanism Target:
RESTORES Defective alveolar macrophage surfactant clearance — Transplanted macrophages are intended to restore alveolar macrophage surfactant-clearance function.
Show evidence (1 reference)
PMID:30100408 SUPPORT Model Organism
"PMT significantly improves alveolar protein deposition and other critical herPAP disease parameters."
The mouse model supports pulmonary macrophage transplantation as a mechanism-directed experimental therapy.
Show evidence (1 reference)
PMID:30100408 SUPPORT Model Organism
"PMT significantly improves alveolar protein deposition and other critical herPAP disease parameters."
The model-organism study supports pulmonary macrophage transplantation as experimental cellular therapy, not established human standard care.
{ }

Source YAML

click to show 
name: Hereditary Pulmonary Alveolar Proteinosis
category: Respiratory Disease
creation_date: "2026-05-09T19:32:00Z"
updated_date: "2026-05-09T19:32:00Z"
synonyms:
- Congenital pulmonary alveolar proteinosis
- Congenital PAP
- Hereditary PAP
- Inborn error of pulmonary surfactant metabolism
description: >
  Hereditary pulmonary alveolar proteinosis is a rare autosomal recessive
  interstitial lung disease caused by biallelic defects in GM-CSF receptor
  subunits encoded by CSF2RA or CSF2RB. Impaired GM-CSF receptor signaling
  prevents normal alveolar macrophage maturation and surfactant/cholesterol
  clearance, allowing periodic acid-Schiff-positive proteinaceous surfactant
  material and foamy macrophages to accumulate in alveoli while alveolar walls
  are relatively preserved. Clinical severity ranges from asymptomatic disease
  to childhood-onset dyspnea, cough, hypoxemia, restrictive ventilatory defect,
  infections, and respiratory failure requiring assisted ventilation.
disease_term:
  preferred_term: hereditary pulmonary alveolar proteinosis
  term:
    id: MONDO:0012580
    label: hereditary pulmonary alveolar proteinosis
parents:
- Pulmonary alveolar proteinosis
- Hereditary disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012580
      label: hereditary pulmonary alveolar proteinosis
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:264675
    mapping_justification: >
      Orphanet ORPHA:264675 lists MONDO:0012580 as an exact cross-reference for
      hereditary pulmonary alveolar proteinosis.
external_assertions:
- name: Orphanet hereditary pulmonary alveolar proteinosis record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:264675
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=264675
  description: >
    Orphanet's ORPHA:264675 structured record provides the disease definition,
    inheritance, age-of-onset range, epidemiology, CSF2RA/CSF2RB gene
    assertions, exact MONDO mapping, and HPO phenotype rows used in this entry.
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0012580 | Exact"
    explanation: Orphanet maps ORPHA:264675 exactly to the MONDO identifier used by this entry.
definitions:
- name: Orphanet hereditary PAP definition
  definition_type: OTHER
  description: >
    A rare genetic interstitial lung disease due to CSF2RA or CSF2RB mutations,
    with alveolar accumulation of pulmonary surfactant and variable severity
    from asymptomatic disease to severe respiratory failure.
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare, genetic, interstitial lung disease due to mutations in the CSF2R (colony-stimulating factor 2 receptor) alpha or beta subunits and characterized by alveolar accumulation of pulmonary surfactant"
    explanation: Orphanet defines hereditary PAP by CSF2R subunit mutations and surfactant accumulation.
  - reference: PMID:30846703
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hereditary (due to mutations in CSF2RA or CSF2RB, encoding GM-CSF receptor subunits)"
    explanation: The disease-primer review confirms the hereditary PAP molecular category.
inheritance:
- name: Autosomal recessive
  description: Hereditary PAP due to CSF2RA or CSF2RB follows autosomal recessive inheritance.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance.
  - reference: PMID:21075760
    reference_title: "Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the mutant allele may give rise to PAP in an autosomal recessive manner."
    explanation: The CSF2RB family report supports recessive inheritance.
prevalence:
- population: Worldwide
  percentage: "<1 / 1,000,000 point prevalence"
  notes: Orphanet records worldwide point prevalence below one per million.
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:20622029"
    explanation: Orphanet records worldwide point prevalence below one per million.
progression:
- phase: Variable onset
  age_range: Infancy through elderly adulthood
