👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

ACDMPV results from heterozygous point mutations or deletion copy-number variants at the FOXF1 locus, so inheritance is formally autosomal dominant, but essentially all cases are de novo and parental transmission is exceptional given the lethality.

Autosomal dominant inheritance De novo rate: Essentially all reported cases are de novo

Parent-of-origin effect: Maternal-allele bias from imprinting of the FOXF1 locus in lung: 30 of 31 parentally resolved pathogenic 16q24.1 deletions arose on the maternally inherited chromosome 16. Four families with pathogenic paternal-chromosome lesions are known, so the imprint is not absolute.

Show evidence (1 reference)

PMID:27071622 SUPPORT Human Clinical

"Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes..."

Establishes heterozygous coding and enhancer lesions at the FOXF1 locus as the cause, including the long non-coding RNA enhancer element.

?

Discussions and Knowledge Gaps

2

What silences the paternal FOXF1 allele in human lung, and why do a minority of pathogenic lesions on the paternal chromosome still cause ACDMPV?

KNOWLEDGE GAP OPEN gap_acdmpv_imprinting_mechanism

Attached to

pathophysiology#Genomic Imprinting of the FOXF1 Locus

Thirty of thirty-one parentally resolved deletions arose on the maternal chromosome, which is a strong imprinting signal, yet four families carry pathogenic paternal-chromosome lesions. So the paternal allele is neither fully silenced nor fully active. The imprinting control element, the tissue and developmental window over which it operates, and what determines escape are all unresolved. This matters practically because it governs recurrence counselling and the interpretation of an apparently benign paternal deletion found incidentally.

Proposed experiments

Allele-specific FOXF1 expression across human fetal lung development

exp_acdmpv_allele_specific_lung_expression

Perform allele-specific expression and methylation profiling across the 16q24.1 locus in human fetal lung at successive gestational ages, in parallel with the same measurements in intestine and heart, to map where and when the imprint is established and whether escape correlates with lesion position relative to the enhancer.

Decision criterion

A developmental window or lesion-position dependence that separates the four paternal cases from the maternal majority would define the escape condition.

Would support

Paternal silencing is partial and window-dependent, so paternal lesions cause disease when they remove enhancer sequence needed by both alleles

Would refute

Paternal silencing is uniform, implicating a second modifier locus in the escape cases

Is there any postnatal window in which restoring FOXF1 or STAT3 signalling can build a functional alveolar capillary bed, or is the defect fixed before birth?

KNOWLEDGE GAP OPEN gap_acdmpv_developmental_window_for_rescue

Attached to

pathophysiology#Failed Pulmonary Microvascular Angiogenesis pathophysiology#Impaired Alveolar Gas Exchange

The STAT3 nanoparticle strategy presupposes that neonatal lung angiogenesis is still tractable after birth, and FOXF1 is described as stimulating neonatal rather than purely fetal angiogenesis, which is encouraging. But ACDMPV also involves a fixed architectural error, the misalignment of the pulmonary veins, which no angiogenic stimulus can re-route. Whether restoring capillary density in a lung with misaligned veins yields usable gas exchange is the question that determines whether any medical therapy is possible at all, or whether transplant will remain the only option.

Proposed experiments

Staged postnatal STAT3 restoration in the Foxf1 S52F knock-in mouse

exp_acdmpv_postnatal_rescue_window

Deliver STAT3 to Foxf1 S52F knock-in mice at a series of postnatal timepoints and measure capillary density, capillary-to-epithelium apposition, venous position, pulmonary artery pressure and survival, to establish whether a rescue window exists and whether corrected capillary density is sufficient without corrected venous anatomy.

Decision criterion

Survival benefit with restored gas exchange despite persistent venous misalignment would show the capillary deficit is the rate-limiting lesion.

Would support

Capillary density is rate-limiting and postnatal angiogenic rescue is viable

Would refute

Venous misalignment alone sustains lethal physiology, confining treatment to transplant

⚙

Pathophysiology

8

FOXF1 Coding or Upstream Enhancer Lesion

The causal lesion is either a heterozygous point mutation in FOXF1 itself or, frequently, a deletion of the distant upstream enhancer region at 16q24.1 that contains the fetal lung-expressed long non-coding RNA genes LINC01081 and LINC01082. The enhancer route is what makes exome-only testing an incomplete strategy here: the coding sequence can be entirely normal while the gene is functionally silenced in lung.

FOXF1 hgnc:3809

Downstream

Loss of Mesenchymal FOXF1 Transcriptional Output Either lesion class reduces FOXF1 protein available to drive its transcriptional programme in lung mesenchyme.

Show evidence (1 reference)

PMID:27071622 SUPPORT Human Clinical

"We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients."

Documents the deletion copy-number variant class at the FOXF1 locus in a large ACDMPV series.

Genomic Imprinting of the FOXF1 Locus

A striking parent-of-origin effect: of 31 pathogenic 16q24.1 deletions with determined parental origin, all arose de novo and 30 were on the maternally inherited chromosome 16. The paternal allele appears to be silenced in human lung, so only a maternally inherited hit removes the expressed copy. A small number of paternal-chromosome cases exist, so the imprint is not absolute. This also explains why maternal uniparental disomy 16 shares key phenotypic features.

Downstream

FOXF1 Coding or Upstream Enhancer Lesion The imprint gates the lesion rather than following from it: silencing of the paternal allele in lung is what makes a maternally inherited hit sufficient to cause disease.

Loss of Mesenchymal FOXF1 Transcriptional Output A maternally inherited lesion removes the transcriptionally active copy in lung.

Show evidence (2 references)

PMID:27071622 SUPPORT Human Clinical

"all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs"

Quantifies the parent-of-origin skew that implicates imprinting at the FOXF1 locus.

PMID:27071622 PARTIAL Human Clinical

"Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16."

Qualifies the imprinting model: a minority of pathogenic lesions arise on the paternal chromosome, so silencing is incomplete.

Loss of Mesenchymal FOXF1 Transcriptional Output

FOXF1 is expressed in lung mesenchyme and endothelium and drives the angiogenic programme that builds the pulmonary microvasculature. Mouse haploinsufficiency reproduces alveolar capillary dysplasia together with intestinal and gall bladder maldevelopment, matching the extrapulmonary anomalies seen in patients.

endothelial cell CL:0000115

DNA-binding transcription factor activity GO:0003700 ↓ DECREASED

Downstream

Failed Pulmonary Microvascular Angiogenesis Loss of the FOXF1-driven angiogenic programme prevents formation of the alveolar capillary network.

Misalignment of Pulmonary Veins The same mesenchymal patterning programme positions the pulmonary veins, so its loss misplaces them into the bronchovascular bundle.

Show evidence (2 references)

PMID:25091710 SUPPORT Model Organism

"In mice, haploinsufficiency of the Foxf1 gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal, and gall bladder morphogenesis."

Model-organism evidence that FOXF1 dosage reduction is sufficient to cause the pulmonary and extrapulmonary phenotype.

PMID:25091710 SUPPORT Model Organism

"FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells."

Identifies VEGF signalling in endothelium as the transcriptional output through which FOXF1 builds the vasculature.

Failed Pulmonary Microvascular Angiogenesis

The alveolar capillary bed fails to form in adequate density and, critically, fails to appose itself to the alveolar epithelium. FOXF1 acts through STAT3 to drive neonatal lung angiogenesis, and a knock-in mouse carrying the human S52F FOXF1 mutation recapitulates the histopathology, establishing that a single patient allele is sufficient.

endothelial cell CL:0000115

angiogenesis GO:0001525 ↓ DECREASED

Downstream

Impaired Alveolar Gas Exchange A capillary bed that is sparse and not apposed to alveolar epithelium cannot support gas exchange.

Increased Pulmonary Vascular Resistance An absent distal capillary bed and abnormally muscularized arterioles raise resistance across the pulmonary circulation.

Show evidence (2 references)

PMID:31199666 SUPPORT Model Organism

"FOXF1 acts through STAT3 to stimulate neonatal lung angiogenesis."

Identifies STAT3 as the signalling intermediary through which FOXF1 drives neonatal lung angiogenesis.

PMID:31199666 SUPPORT Model Organism

"We generated a clinically relevant mouse model of ACDMPV by introducing the S52F FOXF1 mutation into the mouse Foxf1 gene locus using CRISPR/Cas9 technology."

Establishes a knock-in model carrying an actual patient allele rather than a generic null.

Misalignment of Pulmonary Veins

The eponymous and diagnostically decisive lesion: pulmonary veins run anomalously within the bronchovascular bundle alongside the arteries, instead of in the interlobular septa where they belong. It is a patterning failure of the same mesenchymal programme, and it is what a pathologist looks for to confirm the diagnosis on lung biopsy or at autopsy.

Show evidence (1 reference)

PMID:30058937 SUPPORT Human Clinical

"the majority of ACD/MPV patients present with peripheral veins in the bronchovascular bundle adjacent to the pulmonary arteries outside the interlobular septa while normally they are located within the septa"

States the misalignment lesion directly, including the normal comparator, rather than implying it from a general definition of the disorder.

Impaired Alveolar Gas Exchange

Because the capillaries are neither numerous enough nor close enough to the alveolar epithelium, the diffusion barrier is effectively unusable. This produces the refractory hypoxaemia that does not respond to ventilation or oxygen, and is the reason ACDMPV is fatal without transplant.

Show evidence (2 references)

PMID:30058937 SUPPORT Human Clinical

"these scanty alveolar capillaries are located away from the alveolar epithelium"

The decisive histological fact for gas exchange: the capillaries that do form are not apposed to the alveolar epithelium.

PMID:30058937 SUPPORT Human Clinical

"The clinical presentation of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is characterized by respiratory distress and cyanosis caused by severe pulmonary hypertension (PH) and insufficient oxygen uptake"

Human clinical description of the presenting picture, replacing a background sentence previously borrowed from a mouse study.

Increased Pulmonary Vascular Resistance

ACDMPV enters the conserved pulmonary hypertension pathway at this node rather than at its usual trigger. In the module, raised resistance follows obstructive remodeling of a vascular bed that formed normally and then degenerated; in ACDMPV the distal bed was never built, so the substitution is developmental absence in place of acquired obstruction, with muscularized arterioles compounding it.

Downstream

Suprasystemic Pulmonary Arterial Hypertension Raised resistance across an absent distal bed drives pulmonary artery pressure above systemic.

Show evidence (1 reference)

PMID:30058937 PARTIAL Human Clinical

"the walls of small peripheral pulmonary arteries are thickened due to hypertrophic smooth muscle cells in the media"

Human histological evidence for the arteriolar muscularization that compounds the resistance rise; the resistance measurement itself is supplied by the conserved module, hence PARTIAL.

Suprasystemic Pulmonary Arterial Hypertension

Severe, typically suprasystemic pulmonary arterial hypertension with right-to-left shunting, presenting within hours to days of birth in a term infant and characteristically refractory to inhaled nitric oxide and other pulmonary vasodilators, because the problem is a missing vascular bed rather than a constricted one.

cardiac muscle hypertrophy GO:0003300 ↑ INCREASED

Show evidence (1 reference)

PMID:30058937 SUPPORT Human Clinical

"The vast majority succumb to hypoxemic respiratory failure within days to weeks after presentation despite receiving supportive care including extracorporeal membrane oxygenation"

Human outcome data showing that maximal supportive care, including ECMO, does not overcome the physiology.

✶

Histopathology

3

Reduced and malpositioned alveolar capillaries

The diagnostic microscopic picture: diffuse thickening of the interalveolar septa with a marked reduction in alveolar capillaries, and the few capillaries that are present sitting away from the alveolar epithelium, which is itself composed predominantly of hyperplastic cuboidal type 2 pneumocytes rather than the flattened type 1 cells needed for gas exchange.

Show evidence (2 references)

PMID:30058937 SUPPORT Human Clinical

"the lung tissue is characterized by diffuse thickening of interalveolar septa and marked reduction of pulmonary alveolar capillaries"

The core histological finding on which the diagnosis rests.

