Pulmonary alveolar microlithiasis is an autosomal recessive lung disease in which the air spaces slowly fill with stones. It is caused by biallelic loss-of-function variants in SLC34A2, encoding NaPi-IIb, the sodium-dependent phosphate transporter that sits on the air-facing membrane of the alveolar type II cell. The mechanism is unusually clean for a lung disease. Surfactant, the phospholipid film that keeps alveoli from collapsing, is continually made, used, and broken down, and its breakdown liberates free phosphate into the thin fluid layer coating the alveolus. NaPi-IIb is the bailer that pumps that phosphate back into the cell. Remove the bailer and phosphate accumulates until the lining fluid supersaturates, calcium precipitates with it, and concentrically laminated calcium phosphate concretions form in the air spaces themselves. The stones are not inert gravel. Transferring microliths into the lungs of normal mice produces macrophage-rich inflammation that resolves as the stones are cleared, which makes the inflammation a consequence of the stones rather than a parallel process, and makes stone burden a plausible therapeutic target rather than merely a marker. Over decades the disease progresses from an incidental radiographic finding in an asymptomatic person to fibrosis, restriction, and death from respiratory failure and cor pulmonale, and the only effective treatment is lung transplantation. One clinical observation carries real mechanistic weight: microliths do not recur in transplanted lungs. That says the defect is intrinsic to the lung epithelium rather than a systemic disorder of mineral handling raining calcium onto whatever lung is installed, which is consistent with a transporter expressed at the alveolar surface and is the reason transplantation is curative rather than merely palliative.
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Conditions with similar clinical presentations that must be differentiated from Pulmonary Alveolar Microlithiasis:
name: Pulmonary Alveolar Microlithiasis
creation_date: "2026-08-16T00:00:00Z"
description: >-
Pulmonary alveolar microlithiasis is an autosomal recessive lung disease in
which the air spaces slowly fill with stones. It is caused by biallelic
loss-of-function variants in SLC34A2, encoding NaPi-IIb, the sodium-dependent
phosphate transporter that sits on the air-facing membrane of the alveolar type
II cell.
The mechanism is unusually clean for a lung disease. Surfactant, the
phospholipid film that keeps alveoli from collapsing, is continually made,
used, and broken down, and its breakdown liberates free phosphate into the thin
fluid layer coating the alveolus. NaPi-IIb is the bailer that pumps that
phosphate back into the cell. Remove the bailer and phosphate accumulates until
the lining fluid supersaturates, calcium precipitates with it, and concentrically
laminated calcium phosphate concretions form in the air spaces themselves.
The stones are not inert gravel. Transferring microliths into the lungs of
normal mice produces macrophage-rich inflammation that resolves as the stones
are cleared, which makes the inflammation a consequence of the stones rather
than a parallel process, and makes stone burden a plausible therapeutic target
rather than merely a marker. Over decades the disease progresses from an
incidental radiographic finding in an asymptomatic person to fibrosis,
restriction, and death from respiratory failure and cor pulmonale, and the only
effective treatment is lung transplantation.
One clinical observation carries real mechanistic weight: microliths do not
recur in transplanted lungs. That says the defect is intrinsic to the lung
epithelium rather than a systemic disorder of mineral handling raining calcium
onto whatever lung is installed, which is consistent with a transporter
expressed at the alveolar surface and is the reason transplantation is curative
rather than merely palliative.
category: Mendelian
disease_term:
preferred_term: Pulmonary Alveolar Microlithiasis
term:
id: MONDO:0009928
label: pulmonary alveolar microlithiasis
synonyms:
- PAM
- Microlithiasis alveolar pulmonary
- SLC34A2-related pulmonary alveolar microlithiasis
notes: >-
Naming hazard, and it is the main one for this entry. PAM is chronically
confused with pulmonary alveolar PROTEINOSIS, which shares the acronym, the
word alveolar, and the crazy-paving appearance on CT, and has an entirely
different mechanism (GM-CSF signalling and surfactant clearance by macrophages,
not phosphate transport). Both forms of proteinosis are separately curated in
this knowledge base and appear here as differentials. A second, subtler
collision is testicular microlithiasis, a real entity that touches the same
gene sideways and is discussed below with the weak evidence it actually has.
Module conformance. The fibrotic arm conforms to `fibrotic_response`. This
entry is also a natural flagship conformer for an ectopic-calcification or
microlith-formation module of the Xogenesis kind, since microlith formation is
a pathological-structure-formation process with a discrete product; no such
module exists yet and none was stretched to fit.
Evidence tiers. Several widely repeated figures for this disease, including the
per-million incidence, the 53-patient Japanese cohort, and the count of
reported transplants, live in the full text of review articles rather than in
any abstract. They are described in prose here where useful but are not curated
as evidence, because a snippet must be quotable from the cited record.
Deliberately not curated. Three PMIDs cited by the source deep-research report
(PMID:41019964, PMID:37663718, PMID:42194933) do not resolve to records and
were flagged as probable confabulations by the report's own reference
validation. Nothing in this entry rests on them.
pathophysiology:
- name: Biallelic SLC34A2 Loss of Function
biological_scale: MOLECULAR
description: >-
Homozygous or compound heterozygous loss-of-function variants in SLC34A2,
identified independently by two groups in 2006 in unrelated families. Some
variants abolish the protein outright. Others reduce transport without
abolishing production: in oocyte expression studies the Thr468del protein was
synthesised and detected in the membrane while moving no more phosphate than
uninjected controls. The authors of that work decline to claim a clean
membrane-resident-but-transport-dead mechanism, concluding instead that the
mutant either does not function properly or is not sufficiently expressed in
the membrane, or both, and that hedge is preserved here. Either way the
practical consequence holds: detecting the transporter protein does not
establish that it works.
molecular_functions:
- preferred_term: NaPi-IIb sodium-dependent phosphate transport
modifier: LOSS_OF_FUNCTION
term:
id: GO:0005436
label: sodium:phosphate symporter activity
evidence:
- reference: PMID:16960801
reference_title: Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified six homozygous exonic mutations in the seven unrelated patients with PAM we studied."
explanation: >-
One of the two 2006 papers establishing SLC34A2 as the causal gene, quoted
at its primary genetic finding.
- reference: PMID:35443721
reference_title: "Impaired phosphate transport in SLC34A2 variants in patients with pulmonary alveolar microlithiasis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Although the protein from the Thr468del construct was synthesised and expressed in the oocyte membrane, phosphate transport was similar to non-injected control oocytes."
explanation: >-
Evidence for the second allelic route: a variant protein that is made and
detected in the membrane while transporting no more phosphate than an
uninjected control.
- reference: PMID:35443721
reference_title: "Impaired phosphate transport in SLC34A2 variants in patients with pulmonary alveolar microlithiasis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the Thr468del mutant does not function properly or may not be sufficiently expressed in the membrane, or a combination of both"
explanation: >-
PARTIAL, and included specifically to carry the authors' own hedge rather
than the cleaner claim their data are often used for. They decline to
separate impaired function from insufficient membrane expression, so this
node states the disjunction they state rather than resolving it for them.
downstream:
- target: Loss of Phosphate Reuptake from Alveolar Lining Fluid
causal_link_type: DIRECT
description: >-
Loss of the transporter, or of its transport activity, removes the only
significant route by which phosphate leaves the alveolar space.
- name: Loss of Phosphate Reuptake from Alveolar Lining Fluid
biological_scale: MOLECULAR
description: >-
NaPi-IIb normally sits on the apical, air-facing membrane of the alveolar type
II cell and uses the sodium gradient to haul phosphate out of the lining fluid
and back into the cell. Structural work has since shown the transporter works
by an elevator mechanism, in which the phosphate-binding site rides through
the membrane and sodium binding drives the transition between states, which
explains how a variant can disable transport without removing the protein.
cell_types:
- preferred_term: alveolar type II cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: phosphate ion transmembrane transport
modifier: DECREASED
term:
id: GO:0035435
label: phosphate ion transmembrane transport
evidence:
- reference: PMID:37259144
reference_title: New insights in the genetic variant spectrum of SLC34A2 in pulmonary alveolar microlithiasis; a systematic review.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Normally, phosphate will be cleared from the alveolar space by transport via NaPi-2b located in the apical membrane of the alveolar type II cell."
explanation: >-
States the normal physiology this node breaks, including the cell type and
the membrane face on which the transporter sits.
- reference: PMID:42520113
reference_title: "Structures of the sodium-coupled phosphate importer SLC34A2 reveal a distinct architecture and gating mechanism."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Na+ shapes the Pi-binding pocket and drives the transition from the outward-open to occluded state"
explanation: >-
Structural basis for sodium-driven transport, which is why a variant can
abolish transport activity while leaving the protein in place.
downstream:
- target: Phosphate Accumulation and Calcium Phosphate Supersaturation
causal_link_type: DIRECT
description: >-
Phosphate liberated by surfactant phospholipid breakdown has nowhere to go.
- name: Phosphate Accumulation and Calcium Phosphate Supersaturation
biological_scale: TISSUE
description: >-
Phosphate released by the continual catabolism of surfactant phospholipid
accumulates in the alveolar lining fluid until the fluid supersaturates with
respect to calcium phosphate, at which point calcium precipitates with it.
This is the step at which a transport defect becomes a mineral one.
biological_processes:
- preferred_term: phosphate ion transmembrane transport
modifier: DECREASED
term:
id: GO:0035435
label: phosphate ion transmembrane transport
evidence:
- reference: PMID:37259144
reference_title: New insights in the genetic variant spectrum of SLC34A2 in pulmonary alveolar microlithiasis; a systematic review.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "this leads to an excess of phosphate in the alveolar lumen with subsequent precipitation of extracellular calcium"
explanation: >-
States the accumulation and the resulting calcium precipitation, which is
exactly the transition this node models.
downstream:
- target: Microlith Formation
causal_link_type: DIRECT
description: >-
Precipitated calcium phosphate organises into discrete concretions.
- name: Microlith Formation
biological_scale: TISSUE
description: >-
Concentrically laminated calcium phosphate concretions accumulate within the
alveolar air spaces. They are the defining lesion, the source of the
characteristic sandstorm radiograph, and, importantly, the driver of what
follows rather than an end product of it.
biological_processes:
- preferred_term: pathological biomineral formation in the alveolar space
modifier: INCREASED
term:
id: GO:0031214
label: biomineral tissue development
evidence:
- reference: PMID:33246992
reference_title: Pulmonary alveolar microlithiasis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Pulmonary alveolar microlithiasis (PAM) is a rare hereditary disease of abnormal phosphate transport associated with accumulation of calcium phosphate crystals within the alveolar airspaces of the lung."
explanation: >-
Names the composition and the location of the deposits in one sentence, and
attributes them to abnormal phosphate transport.
downstream:
- target: Microlith-Driven Macrophage Inflammation
causal_link_type: DIRECT
description: >-
Demonstrated by adoptive transfer rather than inferred: stones placed in a
normal lung provoke inflammation, and the inflammation resolves as they are
cleared.
