🏷

Classifications

Harrison's Part

IUIS Category

🔗

Mappings

MONDO

MONDO:0012580 hereditary pulmonary alveolar proteinosis

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.

◆

Subtypes

2

SMDP4 (CSF2RA-associated hereditary PAP) MONDO:0010424

CSF2RA hgnc:2435

Biallelic CSF2RA variants abolishing or severely reducing GM-CSF receptor alpha-chain function. The reported childhood cohort ranged from asymptomatic to progressive dyspnoea. MONDO:0010424 carries OMIM:300770 as its cross-reference.

Show evidence (1 reference)

PMID:20622029 SUPPORT Human Clinical

"Eight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations."

Source for assigning the CSF2RA gene to this subtype row.

SMDP5 (CSF2RB-associated hereditary PAP) MONDO:0013712

CSF2RB hgnc:2436

Biallelic CSF2RB variants impairing the shared GM-CSF receptor beta chain. The report cited here is an adult-onset case with a homozygous single-base deletion that reduced GM-CSF-dependent signalling and function.

Show evidence (1 reference)

PMID:21075760 SUPPORT Human Clinical

"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."

Source for assigning the CSF2RB gene to this subtype row.

⚙

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 CL:0000583

CSF2RA hgnc:2435 CSF2RB hgnc:2436

cytokine-mediated signaling pathway GO:0019221 ↓ DECREASED JAK-STAT signaling downstream of GM-CSF receptor GO:0007259 ↓ DECREASED

alveolus of lung UBERON:0002299

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 CL:0000583

cholesterol efflux GO:0033344 ↓ DECREASED lipid metabolic process GO:0006629 ↕ DYSREGULATED phagocytosis GO:0006909 ↕ DYSREGULATED

alveolus of lung UBERON:0002299

Downstream

Acute infectious pneumonia Alveolar macrophages that cannot clear surfactant are also impaired at clearing organisms, so secondary infection is a recognised complication rather than a coincidence.

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 CL:0002063 alveolar macrophage CL:0000583

lipid metabolic process GO:0006629 ↕ DYSREGULATED

alveolus of lung UBERON:0002299

Downstream

Respiratory distress The presenting problem: airspaces filled with surfactant cannot exchange gas.

Tachypnea Compensatory increase in respiratory rate.

Tachycardia Compensatory cardiovascular response to hypoxaemia.

Cough Usually dry or with scant sputum, from airway irritation by the accumulated material.

Crackles The auscultatory sign of alveolar filling.

Restrictive ventilatory defect The physiological signature on pulmonary function testing: filled airspaces reduce compliance and volumes.

Failure to thrive in infancy Growth failure from the work of breathing and chronic hypoxaemia in the infantile presentation.

Elevated circulating CEA concentration An occasional biomarker abnormality, reported alongside the disease rather than mechanistically traced to it. Drawn from the accumulation node as the only plausible parent, and marked accordingly.

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.

●

Phenotypes

15

Cardiovascular 2

Tachycardia OCCASIONAL HP:0001649

Show evidence (1 reference)

ORPHA:264675 SUPPORT Other

"HP:0001649 | Tachycardia | Occasional (29-5%)"

Orphanet records tachycardia as occasional.

Foam cells OCCASIONAL HP:0003651

Show evidence (1 reference)

ORPHA:264675 SUPPORT Other

"HP:0003651 | Foam cells | Occasional (29-5%)"

Orphanet records foam cells as occasional.

Immune 2

Acute infectious pneumonia OCCASIONAL 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.

Autoimmune antibody positivity OCCASIONAL HP:0030057

No incoming causal edge, deliberately. Orphanet reports general autoimmune antibody positivity as occasional here, which is what the evidence supports, but no node in this entry describes a mechanism that would produce autoantibodies — the chain runs from receptor dysfunction through failed surfactant clearance to alveolar filling, and none of those steps reaches B-cell tolerance by any cited route. Worth keeping distinct from the differential point the description makes: the anti-GM-CSF autoantibodies that DEFINE autoimmune PAP are absent in the hereditary form. General autoantibody positivity being occasionally present and the specific pathogenic autoantibody being absent are two different claims, and the entry carries both.

Show evidence (1 reference)

ORPHA:264675 SUPPORT Other

"HP:0030057 | Autoimmune antibody positivity | Occasional (29-5%)"

Orphanet records autoimmune antibody positivity as occasional.