PMID:30058937 SUPPORT Human Clinical

"these scanty alveolar capillaries are located away from the alveolar epithelium which is predominantly composed of hyperplastic cuboidal type 2 pneumocytes"

Documents both the malposition of the capillaries and the type 2 pneumocyte hyperplasia of the overlying epithelium.

Muscularized peripheral pulmonary arteries

The walls of small peripheral pulmonary arteries are thickened by hypertrophic medial smooth muscle, the structural correlate of the raised pulmonary vascular resistance.

Show evidence (1 reference)

PMID:30058937 SUPPORT Human Clinical

"the walls of small peripheral pulmonary arteries are thickened due to hypertrophic smooth muscle cells in the media"

Histological basis for the arteriolar contribution to raised resistance.

Misaligned pulmonary veins in the bronchovascular bundle

Pulmonary veins sit in the bronchovascular bundle beside the arteries instead of within the interlobular septa. This is the eponymous finding and what a pathologist looks for to confirm the diagnosis.

Show evidence (1 reference)

PMID:30058937 SUPPORT Human Clinical

"the majority of ACD/MPV patients present with peripheral veins in the bronchovascular bundle adjacent to the pulmonary arteries outside the interlobular septa while normally they are located within the septa"

Defines the misalignment lesion against its normal comparator.

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Pathograph

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Phenotypes

5

Cardiovascular 1

Pulmonary arterial hypertension VERY_FREQUENT Pulmonary arterial hypertension HP:0002092

Show evidence (1 reference)

PMID:30058937 SUPPORT Human Clinical

"respiratory distress and cyanosis caused by severe pulmonary hypertension (PH) and insufficient oxygen uptake"

Human clinical description establishing severe pulmonary hypertension as the presenting physiology.

Digestive 1

Intestinal malrotation Intestinal malrotation HP:0002566

Show evidence (1 reference)

PMID:30058937 PARTIAL Human Clinical

"These malformations predominantly affect the gastrointestinal tract, but also affect the cardiovascular and urogenital system."

Human cohort evidence that associated malformations are predominantly gastrointestinal; the specific malrotation phenotype is not named directly, hence PARTIAL.

Respiratory 1

Neonatal respiratory distress VERY_FREQUENT Neonatal respiratory distress HP:0002643

Show evidence (2 references)

PMID:30058937 SUPPORT Human Clinical

"most patients develop symptoms within the first 24 h of life"

Quantifies onset timing in human patients.

PMID:30058937 SUPPORT Human Clinical

"Ninety-five percent of ACD/MPV patients are born at full term with normal birth weights and Apgar scores"

Establishes that affected infants are typically term with normal birth parameters, which is why the deterioration is so unexpected.

Other 2

Hypoplastic left ventricle OCCASIONAL Hypoplastic left ventricle HP:0004383

Show evidence (1 reference)

PMID:27071622 SUPPORT Human Clinical

"a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer"

Establishes the genotype restriction of the severe cardiac phenotype to deletions spanning both gene and enhancer.

Single umbilical artery OCCASIONAL Single umbilical artery HP:0001195

Show evidence (1 reference)

PMID:27071622 SUPPORT Human Clinical

"single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer"

Documents single umbilical artery as part of the enhancer-deletion phenotype.

🧬

Genetic Associations

2

FOXF1 (Pathogenic Variants)

Gene: FOXF1 hgnc:3809 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:25091710 SUPPORT Other

"Inactivating mutations in the Forkhead Box transcription factor F1 (FOXF1) gene locus are frequently found in patients with alveolar capillary dysplasia with misalignment of pulmonary veins"

Establishes FOXF1 locus inactivation as the recurrent cause of ACDMPV. Tagged OTHER because this is the framing sentence of a mouse study rather than a human result reported by it.

ESRP1 (Candidate Gene)

Gene: ESRP1 hgnc:25966 relationship_type: UNKNOWN

Show evidence (1 reference)

PMID:27071622 PARTIAL Human Clinical

"in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV"

The authors themselves frame this as a single-family, potential implication, so the association is recorded as partial and disputed.

💊

Medical Actions

2

Lung transplantation

Action: organ transplantation Ontology label: Organ Transplantation NCIT:C15289

The only intervention that alters survival. Everything else is supportive, and the pulmonary hypertension is characteristically refractory to vasodilator therapy because the vascular bed is absent rather than constricted.

Mechanism Target:

INHIBITS Impaired Alveolar Gas Exchange — Transplant replaces the maldeveloped gas-exchange surface rather than addressing the FOXF1 lesion.

Show evidence (1 reference)

PMID:31199666 SUPPORT Other

"There are no effective treatments for ACDMPV other than lung transplant, and new therapeutic approaches are urgently needed."

Establishes transplant as the only effective treatment. Tagged OTHER because this is the framing sentence of a mouse study rather than a clinical result reported by it.

Nanoparticle STAT3 delivery (investigational)

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

Not a current therapy. Because FOXF1 drives neonatal lung angiogenesis through STAT3, nanoparticle delivery of STAT3 has been proposed as a strategy for the subset of ACDMPV with reduced STAT3 signalling. This is preclinical and mechanism-directed rather than supportive, which is what makes it notable in a disease whose only other option is transplant.

Mechanism Target:

ACTIVATES Failed Pulmonary Microvascular Angiogenesis — Restoring STAT3 signalling aims to reactivate the angiogenic programme that the FOXF1 lesion silenced.

Show evidence (1 reference)

PMID:31199666 PARTIAL Model Organism

"Nanoparticle delivery of STAT3 is a promising strategy to treat ACDMPV associated with decreased STAT3 signaling."

Identifies the candidate therapeutic direction; the evidence is preclinical mouse work, not clinical.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Alveolar capillary dysplasia with misalignment of pulmonary veins:

Idiopathic pulmonary arterial hypertension Not Yet Curated MONDO:0001999

Overlapping Features The differential that matters most in practice. ACDMPV presents as severe neonatal pulmonary hypertension refractory to vasodilators, which is exactly how idiopathic pulmonary hypertension looks at the bedside, and because confirmation requires lung biopsy or autopsy the misattribution both delays diagnosis and hides cases from incidence estimates.

Distinguishing Features

Misaligned pulmonary veins and a deficient, malpositioned alveolar capillary bed on lung histology
A pathogenic FOXF1 coding variant or 16q24.1 deletion spanning the gene or its upstream enhancer
Associated gastrointestinal, cardiovascular or urogenital malformations in up to 80% of cases

Show evidence (1 reference)

PMID:30058937 SUPPORT Human Clinical

"it is likely that ACD/MPV is underdiagnosed and sometimes misdiagnosed as idiopathic PH due to the lack of autopsies"

Documents the misdiagnosis directly and its effect on ascertainment.