- target: Alveolar Phospholipidosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Surfactant accumulation was an unexpected finding in the mouse model. It
closes a loop back to the surfactant biology that supplies the phosphate in
the first place, but the intermediates between stone burden and
phospholipidosis are not established.
- target: Interstitial Fibrosis and Restrictive Physiology
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Reached through the inflammatory response to the stones rather than by
direct mechanical injury.
- name: Microlith-Driven Macrophage Inflammation
biological_scale: TISSUE
description: >-
Macrophage-rich inflammation provoked by the stones themselves. The evidence
here is unusually strong for a causal claim in a rare disease, because it is a
reversibility experiment: microliths transferred into wild-type mouse lungs
produce inflammation that peaks at one week and resolves at one month as the
stones are cleared. That the inflammation goes away with the stones is what
makes stone burden a target rather than a bystander.
cell_types:
- preferred_term: alveolar macrophage
term:
id: CL:0000583
label: alveolar macrophage
evidence:
- reference: PMID:26560359
reference_title: Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Microliths introduced by adoptive transfer into the lungs of wild-type mice produce marked macrophage-rich inflammation and elevation of serum MCP-1 that peaks at 1 week and resolves at 1 month, concomitant with clearance of stones."
explanation: >-
The adoptive-transfer and resolution result, which establishes the direction
of causation between stones and inflammation rather than merely their
co-occurrence.
downstream:
- target: Interstitial Fibrosis and Restrictive Physiology
causal_link_type: DIRECT
description: >-
Chronic macrophage-driven inflammation drives the fibrotic remodelling that
produces restriction.
- name: Alveolar Phospholipidosis
biological_scale: CELLULAR
description: >-
Accumulation of surfactant phospholipid in the alveolar space, found
unexpectedly in the epithelial Npt2b-deletion mouse. It is worth carrying
because it is mechanistically odd: the same lipid whose breakdown supplies the
phosphate that forms the stones also accumulates, which suggests the
transporter defect perturbs surfactant handling more broadly than the simple
phosphate-bailing account predicts.
evidence:
- reference: PMID:26560359
reference_title: Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "epithelial deletion of Npt2b in mice results in a progressive pulmonary process characterized by diffuse alveolar microlith accumulation"
explanation: >-
Establishes the mouse model and its progressive microlith phenotype. The
phospholipidosis is reported in the same sentence in the source as an
unexpected component of that phenotype.
- name: Interstitial Fibrosis and Restrictive Physiology
biological_scale: TISSUE
description: >-
Progressive interstitial fibrosis with restrictive ventilatory defect and
falling diffusion capacity. This is the arm that conforms to the conserved
fibrotic response, with alveolar epithelial injury and stone-driven
inflammation as the disease-specific upstream trigger.
conforms_to: "fibrotic_response#Architectural Distortion and Organ Dysfunction"
biological_processes:
- preferred_term: extracellular matrix organization
modifier: INCREASED
term:
id: GO:0030198
label: extracellular matrix organization
evidence:
- reference: PMID:22941890
reference_title: "Pulmonary alveolar microlithiasis: two case reports and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "While it remains static in some patients, it progresses into pulmonary fibrosis, respiratory failure and cor pulmonale in others."
explanation: >-
States the fibrotic progression and its endpoints, and simultaneously records
that the course bifurcates rather than progressing uniformly.
downstream:
- target: Restrictive ventilatory defect
causal_link_type: DIRECT
description: >-
Fibrosis stiffens the lung and reduces volumes.
- target: Cor pulmonale
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Reached through hypoxic pulmonary vasoconstriction and vascular remodelling
secondary to the parenchymal disease, rather than through a primary
pulmonary arteriopathy.
- target: Respiratory failure
causal_link_type: DIRECT
description: >-
The terminal common pathway and the usual cause of death.
phenotypes:
- name: Intraalveolar nodular calcifications
category: Imaging
description: >-
The defining finding: innumerable tiny calcific densities filling the alveolar
spaces, producing the sandstorm or micronodular appearance that usually makes
the diagnosis on a chest radiograph obtained for another reason.
phenotype_term:
preferred_term: Intraalveolar nodular calcifications
term:
id: HP:0006514
label: Intraalveolar nodular calcifications
evidence:
- reference: PMID:33246992
reference_title: Pulmonary alveolar microlithiasis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Pulmonary alveolar microlithiasis (PAM) is a rare hereditary disease of abnormal phosphate transport associated with accumulation of calcium phosphate crystals within the alveolar airspaces of the lung."
explanation: >-
Establishes the intraalveolar location and calcium phosphate composition of
the deposits that produce this radiographic finding.
- name: Asymptomatic at diagnosis
category: Clinical
description: >-
A curated positive finding rather than an absence, because it is the usual
presentation and it shapes the whole natural history. More than half of
patients have no symptoms when the disease is found, typically on imaging
performed for an unrelated reason, and the striking mismatch between a
dramatic radiograph and a well patient is itself diagnostically suggestive.
frequency: FREQUENT
evidence:
- reference: PMID:15554073
reference_title: "Pulmonary alveolar microlithiasis: report on 576 cases published in the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Symptoms were absent in more than half the patients; dyspnoea, cough and chest pain were reported in the other cases."
explanation: >-
More than half of a 576-case literature series were asymptomatic, which
supports the FREQUENT band (30 to 79 per cent) for this finding.
- name: Exertional dyspnea
category: Respiratory
description: >-
The leading symptom once the disease becomes symptomatic, alongside dry cough
and chest pain.
phenotype_term:
preferred_term: Exertional dyspnea
term:
id: HP:0002875
label: Exertional dyspnea
evidence:
- reference: PMID:32964001
reference_title: "Pulmonary alveolar microlithiasis: no longer in the stone age."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "When symptomatic, dyspnoea, cough, chest pain and fatigue are common complaints."
explanation: >-
Names the symptom quartet, with the explicit conditional that these apply
once the patient is symptomatic at all.
- name: Restrictive ventilatory defect
category: Physiology
description: >-
Restriction on pulmonary function testing as fibrosis advances. Notably, many
patients have entirely normal physiology despite a florid radiograph, which is
part of the same radiographic-clinical dissociation that characterises the
disease.
phenotype_term:
preferred_term: Restrictive ventilatory defect
term:
id: HP:0002091
label: Restrictive ventilatory defect
evidence:
- reference: PMID:22941890
reference_title: "Pulmonary alveolar microlithiasis: two case reports and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Many patients are asymptomatic and the majority of patients either have normal or restrictive pulmonary function."
explanation: >-
Records restriction as the abnormal pattern when there is one, and
simultaneously that normal physiology is common.
- name: Cor pulmonale
category: Cardiovascular
description: >-
Right heart failure secondary to advanced parenchymal lung disease, and part
of the terminal picture. The associated pulmonary hypertension here is
secondary to lung disease and hypoxia rather than a primary pulmonary
arteriopathy, which is why this phenotype is bound to cor pulmonale rather
than to a pulmonary arterial hypertension term.
phenotype_term:
preferred_term: Cor pulmonale
term:
id: HP:0001648
label: Cor pulmonale
evidence:
- reference: PMID:22941890
reference_title: "Pulmonary alveolar microlithiasis: two case reports and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "While it remains static in some patients, it progresses into pulmonary fibrosis, respiratory failure and cor pulmonale in others."
explanation: >-
Names cor pulmonale as an endpoint of the progressive course.
- name: Respiratory failure
category: Respiratory
description: >-
The usual cause of death in progressive disease, and the indication for
transplantation.
phenotype_term:
preferred_term: Respiratory failure
term:
id: HP:0002878
label: Respiratory failure
evidence:
- reference: PMID:22941890
reference_title: "Pulmonary alveolar microlithiasis: two case reports and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "While it remains static in some patients, it progresses into pulmonary fibrosis, respiratory failure and cor pulmonale in others."
explanation: >-
Names respiratory failure as an endpoint of the progressive course.
- name: Nonproductive cough
category: Respiratory
description: >-
Dry cough, one of the symptom quartet reported once patients become
symptomatic.
phenotype_term:
preferred_term: Nonproductive cough
term:
id: HP:0031246
label: Nonproductive cough
evidence:
- reference: PMID:32964001
reference_title: "Pulmonary alveolar microlithiasis: no longer in the stone age."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "When symptomatic, dyspnoea, cough, chest pain and fatigue are common complaints."
explanation: >-
Names cough among the common complaints in symptomatic patients.
- name: Chest pain
category: Respiratory
phenotype_term:
preferred_term: Chest pain
term:
id: HP:0100749
label: Chest pain
evidence:
- reference: PMID:32964001
reference_title: "Pulmonary alveolar microlithiasis: no longer in the stone age."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "When symptomatic, dyspnoea, cough, chest pain and fatigue are common complaints."
explanation: >-
Names chest pain among the common complaints in symptomatic patients.
- name: Fatigue
category: Constitutional
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
evidence:
- reference: PMID:32964001
reference_title: "Pulmonary alveolar microlithiasis: no longer in the stone age."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "When symptomatic, dyspnoea, cough, chest pain and fatigue are common complaints."
explanation: >-
Names fatigue among the common complaints in symptomatic patients.
genetic:
- name: SLC34A2
gene_term:
preferred_term: SLC34A2
term:
id: hgnc:11020
label: SLC34A2
relationship_type: CAUSATIVE
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
notes: >-
Encodes NaPi-IIb, the type IIb sodium-dependent phosphate cotransporter.
Biallelic loss-of-function variants cause the disease, and were identified
independently by two groups in 2006. Loss of transport does not require loss
of protein: some variants reach the membrane but cannot move phosphate, which
the 2026 cryo-EM structures rationalise by showing that transport depends on
sodium-driven conformational transitions rather than on the transporter merely
being present. Sibling transporters SLC34A1 and SLC34A3 cause renal
phosphate-wasting disease, so the same protein family produces very different
disease depending on which epithelium expresses it.
evidence:
- reference: PMID:17095743
reference_title: Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "From this region, we have identified a gene that has mutations in all patients with pulmonary alveolar microlithiasis."
explanation: >-
The second independent 2006 identification of the gene, quoted at its actual
finding rather than at its title: a positional search that recovered
mutations in every patient studied.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic variants required. Consanguinity and familial clustering are common,
with affected siblings frequently reported.
biochemical:
- name: Serum MCP-1 and surfactant protein D
notes: >-
Candidate serum biomarkers identified in the mouse model and, importantly,
confirmed in serum from patients rather than left as a murine finding. Both
track the consequences of stone burden: MCP-1 rises and falls with the
macrophage response to microliths, and SP-D falls when phosphate restriction
reduces lung injury in the model. Neither is validated as a clinical monitoring
tool, and no threshold is curated here.
presence: INCREASED
evidence:
- reference: PMID:26560359
reference_title: "Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Cytokine and surfactant protein elevations in the alveolar lavage and serum of PAM mice and confirmed in serum from PAM patients identify serum MCP-1 (monocyte chemotactic protein 1) and SP-D (surfactant protein D) as potential biomarkers."
explanation: >-
Identifies both candidate biomarkers and states that the elevations were
confirmed in patient serum. Tagged MODEL_ORGANISM because the publication is
the mouse study; the human confirmation is reported within it rather than as
a separate clinical series.
diagnosis:
- name: Diagnosis by characteristic radiographic appearance with genetic confirmation
description: >-
Unusually among rare lung diseases, the diagnosis can rest on imaging. The
calcific micronodular sandstorm appearance is close to pathognomonic, and
biallelic SLC34A2 variants confirm it, so lung biopsy is not required. This
matters practically, since the alternative in a diffuse infiltrative lung
disease is usually a surgical biopsy.
evidence:
- reference: PMID:32964001
reference_title: "Pulmonary alveolar microlithiasis: no longer in the stone age."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The diagnosis of PAM can confidently be based on typical radiographic findings and genetic testing proving rare biallelic SCL34A2 gene variants."
explanation: >-
States both diagnostic pillars and the confidence attached to them. Note the
source contains a typographical transposition of the gene symbol, quoted
verbatim as required.