Metabolism 2

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.

Elevated circulating CEA concentration OCCASIONAL 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.

Respiratory 8

Restrictive ventilatory defect FREQUENT 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 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 HP:0002789

Show evidence (1 reference)

ORPHA:264675 SUPPORT Other

"HP:0002789 | Tachypnea | Occasional (29-5%)"

Orphanet records tachypnea as occasional.

Respiratory failure requiring assisted ventilation FREQUENT 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.

Hypoxemia FREQUENT HP:0012418

Show evidence (1 reference)

ORPHA:264675 SUPPORT Other

"HP:0012418 | Hypoxemia | Frequent (79-30%)"

Orphanet records hypoxemia as frequent.

Cough OCCASIONAL HP:0012735

Show evidence (1 reference)

ORPHA:264675 SUPPORT Other

"HP:0012735 | Cough | Occasional (29-5%)"

Orphanet records cough as occasional.

Crazy paving pattern on pulmonary HRCT FREQUENT 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.

Crackles OCCASIONAL HP:0030830

Show evidence (1 reference)

ORPHA:264675 SUPPORT Other

"HP:0030830 | Crackles | Occasional (29-5%)"

Orphanet records crackles as occasional.

Growth 1

Failure to thrive in infancy FREQUENT 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.

🧬

Genetic Associations

2

CSF2RA pathogenic variants

Gene: CSF2RA hgnc:2435 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

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.

Variants (1)

Biallelic CSF2RA loss-of-function variants

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.

Show evidence (2 references)

PMID:20622029 SUPPORT Human Clinical

"Eight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations."

The cohort identifies recessive CSF2RA mutations as causal in children with hereditary PAP.

PMID:20622029 SUPPORT Human Clinical

"Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing."

The cohort details CSF2RA variant classes.

CSF2RB pathogenic variants

Gene: CSF2RB hgnc:2436 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

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.

Variants (1)

Biallelic CSF2RB pathogenic variants

Homozygous CSF2RB variants can impair GM-CSF receptor beta-chain expression and downstream signaling, producing hereditary PAP.

Show evidence (1 reference)

PMID:21075760 SUPPORT Human Clinical

"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."

The report identifies a homozygous CSF2RB deletion that reduces GM-CSF signaling and function.

🗃️

External Assertions

1

Orphanet hereditary pulmonary alveolar proteinosis record

Orphanet structured disease record ORPHA:264675

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.

Show evidence (1 reference)

ORPHA:264675 SUPPORT Other

"MONDO:0012580 | Exact"

Orphanet maps ORPHA:264675 exactly to the MONDO identifier used by this entry.

💊

Medical Actions

3

Whole-lung lavage

Action: therapeutic irrigation Ontology label: Therapeutic Procedure NCIT:C49236

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 Ontology label: Supportive Care NCIT:C15747

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 Ontology label: Cellular Therapy NCIT:C70601

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.

🔬

Diagnosis

3

GM-CSF receptor dysfunction and autoantibody testing

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.

diagnostic procedure NCIT:C18020

Show evidence (2 references)

ORPHA:264675 SUPPORT Other

"The Granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function is impaired but GM-CSF receptor autoantibodies are absent."

Orphanet identifies impaired receptor function with absent GM-CSF receptor autoantibodies.

PMID:20622029 SUPPORT Human Clinical

"Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP"

The cohort supports using high GM-CSF and absent autoantibodies to separate hereditary from autoimmune/secondary PAP.

CSF2RA and CSF2RB genetic testing

Molecular testing of CSF2RA and CSF2RB confirms hereditary PAP and separates receptor-subunit disease from autoimmune and secondary forms.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:20622029 SUPPORT Human Clinical

"CSF2RA mutations cause a genetic form of PAP"

The CSF2RA cohort supports genetic testing for hereditary PAP.

PMID:21075760 SUPPORT Human Clinical

"This is the first report identifying a genetic defect in CSF2RB"

The CSF2RB report supports including CSF2RB in molecular testing.

HRCT and PAS-positive lavage or biopsy material

HRCT can show a crazy-paving pattern, while bronchoalveolar lavage or transbronchial biopsy can show PAS-positive material consistent with PAP.

diagnostic procedure NCIT:C18020

Show evidence (1 reference)

PMID:23001804 SUPPORT Human Clinical

"a combination of typical clinical and imaging features with periodic acid-Schiff (PAS)-positive material on bronchoalveolar lavage and transbronchial biopsies is usually sufficient."