{ }

Source YAML

click to show

name: Alveolar capillary dysplasia with misalignment of pulmonary veins
creation_date: "2026-08-01T05:14:29Z"
description: >-
  Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a
  lethal congenital lung developmental disorder caused by loss of the mesenchymal
  transcription factor FOXF1 or of its distant upstream lung enhancer. The
  alveolar capillary bed fails to form and appose itself to the alveolar
  epithelium, and pulmonary veins run misplaced alongside the arteries in the
  bronchovascular bundle rather than in the interlobular septa. Term infants
  present within hours to days with refractory hypoxaemia and suprasystemic
  pulmonary hypertension. Two features make it unusual among Mendelian disorders:
  the causal lesion is very often a deletion of a non-coding enhancer rather than
  of the gene itself, and the pathogenic events are overwhelmingly de novo on the
  maternally inherited chromosome, implicating genomic imprinting.
category: Mendelian
parents:
- congenital lung disorder
- autosomal dominant disease
synonyms:
- ACDMPV
- ACD/MPV
- alveolar capillary dysplasia
- congenital alveolar capillary dysplasia
disease_term:
  preferred_term: alveolar capillary dysplasia with misalignment of pulmonary veins
  term:
    id: MONDO:0009934
    label: alveolar capillary dysplasia with misalignment of pulmonary veins
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    ACDMPV results from heterozygous point mutations or deletion copy-number
    variants at the FOXF1 locus, so inheritance is formally autosomal dominant,
    but essentially all cases are de novo and parental transmission is
    exceptional given the lethality.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: "Essentially all reported cases are de novo"
  parent_of_origin_effect: >-
    Maternal-allele bias from imprinting of the FOXF1 locus in lung: 30 of 31
    parentally resolved pathogenic 16q24.1 deletions arose on the maternally
    inherited chromosome 16. Four families with pathogenic paternal-chromosome
    lesions are known, so the imprint is not absolute.
  evidence:
  - reference: PMID:27071622
    reference_title: "Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082."
    explanation: >-
      Establishes heterozygous coding and enhancer lesions at the FOXF1 locus as
      the cause, including the long non-coding RNA enhancer element.
pathophysiology:
- name: FOXF1 Coding or Upstream Enhancer Lesion
  biological_scale: MOLECULAR
  description: >-
    The causal lesion is either a heterozygous point mutation in FOXF1 itself or,
    frequently, a deletion of the distant upstream enhancer region at 16q24.1
    that contains the fetal lung-expressed long non-coding RNA genes LINC01081
    and LINC01082. The enhancer route is what makes exome-only testing an
    incomplete strategy here: the coding sequence can be entirely normal while
    the gene is functionally silenced in lung.
  genes:
  - preferred_term: FOXF1
    term:
      id: hgnc:3809
      label: FOXF1
  evidence:
  - reference: PMID:27071622
    reference_title: "Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients."
    explanation: >-
      Documents the deletion copy-number variant class at the FOXF1 locus in a
      large ACDMPV series.
  downstream:
  - target: Loss of Mesenchymal FOXF1 Transcriptional Output
    description: >-
      Either lesion class reduces FOXF1 protein available to drive its
      transcriptional programme in lung mesenchyme.
- name: Genomic Imprinting of the FOXF1 Locus
  biological_scale: MOLECULAR
  description: >-
    A striking parent-of-origin effect: of 31 pathogenic 16q24.1 deletions with
    determined parental origin, all arose de novo and 30 were on the maternally
    inherited chromosome 16. The paternal allele appears to be silenced in human
    lung, so only a maternally inherited hit removes the expressed copy. A small
    number of paternal-chromosome cases exist, so the imprint is not absolute.
    This also explains why maternal uniparental disomy 16 shares key phenotypic
    features.
  evidence:
  - reference: PMID:27071622
    reference_title: "Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs"
    explanation: >-
      Quantifies the parent-of-origin skew that implicates imprinting at the
      FOXF1 locus.
  - reference: PMID:27071622
    reference_title: "Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16."
    explanation: >-
      Qualifies the imprinting model: a minority of pathogenic lesions arise on
      the paternal chromosome, so silencing is incomplete.
  downstream:
  - target: FOXF1 Coding or Upstream Enhancer Lesion
    description: >-
      The imprint gates the lesion rather than following from it: silencing of
      the paternal allele in lung is what makes a maternally inherited hit
      sufficient to cause disease.
  - target: Loss of Mesenchymal FOXF1 Transcriptional Output
    description: >-
      A maternally inherited lesion removes the transcriptionally active copy in
      lung.
- name: Loss of Mesenchymal FOXF1 Transcriptional Output
  biological_scale: CELLULAR
  description: >-
    FOXF1 is expressed in lung mesenchyme and endothelium and drives the
    angiogenic programme that builds the pulmonary microvasculature. Mouse
    haploinsufficiency reproduces alveolar capillary dysplasia together with
    intestinal and gall bladder maldevelopment, matching the extrapulmonary
    anomalies seen in patients.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:25091710
    reference_title: "FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice, haploinsufficiency of the Foxf1 gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal, and gall bladder morphogenesis."
    explanation: >-
      Model-organism evidence that FOXF1 dosage reduction is sufficient to cause
      the pulmonary and extrapulmonary phenotype.
  - reference: PMID:25091710
    reference_title: "FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells."
    explanation: >-
      Identifies VEGF signalling in endothelium as the transcriptional output
      through which FOXF1 builds the vasculature.
  downstream:
  - target: Failed Pulmonary Microvascular Angiogenesis
    description: >-
      Loss of the FOXF1-driven angiogenic programme prevents formation of the
      alveolar capillary network.
  - target: Misalignment of Pulmonary Veins
    description: >-
      The same mesenchymal patterning programme positions the pulmonary veins,
      so its loss misplaces them into the bronchovascular bundle.
- name: Failed Pulmonary Microvascular Angiogenesis
  biological_scale: TISSUE
  description: >-
    The alveolar capillary bed fails to form in adequate density and, critically,
    fails to appose itself to the alveolar epithelium. FOXF1 acts through STAT3
    to drive neonatal lung angiogenesis, and a knock-in mouse carrying the human
    S52F FOXF1 mutation recapitulates the histopathology, establishing that a
    single patient allele is sufficient.
  biological_processes:
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: DECREASED
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:31199666
    reference_title: "The S52F FOXF1 Mutation Inhibits STAT3 Signaling and Causes Alveolar Capillary Dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "FOXF1 acts through STAT3 to stimulate neonatal lung angiogenesis."
    explanation: >-
      Identifies STAT3 as the signalling intermediary through which FOXF1 drives
      neonatal lung angiogenesis.
  - reference: PMID:31199666
    reference_title: "The S52F FOXF1 Mutation Inhibits STAT3 Signaling and Causes Alveolar Capillary Dysplasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated a clinically relevant mouse model of ACDMPV by introducing the S52F FOXF1 mutation into the mouse Foxf1 gene locus using CRISPR/Cas9 technology."
    explanation: >-
      Establishes a knock-in model carrying an actual patient allele rather than
      a generic null.
  downstream:
  - target: Impaired Alveolar Gas Exchange
    description: >-
      A capillary bed that is sparse and not apposed to alveolar epithelium
      cannot support gas exchange.
  - target: Increased Pulmonary Vascular Resistance
    description: >-
      An absent distal capillary bed and abnormally muscularized arterioles raise
      resistance across the pulmonary circulation.
- name: Misalignment of Pulmonary Veins
  biological_scale: TISSUE
  description: >-
    The eponymous and diagnostically decisive lesion: pulmonary veins run
    anomalously within the bronchovascular bundle alongside the arteries, instead
    of in the interlobular septa where they belong. It is a patterning failure of
    the same mesenchymal programme, and it is what a pathologist looks for to
    confirm the diagnosis on lung biopsy or at autopsy.
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the majority of ACD/MPV patients present with peripheral veins in the bronchovascular bundle adjacent to the pulmonary arteries outside the interlobular septa while normally they are located within the septa"
    explanation: >-
      States the misalignment lesion directly, including the normal comparator,
      rather than implying it from a general definition of the disorder.
- name: Impaired Alveolar Gas Exchange
  biological_scale: ORGANISM
  description: >-
    Because the capillaries are neither numerous enough nor close enough to the
    alveolar epithelium, the diffusion barrier is effectively unusable. This
    produces the refractory hypoxaemia that does not respond to ventilation or
    oxygen, and is the reason ACDMPV is fatal without transplant.
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these scanty alveolar capillaries are located away from the alveolar epithelium"
    explanation: >-
      The decisive histological fact for gas exchange: the capillaries that do
      form are not apposed to the alveolar epithelium.
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is characterized by respiratory distress and cyanosis caused by severe pulmonary hypertension (PH) and insufficient oxygen uptake"
    explanation: >-
      Human clinical description of the presenting picture, replacing a
      background sentence previously borrowed from a mouse study.
- name: Increased Pulmonary Vascular Resistance
  biological_scale: ORGANISM
  conforms_to: "pulmonary_vascular_remodeling#Increased Pulmonary Vascular Resistance"
  description: >-
    ACDMPV enters the conserved pulmonary hypertension pathway at this node
    rather than at its usual trigger. In the module, raised resistance follows
    obstructive remodeling of a vascular bed that formed normally and then
    degenerated; in ACDMPV the distal bed was never built, so the substitution is
    developmental absence in place of acquired obstruction, with muscularized
    arterioles compounding it.
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the walls of small peripheral pulmonary arteries are thickened due to hypertrophic smooth muscle cells in the media"
    explanation: >-
      Human histological evidence for the arteriolar muscularization that
      compounds the resistance rise; the resistance measurement itself is
      supplied by the conserved module, hence PARTIAL.
  downstream:
  - target: Suprasystemic Pulmonary Arterial Hypertension
    description: >-
      Raised resistance across an absent distal bed drives pulmonary artery
      pressure above systemic.
- name: Suprasystemic Pulmonary Arterial Hypertension
  biological_scale: ORGANISM
  conforms_to: "pulmonary_vascular_remodeling#Pulmonary Arterial Hypertension"
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  description: >-
    Severe, typically suprasystemic pulmonary arterial hypertension with
    right-to-left shunting, presenting within hours to days of birth in a term
    infant and characteristically refractory to inhaled nitric oxide and other
    pulmonary vasodilators, because the problem is a missing vascular bed rather
    than a constricted one.
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The vast majority succumb to hypoxemic respiratory failure within days to weeks after presentation despite receiving supportive care including extracorporeal membrane oxygenation"
    explanation: >-
      Human outcome data showing that maximal supportive care, including ECMO,
      does not overcome the physiology.
phenotypes:
- name: Pulmonary arterial hypertension
  category: Cardiovascular
  description: >-
    Severe, typically suprasystemic pulmonary hypertension presenting in the
    neonatal period and refractory to standard pulmonary vasodilator therapy.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "respiratory distress and cyanosis caused by severe pulmonary hypertension (PH) and insufficient oxygen uptake"
    explanation: >-
      Human clinical description establishing severe pulmonary hypertension as
      the presenting physiology.
- name: Neonatal respiratory distress
  category: Respiratory
  description: >-
    Refractory hypoxaemic respiratory failure in a term infant, usually within
    the first hours to days of life and typically after a deceptively normal
    initial period.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most patients develop symptoms within the first 24 h of life"
    explanation: >-
      Quantifies onset timing in human patients.
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ninety-five percent of ACD/MPV patients are born at full term with normal birth weights and Apgar scores"
    explanation: >-
      Establishes that affected infants are typically term with normal birth
      parameters, which is why the deterioration is so unexpected.
- name: Hypoplastic left ventricle
  category: Cardiovascular
  description: >-
    Severe cardiac defects including hypoplastic left heart occur specifically in
    the subgroup whose deletion removes both FOXF1 and its upstream enhancer,
    making the cardiac phenotype a marker of lesion extent rather than a general
    feature.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypoplastic left ventricle
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  evidence:
  - reference: PMID:27071622
    reference_title: "Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer"
    explanation: >-
      Establishes the genotype restriction of the severe cardiac phenotype to
      deletions spanning both gene and enhancer.
- name: Single umbilical artery
  category: Cardiovascular
  description: >-
    Seen together with the severe cardiac defects in the same enhancer-spanning
    deletion subgroup, and detectable prenatally.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Single umbilical artery
    term:
      id: HP:0001195
      label: Single umbilical artery
  evidence:
  - reference: PMID:27071622
    reference_title: "Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer"
    explanation: >-
      Documents single umbilical artery as part of the enhancer-deletion
      phenotype.
- name: Intestinal malrotation
  category: Gastrointestinal
  description: >-
    Gastrointestinal anomalies including malrotation accompany the pulmonary
    disease, consistent with the role of FOXF1 in intestinal as well as lung
    mesenchymal development.
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "These malformations predominantly affect the gastrointestinal tract, but also affect the cardiovascular and urogenital system."
    explanation: >-
      Human cohort evidence that associated malformations are predominantly
      gastrointestinal; the specific malrotation phenotype is not named
      directly, hence PARTIAL.
genetic:
- name: FOXF1
  gene_term:
    preferred_term: FOXF1
    term:
      id: hgnc:3809
      label: FOXF1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    A forkhead box transcription factor expressed in lung mesenchyme and
    endothelium. Both coding point mutations and 16q24.1 deletion copy-number
    variants cause ACDMPV, and the deletions frequently spare the gene entirely
    while removing its upstream enhancer. The locus is imprinted in human lung,
    so parent of origin governs whether a lesion is pathogenic.
  evidence:
  - reference: PMID:25091710
    reference_title: "FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inactivating mutations in the Forkhead Box transcription factor F1 (FOXF1) gene locus are frequently found in patients with alveolar capillary dysplasia with misalignment of pulmonary veins"
    explanation: >-
      Establishes FOXF1 locus inactivation as the recurrent cause of ACDMPV.
      Tagged OTHER because this is the framing sentence of a mouse study rather
      than a human result reported by it.
- name: ESRP1
  gene_term:
    preferred_term: ESRP1
    term:
      id: hgnc:25966
      label: ESRP1
  association: Candidate Gene
  relationship_type: UNKNOWN
  notes: >-
    A single de novo missense variant reported in one ACDMPV family, raising the
    possibility of FGF signalling involvement. Recorded as UNKNOWN rather than
    DISPUTED: nobody has actively contested it, it is simply unreplicated, which
    corresponds to a ClinGen Limited rather than Disputed classification. The
    candidacy is weaker than a single variant implies, since ESRP1 was one of
    four de novo variants in that same proband and the authors declined to
    exclude any of them.
  evidence:
  - reference: PMID:27071622
    reference_title: "Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV"
    explanation: >-
      The authors themselves frame this as a single-family, potential
      implication, so the association is recorded as partial and disputed.
histopathology:
- name: Reduced and malpositioned alveolar capillaries
  description: >-
    The diagnostic microscopic picture: diffuse thickening of the interalveolar
    septa with a marked reduction in alveolar capillaries, and the few
    capillaries that are present sitting away from the alveolar epithelium,
    which is itself composed predominantly of hyperplastic cuboidal type 2
    pneumocytes rather than the flattened type 1 cells needed for gas exchange.
  diagnostic: true
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the lung tissue is characterized by diffuse thickening of interalveolar septa and marked reduction of pulmonary alveolar capillaries"
    explanation: >-
      The core histological finding on which the diagnosis rests.
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these scanty alveolar capillaries are located away from the alveolar epithelium which is predominantly composed of hyperplastic cuboidal type 2 pneumocytes"
    explanation: >-
      Documents both the malposition of the capillaries and the type 2
      pneumocyte hyperplasia of the overlying epithelium.
- name: Muscularized peripheral pulmonary arteries
  description: >-
    The walls of small peripheral pulmonary arteries are thickened by
    hypertrophic medial smooth muscle, the structural correlate of the raised
    pulmonary vascular resistance.
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the walls of small peripheral pulmonary arteries are thickened due to hypertrophic smooth muscle cells in the media"
    explanation: >-
      Histological basis for the arteriolar contribution to raised resistance.
- name: Misaligned pulmonary veins in the bronchovascular bundle
  description: >-
    Pulmonary veins sit in the bronchovascular bundle beside the arteries
    instead of within the interlobular septa. This is the eponymous finding and
    what a pathologist looks for to confirm the diagnosis.
  diagnostic: true
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the majority of ACD/MPV patients present with peripheral veins in the bronchovascular bundle adjacent to the pulmonary arteries outside the interlobular septa while normally they are located within the septa"
    explanation: >-
      Defines the misalignment lesion against its normal comparator.
prevalence:
- population: Manitoba, Canada (autopsy-based)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.0
  notes: >-
    Estimated from two ACD/MPV cases among 226 infants autopsied over ten years
    against 170,000 deliveries. An independent Dutch estimate gives 1/200,000,
    and both are likely underestimates: diagnosis requires autopsy or biopsy,
    and the review notes the disorder is underdiagnosed and sometimes
    misdiagnosed as idiopathic pulmonary hypertension.
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on this study, the incidence can be estimated at approximately 1/100,000."
    explanation: >-
      The autopsy-based Manitoba incidence estimate.
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "In The Netherlands, the incidence can be estimated at 1/200,000"
    explanation: >-
      An independent national estimate, roughly half the Manitoba figure,
      illustrating the ascertainment uncertainty.
progression:
- phase: Neonatal presentation and death
  notes: >-
    Term infants with normal birth parameters deteriorate within the first day
    of life and almost all die within days to weeks of hypoxaemic respiratory
    failure, despite maximal support including ECMO. Atypical milder cases
    presenting after 24 hours or surviving beyond the neonatal period are
    sporadically described.
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Irrespective of the co-morbidities, the mortality of ACD/MPV is almost 100%."
    explanation: >-
      The defining prognostic fact of the disorder.
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The vast majority succumb to hypoxemic respiratory failure within days to weeks after presentation despite receiving supportive care including extracorporeal membrane oxygenation"
    explanation: >-
      Establishes the mode and timing of death and the failure of maximal
      supportive care.
diagnosis:
- name: Lung biopsy histopathology
  description: >-
    Definitive diagnosis rests on lung histology showing the misaligned pulmonary
    veins within bronchovascular bundles together with a deficient, poorly
    apposed alveolar capillary bed. Historically this was made at autopsy; open
    lung biopsy is used antemortem when the diagnosis would change management.
  diagnosis_term:
    preferred_term: lung biopsy
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The current gold standard to unambiguously diagnose ACD/MPV is histological examination of the lungs."
    explanation: >-
      States the diagnostic gold standard directly, replacing a sentence about
      the review's own structure.
- name: Molecular testing including copy-number analysis
  description: >-
    Molecular confirmation requires sequencing FOXF1 together with copy-number
    analysis spanning the upstream enhancer region. Sequencing alone will miss
    the substantial fraction of patients whose lesion is an enhancer deletion
    leaving the coding sequence intact.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:27071622
    reference_title: "Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV."
    explanation: >-
      Documents the combined copy-number and sequencing strategy required to
      detect both lesion classes.
treatments:
- name: Lung transplantation
  description: >-
    The only intervention that alters survival. Everything else is supportive,
    and the pulmonary hypertension is characteristically refractory to
    vasodilator therapy because the vascular bed is absent rather than
    constricted.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Impaired Alveolar Gas Exchange
    treatment_effect: INHIBITS
    description: >-
      Transplant replaces the maldeveloped gas-exchange surface rather than
      addressing the FOXF1 lesion.
  evidence:
  - reference: PMID:31199666
    reference_title: "The S52F FOXF1 Mutation Inhibits STAT3 Signaling and Causes Alveolar Capillary Dysplasia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There are no effective treatments for ACDMPV other than lung transplant, and new therapeutic approaches are urgently needed."
    explanation: >-
      Establishes transplant as the only effective treatment. Tagged OTHER
      because this is the framing sentence of a mouse study rather than a
      clinical result reported by it.
- name: Nanoparticle STAT3 delivery (investigational)
  description: >-
    Not a current therapy. Because FOXF1 drives neonatal lung angiogenesis
    through STAT3, nanoparticle delivery of STAT3 has been proposed as a strategy
    for the subset of ACDMPV with reduced STAT3 signalling. This is preclinical
    and mechanism-directed rather than supportive, which is what makes it notable
    in a disease whose only other option is transplant.
  treatment_term:
    preferred_term: therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Failed Pulmonary Microvascular Angiogenesis
    treatment_effect: ACTIVATES
    description: >-
      Restoring STAT3 signalling aims to reactivate the angiogenic programme that
      the FOXF1 lesion silenced.
  evidence:
  - reference: PMID:31199666
    reference_title: "The S52F FOXF1 Mutation Inhibits STAT3 Signaling and Causes Alveolar Capillary Dysplasia."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Nanoparticle delivery of STAT3 is a promising strategy to treat ACDMPV associated with decreased STAT3 signaling."
    explanation: >-
      Identifies the candidate therapeutic direction; the evidence is preclinical
      mouse work, not clinical.
differential_diagnoses:
- name: Idiopathic pulmonary arterial hypertension
  description: >-
    The differential that matters most in practice. ACDMPV presents as severe
    neonatal pulmonary hypertension refractory to vasodilators, which is exactly
    how idiopathic pulmonary hypertension looks at the bedside, and because
    confirmation requires lung biopsy or autopsy the misattribution both delays
    diagnosis and hides cases from incidence estimates.
  disease_term:
    preferred_term: idiopathic pulmonary arterial hypertension
    term:
      id: MONDO:0001999
      label: idiopathic pulmonary arterial hypertension
  distinguishing_features:
  - Misaligned pulmonary veins and a deficient, malpositioned alveolar capillary bed on lung histology
  - A pathogenic FOXF1 coding variant or 16q24.1 deletion spanning the gene or its upstream enhancer
  - Associated gastrointestinal, cardiovascular or urogenital malformations in up to 80% of cases
  evidence:
  - reference: PMID:30058937
    reference_title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is likely that ACD/MPV is underdiagnosed and sometimes misdiagnosed as idiopathic PH due to the lack of autopsies"
    explanation: >-
      Documents the misdiagnosis directly and its effect on ascertainment.
discussions:
- discussion_id: gap_acdmpv_imprinting_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What silences the paternal FOXF1 allele in human lung, and why do a minority
    of pathogenic lesions on the paternal chromosome still cause ACDMPV?
  attaches_to:
  - pathophysiology#Genomic Imprinting of the FOXF1 Locus
  rationale: >-
    Thirty of thirty-one parentally resolved deletions arose on the maternal
    chromosome, which is a strong imprinting signal, yet four families carry
    pathogenic paternal-chromosome lesions. So the paternal allele is neither
    fully silenced nor fully active. The imprinting control element, the tissue
    and developmental window over which it operates, and what determines
    escape are all unresolved. This matters practically because it governs
    recurrence counselling and the interpretation of an apparently benign
    paternal deletion found incidentally.
  proposed_experiments:
  - experiment_id: exp_acdmpv_allele_specific_lung_expression
    name: Allele-specific FOXF1 expression across human fetal lung development
    description: >-
      Perform allele-specific expression and methylation profiling across the
      16q24.1 locus in human fetal lung at successive gestational ages, in
      parallel with the same measurements in intestine and heart, to map where
      and when the imprint is established and whether escape correlates with
      lesion position relative to the enhancer.
    decision_criterion: >-
      A developmental window or lesion-position dependence that separates the
      four paternal cases from the maternal majority would define the escape
      condition.
    would_support:
    - Paternal silencing is partial and window-dependent, so paternal lesions cause disease when they remove enhancer sequence needed by both alleles
    would_refute:
    - Paternal silencing is uniform, implicating a second modifier locus in the escape cases
- discussion_id: gap_acdmpv_developmental_window_for_rescue
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is there any postnatal window in which restoring FOXF1 or STAT3 signalling
    can build a functional alveolar capillary bed, or is the defect fixed before
    birth?
  attaches_to:
  - pathophysiology#Failed Pulmonary Microvascular Angiogenesis
  - pathophysiology#Impaired Alveolar Gas Exchange
  rationale: >-
    The STAT3 nanoparticle strategy presupposes that neonatal lung angiogenesis
    is still tractable after birth, and FOXF1 is described as stimulating
    neonatal rather than purely fetal angiogenesis, which is encouraging. But
    ACDMPV also involves a fixed architectural error, the misalignment of the
    pulmonary veins, which no angiogenic stimulus can re-route. Whether restoring
    capillary density in a lung with misaligned veins yields usable gas exchange
    is the question that determines whether any medical therapy is possible at
    all, or whether transplant will remain the only option.
  proposed_experiments:
  - experiment_id: exp_acdmpv_postnatal_rescue_window
    name: Staged postnatal STAT3 restoration in the Foxf1 S52F knock-in mouse
    description: >-
      Deliver STAT3 to Foxf1 S52F knock-in mice at a series of postnatal
      timepoints and measure capillary density, capillary-to-epithelium
      apposition, venous position, pulmonary artery pressure and survival, to
      establish whether a rescue window exists and whether corrected capillary
      density is sufficient without corrected venous anatomy.
    decision_criterion: >-
      Survival benefit with restored gas exchange despite persistent venous
      misalignment would show the capillary deficit is the rate-limiting lesion.
    would_support:
    - Capillary density is rate-limiting and postnatal angiogenic rescue is viable
    would_refute:
    - Venous misalignment alone sustains lethal physiology, confining treatment to transplant
references:
- reference: PMID:27071622
  title: "Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins"
- reference: PMID:30058937
  title: "Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects"