  notes: Orphanet lists onset across infancy, childhood, adolescence, adulthood, and elderly adulthood.
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infancy as an onset category.
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adult"
    explanation: Orphanet records adult onset as an onset category.
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Elderly"
    explanation: Orphanet records elderly onset as an onset category.
- phase: Progressive respiratory burden in symptomatic disease
  notes: >
    Symptomatic patients can develop insidious progressive dyspnea, hypoxemic
    respiratory failure, infection, and pulmonary fibrosis, although severity is
    highly variable.
  evidence:
  - reference: PMID:20622029
    reference_title: "Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years."
    explanation: The CSF2RA cohort documents variable symptomatic versus asymptomatic childhood presentation.
  - reference: PMID:30846703
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis."
    explanation: The disease-primer review summarizes the main disease trajectory and complications.
genetic:
- name: CSF2RA pathogenic variants
  gene_term:
    preferred_term: CSF2RA
    term:
      id: hgnc:2435
      label: CSF2RA
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: ORPHA:264675
      reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Autosomal recessive"
      explanation: Orphanet records recessive inheritance for the disease.
  variants:
  - name: Biallelic CSF2RA loss-of-function variants
    description: >
      Reported CSF2RA alleles include missense, duplication, frameshift,
      nonsense, exon or gene deletion, and splicing abnormalities that abolish
      or severely reduce GM-CSF receptor alpha-chain function.
    evidence:
    - reference: PMID:20622029
      reference_title: "Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Eight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations."
      explanation: The cohort identifies recessive CSF2RA mutations as causal in children with hereditary PAP.
    - reference: PMID:20622029
      reference_title: "Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing."
      explanation: The cohort details CSF2RA variant classes.
  features: >
    CSF2RA encodes the GM-CSF receptor alpha subunit; biallelic pathogenic
    variants impair GM-CSF signaling in alveolar macrophages.
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CSF2RA | colony stimulating factor 2 receptor subunit alpha | hgnc:2435 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline CSF2RA mutations.
- name: CSF2RB pathogenic variants
  gene_term:
    preferred_term: CSF2RB
    term:
      id: hgnc:2436
      label: CSF2RB
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:21075760
      reference_title: "Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the mutant allele may give rise to PAP in an autosomal recessive manner."
      explanation: The CSF2RB family report supports recessive inheritance.
  variants:
  - name: Biallelic CSF2RB pathogenic variants
    description: >
      Homozygous CSF2RB variants can impair GM-CSF receptor beta-chain expression
      and downstream signaling, producing hereditary PAP.
    evidence:
    - reference: PMID:21075760
      reference_title: "Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic screening revealed a homozygous, single-base deletion at nt 631 in exon 6 of CSF2RB on chromosome 22, which caused reductions in GM-CSF dependent signalling and function."
      explanation: The report identifies a homozygous CSF2RB deletion that reduces GM-CSF signaling and function.
  features: >
    CSF2RB encodes the shared GM-CSF receptor beta subunit; biallelic pathogenic
    variants impair receptor signaling and alveolar macrophage surfactant
    clearance.
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CSF2RB | colony stimulating factor 2 receptor subunit beta | hgnc:2436 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline CSF2RB mutations.
pathophysiology:
- name: Biallelic GM-CSF receptor subunit dysfunction
  description: >
    Germline pathogenic variants in CSF2RA or CSF2RB disrupt the alpha or beta
    subunits of the GM-CSF receptor, reducing or abolishing GM-CSF receptor
    signaling in myeloid cells.
  role: trigger
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: cytokine-mediated signaling pathway
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: JAK-STAT signaling downstream of GM-CSF receptor
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: DECREASED
  evidence:
  - reference: PMID:20622029
    reference_title: "Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients."