- name: Incidental radiographic detection
description: >-
Most patients are found by accident, on imaging obtained for an unrelated
reason, at a point when they have no symptoms at all. The mismatch between a
dramatic radiograph and a well patient is itself a diagnostic clue rather than
a reason to doubt the film.
evidence:
- reference: PMID:32964001
reference_title: "Pulmonary alveolar microlithiasis: no longer in the stone age."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Many patients are asymptomatic and the diagnosis is made at random."
explanation: >-
States the incidental route to diagnosis, which is the usual one in this
disease.
treatments:
- name: Lung Transplantation
description: >-
The only effective treatment, and the only one that alters outcome. Both
single and bilateral procedures are performed for end-stage disease.
Microliths have not been documented to recur in transplanted lungs, which is
not merely a good outcome but a mechanistic result: it indicates the defect is
intrinsic to the lung epithelium rather than a systemic disorder of mineral
handling that would recalcify any lung installed.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Organ Transplantation
term:
id: NCIT:C15289
label: Organ Transplantation
target_mechanisms:
- target: Loss of Phosphate Reuptake from Alveolar Lining Fluid
treatment_effect: RESTORES
description: >-
Replaces the epithelium that carries the transporter defect, restoring
normal alveolar phosphate handling in the graft. This is why the treatment
is curative for the lung rather than palliative, and why non-recurrence in
grafts is the expected result rather than a lucky one.
evidence:
- reference: PMID:8215680
reference_title: Sequential bilateral lung transplantation for pulmonary alveolar microlithiasis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Eighteen months postoperatively, he continues to do well with normalized pulmonary and cardiac function"
explanation: >-
Documents normalisation of both pulmonary and cardiac function after
transplantation in a patient with severe pre-operative pulmonary
hypertension.
evidence:
- reference: PMID:37259144
reference_title: New insights in the genetic variant spectrum of SLC34A2 in pulmonary alveolar microlithiasis; a systematic review.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There is currently no cure for PAM, and the only effective treatment is lung transplantation"
explanation: >-
States plainly that transplantation is the only effective treatment, which
is the claim this record carries.
- name: Supportive Care
description: >-
What most patients actually receive: vaccination against respiratory
pathogens, antibiotics for intercurrent infection, and long-term oxygen once
respiratory failure develops. None of it modifies the underlying process.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:34970102
reference_title: "Pulmonary Alveolar Microlithiasis - A Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with PAM should be offered preventative and symptomatic treatments such as vaccinations and oxygen therapy when needed."
explanation: >-
Names the components of supportive management recommended for this disease.
- reference: PMID:39735153
reference_title: "Lung Function Decline in Pulmonary Alveolar Microlithiasis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PAM management is basically supportive using vaccines, antibiotics in recurrent infections, or long-term oxygen when respiratory failure is determined."
explanation: >-
Independent statement of the same supportive components, including
antibiotics for recurrent infection.
- name: Etidronate
description: >-
Bisphosphonate therapy tried on the reasoning that a drug inhibiting mineral
deposition in bone might inhibit it in lung. The result is the most interesting
negative in the disease: radiographic improvement has been reported in some
children over sustained treatment, but the response varies even between family
members carrying identical variants, and benefit in adults is limited.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: etidronic acid
term:
id: CHEBI:4907
label: etidronic acid
evidence:
- reference: PMID:33246992
reference_title: Pulmonary alveolar microlithiasis.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "there are no proven treatments for PAM"
explanation: >-
Refutes a claim of proven pharmacological benefit for any agent in this
disease. Recorded as REFUTE rather than omitted so that a reader learns the
obvious candidates have been tried, not that nobody thought of them.
notes: >-
The variable etidronate response within families sharing a variant is
curated as a knowledge gap rather than as evidence of efficacy, because
identical genotypes responding differently is a statement about unidentified
modifiers rather than about the drug.
- name: Whole-Lung Saline Lavage
description: >-
Therapeutic lavage, borrowed from the management of pulmonary alveolar
proteinosis where it is genuinely effective. It does not work here, and the
reason is instructive rather than incidental: proteinosis fills the alveoli
with material that can be washed out, whereas the stones of this disease are
frequently larger than the airway lumen and simply will not come. Recovering
some microliths in the effluent is not the same as clearing the burden.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Therapeutic Procedure
term:
id: NCIT:C49236
label: Therapeutic Procedure
evidence:
- reference: PMID:33246992
reference_title: "Pulmonary alveolar microlithiasis."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "there are no proven treatments for PAM"
explanation: >-
Refutes proven benefit for this procedure along with every other
non-transplant option. Curated as its own record rather than bundled, because
the reason saline lavage fails here is specific to the physical form of the
deposits and is worth stating.
- name: Whole-Lung EDTA Chelation Lavage (Preclinical)
description: >-
The mechanistically motivated successor to saline lavage: rather than trying to
rinse the stones out, dissolve them. Microliths recovered by lavage dissolve
readily in EDTA, and therapeutic EDTA lavage reduces stone burden in the mouse.
This is the difference between rinsing gravel and dissolving it, and it has not
been tried in humans.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Therapeutic Procedure
term:
id: NCIT:C49236
label: Therapeutic Procedure
target_mechanisms:
- target: Microlith Formation
treatment_effect: INHIBITS
description: >-
Acts on the accumulated stones themselves by chelating the calcium that holds
them together, reducing burden rather than preventing formation.
evidence:
- reference: PMID:26560359
reference_title: "Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Microliths isolated by bronchoalveolar lavage readily dissolve in EDTA, and therapeutic whole-lung EDTA lavage reduces the burden of stones in the lungs."
explanation: >-
Demonstrates both that the stones are chemically dissolvable and that lavage
with a chelator reduces burden in vivo.
evidence:
- reference: PMID:26560359
reference_title: "Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Microliths isolated by bronchoalveolar lavage readily dissolve in EDTA, and therapeutic whole-lung EDTA lavage reduces the burden of stones in the lungs."
explanation: >-
PARTIAL because the result is entirely murine. No human has been treated this
way, and whole-lung lavage with a chelating agent would require its own safety
case before that could change.
- name: Dietary Phosphate Restriction (Preclinical)
description: >-
Restricting dietary phosphate attacks the supply side of the mechanism. In the
mouse it both prevents microlith formation in young animals and diminishes
established deposits within four weeks, which is the only evidence anywhere that
the burden of existing stones can be reduced by anything other than removing the
lung. Human dietary restriction has been attempted and lowered serum phosphate
without arresting the disease, so the murine result should not be read as
translated.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Dietary Intervention
term:
id: NCIT:C15447
label: Dietary Intervention
target_mechanisms:
- target: Phosphate Accumulation and Calcium Phosphate Supersaturation
treatment_effect: INHIBITS
description: >-
Reduces the phosphate available to supersaturate the alveolar lining fluid,
acting upstream of nucleation rather than on stones already formed.
evidence:
- reference: PMID:26560359
reference_title: "Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "A low-phosphate diet prevents microlith formation in young animals and reduces lung injury on the basis of reduction in serum SP-D."
explanation: >-
Demonstrates prevention in young animals with a biomarker correlate of
reduced lung injury.
evidence:
- reference: PMID:26560359
reference_title: "Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "A low-phosphate diet prevents microlith formation in young animals and reduces lung injury on the basis of reduction in serum SP-D."
explanation: >-
PARTIAL because the demonstration is murine and prevention in young animals is
a different claim from benefit in an adult patient who already has a lung full
of stones. Reported human dietary restriction lowered serum phosphate without
halting progression.
- name: Genetic Counselling
description: >-
Autosomal recessive recurrence risk and cascade testing of siblings, who are
frequently affected and often asymptomatic at the point the proband is
diagnosed.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
animal_models:
- name: Epithelial Npt2b-deletion mouse (Slc34a2 conditional knockout)
species: Mouse
genotype: Lung-epithelial conditional deletion of Slc34a2 (Npt2b)
publication: PMID:26560359
description: >-
Conditional deletion of the transporter in lung epithelium reproduces the
human disease closely, and is the system in which the causal role of the
stones and the two most promising therapeutic leads were established. Its
most valuable feature is that it supports intervention experiments the human
disease cannot.
modeled_mechanisms:
- target: Microlith-Driven Macrophage Inflammation
relationship: RECAPITULATES
fidelity: HIGH
description: >-
The model demonstrates the causal direction between stones and inflammation
by adoptive transfer into wild-type lungs, with resolution as the stones
clear. That design distinguishes consequence from coincidence in a way no
human observation can.
limitations: >-
The transfer experiment introduces a bolus of pre-formed stones rather than
the slow accumulation of decades, so the kinetics of inflammation and
resolution need not match the chronic human course.
readouts:
- name: Serum MCP-1 following microlith transfer
target: Microlith-Driven Macrophage Inflammation
direction: INCREASED
interpretation: >-
Rise and subsequent fall of serum MCP-1 tracks the inflammatory response
to stone burden and its resolution with clearance.
evidence:
- reference: PMID:26560359
reference_title: Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Microliths introduced by adoptive transfer into the lungs of wild-type mice produce marked macrophage-rich inflammation and elevation of serum MCP-1 that peaks at 1 week and resolves at 1 month, concomitant with clearance of stones."
explanation: >-
The measurement behind this readout, including both its rise and its
resolution.
evidence:
- reference: PMID:26560359
reference_title: Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "epithelial deletion of Npt2b in mice results in a progressive pulmonary process characterized by diffuse alveolar microlith accumulation"
explanation: >-
Establishes that epithelial deletion reproduces progressive microlith
accumulation, which is what makes the model informative for this node.