📚

References & Deep Research

References

2

PMID:27071622

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

No top-level findings curated for this source.

PMID:30058937

Alveolar capillary dysplasia with misalignment of the pulmonary veins: clinical, histological, and genetic aspects

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 27 citations 2026-08-01T13:31:32.733042

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

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

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

Disease Characteristics Research Template

Target Disease

Disease Name: Alveolar capillary dysplasia with misalignment of pulmonary veins
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Alveolar capillary dysplasia with misalignment of pulmonary veins covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV)

Executive summary

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is an ultra-rare, congenital developmental disorder of the pulmonary microvasculature and alveolar gas-exchange unit. Most affected infants develop cyanosis, profound hypoxemia, persistent pulmonary hypertension, and respiratory failure within hours to two days after birth. Typical disease is resistant to mechanical ventilation, pulmonary vasodilators, and extracorporeal membrane oxygenation (ECMO), and is usually fatal in the neonatal period. A minority have patchy or atypical disease with delayed presentation and may survive long enough for bilateral lung transplantation. Human genetic evidence establishes heterozygous loss of FOXF1 function—through coding variants, gene deletions, or deletion/disruption of its distant regulatory region at chromosome 16q24.1—as the principal cause. The major recent advance is a 2023 human single-cell RNA/ATAC study showing that FOXF1 insufficiency depletes pulmonary CAP1/CAP2 endothelial progenitors, pericytes, and mature capillary endothelium, secondarily disrupting alveolar epithelial differentiation and expanding systemic bronchial-type vessels. (guo2023singlecellmultiomics pages 2-3, guo2023singlecellmultiomics pages 1-2, guo2023singlecellmultiomics pages 4-6)