The clinical review supports combined imaging plus PAS-positive lavage/biopsy findings.

📈

Progression

2

Variable onset

Age: Infancy through elderly adulthood

Orphanet lists onset across infancy, childhood, adolescence, adulthood, and elderly adulthood.

Show evidence (3 references)

ORPHA:264675 SUPPORT Other

"Age of onset: Infancy"

Orphanet records infancy as an onset category.

ORPHA:264675 SUPPORT Other

"Age of onset: Adult"

Orphanet records adult onset as an onset category.

ORPHA:264675 SUPPORT Other

"Age of onset: Elderly"

Orphanet records elderly onset as an onset category.

Progressive respiratory burden in symptomatic disease

Symptomatic patients can develop insidious progressive dyspnea, hypoxemic respiratory failure, infection, and pulmonary fibrosis, although severity is highly variable.

Show evidence (2 references)

PMID:20622029 SUPPORT Human Clinical

"Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years."

The CSF2RA cohort documents variable symptomatic versus asymptomatic childhood presentation.

PMID:30846703 SUPPORT Human Clinical

"PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis."

The disease-primer review summarizes the main disease trajectory and complications.

📊

Prevalence

1

Worldwide

Point Prevalence ≤0.1 per 100,000 <1 in 1,000,000

Orphanet records worldwide point prevalence below one per million.

Show evidence (1 reference)

ORPHA:264675 SUPPORT Other

"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:20622029"

Orphanet records worldwide point prevalence below one per million.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Hereditary Pulmonary Alveolar Proteinosis:

Surfactant metabolism dysfunction due to SFTPB deficiency (SMDP1) Not Yet Curated MONDO:0009929

Overlapping Features Loss-of-function variants in SFTPB disrupt surfactant protein B production, so surfactant is not made correctly rather than not cleared. MONDO files this disease under hereditary pulmonary alveolar proteinosis, but the field's own pathogenetic classification separates the two: hereditary PAP means the GM-CSF receptor disease, and a surfactant-production defect is congenital PAP. It is recorded here as a differential rather than a subtype of this entry.

Distinguishing Features

Failure of surfactant production, not of GM-CSF-dependent clearance
GM-CSF autoantibody and GM-CSF signalling studies are not informative
Typically presents as neonatal respiratory distress at or near term

Show evidence (2 references)

PMID:40306683 SUPPORT REVIEW SYNTHESIS Human Clinical

"Pathogenic variants in surfactant pulmonary-associated protein B (SFTPB) are typically loss-of-function and disrupt surfactant protein B (SP-B) production and surfactant function."

Source for the SFTPB mechanism and for placing it in the surfactant-production rather than the surfactant-clearance arm.

PMID:30846703 SUPPORT REVIEW SYNTHESIS Human Clinical

"congenital PAP is caused by mutations in genes involved in surfactant production"

The disease-primer classification that separates congenital PAP from the hereditary GM-CSF-receptor PAP this entry models.

Surfactant metabolism dysfunction due to SFTPC variants (SMDP2) Not Yet Curated MONDO:0024465

Overlapping Features Dominant SFTPC variants act as a toxic gain of function, disrupting surfactant protein C processing and trafficking in alveolar epithelial type 2 cells. This is both a different mechanism and a different mode of inheritance from the recessive GM-CSF receptor disease this entry models. Two further MONDO classes denote the same SFTPC concept under this parent: MONDO:0018603 (SFTPC-related interstitial lung disease), which MONDO records as scheduled for merge into MONDO:0024465, and MONDO:0016323 (chronic respiratory distress with surfactant metabolism deficiency, Orphanet:217566), which the Monarch knowledge graph also keys on SFTPC from an Orphanet source.

Distinguishing Features

Autosomal dominant, unlike the recessive GM-CSF receptor forms
Toxic gain of function in surfactant protein C processing, not failed clearance

Show evidence (1 reference)

PMID:40306683 SUPPORT REVIEW SYNTHESIS Human Clinical

"Dominant variants in surfactant pulmonary-associated protein C (SFTPC) generally result in a toxic gain-of-function with disruption of surfactant protein C (SP-C) processing and trafficking in the alveolar epithelial type 2 cells."

