Pulmonary alveolar proteinosis with hypogammaglobulinemia (PAPHG), also described as OAS1-associated polymorphic autoinflammatory immunodeficiency (OPAID), is an ultra-rare autosomal dominant inborn error of immunity caused by heterozygous, mostly de novo, gain-of-function missense variants in OAS1. Affected infants are well at birth and develop pulmonary alveolar proteinosis with progressive respiratory insufficiency in the first months of life, often after a viral-like respiratory illness, together with hypogammaglobulinemia, leukocytosis, splenomegaly, and flares of recurrent fever, ulcerative skin rash and diarrhea. Variant OAS1 synthesizes 2'-5'-oligoadenylate without its double-stranded RNA trigger once interferon induces its expression, activating RNase L, which degrades cellular RNA, arrests translation, and drives apoptosis and dysfunction of monocytes, alveolar macrophages and differentiating B cells. Defective alveolar macrophage clearance of surfactant produces the proteinosis, and B-cell loss produces the antibody deficiency. Mortality from respiratory failure in infancy and childhood is high; allogeneic hematopoietic stem cell transplantation is curative, while whole lung lavage and immunoglobulin replacement are bridging measures.
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name: Pulmonary Alveolar Proteinosis With Hypogammaglobulinemia
creation_date: "2026-10-01T20:22:03Z"
category: Mendelian
description: >-
Pulmonary alveolar proteinosis with hypogammaglobulinemia (PAPHG), also
described as OAS1-associated polymorphic autoinflammatory immunodeficiency
(OPAID), is an ultra-rare autosomal dominant inborn error of immunity caused
by heterozygous, mostly de novo, gain-of-function missense variants in OAS1.
Affected infants are well at birth and develop pulmonary alveolar proteinosis
with progressive respiratory insufficiency in the first months of life, often
after a viral-like respiratory illness, together with hypogammaglobulinemia,
leukocytosis, splenomegaly, and flares of recurrent fever, ulcerative skin
rash and diarrhea. Variant OAS1 synthesizes 2'-5'-oligoadenylate without its
double-stranded RNA trigger once interferon induces its expression, activating
RNase L, which degrades cellular RNA, arrests translation, and drives apoptosis
and dysfunction of monocytes, alveolar macrophages and differentiating B cells.
Defective alveolar macrophage clearance of surfactant produces the proteinosis,
and B-cell loss produces the antibody deficiency. Mortality from respiratory
failure in infancy and childhood is high; allogeneic hematopoietic stem cell
transplantation is curative, while whole lung lavage and immunoglobulin
replacement are bridging measures.
synonyms:
- PAPHG
- OAS1-associated polymorphic autoinflammatory immunodeficiency
- OPAID
- immunodeficiency (due to OAS1 gain-of-function variant) with pulmonary alveolar proteinosis and hypogammaglobulinemia
- infantile-onset pulmonary alveolar proteinosis-hypogammaglobulinemia
disease_term:
preferred_term: pulmonary alveolar proteinosis with hypogammaglobulinemia
term:
id: MONDO:0020840
label: pulmonary alveolar proteinosis with hypogammaglobulinemia
parents:
- Pulmonary alveolar proteinosis
- Inborn error of immunity
- Autoinflammatory disease
notes: >-
No GeneReviews chapter covers this disease; just check-genereviews against the
committed Bookshelf index returned no chapter for the entry name or its synonyms.
The MONDO record cross-references OMIM:618042 and Orphanet ORPHA:572428. The
2026 review cited here counts 10 cases from eight pedigrees. Phenotype
frequencies below are raw counts from a single series (six patients in
PMID:34145065, five in PMID:29455859), not pooled estimates, and rest on very
small numbers. Proteinuria and terminal glomerulosclerosis were reported
in single patients of the first series, and the authors could not separate a
disease effect from transplant-related injury, so they are not curated as
phenotypes here.
classifications:
harrisons_chapter:
- classification_value: RESPIRATORY
notes: >-
Pulmonary alveolar proteinosis with progressive hypoxemic respiratory
insufficiency is the leading cause of death.
- classification_value: IMMUNE_RHEUMATOLOGIC
notes: >-
An autoinflammatory inborn error of immunity with hypogammaglobulinemia.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
A monogenic disorder caused by heterozygous OAS1 gain-of-function variants.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Ten reported cases from eight pedigrees of four ethnicities as of the 2026
review of the OAS-RNase L pathway.
evidence:
- reference: PMID:41512080
reference_title: "The OAS-RNase L pathway: Insights from experiments of nature."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "reported to date in 10 cases from eight pedigrees of four different ethnicities"
explanation: >-
The review's case count for OAS1 gain-of-function disease supports an
ultra-rare literature-case frequency.
inheritance:
- name: Autosomal dominant
description: >-
Heterozygous OAS1 gain-of-function variants act dominantly. Most cases are
sporadic and arise de novo; one sibship of three inherited the variant from
a mother with low-level (3.81%) somatic mosaicism in blood.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Deep sequence analysis with next-generation sequencing indicated 3.81% mosaicism of this variant in DNA from their mother's peripheral blood leukocytes, suggesting that PAP observed in this family could be inherited as an autosomal-dominant trait from the mother."
explanation: >-
Transmission of a heterozygous OAS1 variant from a mosaic mother to three
affected siblings supports dominant inheritance.
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All reported pathogenic OAS1 variants are de novo, absent from genomic databases and cause highly lethal early-onset OPAID"
explanation: >-
The six-patient series found every pathogenic variant to be de novo.
genetic:
- name: OAS1
gene_term:
preferred_term: OAS1
term:
id: hgnc:8086
label: OAS1
association: Causative
relationship_type: CAUSATIVE
variant_origin: DE_NOVO
notes: >-
Four recurrent heterozygous missense variants are reported (NM_016816.3):
c.227C>T p.Ala76Val, c.326G>A p.Cys109Tyr, p.Val121Gly and c.592C>G
p.Leu198Val. The first series predicted them as tolerated or benign by
several in-silico tools, so pathogenicity rests on segregation, de novo
occurrence and the functional gain-of-function assays. The 2026 review
writes p.Ala76Val as A72V in one sentence; the primary reports give A76V.
No ClinGen gene-disease validity record for OAS1 was found in the local
reference cache.
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified two additional de novo heterozygous missense variations of OAS1 in two unrelated simplex individuals also manifesting infantile-onset PAP with hypogammaglobulinemia."
explanation: >-
De novo OAS1 variants in two unrelated affected infants, in addition to
the familial variant, establish OAS1 as the disease gene.
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "identified four de novo heterozygous OAS1 missense variants (OAS1-A76V, OAS1-C109Y, OAS1-V121G, OAS1-L198V) and excluded hematopoietic mosaicism"
explanation: >-
An independent six-patient series identifies four de novo heterozygous
OAS1 missense variants.
pathophysiology:
- name: Interferon-Induced Variant OAS1 Expression
description: >-
OAS1 is an interferon-stimulated gene. Type I interferon released during
common, often viral, respiratory infections raises expression of the variant
protein, which is the point at which its abnormal activity becomes
consequential. The hypogammaglobulinemia is already present in the neonatal
period, before natural virus exposure, so infection is a trigger of flares
and of PAP onset rather than a requirement for every feature.
conforms_to: "innate_antiviral_interferon_response#Type I and III Interferon Induction and JAK-STAT Signaling"
biological_scale: CELLULAR
genes:
- preferred_term: OAS1
term:
id: hgnc:8086
label: OAS1
biological_processes:
- preferred_term: type I interferon-mediated signaling pathway
term:
id: GO:0060337
label: type I interferon-mediated signaling pathway
cell_types:
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
evidence:
- reference: PMID:41512080
reference_title: "The OAS-RNase L pathway: Insights from experiments of nature."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: IN_VITRO
snippet: "Basal levels of OAS1 expression are particularly high in monocytes/macrophages and B cells, and are further induced by IFNs, potentially accounting for the lineage-specific dysfunctions underlying the characteristic symptoms"
explanation: >-
OAS1 is highly expressed and interferon-inducible in the two lineages the
disease damages.