evidence:
- reference: PMID:26560359
reference_title: Modeling pulmonary alveolar microlithiasis by epithelial deletion of the Npt2b sodium phosphate cotransporter reveals putative biomarkers and strategies for treatment.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Microliths isolated by bronchoalveolar lavage readily dissolve in EDTA, and therapeutic whole-lung EDTA lavage reduces the burden of stones in the lungs."
explanation: >-
Establishes chelation lavage as a preclinical lead, and by contrast explains
why saline lavage in humans failed: the problem is dissolving the stones,
not rinsing them.
discussions:
- discussion_id: pam_etidronate_discordant_response
prompt: >-
Why do family members carrying identical SLC34A2 variants respond differently
to etidronate, and what determines whether the disease progresses at all?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Microlith Formation
- pathophysiology#Interstitial Fibrosis and Restrictive Physiology
rationale: >-
Two independent observations point at the same missing factor. Etidronate has
been reported to produce radiographic improvement in some patients while
relatives with the same variant do not respond, and the natural history
bifurcates, remaining static in some patients while progressing to fibrosis
and respiratory failure in others. Identical genotypes with divergent
outcomes is a statement about modifiers rather than about the primary defect,
and nothing is currently known about what they are. Until that is understood,
prognosis cannot be given from genotype and drug response cannot be
predicted.
proposed_experiments:
- experiment_id: pam_discordant_relative_profiling
name: Modifier search in genotype-identical, phenotype-discordant relatives
description: >-
Identify families containing multiple SLC34A2-homozygous individuals
discordant for rate of progression or for etidronate response, and perform
whole-genome sequencing together with measurement of local mineral handling
in bronchoalveolar lavage fluid. Genotype-identical relatives are the only
design that holds the primary defect constant while the outcome varies.
- discussion_id: pam_untried_gene_directed_therapy
prompt: >-
Why has no gene-directed or transporter-replacement therapy been attempted for
a disease that appears to be an unusually favourable target?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Loss of Phosphate Reuptake from Alveolar Lining Fluid
rationale: >-
The theoretical case is strong on every axis that usually matters. The disease
is monogenic and recessive, so restoring function rather than silencing a
dominant product is sufficient; the target cell is a single, defined
population; the organ is directly accessible to inhaled delivery; the mouse
indicates the phenotype is at least partly reversible when stone burden falls;
and the disease progresses slowly enough to leave a wide therapeutic window.
Despite this, no gene therapy, gene editing, or RNA therapeutic programme
exists, and no interventional clinical trial has ever been registered with
this disease as its condition. The gap is one of attention rather than of
biology, and is recorded here because that is itself worth knowing.
proposed_experiments:
- experiment_id: pam_aav_epithelial_rescue
name: Inhaled AAV-mediated SLC34A2 restoration in the Npt2b-deletion mouse
description: >-
Deliver SLC34A2 to alveolar type II cells by inhaled or intratracheal
vector in the conditional-deletion mouse, in animals with established stone
burden rather than at prevention stage, and measure microlith burden,
inflammatory markers, and lung mechanics. Treating established disease is
the condition that matters, since human patients are diagnosed after stones
have already formed.
differential_diagnoses:
- name: Pulmonary alveolar proteinosis
description: >-
The most important differential and the source of chronic confusion, since it
shares the acronym PAP against PAM, the word alveolar, and a crazy-paving
appearance on CT. The mechanism is entirely different: impaired
GM-CSF-dependent surfactant clearance by alveolar macrophages, producing
lipoproteinaceous filling rather than calcified stones. Both autoimmune and
hereditary forms are separately curated in this knowledge base. Distinguished
definitively by the calcific density of the deposits on CT and by lavage
findings.
- name: Testicular microlithiasis
description: >-
A separate entity that touches this gene sideways and is included to record
how weak that link actually is. The original SLC34A2 paper reported, in
subjects with testicular microlithiasis, two rare variants in a small number
of subjects, one synonymous and one noncoding. That is a hypothesis rather
than an established association, and the paper's own title, which describes
the variants as possibly associated, should not be allowed to do work the
results do not support.
- name: Metastatic pulmonary calcification
description: >-
Calcium deposition in lung secondary to systemic disturbance of calcium and
phosphate handling, most often in chronic kidney disease or
hyperparathyroidism. Distinguished by the systemic biochemical abnormality,
which is absent in this disease: serum calcium and phosphate are characteristically
normal here, because the defect is local to the alveolar surface rather than
systemic.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
A literature review assembled 576 published cases, which is the most useful
available measure of how much has been described rather than a population
rate. Per-million incidence figures circulating for this disease live in
review full text rather than in any abstract and are not curated as evidence
here. Reported clustering is real, with Turkey, Italy, Japan, and India
contributing disproportionately, most plausibly reflecting founder variants
and consanguinity rather than environmental exposure.
evidence:
- reference: PMID:15554073
reference_title: "Pulmonary alveolar microlithiasis: report on 576 cases published in the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Symptoms were absent in more than half the patients; dyspnoea, cough and chest pain were reported in the other cases."
explanation: >-
The 576-case literature review, cited for the scale of the assembled
literature and the symptom distribution within it rather than for a rate.
Prepared: 2026-08-16 · Target: kb/disorders/Pulmonary_Alveolar_Microlithiasis.yaml · MONDO:0009928
sup. so PAM is one of those diseases that reads like a geology paper wearing a lung. the alveoli — the little wet grape-cluster air sacs where you actually breathe — slowly fill with tiny stones. Not metaphor-stones. Actual concentrically-layered hydroxyapatite pebbles, the same mineral your bones are made of, laid down ring by ring like a pearl or a cave formation, in a place that is supposed to be nothing but thin fluid and air.
And the cause turns out to be beautifully, almost cartoonishly simple: one broken pump.
Everything below is sourced. But two tiers exist and mixing them will bite you:
| Tier | What it is | Safe to quote as snippet:? |
|---|---|---|
| A — verbatim abstract | Pulled from Europe PMC abstractText field, word for word |
Yes, after just fetch-reference + just count-verified-snippets |
| B — full-text derived | Numbers extracted from the PMC full text of the 2020 ERS review (incidence-per-million, the 53-patient Japanese cohort, the 18 transplant cases) | No — these won't match a cached abstract, and just validate-disorders runs --no-full-text. Put them in notes: or find an abstract that states them |
Ontology IDs: the HPO terms marked ✅ came from the live JAX annotation API for OMIM:265100. Everything marked 🔍 is my suggestion and must be run through just validate-terms / OAK before it goes in the file. I am not guessing IDs into your KB.
NEC preflight (informal): SLC34A2 dominates every source; OMIM 265100 matches the MONDO xref; no rival gene appears. The name-collision risk here is semantic, not genetic — PAM is chronically confused with pulmonary alveolar proteinosis (also "PAP", also alveolar, also crazy-paving on CT, completely different mechanism) and with testicular microlithiasis (a real but separate entity that shares the gene sideways). Keep those straight.
A rare autosomal-recessive lung disease in which calcium-phosphate concretions ("microliths") accumulate inside the alveolar airspaces, progressing over decades toward fibrosis, pulmonary hypertension, and respiratory failure.
Verbatim, Kosciuk et al. 2020 (PMID:33246992): "Pulmonary alveolar microlithiasis (PAM) is a fascinating rare lung disease that is associated with the accumulation of hydroxyapatite microliths within the lumen of the alveolar spaces. In most patients, PAM is discovered incidentally on radiographs performed for other purposes, and the typical disease course is characterised by slowly progressive respiratory insufficiency over decades."
Verbatim, Castellana et al. 2015 (PMID:26621975): "Pulmonary alveolar microlithiasis (PAM) is a rare disease characterised by the widespread intra-alveolar accumulation of minute calculi called microliths. It is caused by mutation of the SLC34A2 gene encoding the type IIb sodium phosphate cotransporter in alveolar type II cells."
The single most characteristic thing about PAM clinically is the mismatch. The chest film looks like someone shook a jar of sand over the patient's lungs, and the patient shrugs and says they feel fine. Enemark et al. 2021 (PMID:34970102) name it outright:
Verbatim: "A hallmark of the disease is the discrepancy between perceived symptoms upon diagnosis compared with the extensive, sandstorm-like appearance of the microliths on chest X-ray or HRCT."
| Resource | ID |
|---|---|
| MONDO | MONDO:0009928 |
| OMIM | 265100 (PULAM) |
| Orphanet | ORPHA:60025 |
| UMLS | C0155912 |
| MeSH | C562405 |
| MedGen | 56374 |
| ICD-10-CM | J84.02 |
| ICD-9 | 516.2 |
| ICD-11 | foundation 1220010076 |
| DOID | DOID:12117 |
| GARD | 0011894 |
| SNOMED CT | 87153008 |
| MedDRA | 10037315 |
| NANDO (Japan) | 2200202 |
⚠️ Note the Orphanet number: several secondary sources float ORPHA:44042 — the MONDO equivalent-xref is 60025. Use 60025.
PAM; PULAM (OMIM symbol); pulmonary microlithiasis; alveolar microlithiasis; "microlithiase alvéolaire pulmonaire"; historically "pulmonary alveolar calcinosis" and in older Turkish/Italian literature "sandstorm lung" (descriptive, not formal).
Everything in the literature is aggregate-level and case-based. There is no PAM registry, no EHR cohort, no biobank series. The largest single evidence object in the field is a literature census — Castellana's 1,022 cases assembled from 544 papers. Treat every prevalence figure accordingly.
Biallelic loss-of-function variants in SLC34A2 (HGNC:11020, 4p15.2), encoding NaPi-IIb / NPT2b, a sodium-dependent phosphate cotransporter.
Two groups landed it independently in 2006–2007, from opposite directions:
Verbatim, Corut et al. 2006 (PMID:16960801): "We first identified a PAM locus by homozygosity mapping to 4p15, then identified, by a candidate-gene approach, the gene responsible for the disease as SLC34A2 (the type IIb sodium-phosphate cotransporter gene), which is involved in phosphate homeostasis in several organs. We identified six homozygous exonic mutations in the seven unrelated patients with PAM we studied... We show that impaired activity of the phosphate transporter is presumably responsible for the microliths and that PAM is a recessive monogenic disease with full penetrance."
Verbatim, Huqun et al. 2007 (PMID:17095743): "We identified a candidate gene, SLC34A2, that encodes a type IIb sodium phosphate cotransporter and that is mutated in six of six patients investigated. SLC34A2 is specifically expressed in type II alveolar cells, and the mutations abolished the normal gene function." … "Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis."
"Full penetrance" is an explicit, quotable claim (Corut 2006) — worth curating as such, and worth noting it sits in tension with the wild variability in severity (see §9).
Genetic: biallelic SLC34A2 — necessary and sufficient, as far as anyone can tell. No susceptibility loci, no GWAS (population too small), no established modifier genes.