Source for the SFTPC mechanism and dominant inheritance, both of which differ from this entry's disease.

Interstitial lung disease due to ABCA3 deficiency (SMDP3) Not Yet Curated MONDO:0012582

Overlapping Features ABCA3 transports the phospholipids that assemble with surfactant proteins to make surfactant, so pathogenic variants impair surfactant production rather than surfactant clearance. Null and trafficking-defective missense allele classes are distinguished in the source. MONDO files this disease under both hereditary pulmonary alveolar proteinosis and inherited interstitial lung disease; it is recorded here as a differential.

Distinguishing Features

Impaired phospholipid transport into the lamellar body, not failed clearance
Null versus trafficking-defective missense alleles give different severity

Show evidence (1 reference)

PMID:40306683 SUPPORT REVIEW SYNTHESIS Human Clinical

"Adenosine triphosphate binding cassette transporter A3 (ABCA3) variants include loss-of-function or "null" variants in which no ABCA3 protein is made or missense variants that disrupt intracellular trafficking of ABCA3 or impair phospholipid transport."

Source for the ABCA3 allele classes and for placing this disease in the surfactant-production arm.

Severe early-onset pulmonary alveolar proteinosis due to MARS1 deficiency Not Yet Curated MONDO:0014206

Overlapping Features Biallelic MARS1 missense variants attenuate methionyl-tRNA synthetase activity, a general protein-biosynthesis defect rather than a GM-CSF signalling or surfactant-clearance defect. A founder allele makes the disease prevalent on Réunion Island, and in the yeast assay the attenuated enzyme activity was restored by methionine supplementation, which the authors describe as possibly opening new treatment opportunities. MONDO's synonyms for this disease include interstitial lung and liver disease and hereditary pulmonary alveolar proteinosis with hepatic involvement. Recorded here as a differential rather than a subtype. MONDO's label uses the previous gene symbol MARS; the approved symbol is MARS1.

Distinguishing Features

Attenuated methionyl-tRNA synthetase activity, not impaired GM-CSF signalling
Founder allele concentrated on Réunion Island and nearby islands
MONDO's synonyms for the disease name hepatic as well as pulmonary involvement

Show evidence (2 references)

PMID:25913036 SUPPORT PRIMARY RESULT Human Clinical

"We identified biallelic missense mutations in MARS in a specific form of pediatric pulmonary alveolar proteinosis (PAP), a severe lung disorder that is prevalent on the island of Réunion and the molecular basis of which is unresolved."

Establishes the MARS1 gene and the Réunion Island prevalence recorded in this differential.

PMID:25913036 SUPPORT Other

"Enzyme activity was attenuated in a liquid medium without methionine but could be restored by methionine supplementation."

Source for the enzymatic lesion and for the methionine-restoration result referenced in this differential's description.

📊

Related Datasets

2

A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [CRISPR] geo:GSE299696

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain largely elusive. Here, through a genome-wide CRISPR activation screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify Deltex E3 Ubiquitin Ligase 4 (DTX4) as a pivotal regulator of cholesterol efflux in AMs.

human n=6

Identified by GEO DataSets index search for Hereditary Pulmonary Alveolar Proteinosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [RNA-seq II] geo:GSE299693

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain largely elusive. Here, through a genome-wide CRISPR activation screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify Deltex E3 Ubiquitin Ligase 4 (DTX4) as a pivotal regulator of cholesterol efflux in AMs.

human BULK RNA SEQ n=6

Identified by GEO DataSets index search for Hereditary Pulmonary Alveolar Proteinosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