    explanation: The CSF2RA cohort directly supports absent or severely reduced GM-CSF signaling.
  - reference: PMID:21075760
    reference_title: "Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signalling causes pulmonary alveolar proteinosis (PAP)."
    explanation: The CSF2RB report supports GM-CSF signaling disruption as causal for PAP.
  downstream:
  - target: Defective alveolar macrophage surfactant clearance
    causal_link_type: DIRECT
- name: Defective alveolar macrophage surfactant clearance
  description: >
    Impaired GM-CSF-dependent macrophage function reduces cholesterol and
    surfactant clearance from alveoli, producing dysfunctional alveolar
    macrophages and progressive surfactant retention.
  role: central_effector
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: cholesterol efflux
    term:
      id: GO:0033344
      label: cholesterol efflux
    modifier: DECREASED
  - preferred_term: lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
    modifier: DYSREGULATED
  - preferred_term: phagocytosis
    term:
      id: GO:0006909
      label: phagocytosis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:30846703
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages."
    explanation: The disease-primer review supports surfactant accumulation with alveolar macrophage dysfunction.
  - reference: PMID:30846703
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduced GM-CSF-dependent cholesterol clearance in alveolar macrophages, which impairs alveolar surfactant clearance."
    explanation: The review directly connects reduced GM-CSF-dependent cholesterol clearance to impaired surfactant clearance.
  downstream:
  - target: Alveolar surfactant and proteinaceous material accumulation
    causal_link_type: DIRECT
  - target: Foam cells
    causal_link_type: DIRECT
- name: Alveolar surfactant and proteinaceous material accumulation
  description: >
    Unprocessed surfactant lipids and proteins accumulate in alveolar spaces,
    creating proteinaceous material, foamy macrophages, crazy-paving HRCT, gas
    exchange impairment, hypoxemia, and respiratory failure in severe disease.
  role: effector
  cell_types:
  - preferred_term: pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
    modifier: DYSREGULATED
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "alveolar accumulation of pulmonary surfactant"
    explanation: Orphanet supports surfactant accumulation as the defining downstream pathology.
  - reference: PMID:23001804
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by the accumulation of surfactant lipids and protein in the alveolar spaces, with resultant impairment in gas exchange."
    explanation: The clinical review supports alveolar surfactant/protein accumulation and impaired gas exchange.
  downstream:
  - target: Crazy paving pattern on pulmonary HRCT
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypoxemia
    causal_link_type: DIRECT
  - target: Respiratory failure requiring assisted ventilation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
histopathology:
- name: PAS-positive proteinaceous alveolar material with foamy macrophages
  description: >
    Characteristic biopsy or lavage findings include PAS-positive granular
    eosinophilic material, enlarged foamy alveolar macrophages, and relatively
    preserved alveolar walls.
  diagnostic: true
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Characteristic lung biopsy findings include periodic acid-Schiff-positive, granular eosinophilic material, enlarged foamy alveolar macrophages, and well-preserved alveolar walls."
    explanation: Orphanet describes the characteristic histopathology of hereditary PAP.
  - reference: PMID:23001804
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "periodic acid-Schiff (PAS)-positive material on bronchoalveolar lavage and transbronchial biopsies is usually sufficient."
    explanation: The clinical review supports PAS-positive material in BAL or biopsy as diagnostic.
phenotypes:
- category: Growth
  name: Failure to thrive in infancy
  frequency: FREQUENT
  description: Failure to thrive in infancy is a frequent pediatric presentation.
  phenotype_term:
    preferred_term: failure to thrive in infancy
    term:
      id: HP:0001531
      label: Failure to thrive in infancy
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001531 | Failure to thrive in infancy | Frequent (79-30%)"
    explanation: Orphanet records failure to thrive in infancy as frequent.
- category: Cardiac
  name: Tachycardia
  frequency: OCCASIONAL
  description: Tachycardia can occur with hypoxemia or respiratory distress.
  phenotype_term:
    preferred_term: tachycardia
    term:
      id: HP:0001649
      label: Tachycardia