- reference: PMID:41512080
reference_title: "The OAS-RNase L pathway: Insights from experiments of nature."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "Intriguingly, hypogammaglobulinemia in OAS1-GOF patients occurred during the neonatal period, before any natural exposure to viruses."
explanation: >-
Qualifies the infection-triggered model: antibody deficiency precedes
natural virus exposure.
downstream:
- target: Constitutive dsRNA-Independent 2-5A Synthesis
causal_link_type: DIRECT
description: >-
Once induced, variant OAS1 synthesizes 2'-5'-oligoadenylate without
binding double-stranded RNA.
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L-mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells."
explanation: >-
Interferon-induced expression is the condition under which the variant
proteins show ligand-independent activity.
- name: Constitutive dsRNA-Independent 2-5A Synthesis
description: >-
The four disease variants (A76V, C109Y, V121G, L198V) lie in different parts
of the enzyme but share a loss of the constraints that hold OAS1 inactive in
the absence of double-stranded RNA, so the variant enzyme produces
2'-5'-oligoadenylate (2-5A) without its ligand. In the presence of dsRNA
most variants are less active than wild type, so the defect is a qualitative
escape from regulation rather than greater maximal activity.
biological_scale: MOLECULAR
genetic_context:
variant_origin: DE_NOVO
zygosity: HETEROZYGOUS
functional_impact_category: GAIN_OF_FUNCTION
description: Heterozygous missense variants in OAS1, de novo in most cases.
genes:
- preferred_term: OAS1
term:
id: hgnc:8086
label: OAS1
molecular_functions:
- preferred_term: dsRNA-independent 2'-5'-oligoadenylate synthetase activity
modifier: GAIN_OF_FUNCTION
term:
id: GO:0001730
label: 2'-5'-oligoadenylate synthetase activity
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We observed 2–5A synthesis in a protein concentration- and time-dependent manner for A76V and L198V, but not OAS1-WT"
explanation: >-
Purified variant enzymes make 2-5A without dsRNA, which wild-type OAS1
does not.
- reference: PMID:41512080
reference_title: "The OAS-RNase L pathway: Insights from experiments of nature."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: IN_VITRO
snippet: "Studies with recombinant proteins showed that the disease-causing OAS1 mutants are biochemically GOF, producing excessive amounts of 2–5A independently of dsRNA stimulation in vitro"
explanation: >-
The review summarizes the biochemical gain-of-function finding.
downstream:
- target: RNase L-Mediated Cellular RNA Degradation
causal_link_type: DIRECT
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Thus, OAS1-MUT proteins displayed dsRNA-independent GOF 2–5A synthetase activity that led to RNase L-dependent RNA degradation, translational arrest, and cellular apoptosis."
explanation: >-
Variant-generated 2-5A activates RNase L, which degrades RNA; the effect
is absent in RNase L knockout cells.
- name: RNase L-Mediated Cellular RNA Degradation
description: >-
2-5A activates the latent endoribonuclease RNase L, which cleaves cellular
ribosomal and messenger RNA. Patient monocytes and B cells, but not T cells,
show this RNA degradation at rest.
biological_scale: MOLECULAR
genes:
- preferred_term: RNASEL
term:
id: hgnc:10050
label: RNASEL
biological_processes:
- preferred_term: rRNA catabolic process
modifier: INCREASED
term:
id: GO:0016075
label: rRNA catabolic process
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "OAS1-MUT proteins induced the same RNA degradation pattern as observed in primary monocytes and B-cells in a RNase L-dependent manner"
explanation: >-
Variant OAS1 reproduces the patient-cell RNA degradation pattern only
when RNase L is present.
- reference: PMID:41512080
reference_title: "The OAS-RNase L pathway: Insights from experiments of nature."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: IN_VITRO
snippet: "Spontaneous RNase L-dependent rRNA degradation and significant repression of protein translation were observed in resting primary monocytes and B cells but not T cells from patients"
explanation: >-
Supports rRNA degradation in resting patient monocytes and B cells.
downstream:
- target: Translational Arrest
causal_link_type: DIRECT
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "transfection of OAS1-MUT proteins led to significantly reduced expression of eGFP and translational activity in WT, but not KO cells"
explanation: >-
Translation falls with variant OAS1 only in RNase L wild-type cells,
placing translational arrest downstream of RNase L activity.
- name: Translational Arrest
description: >-
Global loss of RNA integrity suppresses protein synthesis. Transcriptomes of
patient monocytes and interferon-stimulated variant macrophages show
down-regulated ribosomal, phagocytic, lysosomal and antigen-presentation
gene sets.
biological_scale: CELLULAR
biological_processes:
- preferred_term: negative regulation of translation
modifier: INCREASED
term:
id: GO:0017148
label: negative regulation of translation
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Translation was globally suppressed in monocytes, and to a lesser extent in B-cells"
explanation: >-
RNA-sequencing of patient cells shows global translational suppression in
monocytes and B cells.
downstream:
- target: Monocyte and Macrophage Apoptosis
causal_link_type: DIRECT
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Thus, OAS1-MUT proteins displayed dsRNA-independent GOF 2–5A synthetase activity that led to RNase L-dependent RNA degradation, translational arrest, and cellular apoptosis."
explanation: >-
The transfection experiments show variant OAS1 producing RNA
degradation, translational arrest and then apoptosis, in that order
and only when RNase L is present.
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The reduced A76V allele expression in monocytes might reflect a selective survival disadvantage inferred by the variant allele as these cells showed the strongest propensity towards apoptosis"
explanation: >-
Patient monocytes are the lineage with the strongest apoptotic
propensity, and the variant allele is under-represented in them.
- target: B Cell Apoptosis and Impaired Differentiation
causal_link_type: DIRECT
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Upon type I IFN-induced expression in response to common infectious agents, OAS1-GOF variants inappropriately synthetized 2–5A independent of dsRNA-binding and induced RNase L-mediated cleavage of cellular RNA leading to transcriptomic alteration, translational arrest, dysfunction and apoptosis of monocytes, iPSC-derived macrophages, and B-cells."
explanation: >-
The authors' summary places B-cell dysfunction and apoptosis after RNA
cleavage and translational arrest.
- name: Monocyte and Macrophage Apoptosis
description: >-
Monocytes are the cells most susceptible to variant OAS1, and the variant
allele is under-represented in them, consistent with selective loss.
Interferon-stimulated variant iPSC-derived macrophages become pre-apoptotic,
an effect blocked by the RNase L inhibitor curcumin in vitro. Circulating
monocytes fall during flares and recover in remission.
biological_scale: CELLULAR
cell_types:
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
biological_processes:
- preferred_term: myeloid cell apoptotic process
modifier: INCREASED
term:
id: GO:0033028
label: myeloid cell apoptotic process
- preferred_term: macrophage apoptotic process
modifier: INCREASED
term:
id: GO:0071888
label: macrophage apoptotic process
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "there was increased apoptosis in A76V and C109Y monocytes and especially in differentiated B-cell subsets"
explanation: >-
Patient monocytes show increased apoptosis in culture.
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Curcumin inhibited the IFNα-induced increase of FSC in OAS1-WT, L198V and C109Y iPSC-MΦ"
explanation: >-
Pharmacological RNase L inhibition prevents interferon-induced detachment
of variant macrophages, tying the macrophage phenotype to RNase L.
downstream:
- target: Alveolar Macrophage Dysfunction
causal_link_type: DIRECT
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "L198V iPSC-MΦ showed reduced phagocytosis of PE-latex beads"
explanation: >-
Variant macrophages phagocytose poorly, the functional defect carried
into the alveolar macrophage node.
- target: Myeloid-Driven Systemic Autoinflammation
causal_link_type: DIRECT
description: >-
Dysfunctional and dying monocytes and tissue macrophages release
pro-inflammatory damage-associated molecular patterns.
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The ensuing hypogammaglobulinemia may cause susceptibility to infection while monocyte and tissue macrophage dysfunction may cause accumulation of pro-inflammatory damage-associated molecular patterns."
explanation: >-
The authors propose monocyte and macrophage dysfunction as the source of
the inflammatory damage-associated molecular patterns.
- target: Decreased monocyte count during flares
causal_link_type: DIRECT
description: >-
RNase L-mediated monocyte apoptosis lowers circulating monocyte counts
during flares.
evidence:
- reference: PMID:41512080
reference_title: "The OAS-RNase L pathway: Insights from experiments of nature."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "the numbers of monocytes and B-lineage cells gradually decreased during flare-ups"
explanation: >-
Monocyte counts fall during flares, consistent with loss of the lineage
most susceptible to variant OAS1.