{ }

Source YAML

click to show

name: Hereditary Pulmonary Alveolar Proteinosis
category: Respiratory Disease
creation_date: "2026-05-09T19:32:00Z"
synonyms:
- Hereditary PAP
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
has_subtypes:
- name: SMDP4
  display_name: SMDP4 (CSF2RA-associated hereditary PAP)
  classification: molecular
  subtype_term:
    preferred_term: surfactant metabolism dysfunction, pulmonary, 4
    term:
      id: MONDO:0010424
      label: surfactant metabolism dysfunction, pulmonary, 4
  genes:
  - preferred_term: CSF2RA
    term:
      id: hgnc:2435
      label: CSF2RA
  description: >
    Biallelic CSF2RA variants abolishing or severely reducing GM-CSF receptor
    alpha-chain function. The reported childhood cohort ranged from asymptomatic
    to progressive dyspnoea. MONDO:0010424 carries OMIM:300770 as its cross-reference.
  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: Source for assigning the CSF2RA gene to this subtype row.
- name: SMDP5
  display_name: SMDP5 (CSF2RB-associated hereditary PAP)
  classification: molecular
  subtype_term:
    preferred_term: surfactant metabolism dysfunction, pulmonary, 5
    term:
      id: MONDO:0013712
      label: surfactant metabolism dysfunction, pulmonary, 5
  genes:
  - preferred_term: CSF2RB
    term:
      id: hgnc:2436
      label: CSF2RB
  description: >
    Biallelic CSF2RB variants impairing the shared GM-CSF receptor beta chain.
    The report cited here is an adult-onset case with a homozygous single-base
    deletion that reduced GM-CSF-dependent signalling and function.
  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: Source for assigning the CSF2RB gene to this subtype row.
classifications:
  harrisons_chapter:
  - classification_value: RESPIRATORY
    notes: >-
      An interstitial lung disease presenting with dyspnea, cough, hypoxemia
      and a restrictive ventilatory defect.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian disorder caused by biallelic defects in the GM-CSF receptor
      subunit genes CSF2RA and CSF2RB.
  iuis_category:
    classification_value: phagocyte defect
    notes: >-
      IUIS 2022 phenotypic classification (Tangye et al., PMID:35748970),
      Table 5 "Congenital defects of phagocyte number or function", section 4
      (Other Non-Lymphoid Defects). This entry covers BOTH pulmonary alveolar
      proteinosis rows of that section, one per receptor subunit: CSF2RA
      (XL, biallelic mutations in a pseudoautosomal gene, MIM 300770) and
      CSF2RB (AR, MIM 614370). Affected cells are alveolar macrophages and the
      affected function is GM-CSF signaling — the phagocyte here is the tissue
      macrophage rather than the neutrophil, which is why a lung disease sits
      in the phagocyte table.

      The published table prints the second gene as "CSFR2B". That is a typo
      in the source: the gene is CSF2RB (hgnc:2436), which is what this entry
      binds. The transposition is preserved inside the quoted snippet because
      the quote belongs to the source, and must not be propagated into any
      gene_term or prose.