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001649 | Tachycardia | Occasional (29-5%)"
    explanation: Orphanet records tachycardia as occasional.
- category: Pulmonary
  name: Restrictive ventilatory defect
  frequency: FREQUENT
  description: Restrictive physiology reflects alveolar filling and interstitial lung disease.
  phenotype_term:
    preferred_term: restrictive ventilatory defect
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002091 | Restrictive ventilatory defect | Frequent (79-30%)"
    explanation: Orphanet records restrictive ventilatory defect as frequent.
- category: Pulmonary
  name: Respiratory distress
  frequency: FREQUENT
  description: Respiratory distress is a frequent symptomatic manifestation.
  phenotype_term:
    preferred_term: respiratory distress
    term:
      id: HP:0002098
      label: Respiratory distress
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002098 | Respiratory distress | Frequent (79-30%)"
    explanation: Orphanet records respiratory distress as frequent.
- category: Pulmonary
  name: Tachypnea
  frequency: OCCASIONAL
  description: Tachypnea can accompany hypoxemia and respiratory distress.
  phenotype_term:
    preferred_term: tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002789 | Tachypnea | Occasional (29-5%)"
    explanation: Orphanet records tachypnea as occasional.
- category: Cellular
  name: Foam cells
  frequency: OCCASIONAL
  description: Foamy alveolar macrophages reflect surfactant and lipid accumulation.
  phenotype_term:
    preferred_term: foam cells
    term:
      id: HP:0003651
      label: Foam cells
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003651 | Foam cells | Occasional (29-5%)"
    explanation: Orphanet records foam cells as occasional.
- category: Pulmonary
  name: Respiratory failure requiring assisted ventilation
  frequency: FREQUENT
  description: Severe hereditary PAP can progress to respiratory failure requiring ventilatory support.
  phenotype_term:
    preferred_term: respiratory failure requiring assisted ventilation
    term:
      id: HP:0004887
      label: Respiratory failure requiring assisted ventilation
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004887 | Respiratory failure requiring assisted ventilation | Frequent (79-30%)"
    explanation: Orphanet records respiratory failure requiring assisted ventilation as frequent.
- category: Laboratory
  name: Abnormal circulating protein level
  frequency: VERY_FREQUENT
  description: Abnormal circulating protein concentration includes biomarker abnormalities such as elevated serum GM-CSF in receptor dysfunction.
  phenotype_term:
    preferred_term: abnormal circulating protein concentration
    term:
      id: HP:0010876
      label: Abnormal circulating protein concentration
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010876 | Abnormal circulating protein level | Very frequent (99-80%)"
    explanation: Orphanet records abnormal circulating protein level as very frequent.
  - reference: PMID:20622029
    reference_title: "Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction."
    explanation: The cohort supports increased serum GM-CSF as a circulating biomarker of GM-CSF receptor dysfunction.
- category: Infectious
  name: Acute infectious pneumonia
  frequency: OCCASIONAL
  description: Infection risk increases as alveolar macrophage immunity and surfactant clearance deteriorate.
  phenotype_term:
    preferred_term: acute infectious pneumonia
    term:
      id: HP:0011949
      label: Acute infectious pneumonia
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011949 | Acute infectious pneumonia | Occasional (29-5%)"
    explanation: Orphanet records acute infectious pneumonia as occasional.
- category: Pulmonary
  name: Hypoxemia
  frequency: FREQUENT
  description: Hypoxemia reflects impaired gas exchange from alveolar surfactant accumulation.
  phenotype_term:
    preferred_term: hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012418 | Hypoxemia | Frequent (79-30%)"
    explanation: Orphanet records hypoxemia as frequent.
- category: Pulmonary
  name: Cough
  frequency: OCCASIONAL
  description: Cough is a common PAP symptom but is listed as occasional for hereditary PAP in Orphanet.
  phenotype_term:
    preferred_term: cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012735 | Cough | Occasional (29-5%)"
    explanation: Orphanet records cough as occasional.
- category: Imaging
  name: Crazy paving pattern on pulmonary HRCT
  frequency: FREQUENT
  description: The HRCT crazy-paving pattern reflects ground-glass opacities with septal thickening.
  phenotype_term:
    preferred_term: crazy paving pattern on pulmonary HRCT
    term:
      id: HP:0025391
      label: Crazy paving pattern
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025391 | Crazy paving pattern on pulmonary HRCT | Frequent (79-30%)"
    explanation: Orphanet records crazy paving pattern on pulmonary HRCT as frequent.
  - reference: PMID:23001804
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high-resolution computed tomography reveals diffuse ground-glass opacities and airspace consolidation with interlobular septal thickening in a characteristic \"crazy paving\" pattern."
    explanation: The clinical review supports the HRCT pattern.
- category: Laboratory
  name: Autoimmune antibody positivity
  frequency: OCCASIONAL
  description: Autoimmune antibody positivity may appear in evaluation, but GM-CSF receptor autoantibodies are absent in hereditary PAP.
  phenotype_term:
    preferred_term: autoimmune antibody positivity
    term:
      id: HP:0030057
      label: Autoimmune antibody positivity
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030057 | Autoimmune antibody positivity | Occasional (29-5%)"
    explanation: Orphanet records autoimmune antibody positivity as occasional.
- category: Pulmonary
  name: Crackles
  frequency: OCCASIONAL
  description: Crackles may be heard with alveolar filling and respiratory compromise.
  phenotype_term:
    preferred_term: crackles
    term:
      id: HP:0030830
      label: Crackles
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030830 | Crackles | Occasional (29-5%)"
    explanation: Orphanet records crackles as occasional.
- category: Laboratory
  name: Elevated circulating CEA concentration
  frequency: OCCASIONAL
  description: Elevated circulating carcinoembryonic antigen concentration is an occasional biomarker abnormality.
  phenotype_term:
    preferred_term: elevated circulating CEA concentration
    term:
      id: HP:0031029
      label: Elevated circulating CEA concentration
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031029 | Elevated carcinoembryonic antigen level | Occasional (29-5%)"
    explanation: Orphanet records elevated carcinoembryonic antigen level as occasional.
diagnosis:
- name: GM-CSF receptor dysfunction and autoantibody testing
  description: >
    Hereditary PAP is suspected when PAP occurs with increased serum GM-CSF,
    impaired GM-CSF receptor function, and absent GM-CSF autoantibodies,
    distinguishing it from autoimmune PAP.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The Granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function is impaired but GM-CSF receptor autoantibodies are absent."
    explanation: Orphanet identifies impaired receptor function with absent GM-CSF receptor autoantibodies.
  - reference: PMID:20622029
    reference_title: "Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP"
    explanation: The cohort supports using high GM-CSF and absent autoantibodies to separate hereditary from autoimmune/secondary PAP.
- name: CSF2RA and CSF2RB genetic testing
  description: >
    Molecular testing of CSF2RA and CSF2RB confirms hereditary PAP and separates
    receptor-subunit disease from autoimmune and secondary forms.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:20622029
    reference_title: "Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CSF2RA mutations cause a genetic form of PAP"
    explanation: The CSF2RA cohort supports genetic testing for hereditary PAP.
  - reference: PMID:21075760
    reference_title: "Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first report identifying a genetic defect in CSF2RB"
    explanation: The CSF2RB report supports including CSF2RB in molecular testing.
- name: HRCT and PAS-positive lavage or biopsy material
  description: >
    HRCT can show a crazy-paving pattern, while bronchoalveolar lavage or
    transbronchial biopsy can show PAS-positive material consistent with PAP.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: PMID:23001804
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a combination of typical clinical and imaging features with periodic acid-Schiff (PAS)-positive material on bronchoalveolar lavage and transbronchial biopsies is usually sufficient."
    explanation: The clinical review supports combined imaging plus PAS-positive lavage/biopsy findings.
treatments:
- name: Whole-lung lavage
  description: >
    Whole-lung lavage mechanically removes excess surfactant and proteinaceous
    material from the alveoli and remains a main symptomatic treatment for PAP,
    including CSF2RA-associated hereditary PAP.
  treatment_term:
    preferred_term: therapeutic irrigation
    term:
      id: MAXO:0000460
      label: therapeutic irrigation
  target_mechanisms:
  - target: Alveolar surfactant and proteinaceous material accumulation