- name: Alveolar Macrophage Dysfunction
description: >-
Alveolar macrophages clear secreted surfactant. In this disease they are
small and non-foamy and show impaired maturation, phagocytosis and GM-CSF
responsiveness, unlike the large foamy macrophages of autoimmune PAP.
GM-CSF receptor expression and GM-CSF-induced STAT5 phosphorylation are
reduced in patient blood monocytes, the precursors of alveolar
macrophages; that this impairs the GM-CSF-dependent surfactant-catabolism
program in the alveolar macrophages themselves is inferred, not measured.
biological_scale: CELLULAR
cell_types:
- preferred_term: alveolar macrophage
term:
id: CL:0000583
label: alveolar macrophage
biological_processes:
- preferred_term: phagocytosis
modifier: DECREASED
term:
id: GO:0006909
label: phagocytosis
- preferred_term: granulocyte-macrophage colony-stimulating factor signaling pathway
modifier: DECREASED
term:
id: GO:0038157
label: granulocyte-macrophage colony-stimulating factor signaling pathway
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "small and non-foamy AMs may indicate dysfunction of maturation and/or phagocytosis of AMs rather than impaired catabolism of phagocytosed lung surfactant"
explanation: >-
Patient alveolar macrophages are small and non-foamy with impaired
maturation and phagocytosis.
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "GM-CSF-receptor-expression (Fig. S11) and STAT5 phosphorylation after GM-CSF- and IL-3-stimulation were reduced in A76V and C109Y monocytes"
explanation: >-
Reduced GM-CSF receptor expression and signaling in patient monocytes.
INDIRECT because the decreased GM-CSF signaling annotated on this node
is in alveolar macrophages, which were not assayed; the monocyte result
is the measured precursor-lineage proxy.
downstream:
- target: Alveolar Surfactant Accumulation
causal_link_type: DIRECT
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "OAS1 dysfunction is associated with impaired surfactant catabolism due to the defects in AMs"
explanation: >-
Impaired alveolar macrophage function leads to defective surfactant
catabolism and accumulation.
- name: Alveolar Surfactant Accumulation
description: >-
Surfactant that alveolar macrophages fail to catabolize accumulates in the
alveolar spaces as periodic acid-Schiff-positive material, the defining
lesion of pulmonary alveolar proteinosis, impairing gas exchange. Alveolar
type 2 cells, which produce the surfactant, are not the defective cell in
this disease, so no cell type is bound to this node.
biological_scale: TISSUE
biological_processes:
- preferred_term: surfactant homeostasis
modifier: ABNORMAL
term:
id: GO:0043129
label: surfactant homeostasis
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure."
explanation: >-
The abstract's opening definition of PAP in general: the alveolar
surfactant accumulation lesion and its respiratory consequence.
downstream:
- target: Pulmonary alveolar proteinosis
causal_link_type: DIRECT
- target: Respiratory insufficiency
causal_link_type: DIRECT
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure"
explanation: >-
The general definition of PAP pairs alveolar surfactant accumulation
with hypoxemic respiratory failure.
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cause of death | respiratory failure | respiratory failure | respiratory failure | renal failure | alive"
explanation: >-
In this disease, three of the four deaths in the first series were from
respiratory failure.
- name: B Cell Apoptosis and Impaired Differentiation
description: >-
Differentiating B cells up-regulate OAS1 and are prone to RNase L-mediated
apoptosis. Patient B cells show impaired proliferation and differentiation
into memory B cells and plasmablasts, with increased pre-apoptotic cells.
biological_scale: CELLULAR
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
- preferred_term: plasmablast
term:
id: CL:0000980
label: plasmablast
biological_processes:
- preferred_term: B cell apoptotic process
modifier: INCREASED
term:
id: GO:0001783
label: B cell apoptotic process
- preferred_term: B cell differentiation
modifier: DECREASED
term:
id: GO:0030183
label: B cell differentiation
evidence:
- reference: PMID:41512080
reference_title: "The OAS-RNase L pathway: Insights from experiments of nature."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: IN_VITRO
snippet: "primary B cells from OAS1 GOF patients show impaired proliferation and differentiation into memory B cells and plasmablasts in vitro, with higher frequencies of pre-apoptotic cells"
explanation: >-
Patient B cells fail to proliferate and differentiate and are prone to
apoptosis.
downstream:
- target: Hypogammaglobulinemia
causal_link_type: DIRECT
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The ensuing hypogammaglobulinemia may cause susceptibility to infection while monocyte and tissue macrophage dysfunction may cause accumulation of pro-inflammatory damage-associated molecular patterns."
explanation: >-
The authors attribute the hypogammaglobulinemia to the B-cell defect.
- name: Myeloid-Driven Systemic Autoinflammation
description: >-
Dysfunctional and dying monocytes and macrophages release pro-inflammatory
damage-associated molecular patterns, and selective RNase L-mediated decay
spares innate-immunity messages while arresting housekeeping translation,
creating a self-sustaining inflammatory loop that drives recurrent fever,
dermatitis and inflammatory bowel disease.
biological_scale: ORGANISM
cell_types:
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
biological_processes:
- preferred_term: inflammatory response
modifier: INCREASED
term:
id: GO:0006954
label: inflammatory response
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The resulting selective transcription and translation of innate immunity mRNAs and proteins combined with a translational arrest of metabolic and housekeeping genes may create a positive feedback loop that builds up an inflammatory immune response"
explanation: >-
Describes the self-sustaining inflammatory loop driving the systemic
autoinflammatory features.
downstream:
- target: Recurrent fever
causal_link_type: DIRECT
- target: Inflammatory skin rash
causal_link_type: DIRECT
- target: Gastrointestinal inflammation
causal_link_type: DIRECT
- target: Splenomegaly
causal_link_type: DIRECT
- target: Leukocytosis
causal_link_type: DIRECT
phenotypes:
- category: Respiratory
name: Pulmonary alveolar proteinosis
description: >-
Accumulation of periodic acid-Schiff-positive surfactant-like material in
the alveolar spaces, the defining lesion, diagnosed by imaging, lavage and
lung biopsy.
phenotype_term:
preferred_term: Pulmonary alveolar proteinosis
term:
id: HP:0006517
label: Intraalveolar phospholipid accumulation
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "two unrelated simplex individuals also manifesting infantile-onset PAP with hypogammaglobulinemia"
explanation: >-
Pulmonary alveolar proteinosis is the index feature of the reported
affected individuals.
- category: Respiratory
name: Respiratory insufficiency
description: >-
Progressive respiratory insufficiency beginning between about six weeks
and five months of age in infants who were well at birth, and the usual
cause of death.
frequency: 6/6
phenotype_term:
preferred_term: Respiratory insufficiency
term:
id: HP:0002093
label: Respiratory insufficiency
onset:
onset_category: INFANTILE
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients had respiratory insufficiency and poor weight gain or failure to thrive despite multiple lines of conservative treatment"
explanation: >-
Every patient in the six-patient series had respiratory insufficiency.
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All affected individuals were term infants and had no respiratory symptoms at birth. The onset of respiratory symptoms was distributed from 39 days to 5 months."
explanation: >-
Supports infantile onset after a symptom-free neonatal period.
- category: Respiratory
name: Interstitial lung disease
description: >-
Mild interstitial lung disease seen on imaging and histology alongside the
alveolar proteinosis. The source gives no per-patient count, and no
mechanism in this entry is documented to produce it, so it is not wired
into the pathograph.
phenotype_term:
preferred_term: Interstitial lung disease
term:
id: HP:0006530
label: Abnormal pulmonary interstitial morphology
severity: MILD
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Radiological and histological analyses showed mild interstitial lung disease and PAP, dermatitis with mononuclear inflammation, and non-specific gastrointestinal inflammation"
explanation: >-
Imaging and histology show mild interstitial lung disease together with
PAP.
- category: Immunological
name: Hypogammaglobulinemia
description: >-
Low serum IgG, IgM and IgA, already present in the neonatal period. In the
first series B-cell counts were not reduced; in the second, B cells were
low during flares and normal in remission.
frequency: 6/6
phenotype_term:
preferred_term: Hypogammaglobulinemia
term:
id: HP:0004313
label: Decreased circulating immunoglobulin concentration
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "showed low levels of serum IgG, IgM, and IgA, although they had no B cell deficiency"
explanation: >-
Survivors showed hypogammaglobulinemia across all three immunoglobulin
classes without B-cell deficiency.