      Not to be confused with the autoimmune disease of the same name.
      Autoimmune pulmonary alveolar proteinosis, caused by neutralizing
      anti-GM-CSF autoantibody, is a Table 10 phenocopy of an inborn error of
      immunity and is curated separately; splitting the two on mechanism
      rather than on gene matters here because both entries bind CSF2RA and
      CSF2RB.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CSF2RA XL (Biallelic mutations in pseudo-autosomal gene) 300770"
      explanation: >-
        The CSF2RA row of IUIS Table 5, quoted verbatim with its inheritance
        qualifier and OMIM number.
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Pulmonary alveolar proteinosis CSFR2B AR 614370"
      explanation: >-
        The second pulmonary alveolar proteinosis row of IUIS Table 5, with
        its inheritance and OMIM number. The gene is printed "CSFR2B" in the
        source; the quote reproduces that typo verbatim rather than correcting
        it.
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Alveolar macrophages GM-CSF signaling Alveolar proteinosis"
      explanation: >-
        The affected-cells, affected-function and associated-features cells
        shared by both rows, identifying the alveolar macrophage as the
        phagocyte compartment and GM-CSF signaling as the defective function.
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"
    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"
    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"
    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
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  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"
    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"
    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"
    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"
    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
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: SMDP4
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: ORPHA:264675
      reference_title: "Hereditary pulmonary alveolar proteinosis"
      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"
    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
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: SMDP5
  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"
    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
  genes:
  - preferred_term: CSF2RA
    term:
      id: hgnc:2435
      label: CSF2RA
  - preferred_term: CSF2RB
    term:
      id: hgnc:2436
      label: CSF2RB
  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: Acute infectious pneumonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Alveolar macrophages that cannot clear surfactant are also impaired at clearing organisms, so secondary infection is a recognised complication rather than a coincidence.
  - 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"
    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: Respiratory distress
    causal_link_type: DIRECT
    description: >-
      The presenting problem: airspaces filled with surfactant cannot exchange gas.
  - target: Tachypnea
    causal_link_type: DIRECT
    description: >-
      Compensatory increase in respiratory rate.
  - target: Tachycardia
    causal_link_type: DIRECT
    description: >-
      Compensatory cardiovascular response to hypoxaemia.
  - target: Cough
    causal_link_type: DIRECT
    description: >-
      Usually dry or with scant sputum, from airway irritation by the accumulated material.
  - target: Crackles
    causal_link_type: DIRECT
    description: >-
      The auscultatory sign of alveolar filling.
  - target: Restrictive ventilatory defect
    causal_link_type: DIRECT
    description: >-
      The physiological signature on pulmonary function testing: filled airspaces reduce compliance and volumes.
  - target: Failure to thrive in infancy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Growth failure from the work of breathing and chronic hypoxaemia in the infantile presentation.
  - target: Elevated circulating CEA concentration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      An occasional biomarker abnormality, reported alongside the disease rather than mechanistically traced to it. Drawn from the accumulation node as the only plausible parent, and marked accordingly.
  - 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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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"
    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.
  reports_on:
  - target: Biallelic GM-CSF receptor subunit dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Serum GM-CSF is elevated because the receptor cannot consume it — the
      ligand accumulates in front of a blocked receptor. That makes it a
      measurement of the receptor defect rather than a consequence of it, and
      it is the finding that separates hereditary PAP from the autoimmune form,
      where GM-CSF is neutralised by autoantibody instead.
- 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"
    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"
    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"
    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"
    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"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030057 | Autoimmune antibody positivity | Occasional (29-5%)"
    explanation: Orphanet records autoimmune antibody positivity as occasional.
  notes: >-
    No incoming causal edge, deliberately. Orphanet reports general autoimmune
    antibody positivity as occasional here, which is what the evidence
    supports, but no node in this entry describes a mechanism that would
    produce autoantibodies — the chain runs from receptor dysfunction through
    failed surfactant clearance to alveolar filling, and none of those steps
    reaches B-cell tolerance by any cited route.