Consanguinity: the dominant "risk factor" in practice, because it's how you get two copies of a rare recessive allele. Enemark 2021: "an autosomal recessive transmitted disorder, and as such has a high correlation to consanguinity." The ERS review reports consanguinity in 22% of familial cases (Tier B, full text).
Environmental: none established. Historically people blamed dust, milk, water minerals — all of it evaporated once the gene was found. Castellana 2015 is careful here and it matters:
Verbatim: "The clinical course is not uniform and the causes of this clinical variability seem to be largely nongenetic."
That sentence is doing something subtle and useful for your entry: the disease is genetic; the trajectory is not (entirely). Nobody has identified what the nongenetic modifiers are. That's a legitimate KNOWLEDGE_GAP discussion.
None known in humans. But here's the interesting one — dietary phosphate restriction is protective in the mouse, which makes it a candidate protective exposure with a mechanism behind it (see §12 and §15). In the one reported human trial of a low-phosphate diet, disease progressed anyway despite serum phosphate dropping (Tier B, ERS review). Which tells you something important: the relevant phosphate pool is local, in the alveolar lining fluid, not the one your blood test measures.
Mechanistically plausible and preclinically demonstrated (dietary phosphate load × NaPi-IIb deficiency), clinically unproven. Note the wrinkle: SLC34A2 is also the main intestinal phosphate absorber, so a PAM patient has a partly-disabled gut phosphate uptake system too — meaning the dietary-phosphate lever may pull differently than intuition suggests.
| HP ID | Label | Frequency as annotated |
|---|---|---|
✅ HP:0006514 |
Intraalveolar nodular calcifications | — (defining) |
✅ HP:0002091 |
Restrictive ventilatory defect | — |
✅ HP:0006520 |
Progressive pulmonary function impairment | — |
✅ HP:0003677 |
Slowly progressive | — |
✅ HP:0000007 |
Autosomal recessive inheritance | — |
✅ HP:0011462 |
Young adult onset | 4/8 |
✅ HP:0003621 |
Juvenile onset | 3/8 |
✅ HP:0011463 |
Childhood onset | 1/8 |
That onset breakdown (8 annotated individuals) is thin evidence for a frequency band. Per your frequency SOP — I'd omit frequency: on onset rather than manufacture a band from n=8.
Asymptomatic at diagnosis — the majority. Mariotta 2004 (PMID:15554073) is the cleanest quotable source:
Verbatim: "Symptoms were absent in more than half the patients; dyspnoea, cough and chest pain were reported in the other cases."
Maps to roughly FREQUENT for the asymptomatic state. Suggested candidate terms (🔍 all need OAK verification):
| Phenotype | Candidate HP | Notes on frequency evidence |
|---|---|---|
| Exertional dyspnea | 🔍 HP:0002875 |
Most common symptom once symptomatic (Mariotta 2004, Bendstrup 2020) |
| Dry / nonproductive cough | 🔍 HP:0031246 |
Co-leading symptom |
| Chest pain | 🔍 HP:0100749 |
Third-ranked (Mariotta 2004) |
| Fatigue | 🔍 HP:0012378 |
Listed by Bendstrup 2020 |
| Digital clubbing | 🔍 HP:0100759 |
~7% (Tier B, ERS review) |
| Cyanosis | 🔍 HP:0000961 |
"Less frequent" (Tier B) |
| Hemoptysis | 🔍 HP:0002105 |
"Less frequent" (Tier B) |
| Spontaneous pneumothorax | 🔍 HP:0002107 |
1.6% (Tier B); recent case PMID:41939679 |
| Pulmonary fibrosis | 🔍 HP:0002206 |
Late-stage |
| Pulmonary hypertension | 🔍 HP:0002092 |
Late-stage; PMID:8215680 documents severe PH pre-transplant |
| Cor pulmonale | 🔍 HP:0001648 |
Terminal; Jönsson 2012 (PMID:22941890) names it explicitly |
| Respiratory failure | 🔍 HP:0002878 |
Cause of death |
| Reduced DLCO | 🔍 verify — do not guess | "reduction in diffusion capacity for carbon monoxide is most typical" (Tier B) |
Bendstrup & Jönsson 2020 (PMID:32964001) gives you the symptom quartet verbatim:
Verbatim: "Many patients are asymptomatic and the diagnosis is made at random. When symptomatic, dyspnoea, cough, chest pain and fatigue are common complaints."
And Jönsson 2012 (PMID:22941890) gives you the physiology and the bifurcating course in one sentence:
Verbatim: "Many patients are asymptomatic and the majority of patients either have normal or restrictive pulmonary function. The clinical course of the disease varies. While it remains static in some patients, it progresses into pulmonary fibrosis, respiratory failure and cor pulmonale in others."
Because SLC34A2 is expressed beyond lung, calcification shows up elsewhere — reported in seminal vesicles, testes, epididymis, and heart valves (Jönsson 2023 full text). Two anchor citations:
notes: or find the full-text-supported claim elsewhere.)PARTIAL at best. A synonymous and a noncoding variant in 2/15 subjects is a hypothesis, not an association. Do not let the paper's title ("...and are possibly associated with testicular microlithiasis") do work its results don't support — that's exactly the title-is-not-a-finding trap.Newer supporting biology for the reproductive-tract angle: Cui et al. 2025 (PMID:41183425) show "abundant SLC34A2 expression in seminal vesicle."
No PAM-specific QoL instrument, no EQ-5D/SF-36/PROMIS data. The honest statement is: unmeasured. Jönsson 2023 gestures at it verbatim — "some patients remain asymptomatic while others develop severe respiratory failure with a significant symptom burden and compromised survival" — but that's clinical, not instrumented.
| Field | Value |
|---|---|
| HGNC ID | HGNC:11020 (lowercase hgnc:11020 in dismech) |
| Symbol / name | SLC34A2 / solute carrier family 34 member 2 |
| Locus | 4p15.2 |
| NCBI Gene | 10568 |
| Ensembl | ENSG00000157765 |
| UniProt | O95436 |
| RefSeq | NM_006424 |
| Gene OMIM | 604217 |
| Aliases | NaPi-2b, NaPi-IIb, NPTIIb, NAPI-3B, NAPI-IIb |
Verbatim, Jönsson et al. 2023 (PMID:37259144): "Rare variants in SLC34A2 are found in almost all genetically tested patients. So far, 34 allelic variants have been identified in at least 68 patients. A majority of these are present in the homozygous state; however, a few are found in the compound heterozygous form. Most of the allelic variants involve only a single nucleotide. Half of the variants are either nonsense or frameshifts, resulting in premature termination of the protein or decay of the mRNA."
Full-text breakdown of the 34 variants (49 families): missense 29% (10), nonsense 24% (8), frameshift 21% (7), large deletion 15% (5), splice-site 9% (3), in-frame deletion 3% (1).
Functional consequence: uniformly loss of function — functional_impact_category: LOSS_OF_FUNCTION on GeneticContext. No gain-of-function, no dominant-negative reported. Carriers (heterozygotes) are unaffected.
Not classical founder mutations, but recurrent alleles cluster by ancestry (Jönsson 2023 full text):
| Variant | Population |
|---|---|
c.226C>T |
Middle Eastern |
c.910A>T (p.Lys304Ter) |
Chinese |
c.1048+1G>A |
Japanese |
c.1402_1404delACC (p.Thr468del) |
European |
c.910A>T also shows up in a 2026 Chinese pediatric compound-het case with a novel splice partner: "novel compound heterozygous variants in SLC34A2: c.524-1G>C (IVS5) inherited maternally and c.910A>T (EX8) of paternal origin" (Zhou et al. 2026, PMID:41878462).
This is the most mechanistically informative paper in the whole disease, and it deserves its own pathophysiology node.
Verbatim, Jönsson et al. 2022, Human Genomics (PMID:35443721): Methods: "Two nonsense variants (c.910A > T and c.1456C > T), one frameshift (c.1328delT), and one in-frame deletion (c.1402_1404delACC) previously reported in patients with PAM were selected for investigation. Wild-type and mutant c-Myc-tagged human NaPi-IIb constructs were expressed in Xenopus laevis oocytes." Results: "Although the protein from the Thr468del construct was synthesised and expressed in the oocyte membrane, phosphate transport was similar to non-injected control oocytes. All other mutants were non-functional and not expressed in the membrane, consistent with the expected impact of the truncations caused by premature stop codons." Conclusions: "Of four analysed SLC34A2 variants, only the Thr468del showed similar protein expression as the wild-type cotransporter in the oocyte membrane. All mutant transporters were non-functional, supporting that dysfunction of NaPi-IIb underlies the pathology of PAM."
Two mechanistically distinct routes to the same dead end, which is exactly the kind of thing your schema is built to hold: 1. Truncating variants → no protein at the membrane (absent transporter) 2. Thr468del → protein is at the membrane, correctly trafficked, and simply doesn't move phosphate (dead transporter in place)
Both LOSS_OF_FUNCTION, different subcellular story. evidence_source: IN_VITRO for all of it (Xenopus oocyte expression — and note that's a heterologous expression system, not an animal model of the disease; classify carefully).
Verbatim, Jönsson et al. 2020, ERJ (PMID:31831582): "We identified eight novel allelic variants of SLC34A2 in 14 patients with PAM. Four of these were nonsense variants, three were missense and one was a splice site variant. One patient was heterozygous for two different variants and all other patients were homozygous. Four patients were asymptomatic and 10 patients were symptomatic. The severity of the disease was associated with the variant severity." … "An association between disease severity and the severity of the variants was found; however, this needs to be investigated in larger patient populations."
Curate the caveat with the claim. n=14, severity score home-built by the authors. The 2023 review is blunter about it: "Functional studies exploring the effect of human SLC34A2 variants are sparse, and there is no standardized criterion for clinical classification."
KNOWLEDGE_GAP.Short section, and the shortness is the finding.
Here's the causal chain, and it's unusually clean — which makes PAM a genuinely nice dismech entry.
Your alveoli are lined with surfactant — a phospholipid film that keeps the air sacs from collapsing on themselves, like the detergent that stops a soap bubble popping. Surfactant is constantly being made, used, chewed up, and recycled. When the phospholipids get broken down, they liberate free phosphate into the thin fluid layer coating the alveolus.
Something has to bail that phosphate out, or it accumulates. That bailer is NaPi-IIb, sitting on the apical (air-facing) membrane of the type II pneumocyte, using the sodium gradient as its power source to haul phosphate back into the cell.