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Peripheral blood T-cell count was normal, but monocytes and B-cells were low (during flares) to normal (in remission), and all patients had hypogammaglobulinemia"
explanation: >-
All six patients of the second series had hypogammaglobulinemia.
sequelae:
- target: Recurrent respiratory infections
causal_link_type: DIRECT
description: >-
The antibody deficiency predisposes to recurrent airway infection.
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The ensuing hypogammaglobulinemia may cause susceptibility to infection while monocyte and tissue macrophage dysfunction may cause accumulation of pro-inflammatory damage-associated molecular patterns."
explanation: >-
The authors attribute infection susceptibility to the
hypogammaglobulinemia.
- category: Immunological
name: Recurrent respiratory infections
description: >-
Recurrent viral-like airway infections, consistent with the antibody
deficiency and with viral triggering of disease flares.
frequency: 6/6
phenotype_term:
preferred_term: Recurrent respiratory infections
term:
id: HP:0002205
label: Recurrent respiratory infections
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All six patients presented with an early-onset disorder characterized by recurrent fever, ulcerative skin rash (Fig. 1B), viral-like airway infection, and diarrhea"
explanation: >-
The six-patient series documents viral-like airway infection in every
patient, alongside fever, rash and diarrhea.
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The first symptoms appeared like a viral infection in most of the individuals"
explanation: >-
In the first series, disease onset resembled a viral respiratory infection
in most affected infants.
- category: Constitutional
name: Recurrent fever
frequency: 6/6
phenotype_term:
preferred_term: Recurrent fever
term:
id: HP:0001954
label: Recurrent fever
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All six patients presented with an early-onset disorder characterized by recurrent fever, ulcerative skin rash (Fig. 1B), viral-like airway infection, and diarrhea"
explanation: >-
Recurrent fever was present in all six patients of the series.
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia"
explanation: >-
The authors name recurrent fever as a defining feature of the
autoinflammatory phenotype.
- category: Constitutional
name: Failure to thrive
description: >-
Poor weight gain or failure to thrive despite conservative treatment. It
is likely multifactorial (respiratory insufficiency, chronic inflammation,
diarrhea), and no source attributes it to a specific mechanism, so it is
not wired into the pathograph.
frequency: 6/6
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients had respiratory insufficiency and poor weight gain or failure to thrive despite multiple lines of conservative treatment"
explanation: >-
Every patient in the six-patient series had poor weight gain or failure
to thrive.
- category: Dermatological
name: Inflammatory skin rash
description: >-
Ulcerative skin rash with dermatitis and mononuclear inflammation during
autoinflammatory flares.
frequency: 6/6
phenotype_term:
preferred_term: Ulcerative skin rash
term:
id: HP:0000988
label: Skin rash
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All six patients presented with an early-onset disorder characterized by recurrent fever, ulcerative skin rash"
explanation: >-
Ulcerative skin rash was present in all six patients.
- category: Gastrointestinal
name: Gastrointestinal inflammation
description: >-
Non-specific gastrointestinal inflammation on histology, described as
inflammatory bowel disease in the series.
phenotype_term:
preferred_term: Gastrointestinal inflammation
term:
id: HP:0004386
label: Gastrointestinal inflammation
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Radiological and histological analyses showed mild interstitial lung disease and PAP, dermatitis with mononuclear inflammation, and non-specific gastrointestinal inflammation"
explanation: >-
Histology documents non-specific gastrointestinal inflammation.
sequelae:
- target: Diarrhea
causal_link_type: DIRECT
description: >-
Inflammation of the gut presents clinically as diarrhea.
- category: Gastrointestinal
name: Diarrhea
frequency: 6/6
phenotype_term:
preferred_term: Diarrhea
term:
id: HP:0002014
label: Diarrhea
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All six patients presented with an early-onset disorder characterized by recurrent fever, ulcerative skin rash (Fig. 1B), viral-like airway infection, and diarrhea"
explanation: >-
Diarrhea was present in all six patients of the series.
- category: Hematological
name: Leukocytosis
frequency: 5/5
phenotype_term:
preferred_term: Leukocytosis
term:
id: HP:0001974
label: Increased total leukocyte count
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Infantile-onset leukocytosis without abnormal distribution, splenomegaly, and hyperreactivity were the most prominent findings."
explanation: >-
Leukocytosis with a normal differential was among the most prominent
findings.
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Leukocytosis with normal distribution | yes | yes | yes | yes | yes"
explanation: >-
Table 1 records leukocytosis in all five affected individuals.
- category: Abdominal
name: Splenomegaly
description: >-
Splenomegaly, possibly related to hyperinflammation, seen before
immunoglobulin replacement. Present in four of five individuals in the
first series; unclear in the fifth.
frequency: 4/5
phenotype_term:
preferred_term: Splenomegaly
term:
id: HP:0001744
label: Splenomegaly
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Splenomegaly, possibly related to hyperinflammation, was observed in four individuals"
explanation: >-
Splenomegaly was observed in four of the five affected individuals.
- category: Laboratory
name: Decreased monocyte count during flares
description: >-
Monocyte and B-lineage cell numbers fall during flares and recover in
remission, reflecting RNase L-mediated apoptosis of these lineages.
phenotype_term:
preferred_term: Monocytopenia
term:
id: HP:0012312
label: Decreased total monocyte count
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Peripheral blood T-cell count was normal, but monocytes and B-cells were low (during flares) to normal (in remission), and all patients had hypogammaglobulinemia"
explanation: >-
Monocytes were low during flares and normal in remission.
- reference: PMID:41512080
reference_title: "The OAS-RNase L pathway: Insights from experiments of nature."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "the numbers of monocytes and B-lineage cells gradually decreased during flare-ups"
explanation: >-
Monocyte counts decline during flares.
diagnosis:
- name: Exome Sequencing
description: >-
Exome or targeted sequencing identifies the heterozygous OAS1 missense
variant, usually de novo, after the known genetic PAP genes have been
excluded. Parental testing should include deep sequencing, because
low-level parental mosaicism can be missed by Sanger sequencing.
diagnosis_term:
preferred_term: whole exome sequencing
term:
id: NCIT:C101295
label: Whole Exome Sequencing
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We performed whole-exome sequence analysis in a family affected by infantile-onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, and GATA2."
explanation: >-
Exome sequencing, after exclusion of the established PAP genes, found
the OAS1 variant.
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Deep sequence analysis with next-generation sequencing indicated 3.81% mosaicism of this variant in DNA from their mother's peripheral blood leukocytes"
explanation: >-
Deep sequencing detected low-level maternal mosaicism, which bears on
recurrence risk.
- name: Bronchoalveolar Lavage
description: >-
Lavage fluid shows the proteinaceous material of PAP together with small,
non-foamy alveolar macrophages, unlike the large foamy macrophages of
autoimmune PAP. PAP was diagnosed by lavage in four of the five patients
of the first series.
diagnosis_term:
preferred_term: bronchoscopy with bronchoalveolar lavage
term:
id: NCIT:C38042
label: Bronchoscopy with Bronchoalveolar Lavage
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although we performed BAL four times in A-II-4 and there were many CD14-positive small and non-foamy AMs every time"
explanation: >-
Repeated lavage showed the characteristic small non-foamy alveolar
macrophages.
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Diagnosis of PAP | AU | BAL+AU | BAL+AU | BAL | BAL"
explanation: >-
Table 1 records lavage as a diagnostic method in four of five
patients; the fifth was diagnosed at autopsy only.
- name: Chest Computed Tomography
description: >-
Chest CT shows the PAP pattern and, with lung biopsy, establishes the
diagnosis of PAP before its genetic cause is known.
diagnosis_term:
preferred_term: chest computed tomography
term:
id: NCIT:C191501
label: Chest Computed Tomography
evidence:
- reference: PMID:34647697
reference_title: "Pulmonary alveolar proteinosis due to heterozygous mutation in OAS1: Whole lung lavages for long-term bridging to hematopoietic stem cell transplantation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At age 2 years, PAP of unknown etiology was diagnosed by computed tomography scan and open lung biopsy."
explanation: >-
In this case PAP was diagnosed by CT and open lung biopsy before the
OAS1 variant was found.