domain	established finding	evidence type/strength	key quantitative detail	suggested ontology terms
Identifiers	ACDMPV is a rare, usually lethal developmental lung disorder caused by FOXF1 insufficiency; MIM noted as 265380 in recent primary literature. Synonym: alveolar capillary dysplasia / alveolar capillary dysplasia with misalignment of pulmonary veins.	Human primary genetics + human single-cell multiomics; strong (landmark + recent) (guo2023singlecellmultiomics pages 1-2, stankiewicz2009genomicandgenic pages 1-2)	~200 cases reported in 2009 literature; >80% with additional malformations in early series (stankiewicz2009genomicandgenic pages 1-2)	MONDO: alveolar capillary dysplasia with misalignment of pulmonary veins; MeSH/ICD terms not confirmed from gathered evidence
Cause	Primary cause is germline FOXF1 haploinsufficiency due to heterozygous SNVs/indels, gene deletions, or noncoding/enhancer-region CNVs at 16q24.1.	Human primary genetics; very strong (landmark AJHG + replication) (stankiewicz2009genomicandgenic pages 6-8, kozłowska2020genotype–phenotypecorrelationin pages 1-2, sen2013novelfoxf1mutations pages 10-13)	>100 pathogenic SNVs and >70 CNV deletions reported by 2023 review of primary cases (guo2023singlecellmultiomics pages 1-2)	HGNC: FOXF1; SO: copy_number_loss, nonsense_variant, frameshift_variant, missense_variant, regulatory_region_variant
Regulatory genetics	Disease can result from deletions sparing FOXF1 coding sequence but removing a distant enhancer; LINC01081 positively regulates FOXF1; evidence supports partial paternal imprinting and maternal-origin pathogenic deletions.	Human primary molecular genetics; strong (szafranski2014twodeletionsoverlapping pages 3-5, szafranski2014twodeletionsoverlapping pages 5-6)	Two de novo maternal chr16 deletions; ~75 kb enhancer region implicated; severity varied with enhancer/LINC01081 involvement (szafranski2014twodeletionsoverlapping pages 5-6)	Sequence Ontology: enhancer_variant; Gene: LINC01081; GO: regulation of transcription by RNA polymerase II
Core presentation	Typical presentation is neonatal cyanosis, severe pulmonary hypertension, and hypoxemic respiratory failure shortly after birth, often within 48 hours, refractory to therapy.	Human clinical/pathology literature; strong (guo2023singlecellmultiomics pages 2-3, kozłowska2020genotype–phenotypecorrelationin pages 1-2, stankiewicz2009genomicandgenic pages 1-2)	Death usually in days to weeks/months; first month emphasized in landmark cohort (stankiewicz2009genomicandgenic pages 1-2)	HPO: Cyanosis, Pulmonary hypertension, Respiratory failure, Persistent pulmonary hypertension of the newborn
Core phenotypes	Frequent associated anomalies involve gastrointestinal, cardiovascular, and genitourinary systems; examples include intestinal malrotation, hypoplastic left heart/aortic arch lesions, omphalocele, hydronephrosis, ASD/VSD, hepatosplenomegaly.	Human case series/case reports; moderate-strong (kozłowska2020genotype–phenotypecorrelationin pages 2-4, kozłowska2020genotype–phenotypecorrelationin pages 1-2, stankiewicz2009genomicandgenic pages 1-2)	>80% had additional malformations in early series (stankiewicz2009genomicandgenic pages 1-2)	HPO: Intestinal malrotation, Omphalocele, Hydronephrosis, Atrial septal defect, Ventricular septal defect, Hepatosplenomegaly
Histopathology	Hallmarks are misaligned pulmonary veins adjacent to bronchioles, medial hyperplasia of small pulmonary arteries, thickened/widened alveolar septa, paucity/mislocalization of capillaries, lobular simplification/underdevelopment, and sometimes lymphangiectasis.	Human pathology + genetics; very strong (stankiewicz2009genomicandgenic pages 6-8, kozłowska2020genotype–phenotypecorrelationin pages 2-4, guo2023singlecellmultiomics pages 2-3)	In landmark 2009 series, 10/10 reviewed lungs showed characteristic changes; pulmonary lymphangiectasis seen in all 4 deletion cases and 1/4 mutation cases examined (stankiewicz2009genomicandgenic pages 6-8)	HPO: Misalignment of pulmonary veins, Decreased pulmonary capillaries, Thickened alveolar septa; UBERON: lung, pulmonary vein, pulmonary arteriole
Mechanism / causal chain	FOXF1 loss disrupts endothelial/pericyte developmental programs, preventing CAP1-to-CAP2 maturation and pulmonary vasculogenesis; reduced alveolar microvasculature impairs epithelial-mesenchymal signaling and AT1 differentiation, producing gas-exchange failure and severe PH.	Human single-nucleus RNA/ATAC multiomics; very strong recent mechanistic evidence (guo2023singlecellmultiomics pages 1-2, guo2023singlecellmultiomics pages 4-6, guo2023singlecellmultiomics pages 13-15, guo2023singlecellmultiomics pages 3-4)	6 subjects analyzed; 35 cell types identified; 32,300 ACDMPV nuclei profiled; CAP2 reduction correlated with severity (guo2023singlecellmultiomics pages 3-4, guo2023singlecellmultiomics pages 4-6)	GO: vasculogenesis, angiogenesis, endothelial cell differentiation, epithelial cell differentiation, cell-cell signaling; CL: capillary endothelial cell, pericyte, fibroblast, alveolar type 1 cell, alveolar type 2 cell
Molecular pathways	Downregulated/perturbed pathways include PTEN, ERK/MAPK, STAT3, FAK, integrin, WNT/β-catenin, ID1, semaphorin, and Rho GTPase signaling; abnormal VEGFA signaling accompanies expansion of systemic bronchial-type ECs.	Human multiomics + supporting translational studies; strong (guo2023singlecellmultiomics pages 3-4, guo2023singlecellmultiomics pages 4-6, guo2023singlecellmultiomics pages 13-15, guo2023singlecellmultiomics pages 8-12)	61 genes downregulated in pericytes; 58.8% of predicted FOXF1 targets validated in integrated analysis (guo2023singlecellmultiomics pages 4-6)	GO/Pathways: MAPK cascade, STAT3 signaling, integrin signaling, Wnt signaling, VEGFA-VEGFR2 signaling, semaphorin-plexin signaling
Cell types / anatomy	Major affected cell populations are CAP1/CAP2 capillary ECs, pericytes, AF1 fibroblasts, and alveolar epithelial cells; compensatory COL15A1+ systemic/bronchial EC expansion occurs. Primary organ is lung, with secondary cardiovascular consequences from PH.	Human multiomics + pathology; strong (guo2023singlecellmultiomics pages 4-6, guo2023singlecellmultiomics pages 3-4, guo2023singlecellmultiomics pages 1-2)	FOXF1 RNA absent in CAP1/CAP2 in 3/5 ACDMPV subjects with severe disease (guo2023singlecellmultiomics pages 3-4)	CL: endothelial cell, pericyte, fibroblast, alveolar epithelial type 1 cell, alveolar epithelial type 2 cell; UBERON: alveolus, pulmonary capillary, bronchovascular bundle
Diagnosis	Gold standard remains lung histopathology from biopsy/autopsy; molecular confirmation uses FOXF1 sequencing plus deletion/duplication testing/CMA for coding and enhancer CNVs. CD31/CD34 immunostaining may help.	Human primary case reports/genetics; strong for pathology + moderate for testing workflow (kozłowska2020genotype–phenotypecorrelationin pages 2-4, kozłowska2020genotype–phenotypecorrelationin pages 1-2, szafranski2014twodeletionsoverlapping pages 5-6)	Two 2020 neonates had ~1.45 Mb and ~0.7 Mb deletions identified by array CGH; one spared FOXF1 coding region (kozłowska2020genotype–phenotypecorrelationin pages 2-4)	NCIT: Lung Biopsy, Autopsy, Array Comparative Genomic Hybridization; HPO: Abnormal lung histology
Differential diagnosis	Important clinical differential is persistent pulmonary hypertension of the newborn; developmental lung disease / childhood interstitial lung disease framework is relevant, but tissue/genetic confirmation distinguishes ACDMPV.	Human reviews/consensus + cited genetics literature; moderate (sen2013novelfoxf1mutations pages 10-13)	No validated biomarker-only diagnostic alternative identified in gathered evidence	HPO/NCIT: Persistent pulmonary hypertension of the newborn, Interstitial lung disease
Treatment	Standard supportive measures (mechanical ventilation, inhaled nitric oxide, prostaglandin E1 in selected congenital-heart contexts, surfactant, inotropes, ECMO) are usually temporizing and often ineffective; bilateral lung transplantation can be life-saving in atypical survivors.	Human case reports + expert consensus; moderate-strong (szafranski2014twodeletionsoverlapping pages 3-5, kozłowska2020genotype–phenotypecorrelationin pages 2-4, kozłowska2020genotype–phenotypecorrelationin pages 1-2)	One atypical patient underwent bilateral lung transplant at 15 months; recent multiomics cohort included transplants at 9 months and 3.5 years (szafranski2014twodeletionsoverlapping pages 3-5, guo2023singlecellmultiomics pages 2-3)	NCIT: Mechanical Ventilation, Nitric Oxide, Extracorporeal Membrane Oxygenation, Lung Transplantation
Prognosis	Prognosis is poor and usually fatal in infancy, but variable expressivity exists with atypical late presentation and prolonged survival in a minority, often culminating in transplantation.	Human case series + 2023 multiomics; strong (guo2023singlecellmultiomics pages 2-3, stankiewicz2009genomicandgenic pages 1-2, szafranski2014twodeletionsoverlapping pages 5-6)	Severe subjects died at 2–5 weeks in the 2023 cohort; atypical survivors reached 9 months, 15 months, or 3.5 years with transplantation (guo2023singlecellmultiomics pages 3-4, szafranski2014twodeletionsoverlapping pages 3-5, guo2023singlecellmultiomics pages 2-3)	HPO: Neonatal death, Respiratory insufficiency; NCIT: Overall Survival
Inheritance	Usually de novo, autosomal dominant by mechanism (heterozygous loss), with reported familial cases, variable expressivity, and evidence for parental-origin effects/partial paternal imprinting. Recurrence risk may be increased if parental mosaicism is present, though ACDMPV-specific mosaicism data are limited in gathered sources.	Human primary genetics + reproductive genetics inference; moderate (sen2013novelfoxf1mutations pages 10-13, szafranski2014twodeletionsoverlapping pages 5-6, xu2023parentalmosaicismdetection pages 1-1, xu2023parentalmosaicismdetection pages 6-6)	Early series estimated ~10% familial association; parental mosaicism study in other severe de novo disorders found sperm mosaicism in 2/10 families at 2.88% and 2.5% VAF (disease-nonspecific but relevant to counseling) (stankiewicz2009genomicandgenic pages 1-2, xu2023parentalmosaicismdetection pages 4-5)	HP/GENO terms: De novo mutation, Autosomal dominant inheritance, Genomic imprinting, Germline mosaicism
Prenatal / reproductive testing	Prenatal detection is feasible when familial variant/CNV is known; preimplantation genetic testing and targeted prenatal diagnosis are conceptually applicable for recurrent de novo disorders and mosaicism risk.	Human reproductive genetics + disease-specific prenatal citation trail; moderate (xu2023parentalmosaicismdetection pages 1-1, xu2023parentalmosaicismdetection pages 4-5, kozłowska2020genotype–phenotypecorrelationin pages 7-7)	Deep targeted sequencing >5000× with ~0.5% VAF detection limit used for mosaicism detection in analogous severe DNM disorders (xu2023parentalmosaicismdetection pages 1-1)	NCIT: Prenatal Diagnosis, Preimplantation Genetic Testing, Genetic Counseling
Model / translational evidence	Mouse and integrated human-mouse data support FOXF1 roles in pulmonary endothelial and mesenchymal development; nanoparticle FOXF1 or STAT3 delivery to endothelial cells rescued pulmonary vasculogenesis in newborn mice (preclinical).	Preclinical translational evidence referenced within recent human mechanistic study; moderate (guo2023singlecellmultiomics pages 13-15, guo2023singlecellmultiomics pages 8-12)	Rescue described in newborn mice; no human interventional trial identified in gathered evidence (guo2023singlecellmultiomics pages 13-15)	NCIT: Gene Therapy; GO: lung development, vasculogenesis
Evidence gaps	No disease-specific interventional clinical trials were found; no robust prevalence/incidence estimates from registries were retrieved; no validated circulating biomarkers, proteomic/metabolomic signatures, spatial transcriptomics, natural animal disease, or established protective/environmental factors were identified from gathered evidence.	Evidence-gap assessment from available search results; moderate confidence	ClinicalTrials.gov search yielded no ACDMPV-specific interventional trial in gathered results	Terms as needed: Not available / evidence gap

Table: This compact table summarizes the strongest gathered evidence for alveolar capillary dysplasia with misalignment of pulmonary veins across clinical, genetic, mechanistic, diagnostic, prognostic, and translational domains. It is designed for rapid knowledge-base population with ontology suggestions and citation-backed findings.

Evidence framework

Evidence below is labeled as human clinical/pathology, human genetics, human multiomics, model organism/preclinical, or expert consensus. Most numerical estimates arise from small, selected case series rather than population registries. Consequently, percentages should not be interpreted as population-level penetrance or incidence.