    Worth keeping distinct from the differential point the description makes:
    the anti-GM-CSF autoantibodies that DEFINE autoimmune PAP are absent in the
    hereditary form. General autoantibody positivity being occasionally present
    and the specific pathogenic autoantibody being absent are two different
    claims, and the entry carries both.
- 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"
    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"
    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: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: ORPHA:264675
    reference_title: "Hereditary pulmonary alveolar proteinosis"
    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: NCIT:C15709
      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: NCIT:C18020
      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.
differential_diagnoses:
- name: Surfactant metabolism dysfunction due to SFTPB deficiency (SMDP1)
  disease_term:
    preferred_term: surfactant metabolism dysfunction, pulmonary, 1
    term:
      id: MONDO:0009929
      label: surfactant metabolism dysfunction, pulmonary, 1
  description: >
    Loss-of-function variants in SFTPB disrupt surfactant protein B production,
    so surfactant is not made correctly rather than not cleared. MONDO files this
    disease under hereditary pulmonary alveolar proteinosis, but the field's own
    pathogenetic classification separates the two: hereditary PAP means the
    GM-CSF receptor disease, and a surfactant-production defect is congenital
    PAP. It is recorded here as a differential rather than a subtype of this
    entry.
  distinguishing_features:
  - Failure of surfactant production, not of GM-CSF-dependent clearance
  - GM-CSF autoantibody and GM-CSF signalling studies are not informative
  - Typically presents as neonatal respiratory distress at or near term
  evidence:
  - reference: PMID:40306683
    reference_title: Genetic Disorders of Surfactant Metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Pathogenic variants in surfactant pulmonary-associated protein B (SFTPB)
      are typically loss-of-function and disrupt surfactant protein B (SP-B)
      production and surfactant function.
    explanation: >-
      Source for the SFTPB mechanism and for placing it in the
      surfactant-production rather than the surfactant-clearance arm.
  - reference: PMID:30846703
    reference_title: "Pulmonary alveolar proteinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      congenital PAP is caused by mutations in genes involved in surfactant
      production
    explanation: >-
      The disease-primer classification that separates congenital PAP from the
      hereditary GM-CSF-receptor PAP this entry models.
- name: Surfactant metabolism dysfunction due to SFTPC variants (SMDP2)
  disease_term:
    preferred_term: surfactant metabolism dysfunction, pulmonary, 2
    term:
      id: MONDO:0024465
      label: surfactant metabolism dysfunction, pulmonary, 2
  description: >
    Dominant SFTPC variants act as a toxic gain of function, disrupting
    surfactant protein C processing and trafficking in alveolar epithelial type 2
    cells. This is both a different mechanism and a different mode of
    inheritance from the recessive GM-CSF receptor disease this entry models.
    Two further MONDO classes denote the same SFTPC concept under this parent:
    MONDO:0018603 (SFTPC-related interstitial lung disease), which MONDO records
    as scheduled for merge into MONDO:0024465, and MONDO:0016323 (chronic
    respiratory distress with surfactant metabolism deficiency,
    Orphanet:217566), which the Monarch knowledge graph also keys on SFTPC from
    an Orphanet source.
  distinguishing_features:
  - Autosomal dominant, unlike the recessive GM-CSF receptor forms
  - Toxic gain of function in surfactant protein C processing, not failed clearance
  evidence:
  - reference: PMID:40306683
    reference_title: Genetic Disorders of Surfactant Metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Dominant variants in surfactant pulmonary-associated protein C (SFTPC)
      generally result in a toxic gain-of-function with disruption of surfactant
      protein C (SP-C) processing and trafficking in the alveolar epithelial type
      2 cells.
    explanation: >-
      Source for the SFTPC mechanism and dominant inheritance, both of which
      differ from this entry's disease.
- name: Interstitial lung disease due to ABCA3 deficiency (SMDP3)
  disease_term:
    preferred_term: interstitial lung disease due to ABCA3 deficiency
    term:
      id: MONDO:0012582
      label: interstitial lung disease due to ABCA3 deficiency
  description: >
    ABCA3 transports the phospholipids that assemble with surfactant proteins to
    make surfactant, so pathogenic variants impair surfactant production rather
    than surfactant clearance. Null and trafficking-defective missense allele
    classes are distinguished in the source. MONDO files
    this disease under both hereditary pulmonary alveolar proteinosis and
    inherited interstitial lung disease; it is recorded here as a differential.
  distinguishing_features:
  - Impaired phospholipid transport into the lamellar body, not failed clearance
  - Null versus trafficking-defective missense alleles give different severity
  evidence:
  - reference: PMID:40306683
    reference_title: Genetic Disorders of Surfactant Metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Adenosine triphosphate binding cassette transporter A3 (ABCA3) variants
      include loss-of-function or "null" variants in which no ABCA3 protein is
      made or missense variants that disrupt intracellular trafficking of ABCA3
      or impair phospholipid transport.
    explanation: >-
      Source for the ABCA3 allele classes and for placing this disease in the
      surfactant-production arm.
- name: Severe early-onset pulmonary alveolar proteinosis due to MARS1 deficiency
  disease_term:
    preferred_term: severe early-onset pulmonary alveolar proteinosis due to MARS deficiency
    term:
      id: MONDO:0014206
      label: severe early-onset pulmonary alveolar proteinosis due to MARS deficiency
  description: >
    Biallelic MARS1 missense variants attenuate methionyl-tRNA synthetase
    activity, a general protein-biosynthesis defect rather than a GM-CSF
    signalling or surfactant-clearance defect. A founder allele makes the disease
    prevalent on Réunion Island, and in the yeast assay the attenuated enzyme
    activity was restored by methionine supplementation, which the authors
    describe as possibly opening new treatment opportunities. MONDO's synonyms
    for this disease include interstitial lung and liver disease and hereditary
    pulmonary alveolar proteinosis with hepatic involvement. Recorded here as a
    differential rather than a subtype. MONDO's label uses the previous gene
    symbol MARS; the approved symbol is MARS1.
  distinguishing_features:
  - Attenuated methionyl-tRNA synthetase activity, not impaired GM-CSF signalling
  - Founder allele concentrated on Réunion Island and nearby islands
  - MONDO's synonyms for the disease name hepatic as well as pulmonary involvement
  evidence:
  - reference: PMID:25913036
    reference_title: Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on Réunion Island.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We identified biallelic missense mutations in MARS in a specific form of
      pediatric pulmonary alveolar proteinosis (PAP), a severe lung disorder that
      is prevalent on the island of Réunion and the molecular basis of which is
      unresolved.
    explanation: >-
      Establishes the MARS1 gene and the Réunion Island prevalence recorded in
      this differential.
  - reference: PMID:25913036
    reference_title: Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on Réunion Island.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Enzyme activity was attenuated in a liquid medium without methionine but
      could be restored by methionine supplementation.
    explanation: >-
      Source for the enzymatic lesion and for the methionine-restoration result
      referenced in this differential's description.
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: NCIT:C49236
      label: Therapeutic Procedure
  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: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: ORPHA:264675
    reference_title: "Hereditary pulmonary alveolar proteinosis"
    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"
    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: NCIT:C70601
      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 is scoped to the GM-CSF receptor disease: biallelic CSF2RA (SMDP4)
  or CSF2RB (SMDP5) defects causing failed surfactant clearance. Autoimmune PAP,
  driven by GM-CSF autoantibodies and accounting for most PAP cases, is curated
  separately as Autoimmune_Pulmonary_Alveolar_Proteinosis.