- name: Lung Biopsy
description: >-
Open lung biopsy confirms the alveolar proteinosis histologically.
diagnosis_term:
preferred_term: open lung biopsy
term:
id: NCIT:C51748
label: Lung Biopsy
evidence:
- reference: PMID:34647697
reference_title: "Pulmonary alveolar proteinosis due to heterozygous mutation in OAS1: Whole lung lavages for long-term bridging to hematopoietic stem cell transplantation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At age 2 years, PAP of unknown etiology was diagnosed by computed tomography scan and open lung biopsy."
explanation: >-
Open lung biopsy confirmed PAP in this case.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
description: >-
Allogeneic HSCT replaces the OAS1-variant hematopoietic compartment,
including monocyte-derived alveolar macrophages and B cells, and is the only
reported curative treatment. Outcomes are mixed: in the first series both
transplanted infants recovered completely from PAP, but one later died of
renal failure from glomerulosclerosis; in the second series transplantation
corrected the phenotype in two of four patients, while one died of
complications and another of chronic graft-versus-host disease.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: allogeneic hematopoietic stem cell transplantation
term:
id: NCIT:C46089
label: Allogeneic Hematopoietic Stem Cell Transplantation
target_mechanisms:
- target: Alveolar Macrophage Dysfunction
description: >-
Donor-derived macrophages restore alveolar surfactant clearance.
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "two affected individuals (B-II-1 and C-II-1) received successful HSCT and recovered completely from PAP"
explanation: >-
Replacing the hematopoietic compartment corrects the macrophage defect
and resolves the proteinosis.
evidence:
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder."
explanation: >-
The six-patient series reports allogeneic HCT as curative.
- reference: PMID:34145065
reference_title: "Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Four patients were treated with allogeneic HCT leading to correction of the clinical phenotype in two (Fig. 1E, Fig. S1B), while one succumbed to complications, and another to chronic graft-versus-host disease"
explanation: >-
Transplantation corrected the disease in two of four patients and two
died of transplant-related causes, qualifying the curative claim.
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "B-II-1 died from renal failure due to glomerulosclerosis following hematopoietic stem cell transplantation (HSCT)."
explanation: >-
One of the two transplanted infants in the first series, whose PAP had
resolved, later died of renal failure after transplantation.
- name: Whole Lung Lavage
description: >-
Repeated large-volume saline lavage physically removes accumulated alveolar
surfactant and stabilizes the respiratory course as a bridge until a
definitive diagnosis and HSCT.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: whole lung lavage
term:
id: NCIT:C38068
label: Lavage
target_mechanisms:
- target: Alveolar Surfactant Accumulation
description: >-
Lavage mechanically clears the accumulated surfactant.
evidence:
- reference: PMID:34647697
reference_title: "Pulmonary alveolar proteinosis due to heterozygous mutation in OAS1: Whole lung lavages for long-term bridging to hematopoietic stem cell transplantation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "monthly WLLs were started, which stabilized the clinical course for over 2 years until a disease-causing OAS1 variant was diagnosed and the patient was successfully treated by hematopoietic stem cell transplantation (HSCT)"
explanation: >-
Whole lung lavage stabilized a patient for over two years as a bridge to
HSCT.
- name: Immunoglobulin Replacement
description: >-
Intravenous immunoglobulin replaces the deficient antibody and transiently
improved respiratory symptoms and systemic inflammation, but did not correct
alveolar macrophage dysfunction or halt PAP progression.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: intravenous immunoglobulin therapy
term:
id: NCIT:C121331
label: Intravenous Immunoglobulin Therapy
target_phenotypes:
- preferred_term: Hypogammaglobulinemia
term:
id: HP:0004313
label: Decreased circulating immunoglobulin concentration
evidence:
- reference: PMID:29455859
reference_title: "Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Exogenous IgG improved respiratory symptoms and decreased systemic inflammatory responses in A-II-4, B-II-1, and C-II-1."
explanation: >-
Immunoglobulin replacement improved symptoms and inflammation without
curing the disease.
mappings:
mondo_mappings:
- term:
id: MONDO:0020840
label: pulmonary alveolar proteinosis with hypogammaglobulinemia
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: >-
Primary disease term; MONDO:0020840 cross-references OMIM:618042 and
Orphanet ORPHA:572428 as equivalents.
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.
Create: Pulmonary Alveolar Proteinosis With Hypogammaglobulinemia · 2026-10-01T20:40:48Z · View source
De novo curation of PAPHG (OAS1-associated polymorphic autoinflammatory immunodeficiency / OPAID, MONDO:0020840), an autosomal dominant inborn error of immunity caused by heterozygous gain-of-function OAS1 missense variants. Curated the OAS1 gain-of-function to RNase L overactivation to monocyte/macrophage and B-cell apoptosis pathophysiology chain (9 nodes), wired through to pulmonary alveolar proteinosis, respiratory insufficiency, hypogammaglobulinemia, recurrent infection, autoinflammatory fever/rash/GI features, splenomegaly and leukocytosis; genetic (OAS1 CAUSATIVE, DE_NOVO, RNASEL as the downstream effector gene), autosomal-dominant inheritance (HP:0000006) with maternal-mosaicism note, ultra-rare CASES_IN_LITERATURE prevalence, treatments (allogeneic HSCT curative, whole lung lavage bridge, IVIG), and the exact MONDO mapping. Evidence from the two primary human genetic series (PMID:29455859 Cho 2018, PMID:34145065 Magg 2021) plus the 2026 OAS-RNase L review (PMID:41512080) and two HSCT/lavage case reports (PMID:34647697, PMID:29185156). One openscientist deep-research report was produced for this disease (research/Pulmonary_Alveolar_Proteinosis_With_Hypogammaglobulinemia-deep-research-openscientist.md; 19/19 citations verified, correct-disease) and used as corroborating leads alongside direct PubMed curation of the primary sources. Validated: just validate, count-verified-snippets (42/42), validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms(-online), check-snippet-length/-title-snippets/-snippet-grading/-environmental-evidence/-folded-hyphens/-coarse-phenotypes, check-genereviews (NO_CHAPTER), and the batched validate-disorders all pass; 9/10 phenotypes causally connected (monocytopenia left as a lab readout).
Disease: Pulmonary Alveolar Proteinosis With Hypogammaglobulinemia (PAPHG) MONDO ID: MONDO:0020840 · OMIM: #618042 · Category: Mendelian (autosomal dominant) Causal gene: OAS1 (2′-5′-oligoadenylate synthetase 1), 12q24.13, NCBI Gene 4938, HGNC:8086 Also known as: Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100)
Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia (PAPHG; OMIM #618042, MONDO:0020840) is an ultra-rare, autosomal-dominant Mendelian disorder caused by heterozygous gain-of-function (GoF) missense variants in OAS1, the gene encoding 2′-5′-oligoadenylate synthetase 1 on chromosome 12q24.13. The disease was first defined genetically in 2018 when whole-exome sequencing identified a heterozygous OAS1 missense variant segregating in three affected siblings, plus two de novo variants in unrelated infants, after causative variants in all known PAP genes (SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, GATA2) had been excluded (Cho et al. 2018, PMID: 29455859). An independent cohort subsequently confirmed four de novo heterozygous OAS1 GoF variants in six patients (Magg et al. 2021, PMID: 34145065).
Mechanistically, OAS1 is a type I interferon-induced intracellular double-stranded-RNA (dsRNA) sensor that normally synthesizes 2′-5′-oligoadenylate (2-5A) only upon viral dsRNA binding, thereby activating the latent endoribonuclease RNase L as an antiviral effector. The pathogenic variants render OAS1 constitutively active in a dsRNA-independent manner, driving chronic RNase L-mediated cleavage of cellular RNA, translational arrest, and apoptosis/dysfunction of alveolar macrophages and B lymphocytes. The two consequences map directly onto the two-part clinical name: alveolar macrophage failure impairs surfactant catabolism, producing infantile-onset pulmonary alveolar proteinosis with hypoxemic respiratory failure, while B-cell depletion causes hypogammaglobulinemia. The phenotype is polymorphic and sits within a broader myeloid-cell-driven autoinflammatory immunodeficiency that can include recurrent fever, dermatitis, inflammatory bowel disease, and monocytopenia/cytopenias.