1. Disease information

Definition and classification

ACDMPV is a congenital disorder of lung morphogenesis characterized by deficient alveolar capillary development, abnormal localization of pulmonary veins beside pulmonary arteries and bronchioles, muscularization of small pulmonary arteries, and failure of effective alveolar–capillary gas exchange. Although traditionally grouped among childhood interstitial or diffuse developmental lung diseases, its dominant pathology is pulmonary vascular and alveolar developmental dysmaturity rather than inflammatory interstitial lung disease. The 2023 primary study calls it a “lethal developmental disorder of lung morphogenesis caused by insufficiency of FOXF1 transcription factor function.” (guo2023singlecellmultiomics pages 1-2)

Identifiers and synonyms

Resource	Identifier or preferred term	Qualification
OMIM	265380, Alveolar capillary dysplasia with misalignment of pulmonary veins	Confirmed in recent primary literature.
MONDO	Alveolar capillary dysplasia with misalignment of pulmonary veins; commonly mapped as MONDO:0012071	Database mapping should be revalidated at ingestion because ontology releases change.
Orphanet	ORPHA:210122, ACDMPV	Recommended database-level mapping; revalidate against current Orphanet release.
MeSH	No clearly disease-specific descriptor established in the retrieved evidence	Index through relevant concepts such as lung developmental abnormality/pulmonary hypertension.
ICD-10-CM	No specific ACDMPV code	Typically represented with congenital lung-malformation and pulmonary-hypertension codes; coding is jurisdiction dependent.
ICD-11	No disease-specific code confirmed in the retrieved material	Use the closest congenital lung/vascular-developmental category after local coding review.

Common names include ACDMPV, ACD/MPV, alveolar capillary dysplasia, congenital alveolar capillary dysplasia, and alveolar capillary dysplasia with misaligned pulmonary veins. “Misaligned pulmonary veins” is a historical pathologic description: the anomalous vessels in bronchovascular bundles may have a systemic/bronchial endothelial identity rather than simply representing normally specified pulmonary veins in the wrong position. (stankiewicz2009genomicandgenic pages 6-8, guo2023singlecellmultiomics pages 3-4)

Data provenance

The knowledge base is aggregated primarily from autopsy and biopsy series, molecular diagnostic cohorts, individual transplant cases, and small research tissue cohorts—not longitudinal EHR population data. The 2009 landmark study examined 14 molecularly characterized patients, with histology reviewed in 10; the 2023 multiomics study analyzed six affected subjects and profiled 32,300 affected-lung nuclei. (stankiewicz2009genomicandgenic pages 6-8, guo2023singlecellmultiomics pages 3-4)

2. Etiology, risks, protective factors, and gene–environment interaction

Primary causal factors

The established cause is germline FOXF1 haploinsufficiency or disruption of the FOXF1 regulatory domain at 16q24.1. Disease-producing changes include heterozygous nonsense, frameshift, missense/DNA-binding-domain, stop-loss, splice-disrupting or other inactivating variants; whole-gene or multigene deletions; and structural/regulatory variants deleting a distant lung enhancer while leaving the FOXF1 coding sequence intact. The original 2009 study identified overlapping 16q24 deletions and four heterozygous inactivating FOXF1 variants, establishing causality. (stankiewicz2009genomicandgenic pages 6-8, stankiewicz2009genomicandgenic pages 1-2)

Approximately 80–90% of histopathologically verified cases have a detectable FOXF1 coding or locus abnormality in several clinical summaries. By 2023, more than 100 pathogenic SNVs/indels and 70 CNV deletions had been reported. The remaining molecularly unresolved cases may reflect difficult-to-detect regulatory or structural variants, mosaicism, alternative developmental genes, or non-genetic phenocopies; absence of a detected FOXF1 variant does not exclude pathology-confirmed ACDMPV. (guo2023singlecellmultiomics pages 1-2, kozłowska2020genotype–phenotypecorrelationin pages 1-2)

Genetic risk factors

A heterozygous pathogenic FOXF1 or FOXF1-regulatory variant is a high-penetrance causal risk factor for severe developmental lung disease, but expressivity varies markedly.
Larger 16q24 deletions may encompass FOXC2, FOXL1, or neighboring regulatory elements and produce broader congenital-malformation phenotypes.
Two maternal-chromosome deletions that spared FOXF1 but overlapped an approximately 75-kb distant enhancer implicated both that enhancer and LINC01081, a lung-expressed lncRNA that positively regulates FOXF1. Additional LINC01081 disruption was associated with more severe disease in these two cases. (szafranski2014twodeletionsoverlapping pages 5-6)
Familial disease and variable severity within families demonstrate that variant position, enhancer activity, parent of origin, mosaicism, and other modifiers influence expression. No clinically validated modifier-gene panel currently predicts severity.

Environmental and demographic risks

No toxin, infection, maternal lifestyle, diet, occupation, sex, or postnatal exposure is established as a primary cause. A viral infection and high-altitude exposure preceded decompensation in one child with atypical, previously compensated disease; these are best regarded as physiological triggers that unmasked a congenital limitation, not causes of ACDMPV. (szafranski2014twodeletionsoverlapping pages 3-5)

There is no evidence that smoking, alcohol, nutrition, exercise, vaccination, or avoidance of pollution prevents FOXF1-related ACDMPV. No validated protective genetic allele exists. A 2024 preprint proposed that hyperfunctional enhancer variation may partially compensate for damaging FOXF1 alleles, but this remains investigational and is not a clinically established protective factor. (gomezarroyo2024roleofforkhead pages 11-13)

Gene–environment interaction

A defensible model is that FOXF1 dosage establishes a fixed developmental deficit, while oxygen demand, infection, surgery, altitude, or withdrawal of pulmonary-circulation support can precipitate clinical decompensation in partially compensated disease. Evidence is limited to cases and does not establish a quantitative interaction. In two neonates, surgery and cessation of prostaglandin E1 were temporally associated with deterioration, but causality was not proved. (kozłowska2020genotype–phenotypecorrelationin pages 2-4)

3. Phenotypes

Core pulmonary and cardiovascular phenotype

Phenotype	Type, timing, severity/course	Frequency evidence	Suggested HPO term
Persistent pulmonary hypertension	Clinical sign; congenital/neonatal, severe and rapidly progressive	Defining clinical feature in typical cases	Pulmonary hypertension, HP:0002092; persistent pulmonary hypertension of the newborn where locally available
Hypoxemia/cyanosis	Laboratory abnormality/sign; usually hours to ≤48 h after birth	Typical; may follow a short asymptomatic interval	Hypoxemia, HP:0012418; Cyanosis, HP:0000961
Respiratory distress/failure	Symptom/sign; severe, refractory, progressive	Typical disease is nearly universal and often fatal	Respiratory distress; Respiratory failure, HP:0002878
Abnormal alveolar development	Histopathologic manifestation; congenital	Defining pathology	Abnormal pulmonary alveolar morphology; alveolar simplification
Capillary paucity/malposition	Histopathologic manifestation; congenital	Defining pathology	Decreased number of pulmonary capillaries; abnormal pulmonary capillary morphology
Misalignment of pulmonary veins	Histopathologic manifestation	Characteristic but may be focal in atypical disease	Misalignment of pulmonary veins
Small pulmonary-artery medial hypertrophy	Histopathologic/vascular sign	Characteristic	Pulmonary arterial medial hypertrophy
Intrapulmonary right-to-left shunting	Functional vascular abnormality	Demonstrated in vascular studies	Intrapulmonary shunt

Histology comprises deficient lobular/alveolar development, widened septa with centrally located rather than apposed capillaries, reduced microvascular density, medial hypertrophy of small pulmonary arteries, and anomalous venous/systemic vessels within bronchovascular bundles. In the landmark molecular series, all 10/10 reviewed lungs showed characteristic abnormalities. Pulmonary lymphangiectasis occurred in 4/4 deletion cases and 1/4 coding-variant cases assessed, although these small denominators preclude firm genotype–phenotype conclusions. (stankiewicz2009genomicandgenic pages 6-8)

Extrapulmonary manifestations

More than 80% of patients in early compiled series had at least one additional malformation. Reported abnormalities include intestinal malrotation, omphalocele, congenital heart disease—including atrial or ventricular septal defects, coarctation/aortic-arch abnormalities and hypoplastic left heart—hydronephrosis and other genitourinary abnormalities, polyhydramnios, and hepatosplenomegaly. (kozłowska2020genotype–phenotypecorrelationin pages 2-4, stankiewicz2009genomicandgenic pages 1-2)

Suggested HPO terms include Intestinal malrotation (HP:0002566), Omphalocele (HP:0001539), Hydronephrosis (HP:0000126), Ventricular septal defect (HP:0001629), atrial septal defect, coarctation of the aorta, hypoplastic left heart, polyhydramnios, and hepatosplenomegaly. Frequencies for individual anomalies are not robustly established by modern population-based cohorts.

Quality of life

No ACDMPV-specific EQ-5D, SF-36, PROMIS, or validated caregiver quality-of-life dataset was found. In typical disease, intensive ventilation, sedation, ECMO, and early death dominate morbidity. Atypical survivors have severe pulmonary-hypertension and oxygen/ventilatory burdens and may undergo prolonged hospitalization and transplantation. Thus, functional and family impact is profound, but quantitative patient-reported outcomes are unavailable.

4. Genetic and molecular information

Causal gene

FOXF1 encodes forkhead box F1, a DNA-binding transcription factor expressed in pulmonary endothelial and mesenchymal progenitors, fibroblasts, and pericytes during organogenesis. Its dosage coordinates pulmonary vascular development, mesenchymal–epithelial communication, and maturation of the alveolar gas-exchange unit. Suggested annotation: HGNC:3815; chromosome 16q24.1; disease mechanism haploinsufficiency/loss of function. (guo2023singlecellmultiomics pages 1-2, guo2023singlecellmultiomics pages 13-15)

Variant interpretation

Pathogenic and likely pathogenic variants include truncating and functionally damaging coding changes and deletions affecting FOXF1 or its enhancer. Classification should follow ACMG/AMP sequence-variant criteria and ACMG/ClinGen CNV standards, incorporating de novo status, absence from population databases, predicted loss of function, phenotype/pathology specificity, and functional/regulatory data. Individual variants must be checked in current ClinVar and gnomAD releases; no universal allele frequency can be assigned. Fully penetrant neonatal-lethal variants are expected to be absent or exceptionally rare in adult population databases.

The variants are generally germline, not cancer-associated somatic mutations. Low-level parental somatic/germline mosaicism is possible and relevant to recurrence, although strong ACDMPV-specific frequency estimates are lacking. A disease-nonspecific 2023 study of ten recurrent-de-novo-disorder families found paternal sperm mosaicism in 2/10, at 2.88% and 2.5% variant allele fractions, illustrating why deep parental testing may be useful after recurrent affected pregnancies but not establishing an ACDMPV frequency. (xu2023parentalmosaicismdetection pages 1-1, xu2023parentalmosaicismdetection pages 4-5)

Regulatory and epigenetic architecture

Evidence supports partial paternal imprinting or parent-of-origin-biased FOXF1 regulation: many pathogenic enhancer deletions occur on the maternal chromosome, consistent with greater functional consequence when the more active allele is disrupted. This is not a simple binary imprinting system and should not be encoded as complete paternal silencing. The enhancer and LINC01081 contribute positively to FOXF1 expression. Two de novo maternal deletions produced strikingly different severity, suggesting that the exact regulatory segments removed influence residual dosage. (szafranski2014twodeletionsoverlapping pages 5-6)

No reproducible disease-specific genome-wide DNA-methylation, histone-mark, or chromatin biomarker has entered clinical practice. ATAC-seq evidence demonstrates altered cell-specific chromatin accessibility and FOXF1 regulatory networks, but it is mechanistic rather than diagnostic. (guo2023singlecellmultiomics pages 4-6, guo2023singlecellmultiomics pages 8-12)

Chromosomal abnormalities

Relevant abnormalities include 16q24.1 microdeletions encompassing FOXF1, deletions limited to the upstream enhancer, larger deletions including neighboring FOX genes, and rare inversions or complex structural rearrangements that separate FOXF1 from regulatory elements. Routine karyotyping can miss these submicroscopic or balanced events; chromosomal microarray and, where needed, genome sequencing are more appropriate.