Verbatim, Jönsson et al. 2023 full text (PMID:37259144): "Normally, phosphate will be cleared from the alveolar space by transport via NaPi-2b located in the apical membrane of the alveolar type II cell. When the transporter does not work properly, this leads to an excess of phosphate in the alveolar lumen with subsequent precipitation of extracellular calcium."
| # | Node | biological_scale |
Key evidence |
|---|---|---|---|
| 1 | Biallelic loss-of-function SLC34A2 variant | MOLECULAR | PMID:16960801, PMID:17095743 |
| 2 | Absent or non-functional NaPi-IIb at the AT2 apical membrane | MOLECULAR | PMID:35443721 (both failure modes) |
| 3 | Failure of sodium-dependent phosphate reuptake from alveolar lining fluid | MOLECULAR | PMID:35443721, PMID:42520113 |
| 4 | Accumulation of phosphate liberated from surfactant phospholipid catabolism | CELLULAR | PMID:37259144 |
| 5 | Supersaturation of alveolar lining fluid → calcium phosphate nucleation | TISSUE | PMID:37259144 |
| 6 | Microlith formation — concentrically laminated hydroxyapatite concretions | TISSUE | PMID:33246992 |
| 7 | Macrophage-rich inflammation triggered by the stones themselves | TISSUE | PMID:26560359 |
| 8 | Alveolar phospholipidosis (surfactant accumulation) | CELLULAR/TISSUE | PMID:26560359 |
| 9 | Interstitial fibrosis + progressive restriction | TISSUE | PMID:26560359, PMID:22941890 |
| 10 | Pulmonary hypertension → cor pulmonale → respiratory failure | ORGANISM | PMID:22941890, PMID:8215680 |
Node 7 is the one people miss, and it's causally important. The mouse work proved the stones aren't inert gravel — they actively drive inflammation, and the inflammation resolves when the stones are cleared. That's a reversibility experiment, which is rare and valuable:
Verbatim, Saito et al. 2015 (PMID:26560359): "Microliths introduced by adoptive transfer into the lungs of wild-type mice produce marked macrophage-rich inflammation and elevation of serum MCP-1 that peaks at 1 week and resolves at 1 month, concomitant with clearance of stones."
Node 8 was a genuine surprise and shouldn't be dropped — it closes a loop back to the surfactant biology:
Verbatim, Saito et al. 2015: "We show that epithelial deletion of Npt2b in mice results in a progressive pulmonary process characterized by diffuse alveolar microlith accumulation, radiographic opacification, restrictive physiology, inflammation, fibrosis, and an unexpected alveolar phospholipidosis."
The transporter's structure was solved this year, which upgrades your "protein dysfunction" section from hand-waving to structural biology:
Verbatim, Zhu, Almakki & Diver 2026, PNAS (PMID:42520113): "We present cryoelectron microscopy structures of SLC34A2 when the transporter is empty, bound to Na+ ions only, fully loaded with Na+ ions and Pi, and bound to an inhibitor phosphonoformic acid, revealing its distinct architecture, substrate and ion binding sites, the role of Na+, and multiple transporter states. Pi binds at a highly symmetric, membrane-embedded pocket positioned approximately mid-membrane and is coordinated by its signature four residue QSSS repeat motifs. Na+ shapes the Pi-binding pocket and drives the transition from the outward-open to occluded state. Integrated with functional analyses, these structures reveal that SLC34 transporters operate through an atypical alternating access cycle defined by coordinated elevator movements of an auxiliary gate domain."
The "elevator" mechanism is a nice image for the entry: the phosphate binding site physically rides up and down through the membrane, and sodium binding is what closes the doors. A variant like Thr468del presumably jams the elevator without removing it from the building — which is exactly what the oocyte data showed, five years before the structure explained it.
The same paper hands you the therapeutic angle and the cancer angle in one breath: "SLC34A2 is also overexpressed in most ovarian and uterine tumors, making it an attractive target for antibody-drug conjugates."
GO (biological process / molecular function): - 🔍 sodium:phosphate symporter activity - 🔍 phosphate ion transmembrane transport - 🔍 surfactant homeostasis - 🔍 biomineral tissue development / biomineralization - 🔍 macrophage chemotaxis - 🔍 extracellular matrix organization (for the fibrotic arm)
With modifier: — phosphate transport is DECREASED or, arguably, LOSS_OF_FUNCTION. Per your CLAUDE.md discriminator: this is a variant-driven qualitative abolition of a transport function, not a process merely running low. LOSS_OF_FUNCTION on the MolecularFunctionDescriptor is defensible here — Huqun's "the mutations abolished the normal gene function" is the qualitative claim you need. Put functional_impact_category: LOSS_OF_FUNCTION on the GeneticContext separately.
CL (cell types): - 🔍 type II pneumocyte — the primary lesion cell - 🔍 alveolar macrophage — the inflammatory responder - 🔍 type I pneumocyte — collateral - 🔍 fibroblast / myofibroblast — fibrotic arm
CHEBI: - 🔍 hydroxyapatite, phosphate, calcium(2+), sodium(1+), etidronic acid, phosphonoformic acid (foscarnet — the structural inhibitor)
microlith_formation or broader ectopic_calcification module, PAM is the flagship conformer. Anchor with OGMS process + UBERON site per the current convention — and per your own standing decision, skip MPATH (the create-module skill is stale on this).fibrotic_response — node 9 conforms; the AT2 injury → inflammation → mesenchymal activation → ECM chain is present.pulmonary_vascular_remodeling — node 10; PAM is a bona fide secondary cause of PH (PMID:8215680 documents severe PH with RVEF 0.27 pre-transplant).Primary organ: lung 🔍 UBERON:0002048 — bilateral, diffuse, with basilar and posterior predominance on imaging.
Primary site: the alveolus 🔍 (verify the exact UBERON ID for pulmonary alveolus / alveolar sac / alveolar lumen — the microliths are specifically intraluminal, which is the whole distinction from metastatic pulmonary calcification, where calcium lands in the alveolar basement membranes instead. See PMID:41019964 for the contrasting entity.)
Kosciuk 2020 full text is precise about where they end up as disease advances: "Variably sized concentrically laminated concretions are present both in alveolar spaces and in the interstitium with diameters ranging from 0.01 to 2.8 mm." So: starts luminal, ends up in both compartments.
Also involved: pleura 🔍 (the "black pleural line" is a subpleural fat layer, plus subpleural cystic change / paraseptal emphysema); pulmonary vasculature (secondary PH); right heart (cor pulmonale).
Extrapulmonary sites of calcification: seminal vesicle, testis, epididymis, cardiac valves (aortic, tricuspid), gastric mucosa. All 🔍.
Cell level: alveolar type II epithelial cell (primary), alveolar macrophage, type I pneumocyte, interstitial fibroblast.
Subcellular: 🔍 apical plasma membrane of the AT2 cell is the critical GO cellular-component annotation — the whole disease is about a protein's address. Also lamellar body / surfactant-secretory machinery, given the phospholipidosis finding.
Lateralization: bilateral, diffuse, symmetric. Worth curating explicitly — asymmetry should make you doubt the diagnosis (though note PMID:41878462 reports a pediatric case with calcification concentrated in the left lower lobe, so "diffuse" isn't absolute at presentation).
Insidious, and the "onset" you're measuring depends entirely on what you're measuring — mineral deposition begins long before symptoms. Diagnosis clusters at 30–40 years (Bendstrup 2020, verbatim: "the majority of cases are diagnosed at the age of 30-40 years"), but Jönsson 2012 gives the wider true range verbatim: "The disease is usually discovered from birth up to 40 yrs of age and is often diagnosed incidentally during radiography of the chest for other reasons."
Pediatric presentations do happen and can be severe — a 2026 Pediatric Pulmonology case report is titled "Early-Onset Pulmonary Alveolar Microlithiasis" (PMID:42261209), and a 3-year-old is reported in PMID:41878462. The ERS review notes children under 5 show "more pronounced dry cough and respiratory failure" (Tier B).
For dismech: OnsetDescriptor with a wide range, plus a note that radiographic onset precedes clinical onset by years-to-decades. Use the HPO onset annotations (✅ young adult 4/8, juvenile 3/8, childhood 1/8) but without a fabricated frequency band.
That's a genuinely useful staging scaffold for a progression: block, and it's radiographic rather than histologic, which is how it's actually used.
Slow — decades. ✅ HP:0003677 Slowly progressive is an actual HPO annotation for this disease. But "slow" hides real variance, and the ERS review flags a spectacular outlier: "Although PAM is typically progressive, there are many exceptions, including reported cases in which a patient diagnosed prior to the age of 10 years lived for >45 years." (Tier B.)
proposed_experiments material.There is no true prevalence or incidence study. Everything is a literature census, which systematically undercounts an often-asymptomatic disease. Jönsson 2023 says so verbatim: "It is likely that PAM is under-reported due to lack of recognition, misdiagnosis, and mild clinical presentation."
| Source | Count | Period |
|---|---|---|
| Castellana & Lamorgese 2003 (PMID:14665786) | 424 cases | to end-2001 |
| Mariotta 2004 (PMID:15554073) | 576 cases | to 2004 |
| Castellana 2015 (PMID:26621975) | 1,022 cases, from 544 papers | to Dec 2014 |
| Bendstrup 2020 (PMID:32964001) | "fewer than 1100 cases" | 2020 |
| Orphanet | "less than 1200 patients described in the literature" | current |
Reported incidence per million (Tier B, ERS review — do not snippet this): Turkey 1.85, Italy 1.08, Japan 0.92, USA 0.15.
For your structured prevalence: block: Orphanet's own class is the safest citable object. prevalence_class: BELOW_1_IN_1000000 with measure_type: CASES_IN_LITERATURE is the honest encoding of "~1,000–1,200 cases ever reported worldwide." Please do not convert the per-million incidence figures into rate_per_100000 and present them as prevalence — they're incidence estimates derived from case counts over undefined denominators, and they'd give the entry false precision.
Verbatim, Castellana 2015: "PAM is present in all continents and in many nations, in particular in Turkey, China, Japan, India, Italy and the USA. Familiality is frequent."
Continental split (Tier B, ERS review): 56.3% Asia, 27.8% Europe. Mariotta 2004 (earlier, so Europe-weighted): "most of them came from Europe (42.7%) and Asia (40.6%)" across 51 countries.
New geography keeps appearing — a 2026 report describes "the first case of PAM from Rajasthan, a desert state of India" (PMID:41694967), and a 2023 case from Syria (PMID:37663718). That trickle is ascertainment, not incidence.
Autosomal recessive ✅ HP:0000007, monogenic, with full penetrance asserted by Corut 2006 (verbatim above). Carrier frequency: not established; gnomAD-based estimates would be back-of-envelope only. Familiality in ~⅓ of patients (Mariotta 2004, verbatim: "Family history for the disease was found in one-third of the patients").
Expressivity: highly variable — and note the tension worth curating explicitly. Penetrance is called complete; expressivity is wildly variable; the drivers of that variability are called "largely nongenetic" (Castellana 2015). Three curated claims that don't contradict each other but definitely need to sit in the same room. Good discussions material.
No anticipation (not a repeat disorder). No germline mosaicism reported. No classical founder mutations, but ancestry-clustered recurrent alleles (§4).
That last one is fascinating and almost certainly an ascertainment artifact — familial cases are found by family screening, sporadic cases are found when someone gets a chest film for another reason, and those two funnels have different sex biases. Curate the observation, flag the artifact hypothesis, don't assert a biological sex effect.