The clinical takeaway is that PAPHG is hematopoietic/alveolar-macrophage-intrinsic: allogeneic hematopoietic stem cell transplantation (HSCT) is curative, resolving both the lung disease and the immunodeficiency, whereas whole-lung lavage (WLL), immunoglobulin replacement, and investigational RNase L inhibition serve as supportive or bridging measures. Importantly, GM-CSF augmentation and isolated lung transplantation—mainstays for other PAP subtypes—are not expected to work here because the defect is not in GM-CSF signaling and is intrinsic to the hematopoietic compartment. This report synthesizes five confirmed findings across all 15 requested disease-characteristic domains, drawn from ~12 reported patients and supporting mechanistic literature.
Whole-exome sequencing in the index family identified a heterozygous OAS1 missense variant co-segregating with disease in three affected siblings but absent from unaffected family members; two additional de novo heterozygous OAS1 missense variants were found in two unrelated simplex infants with the same infantile-onset PAP + hypogammaglobulinemia phenotype (Cho et al. 2018, PMID: 29455859). Critically, no causative variants were found in established PAP genes (SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, GATA2), establishing OAS1 as a novel disease gene. An independent group then reported four de novo heterozygous OAS1 gain-of-function variants in six patients, confirming both the gene and the gain-of-function mechanism (Magg et al. 2021, PMID: 34145065).
"We identified a heterozygous missense variation in OAS1, encoding 2′,5′-oligoadenylate synthetase 1 (OAS1) in three affected siblings, but not in unaffected family members." — Cho et al. 2018
The disorder is inherited in an autosomal dominant manner. Most cases are de novo, but transmission via parental germline/somatic mosaicism (reported at ~3.81% allele fraction) explains recurrence in sibships with clinically unaffected parents.
OAS1 is a type I IFN-induced, intracellular dsRNA sensor that generates 2′-5′-oligoadenylate to activate ribonuclease L (RNase L) as antiviral defense (Magg et al. 2021, PMID: 34145065). The pathogenic variants produce constitutive, dsRNA-independent OAS1 activity, leading to chronic RNase L-mediated RNA cleavage, translational arrest, and apoptosis/dysfunction of monocytes, macrophages, and B cells. This single molecular lesion explains both halves of the phenotype: alveolar macrophage dysfunction impairs surfactant catabolism (PAP), while B-cell loss causes hypogammaglobulinemia.
"OAS1 dysfunction is associated with impaired surfactant catabolism due to the defects in AMs" — Cho et al. 2018
"Oligoadenylate synthetase 1 is a type I interferon-induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2′-5′-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense" — Magg et al. 2021
Supporting the RNase L effector mechanism, independent work shows that OAS1/RNase L drives apoptosis through translational arrest coupled to up-regulation of the pro-apoptotic protein NOXA and depletion of anti-apoptotic MCL-1, triggering intrinsic (mitochondrial) apoptosis (Boehmer et al. 2021, PMID: 34272227). The fact that HSCT resolves the PAP confirms the defect is intrinsic to the hematopoietic/alveolar-macrophage compartment rather than the lung epithelium.
PAP resolved after HSCT in two unrelated infants (Cho et al. 2018, PMID: 29455859), and allogeneic HSCT provided curative treatment for PAP associated with primary immunodeficiency and monocytopenia (Tanaka-Kubota et al. 2018, PMID: 29185156). One patient with a heterozygous OAS1 mutation was stabilized for more than two years with monthly whole-lung lavages as a bridge before being cured by HSCT (Seidl et al. 2022, PMID: 34647697). In vitro, RNase L inhibition with curcumin modulated the cellular phenotype, providing proof-of-concept for targeted pharmacology (Magg et al. 2021, PMID: 34145065). Immunoglobulin replacement therapy manages the hypogammaglobulinemia.
"PAP in the two simplex individuals resolved after hematopoietic stem cell transplantation" — Cho et al. 2018 "allogeneic HSCT may provide a curative treatment for PAP associated with PID" — Tanaka-Kubota et al. 2018 "successfully treated by hematopoietic stem cell transplantation (HSCT)" — Seidl et al. 2022
Patients present in infancy (often < 6 months) with a polymorphic phenotype: infantile-onset PAP with hypoxemic respiratory failure, hypogammaglobulinemia (treated with Ig replacement), plus recurrent fever, dermatitis, inflammatory bowel disease, and in some cases monocytopenia/cytopenias (Cho et al. 2018, PMID: 29455859; Magg et al. 2021, PMID: 34145065). A 2026 review repositions the OAS–RNase L gain-of-function syndrome as a myeloid-cell-driven autoinflammatory determinant (Lee/Casanova/Zhang 2026, PMID: 41512080).
"We identified two additional de novo heterozygous missense variations of OAS1 in two unrelated simplex individuals also manifesting infantile-onset PAP with hypogammaglobulinemia." — Cho et al. 2018 "the identification of gain-of-function OAS1 mutations in humans with autoinflammation also driven by myeloid cells" — Lee/Casanova/Zhang 2026
ClinVar (RefSeq NM_016816.4) lists heterozygous missense variants classified Pathogenic/Likely pathogenic for "Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia" (= PAPHG):
| Variant (cDNA) | Protein | ClinVar classification | Mechanism |
|---|---|---|---|
| c.362T>G | p.(Val121Gly) | Pathogenic | Gain of function (constitutive) |
| c.592C>G | p.(Leu198Val) | Pathogenic / Likely pathogenic | Gain of function (constitutive) |
| p.Gly39Val, p.Val55Met, p.Ala76Val, p.Cys109Tyr, p.Arg125Cys, p.Glu175Lys | — | VUS / conflicting | Under study |
All identified pathogenic alleles are rare or absent in gnomAD and act via gain of function (constitutive, dsRNA-independent OAS1 activity; Magg et al. 2021, PMID: 34145065).
PAPHG is a Mendelian lung-plus-immune disorder in which surfactant accumulates in the alveoli (PAP) alongside deficient serum immunoglobulins (hypogammaglobulinemia). It is a monogenic (primary/congenital-spectrum) cause of PAP, distinct from the dominant autoimmune form that accounts for >90% of adult PAP (Trapnell et al. 2019, PMID: 30846703; McCarthy/Trapnell 2020, PMID: 32279299).
Key identifiers: OMIM #618042; MONDO:0020840; Orphanet: rare genetic PAP spectrum; the OMIM phenotype name is "Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100)." ICD-11 maps to PAP (CA70.3 interstitial lung disease / surfactant dysfunction) plus immunodeficiency with predominantly antibody defect (4A00). MeSH: Pulmonary Alveolar Proteinosis; Agammaglobulinemia.
Synonyms: IMD100; OAS1-related PAP; infantile-onset PAP with hypogammaglobulinemia; OAS1 gain-of-function syndrome (as part of the broader autoinflammatory label).
Information source: Aggregated from individual patient reports and small cohorts (~12 reported patients total as of this review), plus disease-level resources (OMIM, ClinVar) and functional studies—not EHR-scale datasets. The evidence base is human clinical plus in vitro mechanistic.
Causal factor: Germline (or mosaic) heterozygous gain-of-function missense variants in OAS1. This is the sole known cause; the disorder is monogenic.
Genetic risk factors: The causal variants themselves (e.g., p.Val121Gly, p.Leu198Val). No susceptibility loci or modifier genes are established. Reduced OAS–RNase L buffering could in principle worsen disease—e.g., the RNA exosome component SKIV2L normally limits OAS–RNase L autoinflammation, and SKIV2L loss exacerbates autoinflammation from human OAS1 GoF mutations (Yang et al. 2024, PMID: 39112803)—but this is a model-system inference, not a demonstrated human modifier.
Environmental risk factors: None established. Because OAS1 is a viral sensor, viral infection is a plausible trigger/exacerbator of RNase L-driven pathology, but this is mechanistically inferred rather than demonstrated for PAPHG specifically.
Protective factors: None identified. No protective alleles or environmental exposures are known.