5. Environmental information

No environmental toxin, radiation exposure, pollutant, occupational agent, lifestyle behavior, or infectious organism is established as etiologic. ACDMPV is not communicable and has no zoonotic component. Infection, altitude, anesthesia, surgery, or altered pulmonary blood flow may expose limited cardiopulmonary reserve in atypical disease, but evidence is anecdotal. Consequently, CTD-style chemical–disease associations should not be encoded as causal without independent validation. (szafranski2014twodeletionsoverlapping pages 3-5, kozłowska2020genotype–phenotypecorrelationin pages 2-4)

6. Mechanism and pathophysiology

Upstream-to-downstream causal chain

Upstream genetic lesion: heterozygous FOXF1 coding loss or disruption of the 16q24.1 enhancer/LINC01081 regulatory domain reduces FOXF1 dosage.
Cell-autonomous developmental effects: FOXF1-dependent transcription fails in KIT-positive CAP1 endothelial progenitors, CAP2 gas-exchange capillary cells, and pericytes, compromising differentiation, survival, migration, and vascular stabilization.
Network disruption: PTEN, ERK/MAPK, STAT3, focal-adhesion kinase, integrin, WNT/β-catenin, ID1, semaphorin, and Rho-GTPase programs are reduced or altered. Direct/predicted FOXF1 targets include ACVRL1, AQP1, BCAM, CASZ1, CDH5, CPNE8, DAAM1, DLL4, and capillary-selective BTNL9. (guo2023singlecellmultiomics pages 4-6, guo2023singlecellmultiomics pages 3-4, guo2023singlecellmultiomics pages 8-12)
Microvascular phenotype: CAP1/CAP2 cells become markedly depleted; pericytes are reduced, whereas COL15A1-positive systemic/bronchial endothelial cells expand. Abnormal VEGFA signaling shifts toward this systemic circulation.
Epithelial–mesenchymal consequence: loss of normal AT1-to-CAP2 VEGFA–VEGFR2 communication and altered fibroblast FGF signaling impair alveolar type 1-cell maturation. Transitional HOPX/SFTPC-coexpressing epithelial cells accumulate while mature AT1 cells decline.
Tissue and physiological outcome: simplified lobules, thick septa, sparse capillaries, arterial muscularization, anomalous bronchovascular vessels, right-to-left shunting, pulmonary hypertension, hypoxemia, and respiratory failure result. (guo2023singlecellmultiomics pages 4-6, guo2023singlecellmultiomics pages 13-15)

2023 single-cell multiomics advance

Guo et al. used single-nucleus RNA-seq, ATAC-seq, microscopy, and in-situ hybridization in six FOXF1-positive ACDMPV subjects. Across affected, preterm, and control tissues they identified 35 cell types; the RNA dataset included 32,300 affected, 15,817 preterm, and 17,692 control nuclei. FOXF1 RNA was absent in CAP1/CAP2 cells in 3/5 evaluable affected subjects, and CAP2 loss tracked clinical severity. Pericytes had 61 downregulated genes, and 58.8% of predicted FOXF1 targets were supported in the integrated analysis. (guo2023singlecellmultiomics pages 4-6, guo2023singlecellmultiomics pages 3-4)

A direct abstract quotation captures the central result: “Pathogenic variants involving the FOXF1 gene locus disrupt gene expression in EC progenitors, inhibiting differentiation or survival of CAP2 ECs and cell-cell interactions necessary for both pulmonary vasculogenesis and AT1 cell differentiation.” The same abstract reports that microvascular loss was associated with “increased VEGFA signalling and marked expansion of systemic bronchial ECs expressing COL15A1.” Publication: September 2023; DOI URL: https://doi.org/10.1164/rccm.202210-2015oc. (guo2023singlecellmultiomics pages 1-2)

Suggested ontology annotations

GO biological processes: lung development; vasculogenesis; angiogenesis; endothelial-cell differentiation; blood-vessel morphogenesis; epithelial-cell differentiation; alveolar development; cell–cell signaling; VEGF-receptor signaling; canonical WNT signaling; MAPK cascade; integrin-mediated signaling.
Cell Ontology: pulmonary capillary endothelial cell; endothelial progenitor cell; pericyte; pulmonary fibroblast; vascular smooth-muscle cell; alveolar type 1 epithelial cell; alveolar type 2 epithelial cell; bronchial endothelial cell.
GO cellular components: nucleus/chromatin and transcription-regulator complex for FOXF1; cell–cell junction, focal adhesion, and plasma membrane for downstream endothelial defects.

Immune, metabolic, and tissue-injury components

ACDMPV is not primarily autoimmune or inflammatory. Hypoxic vasoconstriction, high pulmonary vascular resistance, right-heart strain, and ischemic/hypoxemic injury are downstream. No validated disease-specific metabolic, metabolomic, lipidomic, or proteomic signature was found. Fibrosis is not the initiating mechanism, although prolonged atypical disease and vascular remodeling can produce secondary matrix changes.

Advanced technology gaps

Single-cell transcriptomics and chromatin accessibility are established research tools. Disease-specific spatial transcriptomics, comprehensive proteomics, metabolomics, lipidomics, CRISPR screens, patient-iPSC assays, or validated organoid diagnostics were not identified in the retrieved evidence.

7. Anatomical structures affected

The primary organ is the lung, especially distal lung parenchyma, alveolar septa, pulmonary capillary plexus, small pulmonary arteries, pulmonary venous/systemic bronchial vessels, and bronchovascular bundles. Suggested UBERON mappings include lung, lung alveolus, alveolar septum, pulmonary capillary, pulmonary arteriole, pulmonary vein, bronchus, and bronchovascular bundle.

At tissue and cell level, endothelial, mesenchymal/connective, smooth-muscle, and alveolar epithelial compartments are affected. Secondary involvement includes the right ventricle and systemic organs injured by severe hypoxemia. Congenital gastrointestinal, cardiac, and genitourinary malformations are pleiotropic developmental manifestations rather than consequences of lung failure. Disease is bilateral and diffuse in typical cases; atypical disease may be patchy, creating biopsy sampling error. (guo2023singlecellmultiomics pages 2-3, stankiewicz2009genomicandgenic pages 6-8)

8. Temporal development

The anatomical lesion originates prenatally during pulmonary vascular and alveolar morphogenesis. Typical clinical onset is acute within hours or the first 48 hours, sometimes after a brief apparently normal interval. It progresses rapidly from oxygen requirement and pulmonary hypertension to refractory hypoxemia, right-to-left shunting, multiorgan hypoxic injury, and death in days or weeks. (kozłowska2020genotype–phenotypecorrelationin pages 1-2, stankiewicz2009genomicandgenic pages 1-2)

Atypical disease can present after weeks, months, or rarely later childhood and may fluctuate with infections or physiological stress. In the 2023 research cohort, three severe subjects died or underwent tissue sampling at 2–5 weeks, whereas less severe subjects reached transplant at 9 months and 3.5 years. Another enhancer-deletion patient decompensated at 14 months and received bilateral transplantation at 15 months. (guo2023singlecellmultiomics pages 3-4, szafranski2014twodeletionsoverlapping pages 3-5)

There is no spontaneous anatomical remission. Temporary improvement with inhaled nitric oxide, prostaglandin, ventilation, or ECMO reflects altered vascular tone and support—not restoration of the missing capillary bed. The critical intervention window is therefore early recognition before prolonged futile ECMO or irreversible end-organ injury, while urgently assessing transplant suitability in unusually stable or patchy disease.

9. Inheritance and population characteristics

Epidemiology

Reliable incidence and prevalence per 100,000 are unknown. Approximately 200 cases had been reported by 2009, but underdiagnosis is probable because infants may be classified as idiopathic persistent pulmonary hypertension and because definitive pathology was historically obtained only at autopsy. A 2024 French chILD cohort exists, but no ACDMPV-specific national incidence could be extracted from the retrieved text. (stankiewicz2009genomicandgenic pages 1-2)

No ethnicity, geography, sex, consanguinity, or founder population is known to have a reproducibly increased risk. The age distribution is overwhelmingly neonatal, with rare infantile or childhood survivors.

Inheritance

The molecular mechanism is autosomal dominant, usually caused by a de novo heterozygous pathogenic variant or deletion. Approximately 10% familial association was reported in early literature, but this estimate is based on published cases and may be biased. Partial paternal imprinting/parent-of-origin effects complicate conventional Mendelian counseling. (stankiewicz2009genomicandgenic pages 1-2, szafranski2014twodeletionsoverlapping pages 5-6)

Penetrance is high for clearly loss-of-function variants but not adequately quantified; expressivity ranges from neonatal lethality to patchy, delayed disease. Anticipation and consanguinity are not established. Germline mosaicism is possible, so recurrence after an apparently de novo event is not zero. Testing both parents and considering deep mosaicism assays after recurrent pregnancies is appropriate. Carrier frequency cannot be reliably estimated because severe causal variants are individually ultra-rare and commonly de novo.

10. Diagnostics

When to suspect ACDMPV

Suspect the disease in a term or near-term neonate with severe persistent pulmonary hypertension and hypoxemia that are disproportionate to radiographic parenchymal disease, respond only transiently to pulmonary vasodilators, and recur or worsen despite optimized ventilation and ECMO—especially when congenital gastrointestinal, cardiac, or genitourinary anomalies coexist. Atypical disease should be considered in unexplained infantile/childhood pulmonary hypertension with diffuse developmental lung abnormalities.

Clinical evaluation

Echocardiography: documents pulmonary hypertension, right-to-left ductal/atrial shunting, right-ventricular dysfunction, and associated heart defects, but is not specific.
Blood gases and oxygenation: show severe hypoxemia and often acidosis; no disease-specific laboratory biomarker exists.
Chest radiograph/CT: may show diffuse ground-glass opacity, septal/interstitial thickening, edema-like change, or developmental simplification. Imaging cannot reliably confirm or exclude ACDMPV.
Cardiac catheterization/angiography: may characterize pulmonary vascular resistance and shunting but is not routinely required in unstable neonates.
Histopathology: remains the diagnostic gold standard when molecular testing is negative, delayed, or ambiguous. Adequate tissue from more than one region is desirable because atypical lesions may be patchy. CD31 and CD34 endothelial immunostaining can clarify capillary distribution. (kozłowska2020genotype–phenotypecorrelationin pages 2-4, kozłowska2020genotype–phenotypecorrelationin pages 1-2)

Molecular testing algorithm

Order rapid sequencing of FOXF1, including deletion/duplication analysis and coverage of the known distant enhancer/regulatory domain.
Use chromosomal microarray to detect 16q24.1 gene or enhancer CNVs and associated multigene deletions. In two neonates, array CGH identified approximately 1.45-Mb and 0.7-Mb deletions; the latter left FOXF1 intact and removed its enhancer. (kozłowska2020genotype–phenotypecorrelationin pages 2-4)
If negative and suspicion remains high, pursue trio genome sequencing, which is preferable to exome sequencing for noncoding deletions, inversions, breakpoints, and mosaicism. WES can detect coding variants but may miss the principal regulatory domain.
Analyze parental samples to establish de novo status and recurrence risk. Consider tissue-specific/deep testing when mosaicism is suspected.
Lung biopsy should not be delayed if the molecular result will not arrive rapidly enough to guide ECMO continuation or transplant decisions.

Karyotyping has low sensitivity for submicroscopic CNVs. FISH can test a known deletion but is not comprehensive. Mitochondrial DNA and repeat-expansion testing are not indicated unless a different diagnosis is suspected. RNA-seq/ATAC-seq remain research tools rather than validated clinical assays.