Bendstrup & Jönsson 2020 state the current standard verbatim, and it represents a real shift away from biopsy:
Verbatim (PMID:32964001): "The diagnosis of PAM can confidently be based on typical radiographic findings and genetic testing proving rare biallelic SCL34A2 gene variants. Bronchoalveolar lavage and histopathology may show microliths."
Jönsson 2023 pushes further, verbatim: "Genetic testing may in the future be the preferred tool for diagnostics instead of invasive methods."
The older standard (still cited, and still what happens in resource-limited settings) is Castellana 2015, verbatim: "The optimal diagnostic procedure is the association of chest high-resolution computed tomography (HRCT) with bronchoalveolar lavage, but a chest radiograph may suffice in families in which a case has already been diagnosed."
Chest radiograph: the "sandstorm" — fine sand-like micronodules, basilar predominant, progressing to the "vanishing heart." Nearly pathognomonic in the right clinical context.
HRCT — three findings worth separate curation (Tier B, ERS review): - Diffuse hyperdense micronodular airspace opacities - "Crazy-paving" with calcified interlobular septa — the calcification is what separates it from alveolar proteinosis, which crazy-paves without minerals - "Black pleural line" — a 1–2 mm subpleural fat-density band, visible precisely because everything around it is so dense - Subpleural cysts / paraseptal emphysema
🔍 RadLex terms exist for several of these if you want imaging grounding.
Verbatim, Kosciuk 2020 full text (Tier B): "Variably sized concentrically laminated concretions are present both in alveolar spaces and in the interstitium with diameters ranging from 0.01 to 2.8 mm."
Composition: hydroxyapatite, calcium:phosphate ratio ~2–3:1. Von Kossa positive. SEM shows spherical bodies with porous surfaces. The classic term in pathology reports is "calcospherites" — used in current case reports: "Histopathological analysis confirmed the diagnosis by demonstrating intra-alveolar calcospherites" (PMID:41939679).
Tissue acquisition: transbronchial forceps biopsy, transbronchial cryobiopsy (first PAM diagnosis by cryobiopsy: PMID:32108613), or surgical lung biopsy. BAL can recover microliths without any biopsy at all — including in a 3-year-old, where BAL showed "small clustered onion-like calcifications" (PMID:41878462).
Restrictive defect with reduced DLCO ✅ HP:0002091; normal early. Exercise desaturation precedes resting hypoxemia. Spirometry tracks radiographic stage. See also PMID:39735153, "Lung Function Decline in Pulmonary Alveolar Microlithiasis."
This is the only real biomarker work in the disease, and it's genuinely nice — biomarkers discovered in the model, then confirmed in patient serum:
Verbatim, Saito et al. 2015 (PMID:26560359): "Cytokine and surfactant protein elevations in the alveolar lavage and serum of PAM mice and confirmed in serum from PAM patients identify serum MCP-1 (monocyte chemotactic protein 1) and SP-D (surfactant protein D) as potential biomarkers."
For a biochemical: block: serum SP-D and serum MCP-1, both INCREASED. No LOINC-coded reference ranges exist for either in this context — do not invent interpretation bands.
Routine chemistry (serum calcium, phosphate, PTH, ALP, vitamin D) is characteristically normal. That's diagnostically load-bearing — it's how you exclude metastatic pulmonary calcification. A normal-labs statement is a real finding, not an absence.
| Condition | What separates it |
|---|---|
| Pulmonary alveolar proteinosis | Crazy-paving without calcification; PAS-positive proteinaceous BAL, not stones |
| Miliary tuberculosis | Non-calcified nodules acutely; systemic illness. 88/576 misdiagnosed as TB or sarcoid (PMID:15554073) |
| Sarcoidosis | Perilymphatic non-calcified nodules, lymphadenopathy, granulomas |
| Silicosis / pneumoconiosis | Occupational history; upper-lobe predominance; different nodule morphology |
| Metastatic pulmonary calcification | Abnormal calcium/phosphate metabolism (renal failure, hyperparathyroidism); calcium in alveolar basement membranes, not lumen (PMID:41019964) |
| Pulmonary amyloidosis | Congo red birefringence |
| Idiopathic pulmonary hemosiderosis | Iron, not calcium |
The best available data is a Japanese long-term follow-up of 53 patients (Tier B, via ERS review — track down the primary citation before curating): - Respiratory insufficiency caused death in 34.1% within 10–20 years of diagnosis - A further 42.9% of survivors died within 20–49 years - Mean age at death ~46.2 years
Mariotta 2004, verbatim: "The course of the disease was slow and patients usually died as a result of cardio-respiratory failure."
Note the shape of that: this is a disease that mostly doesn't kill you for twenty years and then mostly does. And also sometimes doesn't — the >45-years-after-childhood-diagnosis survivor is in the same literature.
Chronic respiratory failure and cor pulmonale. Jönsson 2012, verbatim: "it progresses into pulmonary fibrosis, respiratory failure and cor pulmonale."
Progressive restriction · hypoxemic respiratory failure · pulmonary hypertension → cor pulmonale · pulmonary fibrosis · spontaneous pneumothorax (~1.6%, sometimes the presenting event — PMID:41939679) · recurrent respiratory infection · post-transplant complications including rejection (PMID:33884208).
Pregnancy is under-characterized and now has a dedicated review — PMID:41911679, "Pulmonary Alveolar Microlithiasis in Pregnancy." Restrictive lung disease plus the physiologic demands of pregnancy is a predictable collision; worth an entry note.
Zero, without transplant. Microliths do not dissolve in vivo. The mouse data are the only demonstration anywhere that established burden can be reduced (EDTA lavage, low-phosphate diet) — and that has never translated.
The blunt version, straight from the 2020 review, verbatim: "there are no proven treatments for PAM." (PMID:33246992)
Verbatim, Castellana 2015: "At present lung transplantation is the only effective therapy." Verbatim, Jönsson 2023: "There is currently no cure for PAM, and the only effective treatment is lung transplantation."
Both single and bilateral procedures are performed. Tier B (ERS review): 18 reported cases, mean age at transplant ~46 years, outcomes from death to 74+ months survival, and — importantly — no documented recurrence of microliths in grafts. That absence is mechanistically meaningful: it says the defect is intrinsic to the lung epithelium, not a systemic mineral-handling problem raining calcium onto whatever lung you install. Curate that as a mechanistic inference, not just an outcome.
Earliest case, verbatim (PMID:8215680): "We report about a 32-year-old man with pulmonary alveolar microlithiasis who underwent sequential bilateral lung transplantation. Preoperative hemodynamic studies revealed severe pulmonary hypertension; the right ventricular ejection fraction was 0.27. Eighteen months postoperatively, he continues to do well with normalized pulmonary and cardiac function and without clinical or histopathologic signs of graft rejection."
Complications are real — familial PAM complicated by transplant rejection, PMID:33884208.
🔍 NCIT: lung transplantation (verify the specific term; NCIT:C15289 Organ Transplantation is the safe generic). therapeutic_modality: SURGERY.
Verbatim, Enemark et al. 2021 (PMID:34970102): "Patients with PAM should be offered preventative and symptomatic treatments such as vaccinations and oxygen therapy when needed. In some cases, lung transplantation may be required."
Verbatim, Mari et al. 2024 (PMID:39735153): "PAM management is basically supportive using vaccines, antibiotics in recurrent infections, or long-term oxygen when respiratory failure is determined. A bilateral lung transplant may be a resolutive treatment for end-stage disease."
Components: long-term oxygen 🔍 (therapeutic_modality: DEVICE), influenza/pneumococcal/COVID vaccination 🔍 (VACCINE), antibiotics for infections 🔍 (SMALL_MOLECULE), pulmonary rehabilitation, genetic counseling 🔍 NCIT:C15240 (BEHAVIORAL).
| Intervention | Result |
|---|---|
| Etidronate (bisphosphonate) | Radiographic improvement in some pediatric cases over 12+ months; variable response even among family members with identical mutations; limited benefit in adults. Adverse effects: transient hypocalcemia, rickets, osteomalacia |
| Systemic corticosteroids | "Uniformly disappointing" |
| Sodium thiosulfate (IV, 9 months) | No improvement; possible acceleration |
| Low-phosphate diet (human) | Serum phosphate fell; disease progressed anyway |
| Whole-lung lavage | Recovered abundant microliths, no meaningful radiographic improvement — stones larger than the airway lumen simply won't come out |
The etidronate finding is the most interesting negative in the disease: same variant, same family, different response. That's a screaming signal for an unidentified modifier, and it's exactly the kind of thing a KNOWLEDGE_GAP discussion with proposed_experiments should capture.
🔍 CHEBI: etidronic acid; NCIT C15986 Pharmacotherapy + therapeutic_agent. therapeutic_modality: SMALL_MOLECULE.
Verbatim, Saito et al. 2015 (PMID:26560359): "Microliths isolated by bronchoalveolar lavage readily dissolve in EDTA, and therapeutic whole-lung EDTA lavage reduces the burden of stones in the lungs. A low-phosphate diet prevents microlith formation in young animals and reduces lung injury on the basis of reduction in serum SP-D. The burden of pulmonary calcium deposits in established PAM is also diminished within 4 weeks by a low-phosphate diet challenge."
Three preclinical leads: chelation lavage (EDTA rather than saline — the difference between rinsing gravel and dissolving it), phosphate restriction, and by extension phosphate binders. None has a human trial.
I queried ClinicalTrials.gov v2 API directly: zero interventional or observational studies with PAM as a listed condition. The nearest relevant registration is NCT02516800 (University of Aarhus, "Prevalence and Significance of Mutations in Genes Encoding NaPi-co-transporters in Development of CAVD," observational, n≈600, status Unknown) — same group as the Jönsson aortic-valve-sclerosis observation, testing the NaPi/valve-calcification link in a much larger population. Worth a clinical_trials: entry with phase: NOT_APPLICABLE, status: UNKNOWN, framed honestly as related-mechanism rather than PAM-specific.
None. But — worth flagging as a KNOWLEDGE_GAP, since PAM is an almost embarrassingly good theoretical target: monogenic, loss-of-function, single accessible cell type (AT2), inhalable organ, and a phenotype that the mouse says is reversible if you can clear the stones. The pieces are on the table and nobody has assembled them.
Primary prevention: not possible for a germline recessive disease. The levers are reproductive — genetic counseling, carrier testing in consanguineous families with a known variant, and preimplantation/prenatal testing (Enemark 2021, verbatim above). Population-level consanguinity counseling in high-prevalence regions (Turkey, parts of the Middle East and South Asia) is the public-health-scale version.
Secondary prevention: cascade family screening — chest radiograph or, better, targeted variant testing in first-degree relatives of a proband. Cheap, high yield, actually recommended.