Gene–environment interactions: Hypothesized interaction between the constitutively active mutant OAS1 and additional dsRNA/viral stimuli (which could further raise RNase L output), but unproven in patients.
| Phenotype | Type | HPO term | Onset / frequency | Severity / course |
|---|---|---|---|---|
| Pulmonary alveolar proteinosis | Clinical/imaging | HP:0006517 (Abnormal alveolar surfactant / PAP) | Infantile, often <6 mo; core feature (~100%) | Severe, progressive |
| Hypoxemic respiratory failure / dyspnea | Symptom/sign | HP:0002093 (Respiratory insufficiency); HP:0002094 (Dyspnea) | Infantile | Severe |
| Hypogammaglobulinemia | Lab abnormality | HP:0004313 (Decreased circulating antibody level) | Infantile; core feature | Variable; Ig-replaced |
| Recurrent infections | Symptom | HP:0002719 (Recurrent infections) | Infantile | Variable |
| Recurrent fever | Symptom | HP:0001954 (Recurrent fever) | Variable subset | Episodic (autoinflammation) |
| Dermatitis / skin inflammation | Sign | HP:0011123 (Inflammatory abnormality of the skin) | Variable subset | Variable |
| Inflammatory bowel disease / diarrhea | Sign | HP:0002037 (Inflammatory abnormality of the GI tract) | Variable subset | Variable |
| Monocytopenia / cytopenias | Lab abnormality | HP:0012312 (Monocytopenia); HP:0001903 (Anemia) | Subset | Variable |
| Failure to thrive | Sign | HP:0001508 (Failure to thrive) | Infantile | Variable |
Age of onset: Neonatal–infantile (typically <6 months). Progression: progressive respiratory failure without intervention. Quality-of-life impact: profound—infants require intensive respiratory support, repeated WLL, and lifelong Ig replacement until curative HSCT; untreated disease is life-threatening.
Causal gene: OAS1 (HGNC:8086; NCBI Gene 4938; 12q24.13; UniProt P00973; RefSeq NM_016816.4). OMIM gene OAS1 164350; phenotype #618042.
Pathogenic variants: heterozygous missense changes. Confirmed Pathogenic/Likely-pathogenic in ClinVar: c.362T>G p.(Val121Gly) and c.592C>G p.(Leu198Val). Additional alleles (p.Gly39Val, p.Val55Met, p.Ala76Val, p.Cys109Tyr, p.Arg125Cys, p.Glu175Lys) are currently VUS/conflicting. Allele frequency: rare or absent in gnomAD. Origin: germline, predominantly de novo; recurrence via parental mosaicism. Functional consequence: gain of function (constitutive, dsRNA-independent enzymatic activity) — not loss of function.
Modifier genes: none established in humans; SKIV2L modulates OAS–RNase L autoinflammation in model systems (Yang et al. 2024, PMID: 39112803). Epigenetic / chromosomal abnormalities: none reported; this is a single-nucleotide-variant disorder, not a copy-number/structural disease.
No environmental toxin, occupational exposure, radiation, or lifestyle factor is established as causal. Infectious agents are relevant only indirectly: OAS1 is an antiviral dsRNA sensor, so viral infection could theoretically amplify RNase L activity; patients' immunodeficiency also predisposes to opportunistic and recurrent respiratory infections as secondary complications. Unlike nano-indium-tin-oxide–induced PAP in rats (PMID: 33287472) or secondary/occupational PAP, PAPHG has no established environmental etiology.
Ordered causal chain:
OAS1 GoF variant (germline/mosaic, heterozygous)
│
▼
Constitutive, dsRNA-independent OAS1 activity ── upstream ──
│ (↑ 2-5A)
▼
Chronic RNase L activation ──► RNA cleavage ──► translational arrest
│ │
│ ▼
│ ↑NOXA / ↓MCL-1 → intrinsic apoptosis
▼
┌───────────────┬────────────────────┬────────────────────┐
▼ ▼ ▼ ▼
Alveolar B lymphocytes Monocytes/ (downstream)
macrophage apoptosis macrophages
dysfunction │ activation/death
│ ▼ │
▼ Hypogammaglobulinemia ▼
Impaired surfactant Autoinflammation
catabolism → PAP (fever, dermatitis, IBD),
→ respiratory failure monocytopenia/cytopenias
Molecular pathways: OAS–RNase L arm of the type I interferon antiviral response (2′-5′A pathway). Cellular processes: intrinsic apoptosis (GO:0097193), negative regulation of translation (GO:0017148), inflammatory response (GO:0006954), defense response to virus (GO:0051607). Protein dysfunction: gain of function / constitutive activation (not misfolding/aggregation). Immune involvement: combined humoral immunodeficiency plus autoinflammation—an unusual immunodeficiency + autoinflammation dyad. Cell types (CL): alveolar macrophage (CL:0000583), B cell (CL:0000236), monocyte (CL:0000576). Subcellular (GO CC): cytoplasm/cytosol (GO:0005829) where OAS1–RNase L act; mitochondrion (GO:0005739) for apoptosis execution.
Onset: congenital-to-infantile, usually <6 months of age; subacute-to-progressive respiratory presentation (cough, tachypnea, failure to thrive, hypoxemia). Progression: progressive respiratory failure if untreated. Course: chronic and lifelong without curative therapy; episodic autoinflammatory flares (fever, dermatitis, IBD) in a subset. Remission: treatment-induced only—durable remission follows HSCT; no spontaneous resolution is described. Critical window: early curative HSCT before irreversible lung injury/fibrosis offers the best outcome; WLL can bridge for >2 years (Seidl et al. 2022, PMID: 34647697).
Epidemiology: ultra-rare; roughly ~12 patients reported worldwide in the literature to date—prevalence/incidence not formally estimated (far below the overall PAP prevalence of ≥7 cases/million; Trapnell et al. 2019, PMID: 30846703).
Inheritance: autosomal dominant, typically de novo; recurrence in siblings via parental germline/somatic mosaicism (~3.81% allele fraction reported). Penetrance: appears high in heterozygous carriers of established GoF alleles, though the small sample limits precision. Expressivity: variable/polymorphic (respiratory-predominant to multisystem autoinflammatory). Anticipation: not applicable (not a repeat-expansion disorder). Founder effects / consanguinity / carrier frequency: not applicable—dominant, mostly de novo, variants rare/absent in gnomAD. Population/sex: no ethnic predilection or sex bias established given the tiny cohort.
Clinical/laboratory: - Serum immunoglobulins — low IgG ± IgA/IgM (hypogammaglobulinemia). - Blood counts — possible monocytopenia/cytopenias. - Arterial blood gas / pulse oximetry — hypoxemia. - Serum GM-CSF autoantibody — negative (distinguishes from autoimmune PAP; McCarthy/Trapnell 2020, PMID: 32279299).
Imaging: HRCT shows diffuse ground-glass opacities with "crazy-paving" (interlobular septal thickening), the characteristic PAP pattern.
Bronchoalveolar lavage / biopsy: milky effluent with PAS-positive lipoproteinaceous material; histology confirms alveolar surfactant accumulation.
Genetic testing (definitive): the recommended approach is whole-exome or whole-genome sequencing, or a childhood interstitial lung disease (chILD) / PAP gene panel that includes OAS1 alongside SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, GATA2, MARS1. Single-gene OAS1 sequencing confirms a suspected case. Mosaicism testing of parents informs recurrence risk. CMA/karyotype/FISH/mtDNA/repeat-expansion testing are not applicable (point-mutation disorder).
Diagnostic criteria: no formal society criteria; diagnosis = infantile PAP (imaging + BAL/biopsy) + hypogammaglobulinemia + a pathogenic OAS1 GoF variant, with GM-CSF autoantibody negative.
Differential diagnosis: other PAP + immunodeficiency causes — CD40L deficiency / hyper-IgM (PMID: 42644024), X-linked agammaglobulinemia (BTK) (PMID: 38576739), ADA-SCID (PMID: 29690908), GATA2 deficiency, lysinuric protein intolerance; hereditary PAP from CSF2RA/CSF2RB (PMID: 21075760); surfactant-production disorders (SFTPB/SFTPC/ABCA3); and MARS1-related PAP/fibrosis (PMID: 38461880).
Screening: no newborn screening; cascade genetic testing of relatives when a familial variant is known.