  Scope of the MONDO anchor, and why five descendants are differentials rather
  than subtypes. MONDO:0012580 has eight hierarchical descendants (checked via
  the OLS4 hierarchicalDescendants endpoint). Two of them, MONDO:0010424 (SMDP4,
  CSF2RA) and MONDO:0013712 (SMDP5, CSF2RB), are this entry's own disease and are
  bound as has_subtypes rows. The other six denote failures of surfactant
  production or processing rather than of clearance: MONDO:0009929 (SFTPB),
  MONDO:0024465 and MONDO:0018603 and MONDO:0016323 (all SFTPC),
  MONDO:0012582 (ABCA3), and MONDO:0014206 (MARS1). The disease primer
  PMID:30846703 places those in a different pathogenetic category - "congenital
  PAP" - from the "hereditary" GM-CSF-receptor category this entry's name and
  content describe, and the treatments curated here follow from failed clearance.
  They are therefore recorded in differential_diagnoses, each with its MONDO term
  bound, rather than as subtypes of this entry, and each warrants its own dismech
  entry. MONDO:0012580 carries OMIMPS:265120, the OMIM "surfactant metabolism
  dysfunction, pulmonary" phenotypic series, as a cross-reference, and carries
  "congenital PAP" and "inborn error of surfactant metabolism" among the
  synonyms OLS4 reports for it; that breadth, rather than any clinical similarity, is why the
  surfactant-production diseases are descendants of a class whose primary label
  names the GM-CSF-receptor disease.

  NKX2-1 is the fourth gene in the standard surfactant-metabolism-disorder set
  (PMID:40306683) and MONDO records no NKX2-1 descendant under MONDO:0012580, so
  it is neither a subtype nor a differential here; its disease is a combined
  lung, brain and thyroid disorder outside this entry's scope.

  The Orphanet records for the surfactant-production diseases (Orphanet:217563,
  440402, 440427, 217566) are not yet in the reference cache; ORPHA:264675, which
  this entry cites, is cached.
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: []
datasets:
- accession: geo:GSE299696
  title: A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [CRISPR]
  description: Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain largely elusive. Here, through a genome-wide CRISPR activation screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify Deltex E3 Ubiquitin Ligase 4 (DTX4) as a pivotal regulator of cholesterol efflux in AMs.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 6
  notes: Identified by GEO DataSets index search for Hereditary Pulmonary Alveolar Proteinosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE299693
  title: A Genome-Wide CRISPR Screen Identifies DTX4 Modulating Alveolar Macrophage Cholesterol Efflux in Pulmonary Alveolar Proteinosis [RNA-seq II]
  description: Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain largely elusive. Here, through a genome-wide CRISPR activation screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify Deltex E3 Ubiquitin Ligase 4 (DTX4) as a pivotal regulator of cholesterol efflux in AMs.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 6
  notes: Identified by GEO DataSets index search for Hereditary Pulmonary Alveolar Proteinosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

📚

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

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

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.

Hereditary Pulmonary Alveolar Proteinosis

Ask OpenScientist

OpenScientist Report

Classifications

Mappings

Definitions

Inheritance

Subtypes

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Related Datasets

Source YAML

References & Deep Research

References

Deep Research

Hereditary Pulmonary Alveolar Proteinosis Deep-Research Fallback

Scope Confirmation