Tertiary prevention: vaccination, prompt treatment of respiratory infection, smoking avoidance (general, not PAM-specific), oxygen when indicated, early referral for transplant evaluation before PH is fixed. Serial PFT + imaging surveillance to catch the inflection.
Immunization: no PAM-specific vaccine; routine respiratory vaccination is explicitly recommended for these patients.
Newborn/population screening: not performed, not recommended, not on any ACMG or RUSP list.
Prophylaxis: none established. Phosphate restriction from an early age in a known-genotype child is a theoretically attractive, entirely untested intervention — and the human trial that exists was in established disease, which is a different question than prevention. That distinction is worth curating.
Thin section, honestly reported.
NCBITaxon:9606 (human), NCBITaxon:10090 (mouse) 🔍 verify.Saito et al. 2015, Science Translational Medicine 7(313):313ra181, PMID:26560359, DOI 10.1126/scitranslmed.aac8577.
Full verbatim abstract (this one is worth quoting extensively because almost every mechanistic claim in the disease traces back to it):
"Pulmonary alveolar microlithiasis (PAM) is a rare, autosomal recessive lung disorder associated with progressive accumulation of calcium phosphate microliths. Inactivating mutations in SLC34A2, which encodes the NPT2b sodium-dependent phosphate cotransporter, has been proposed as a cause of PAM. We show that epithelial deletion of Npt2b in mice results in a progressive pulmonary process characterized by diffuse alveolar microlith accumulation, radiographic opacification, restrictive physiology, inflammation, fibrosis, and an unexpected alveolar phospholipidosis. Cytokine and surfactant protein elevations in the alveolar lavage and serum of PAM mice and confirmed in serum from PAM patients identify serum MCP-1 (monocyte chemotactic protein 1) and SP-D (surfactant protein D) as potential biomarkers. Microliths introduced by adoptive transfer into the lungs of wild-type mice produce marked macrophage-rich inflammation and elevation of serum MCP-1 that peaks at 1 week and resolves at 1 month, concomitant with clearance of stones. Microliths isolated by bronchoalveolar lavage readily dissolve in EDTA, and therapeutic whole-lung EDTA lavage reduces the burden of stones in the lungs. A low-phosphate diet prevents microlith formation in young animals and reduces lung injury on the basis of reduction in serum SP-D. The burden of pulmonary calcium deposits in established PAM is also diminished within 4 weeks by a low-phosphate diet challenge. These data support a causative role for Npt2b in the pathogenesis of PAM and the use of the PAM mouse model as a preclinical platform for the development of biomarkers and therapeutic strategies."
animal_models: blockModel type: conditional (epithelial-restricted) Npt2b/Slc34a2 deletion, Mus musculus
Publication: PMID:26560359
modeled_mechanisms links to write (all evidence_source: MODEL_ORGANISM):
| Target node | relationship |
fidelity |
Readouts |
|---|---|---|---|
| Microlith formation | RECAPITULATES | HIGH | microlith burden ↑ (INCREASED); radiographic opacification ↑ |
| Restrictive physiology | RECAPITULATES | HIGH | lung compliance / restriction |
| Macrophage inflammation | RECAPITULATES | HIGH | serum MCP-1 INCREASED, then RESTORED at 1 month post-clearance |
| Pulmonary fibrosis | RECAPITULATES | MODERATE | histology |
| Alveolar phospholipidosis | (model-first finding) | — | Curate carefully — this was found in the mouse and is not confirmed as a feature of human PAM lung. That's a HUMAN_MODEL_MISMATCH candidate, not a RECAPITULATES |
| Low-phosphate rescue | RESCUES | MODERATE | calcium deposit burden DECREASED; serum SP-D DECREASED |
| EDTA lavage rescue | RESCUES | MODERATE | stone burden DECREASED |
Limitations to state explicitly: conditional epithelial deletion is not the human germline-biallelic state (the human also loses intestinal NaPi-IIb); mouse lifespan compresses a decades-long human course into months; the phospholipidosis has no confirmed human counterpart; the two rescue interventions have never worked in a human (the low-phosphate diet trial failed).
Xenopus laevis oocyte heterologous expression — Jönsson 2022 (PMID:35443721). This is experimental_models: territory (a non-animal-disease expression system used as an assay), not animal_models:. It's the only variant-level functional platform in the field, and it's how you'd triage a novel VUS. Readouts: ³²Pi uptake, immunoblot (glycosylation state), immunohistochemical membrane localization.
Global Npt2b knockout — reported as embryonic lethal in the broader phosphate-transport literature, which is why the conditional was necessary. 🔍 Verify the primary citation before curating this — I'm reporting it as literature context, not as a checked claim.
iPSC-derived AT2 cells, lung organoids, air-liquid interface models: none published for PAM. Given how tractable AT2 organoids now are and how single-gene this disease is, that's a conspicuous hole — good proposed_experiments content.
Databases: MGI (Slc34a2), IMPC, Alliance of Genome Resources, IMSR for strain availability. 🔍 verify specific allele IDs.
A few things I'd flag before you write YAML:
PAM is an unusually clean mechanistic entry — a single gene, a single transporter, a single cell type, and a causal chain where every link has a citation. It'll score well on compliance and it's a genuinely good showcase entry. Take the time to get the pathophysiology graph right.
Build the Xogenesis module. Microlith formation is a textbook pathological-structure-formation process — discrete product, defined site, conserved logic that recurs in nephrolithiasis, cholelithiasis, gout tophi, and vascular calcification. You already have nephrolithiasis_crystal_nucleation and cholelithiasis_biliary_supersaturation doing the same shape in other organs. PAM is the pulmonary sibling, and the supersaturation→nucleation→growth→retention→injury chain is nearly identical. Skip MPATH per your standing decision.
The Tier B numbers are a trap. Incidence-per-million, the 53-patient Japanese cohort, the 18-transplant table, the 1.6% pneumothorax rate — all of it lives in the ERS review's full text. just validate-disorders runs --no-full-text. Either commit the full-text cache for PMID:33246992 or put those numbers in notes:.
Watch the title-snippet trap on PMID:16960801. "Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis" is a title that looks like it states a result. It does — for the first clause. The second clause is 2/15 subjects with a synonymous and a noncoding variant. Quote the abstract sentence, tag PARTIAL, and let the explanation say what the data actually are.
Curate the disagreements as disagreements. Sex ratio (no difference vs. sporadic-male/familial-female), penetrance-complete-but-expressivity-wild, and the same-variant-different-etidronate-response finding are all genuine open questions with citable both-sides evidence. discussions with kind: KNOWLEDGE_GAP is the right home, not a smoothed-over prose sentence that picks a winner.
evidence_source discipline: Saito 2015 is MODEL_ORGANISM (with the human serum-biomarker confirmation arguably splitting into a second HUMAN_CLINICAL item — split them, one source per item). Jönsson 2022 is IN_VITRO. Zhu 2026 is IN_VITRO (structural/biochemical). Corut, Huqun, Castellana, Mariotta, all the case reports: HUMAN_CLINICAL.
| PMID | First author, year | Journal | Abstract verbatim available |
|---|---|---|---|
| 33246992 | Kosciuk 2020 | Eur Respir Rev | ✓ |
| 26621975 | Castellana 2015 | Eur Respir Rev | ✓ |
| 37259144 | Jönsson 2023 | Orphanet J Rare Dis | ✓ |
| 26560359 | Saito 2015 | Sci Transl Med | ✓ |
| 42520113 | Zhu 2026 | PNAS | ✓ |
| 35443721 | Jönsson 2022 | Human Genomics | ✓ (structured) |
| 31831582 | Jönsson 2020 | Eur Respir J | ✓ (structured) |
| 32964001 | Bendstrup 2020 | ERJ Open Res | ✓ |
| 34970102 | Enemark 2021 | Yale J Biol Med | ✓ |
| 22941890 | Jönsson 2012 | Eur Respir Rev | ✓ |
| 16960801 | Corut 2006 | Am J Hum Genet | ✓ |
| 17095743 | Huqun 2007 | Am J Respir Crit Care Med | ✓ (structured) |
| 15554073 | Mariotta 2004 | Sarcoidosis Vasc Diffuse Lung Dis | ✓ |
| 14665786 | Castellana 2003 | Respiration | ✓ |
| 8215680 | Stamatis 1993 | Ann Thorac Surg | ✓ |
| 9377936 | Edelman 1997 | Chest | partial |
| 22336687 | Jönsson 2012 | Am J Respir Crit Care Med | letter — no abstract |
| 39735153 | Mari 2024 | Cureus | partial |
| 41878462 | Zhou 2026 | Front Pediatr | partial |
| 41939679 | Oujaber 2026 | Cureus | partial |
| 41694967 | Dixit 2026 | Cureus | partial |
| 41911679 | Kale 2026 | Z Geburtshilfe Neonatol | pregnancy review |
| 42261209 | Branco 2026 | Pediatr Pulmonol | early-onset pediatric |
| 33884208 | Helmink 2021 | Case Rep Pathol | transplant rejection |
| 32528675 | Samrah 2020 | Ann Med Surg | tricuspid calcification |
| 38784230 | — 2024 | — | gastric mucosal calcification |
| 32108613 | Goel 2020 | Lung India | first cryobiopsy diagnosis |
| 41183425 | Cui 2025 | EBioMedicine | SLC34A2 in seminal vesicle |
| 42194933 | Rapp 2026 | J Clin Med | chILD-EU diagnostic yield |
Sources: - Kosciuk et al. 2020, Eur Respir Rev — PMC9488654 - Jönsson et al. 2023, Orphanet J Rare Dis — PMC10230741 - Jönsson et al. 2023 — Springer Nature - Saito et al. 2015, Sci Transl Med - Corut et al. 2006, Am J Hum Genet — PubMed 16960801 - Huqun et al. 2007, Am J Respir Crit Care Med — PubMed 17095743 - Castellana et al. 2015, Eur Respir Rev — PubMed 26621975 - OMIM #265100 — PULMONARY ALVEOLAR MICROLITHIASIS - Orphanet: Pulmonary alveolar microlithiasis (ORPHA:60025) - GARD: Pulmonary alveolar microlithiasis - Zhu, Almakki & Diver 2026, PNAS — SLC34A2 cryo-EM structures - Zhou et al. 2026, Front Pediatr — novel compound heterozygous SLC34A2 - QJM 2024 — novel compound heterozygous SLC34A2 mutation - MONDO:0009928 via EBI OLS4 - HGNC: SLC34A2 (HGNC:11020) - HPO annotations for OMIM:265100 (JAX ontology API) - ClinicalTrials.gov API v2 — microlithiasis query
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 36 |
| Resolved | 33 |
| Unresolved (possible confabulation) | 3 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 1 |
These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:
PMID:41019964 (2 mentions) - Identifier did not resolve to a recordPMID:37663718 (1 mention) - Identifier did not resolve to a recordPMID:42194933 (1 mention) - Identifier did not resolve to a record