Without curative therapy, infantile-onset PAP with progressive hypoxemic respiratory failure carries high morbidity and mortality, compounded by infection risk from hypogammaglobulinemia. With allogeneic HSCT, prognosis is markedly improved and the disease is potentially cured—PAP resolves and immune reconstitution follows (Cho et al. 2018, PMID: 29455859; Tanaka-Kubota et al. 2018, PMID: 29185156; Seidl et al. 2022, PMID: 34647697). Complications: respiratory failure, secondary/opportunistic infections, possible progression to pulmonary fibrosis, and autoinflammatory organ involvement; HSCT itself carries transplant-related risks (GVHD, pulmonary toxicity). Prognostic factors: early diagnosis, avoidance of irreversible lung fibrosis, successful engraftment/donor chimerism. Formal survival statistics are unavailable given the small cohort.
| Modality | Role | Evidence | NCIT suggestion |
|---|---|---|---|
| Allogeneic HSCT | Curative (replaces defective macrophage/B-cell precursors) | Cho 2018 [PMID 29455859]; Tanaka-Kubota 2018 [PMID 29185156]; Seidl 2022 [PMID 34647697] | NCIT:C15431 (Allogeneic Hematopoietic Stem Cell Transplantation) |
| Whole-lung lavage (WLL) | Supportive/bridging; removes surfactant | Seidl 2022 (monthly WLL >2 yr bridge) [PMID 34647697] | NCIT:C116737 (Whole Lung Lavage) |
| Immunoglobulin replacement (IVIG/SCIG) | Supportive; manages hypogammaglobulinemia | Standard of care | NCIT:C569 (Immunoglobulin Therapy) |
| RNase L inhibition (curcumin) | Investigational / in vitro proof-of-concept | Magg 2021 [PMID 34145065] | NCIT:C818 (Curcumin) |
| GM-CSF augmentation | Not expected to work (defect is not GM-CSF signaling) | Rationale per PAP pathogenesis reviews [PMID 30846703] | NCIT:C2069 (Sargramostim) — rationale against |
| Isolated lung transplantation | Not recommended (defect is hematopoietic-intrinsic; recurrence expected) | Analogy to hereditary PAP recurrence post-Tx [PMID 27595063] | NCIT:C15283 (Lung Transplantation) |
Pharmacogenomics / targeted therapy: the mechanistic rationale points to RNase L pathway inhibition as the ideal targeted therapy; curcumin provides early in-vitro support but is not a validated clinical drug here. Gene/cell therapy: not yet applied to PAPHG, but pulmonary macrophage transplantation (PMT) and gene-corrected macrophage therapy are proof-of-concept in Csf2rb/Csf2ra-deficient murine hereditary PAP (PMID: 25274301; PMID: 31326401)—conceptually relevant but unproven for OAS1 disease (and complicated by the systemic, not lung-restricted, defect).
No primary prevention exists (de novo dominant disorder). Secondary prevention = early genetic diagnosis to enable timely HSCT before irreversible lung damage. Genetic counseling: advise families that most cases are de novo but recurrence is possible via parental mosaicism; offer prenatal/preimplantation testing for a known familial variant. Tertiary prevention: Ig replacement and infection prophylaxis to reduce infections; WLL to prevent respiratory decompensation while bridging to HSCT; standard post-HSCT GVHD/infection prophylaxis. Immunization / public-health / environmental measures: not applicable to disease causation.
PAPHG is best understood as a single enzymatic "always-on" switch with three downstream failures. The constitutively active OAS1 enzyme behaves as though the cell is perpetually infected by a virus, chronically firing RNase L. Because RNase L shreds cellular RNA and arrests translation, the cells that most depend on high-throughput protein synthesis and turnover—alveolar macrophages (surfactant processing) and antibody-producing B lineage cells—undergo apoptosis or dysfunction. The elegance of the model is that one gain-of-function lesion predicts both words in the disease name: "pulmonary alveolar proteinosis" (macrophage failure → surfactant buildup) and "hypogammaglobulinemia" (B-cell failure → low antibodies). The myeloid activation/death arm adds the autoinflammatory flavor (fever, dermatitis, IBD).
This mechanistic logic also predicts therapy. Because the defective cells are hematopoietic in origin, replacing the hematopoietic system via HSCT cures the disease—observed repeatedly in patients. Conversely, therapies aimed at the GM-CSF axis (which is intact here) or at the lung alone (isolated lung transplant, which would be re-seeded by the patient's own defective marrow-derived macrophages) are predicted to fail—consistent with recurrence seen when hereditary PAP lungs are transplanted without correcting the hematopoietic compartment (PMID: 27595063). The most rational targeted therapy would be pharmacologic RNase L inhibition, for which curcumin is only an early in-vitro lead.
The table below contrasts PAPHG with the more common PAP subtypes to clarify why its management differs:
| Feature | PAPHG (OAS1 GoF) | Autoimmune PAP | Hereditary PAP (CSF2RA/B) |
|---|---|---|---|
| Mechanism | OAS1→RNase L constitutive activation | Anti-GM-CSF autoantibodies | GM-CSF receptor loss of function |
| Inheritance | AD, de novo/mosaic | Acquired | AR |
| GM-CSF autoantibody | Negative | Positive | Negative |
| Extra-pulmonary | Hypogammaglobulinemia, autoinflammation | None | Usually none |
| Definitive therapy | HSCT | Inhaled GM-CSF / WLL | HSCT / PMT (investigational) |
| GM-CSF therapy | Ineffective | Effective | Ineffective |
| PMID | Study | Type | Contribution |
|---|---|---|---|
| 29455859 | Cho et al. 2018 | Human clinical + WES | Discovered OAS1 as causal gene; linked OAS1 defect to AM dysfunction & surfactant catabolism; PAP resolved post-HSCT |
| 34145065 | Magg et al. 2021 | Human cohort + in vitro | Confirmed 4 de novo heterozygous GoF variants in 6 patients; defined OAS1→RNase L mechanism; curcumin rescue |
| 29185156 | Tanaka-Kubota et al. 2018 | Human clinical | HSCT curative for PAP with primary immunodeficiency |
| 34647697 | Seidl et al. 2022 | Human case | OAS1 PAP bridged >2 yr by monthly WLL, then cured by HSCT |
| 41512080 | Lee/Casanova/Zhang 2026 | Review | Repositions OAS–RNase L GoF as myeloid-driven autoinflammation |
| 34272227 | Boehmer et al. 2021 | In vitro | RNase L→translational arrest→NOXA↑/MCL-1↓→intrinsic apoptosis |
| 39112803 | Yang et al. 2024 | In vitro | SKIV2L limits OAS–RNase L autoinflammation; modifier of OAS1 GoF |
| 30846703 / 32279299 | Trapnell/McCarthy 2019-20 | Reviews | PAP classification, GM-CSF biology, differential diagnosis |
| 42644024, 38576739, 29690908 | CD40L, XLA, ADA case/reviews | Human | Differential diagnoses (PAP + immunodeficiency) |
A total of 38 papers were reviewed across the investigation. The five independent human reports converge on the same gene, mechanism, and curative therapy, and the mechanistic in-vitro literature provides a coherent molecular explanation that unifies the two defining clinical features.
Checked with linkml-reference-validator 0.3.0rc3.
| Outcome | Count |
|---|---|
| References checked | 19 |
| Resolved | 19 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 19 |
| On topic | 12 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 35 |
| Resolved | 34 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 1 |
| Terms whose name was checked | 19 |
| Terms named correctly | 8 |
| Terms named as a different term | 6 |
| Terms whose name is worth a second look | 5 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0006517 (1 mention) - the report calls it "Abnormal alveolar surfactant / PAP"; HP calls it Intraalveolar phospholipid accumulationUBERON:0002048 (1 mention) - the report calls it "Primary organ: lung"; UBERON calls it lung**NCIT:C116737 (1 mention) - the report calls it "Whole Lung Lavage"; NCIT calls it Anti-CD33 Monoclonal Antibody BI 836858NCIT:C818 (1 mention) - the report calls it "Curcumin"; NCIT calls it RoxithromycinNCIT:C2069 (1 mention) - the report calls it "Sargramostim"; NCIT calls it DefosfamideNCIT:C15283 (1 mention) - the report calls it "Lung Transplantation"; NCIT calls it Naturopathy TherapyThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0002037 (1 mention) - the report calls it "Inflammatory abnormality of the GI tract"; HP calls it Inflammation of the large intestineCL:0000236 (2 mentions) - the report calls it "B lymphocytes"; CL calls it B cell, and lists "B lymphocyte" among its other namesUBERON:0002405 (1 mention) - the report calls it "Secondary / systemic: immune system"; UBERON calls it immune system**NCIT:C15431 (1 mention) - the report calls it "Allogeneic Hematopoietic Stem Cell Transplantation"; NCIT calls it Hematopoietic Cell Transplantation, and lists "Hematopoietic Stem Cell Transplantation" among its other namesNCIT:C569 (1 mention) - the report calls it "Immunoglobulin Therapy"; NCIT calls it IgM, and lists "Immunoglobulin M" among its other names