    treatment_effect: INHIBITS
    description: Whole-lung lavage removes accumulated surfactant from alveolar spaces.
    evidence:
    - reference: PMID:30846703
      reference_title: "Pulmonary alveolar proteinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "whole-lung lavage effectively removes excessive surfactant."
      explanation: The disease-primer review supports lavage removal of accumulated surfactant.
  evidence:
  - reference: PMID:20622029
    reference_title: "Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All symptomatic patients responded well to whole-lung lavage therapy."
    explanation: The CSF2RA cohort supports whole-lung lavage response in symptomatic hereditary PAP.
  - reference: PMID:23001804
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The standard of care for treatment of PAP remains whole lung lavage"
    explanation: The clinical review supports whole-lung lavage as the standard PAP treatment.
- name: Supportive respiratory care
  description: >
    Oxygen, assisted ventilation, infection treatment, and general supportive
    care are used for hypoxemia, respiratory distress, infection, or respiratory
    failure while disease-specific management is pursued.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "severe respiratory failure"
    explanation: Orphanet records severe respiratory failure as part of the disease spectrum, supporting respiratory support as clinically relevant.
  - reference: ORPHA:264675
    reference_title: Hereditary pulmonary alveolar proteinosis (Orphanet structured-database record)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004887 | Respiratory failure requiring assisted ventilation | Frequent (79-30%)"
    explanation: Orphanet records assisted ventilation-requiring respiratory failure as frequent.
- name: Experimental pulmonary macrophage transplantation
  description: >
    Pulmonary macrophage transplantation or gene-corrected macrophage approaches
    are experimental strategies intended to replace defective alveolar
    macrophage function in hereditary PAP.
  treatment_term:
    preferred_term: cellular therapy
    term:
      id: MAXO:0000016
      label: cellular therapy
  target_mechanisms:
  - target: Defective alveolar macrophage surfactant clearance
    treatment_effect: RESTORES
    description: Transplanted macrophages are intended to restore alveolar macrophage surfactant-clearance function.
    evidence:
    - reference: PMID:30100408
      reference_title: "iPSC-Derived Macrophages Effectively Treat Pulmonary Alveolar Proteinosis in Csf2rb-Deficient Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "PMT significantly improves alveolar protein deposition and other critical herPAP disease parameters."
      explanation: The mouse model supports pulmonary macrophage transplantation as a mechanism-directed experimental therapy.
  evidence:
  - reference: PMID:30100408
    reference_title: "iPSC-Derived Macrophages Effectively Treat Pulmonary Alveolar Proteinosis in Csf2rb-Deficient Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "PMT significantly improves alveolar protein deposition and other critical herPAP disease parameters."
    explanation: The model-organism study supports pulmonary macrophage transplantation as experimental cellular therapy, not established human standard care.
notes: >
  This entry follows the hereditary/congenital PAP concept mapped by
  ORPHA:264675 and MONDO:0012580. Autoimmune PAP, which is driven by GM-CSF
  autoantibodies and accounts for most PAP cases, should be distinguished from
  hereditary PAP with GM-CSF receptor subunit defects.
references:
- reference: ORPHA:264675
  title: Hereditary pulmonary alveolar proteinosis
  findings: []
- reference: PMID:20622029
  title: "Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy."
  found_in:
  - Hereditary_Pulmonary_Alveolar_Proteinosis-deep-research-fallback.md
  findings: []
- reference: PMID:21075760
  title: Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB.
  found_in:
  - Hereditary_Pulmonary_Alveolar_Proteinosis-deep-research-fallback.md
  findings: []
- reference: PMID:23001804
  title: Pulmonary alveolar proteinosis.
  found_in:
  - Hereditary_Pulmonary_Alveolar_Proteinosis-deep-research-fallback.md
  findings: []
- reference: PMID:30100408
  title: iPSC-Derived Macrophages Effectively Treat Pulmonary Alveolar Proteinosis in Csf2rb-Deficient Mice.
  found_in:
  - Hereditary_Pulmonary_Alveolar_Proteinosis-deep-research-fallback.md
  findings: []
- reference: PMID:30846703
  title: Pulmonary alveolar proteinosis.
  found_in:
  - Hereditary_Pulmonary_Alveolar_Proteinosis-deep-research-fallback.md
  findings: []
📚

References & Deep Research

References

6
ORPHA:264675
Hereditary pulmonary alveolar proteinosis
No top-level findings curated for this source.
PMID:20622029
Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy.
No top-level findings curated for this source.
PMID:21075760
Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB.
No top-level findings curated for this source.
PMID:23001804
Pulmonary alveolar proteinosis.
No top-level findings curated for this source.
PMID:30100408
iPSC-Derived Macrophages Effectively Treat Pulmonary Alveolar Proteinosis in Csf2rb-Deficient Mice.
No top-level findings curated for this source.
PMID:30846703
Pulmonary alveolar proteinosis.
No top-level findings curated for this source.

Deep Research

1
Fallback ▸
Hereditary Pulmonary Alveolar Proteinosis Deep-Research Fallback

Hereditary Pulmonary Alveolar Proteinosis Deep-Research Fallback

Initial Falcon deep-research could not run before a draft existed because just research-disorder requires the target YAML path. After the draft was in place, bounded provider attempts were retried:

  • timeout 120s just research-disorder falcon Hereditary_Pulmonary_Alveolar_Proteinosis terminated with signal 15 after the timeout.
  • timeout 90s just research-disorder openai Hereditary_Pulmonary_Alveolar_Proteinosis terminated with signal 15 after the timeout.

No provider artifact was produced by either bounded retry. The local curation therefore used generated caches only:

  • ORPHA:264675 for definition, inheritance, age of onset, epidemiology, genes, phenotype frequencies, and cross-references.
  • PMID:20622029 for CSF2RA-associated hereditary PAP, GM-CSF receptor dysfunction, diagnosis, and whole-lung lavage response.
  • PMID:21075760 for CSF2RB-associated hereditary PAP and autosomal recessive inheritance.
  • PMID:30846703 and PMID:23001804 for PAP pathophysiology, surfactant/cholesterol clearance, imaging, diagnosis, and whole-lung lavage.
  • PMID:30100408 for model-organism pulmonary macrophage transplantation evidence.

Scope Confirmation

The curation covers the ORPHA:264675/MONDO:0012580 hereditary pulmonary alveolar proteinosis concept, not autoimmune or secondary pulmonary alveolar proteinosis. The YAML consumes the structured ORPHA definition, genes, mapping, inheritance, epidemiology, age-of-onset categories, and all 15 ORPHA HPO phenotype rows. Literature-backed additions focus on GM-CSF receptor signaling, CSF2RA/CSF2RB genetics, alveolar macrophage surfactant/cholesterol clearance, PAS-positive alveolar material, HRCT crazy-paving diagnosis, whole-lung lavage, supportive respiratory care, and experimental macrophage transplantation.