Differential diagnosis

Major alternatives include idiopathic or secondary persistent pulmonary hypertension of the newborn; congenital diaphragmatic hernia and pulmonary hypoplasia; congenital heart disease; pulmonary veno-occlusive disease; pulmonary capillary hemangiomatosis; congenital pulmonary lymphangiectasia; acinar dysplasia; congenital alveolar dysplasia; surfactant dysfunction disorders involving SFTPB, SFTPC, ABCA3, or NKX2-1; TBX4-related developmental lung/PAH disease; infection; meconium aspiration; and severe parenchymal lung disease. Histology and comprehensive genetics distinguish these conditions. The 2024 developmental-lung-disease consensus emphasizes interdisciplinary review involving neonatology, pulmonary hypertension, radiology, pathology, genetics, intensive care, and transplantation. Publication: August 2024; DOI URL: https://doi.org/10.1183/13993003.00639-2024.

Screening

ACDMPV is not included in routine newborn biochemical screening, and population screening is inappropriate given its rarity and lack of a simple validated marker. Targeted prenatal diagnosis, cascade testing, and preimplantation genetic testing are appropriate when a familial pathogenic variant or CNV is known.

11. Outcome and prognosis

Typical disease is almost universally fatal without transplantation, usually within the first month, although death from severe respiratory failure may occur over days to months. Mechanical support does not correct the developmental absence of an adequate gas-exchange microvasculature. The 2020 report states that both molecularly confirmed neonates died despite maximal ventilation, inhaled nitric oxide, inotropes, and surfactant. (kozłowska2020genotype–phenotypecorrelationin pages 1-2)

No meaningful 5- or 10-year survival estimate exists because typical neonatal mortality is so high and long-term survivors are exceptionally selected. Favorable prognostic features appear to include later onset, patchy histology, residual CAP2 capillary endothelium, partial vasodilator responsiveness, and absence of prohibitive extrapulmonary anomalies; these are not validated prognostic models. Severe diffuse capillary depletion and early refractory pulmonary hypertension predict poor survival. (guo2023singlecellmultiomics pages 3-4, guo2023singlecellmultiomics pages 4-6)

Long-term morbidity among transplanted survivors includes standard pediatric lung-transplant risks: rejection, infection, chronic lung-allograft dysfunction, medication toxicity, and neurodevelopmental effects of critical illness. Disease-specific quality-of-life and neurodevelopmental statistics are unavailable.

12. Treatment and current applications

Supportive and pharmacological treatment

There is no approved disease-modifying drug. Mechanical ventilation, high inspired oxygen, inhaled nitric oxide, sildenafil or prostacyclin-pathway therapy, inotropes, correction of acidosis, surfactant when another neonatal indication exists, and prostaglandin E1 in selected ductal-dependent or right-heart unloading contexts can transiently improve physiology. They do not rebuild the capillary bed. Relevant NCIT concepts include Mechanical Ventilation, Nitric Oxide Therapy, Vasodilator Therapy, Extracorporeal Membrane Oxygenation, and Supportive Care. (kozłowska2020genotype–phenotypecorrelationin pages 2-4, kozłowska2020genotype–phenotypecorrelationin pages 1-2)

ECMO is generally a bridge to diagnosis, decision-making, or transplantation—not curative therapy. Continuing ECMO after confirmed diffuse typical ACDMPV without a transplant pathway is usually futile and requires careful multidisciplinary and family-centered discussion.

Lung transplantation

Bilateral lung transplantation is the only currently implemented definitive replacement therapy and is feasible only for selected atypical or sufficiently stable infants/children. One child with an upstream enhancer deletion received an orthotopic bilateral transplant at 15 months; the 2023 cohort included transplants at 9 months and 3.5 years. These cases prove feasibility but do not establish a response rate. Donor availability, body size, ECMO complications, neurological injury, and extrapulmonary malformations sharply limit access. NCIT: Bilateral Lung Transplantation. (szafranski2014twodeletionsoverlapping pages 3-5, guo2023singlecellmultiomics pages 2-3)

Experimental therapy

Endothelial-targeted nanoparticle delivery of FOXF1 or STAT3 rescued pulmonary vasculogenesis in newborn mouse experiments cited by the 2023 human mechanistic study. Separate mouse work shows endothelial FOXF1 delivery can improve experimental pulmonary fibrosis, supporting targetability but not efficacy in congenital ACDMPV. No ACDMPV-specific human gene, RNA, cell, CRISPR, or pharmacologic interventional trial was identified in the ClinicalTrials.gov search. (guo2023singlecellmultiomics pages 13-15)

A rational future strategy would require prenatal or very early postnatal restoration of FOXF1 in the correct endothelial/mesenchymal progenitors, with careful dosage control because FOXF1 is a developmental transcription factor. This remains preclinical; no pharmacogenomic prescribing guideline exists.

13. Prevention

There is no lifestyle, environmental, vaccine, or drug-based primary prevention. For sporadic de novo disease, prevention is limited to reproductive genetics after the causal lesion is identified.

Primary/reproductive prevention: genetic counseling, parental testing, preimplantation genetic testing for monogenic/CNV disease, and prenatal diagnosis by chorionic-villus sampling or amniocentesis.
Secondary prevention: targeted fetal testing in known-risk pregnancies and rapid neonatal genetic diagnosis may prevent prolonged ineffective treatment and enable earlier transplant referral; they do not prevent lung maldevelopment after it has occurred.
Tertiary prevention: meticulous oxygenation and hemodynamic support, prevention of ECMO/ventilator complications, and timely transplant evaluation may reduce secondary organ injury.

A 2023 reproductive-genetics study—not ACDMPV-specific—showed that deep sequencing and PGT can prevent transmission in families with recurrent de novo mutations and demonstrated a >5,000× assay with an approximately 0.5% VAF detection limit. This supports methodology for counseling but should not be presented as an ACDMPV outcome study. (xu2023parentalmosaicismdetection pages 1-1)

14. Other species and natural disease

No well-established naturally occurring veterinary counterpart, breed predisposition, or OMIA-defined ACDMPV syndrome was identified. Therefore, prevalence, veterinary importance, and VBO breed terms are unavailable. The disease is noninfectious, nontransmissible, and has no zoonotic potential.

FOXF1 developmental function is evolutionarily conserved across vertebrates. Mouse Foxf1 is the principal comparative ortholog and has supplied most mechanistic evidence. Comparative interpretation must account for species differences in lung developmental timing and placentation.

15. Model organisms

Engineered mouse models

Heterozygous, conditional, or cell-type-specific Foxf1 loss models reproduce important components of human disease, including impaired pulmonary vasculogenesis, capillary deficiency, abnormal endothelial differentiation, alveolar developmental defects, pulmonary hypertension, and neonatal mortality. Mesodermal Pten inactivation can also produce an ACDMPV-like phenotype, supporting the relevance of PTEN/FOXF1-linked developmental signaling. (guo2023singlecellmultiomics pages 3-4, sen2013novelfoxf1mutations pages 10-13)

Applications include mapping FOXF1 transcriptional targets, lineage tracing of endothelial progenitors, testing endothelial–epithelial communication, and evaluating nanoparticle gene delivery. Strengths are experimental control and prenatal developmental access. Limitations include incomplete reproduction of human pulmonary-vein/systemic-vessel anatomy, species-specific developmental timing, and the fact that many human cases involve complex regulatory or multigene CNVs rather than simple coding knockout.

Cellular and other models

Primary human ACDMPV lung tissue and single-nucleus multiomics currently provide the most disease-proximal cellular system. No mature, widely validated ACDMPV patient-iPSC, lung-organoid, zebrafish, rat, Drosophila, or C. elegans platform was established in the retrieved evidence. Relevant resources for future model registration include MGI, IMPC, KOMP, IMSR/MMRRC, ZFIN, and Cellosaurus.

Key recent developments and expert interpretation

Human cellular mechanism resolved, 2023: single-cell RNA/ATAC analysis connected FOXF1 insufficiency to CAP1/CAP2 and pericyte loss, failed AT1 maturation, altered VEGFA communication, and compensatory COL15A1-positive bronchial endothelial expansion. This shifts the model from a nonspecific vascular malformation to a cell- and lineage-specific developmental network disorder. (guo2023singlecellmultiomics pages 1-2, guo2023singlecellmultiomics pages 4-6)
Clinical framing updated, 2024: expert consensus places FOXF1-ACDMPV among developmental lung diseases presenting with neonatal/infantile pulmonary hypertension and recommends interdisciplinary integration of genetics, imaging, pathology, biopsy decisions, ECMO, transplant assessment, and family counseling.
Translational direction: endothelial-targeted FOXF1/STAT3 replacement has preclinical plausibility, but irreversible prenatal developmental loss, narrow timing, delivery specificity, and transcription-factor dosage are major barriers. (guo2023singlecellmultiomics pages 13-15)
Real-world implementation: rapid FOXF1 sequencing plus CNV/enhancer analysis is increasingly capable of replacing postmortem-only diagnosis, while pathology remains essential for negative or ambiguous molecular cases. Selected atypical patients can survive through bilateral transplantation. (szafranski2014twodeletionsoverlapping pages 3-5, kozłowska2020genotype–phenotypecorrelationin pages 2-4)

Evidence gaps requiring explicit knowledge-base flags

No reliable population incidence/prevalence, sex ratio, ethnicity effect, carrier frequency, prospective natural-history registry, validated severity biomarker, quality-of-life instrument, standardized treatment algorithm, disease-specific interventional trial, human gene-therapy result, or established environmental/protective factor was identified. Variant-level ClinVar classification and gnomAD frequency should be imported dynamically rather than generalized. Proteomics, metabolomics, lipidomics, spatial transcriptomics, natural animal disease, and robust patient-derived organoid/iPSC findings remain absent or insufficiently established.

Selected primary references and publication details

Guo M, et al. Single Cell Multiomics Identifies Cells and Genetic Networks Underlying Alveolar Capillary Dysplasia. American Journal of Respiratory and Critical Care Medicine. September 2023;208:709–725. https://doi.org/10.1164/rccm.202210-2015oc. Human lung single-nucleus RNA/ATAC study, six subjects. (guo2023singlecellmultiomics pages 3-4, guo2023singlecellmultiomics pages 1-2)
Stankiewicz P, et al. Genomic and Genic Deletions of the FOX Gene Cluster on 16q24.1 and Inactivating Mutations of FOXF1 Cause Alveolar Capillary Dysplasia and Other Malformations. American Journal of Human Genetics. June 2009;84:780–791. DOI: https://doi.org/10.1016/j.ajhg.2009.05.005; PMID 19500772. Landmark human genetic/pathology study. (stankiewicz2009genomicandgenic pages 6-8, stankiewicz2009genomicandgenic pages 1-2)
Sen P, et al. Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. Human Mutation. June 2013;34:801–811. https://doi.org/10.1002/humu.22313. Human genetics cohort. (sen2013novelfoxf1mutations pages 10-13)
Szafranski P, et al. Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of ACDMPV. American Journal of Medical Genetics Part A. August 2014;164:2013–2019. https://doi.org/10.1002/ajmg.a.36606. Human regulatory genetics and transplant cases. (szafranski2014twodeletionsoverlapping pages 3-5, szafranski2014twodeletionsoverlapping pages 5-6)
Kozłowska Z, et al. Genotype–phenotype correlation in two Polish neonates with alveolar capillary dysplasia. BMC Pediatrics. June 2020;20. https://doi.org/10.1186/s12887-020-02200-y. Human clinical, pathology, and CNV report. Its abstract states: “The diagnosis of ACD is based on histopathological evaluation of lung biopsy or autopsy tissue or genetic testing of FOXF1 on chromosome 16q24.1.” (kozłowska2020genotype–phenotypecorrelationin pages 2-4, kozłowska2020genotype–phenotypecorrelationin pages 1-2)
Varghese NP, et al. An interdisciplinary consensus approach to pulmonary hypertension in developmental lung disease. European Respiratory Journal. August 2024;64:2400639. https://doi.org/10.1183/13993003.00639-2024. Expert consensus, not an ACDMPV treatment trial.

Overall, the strongest current interpretation is that ACDMPV is a FOXF1-dosage-sensitive, predominantly de novo developmental vasculopathy in which failure to establish the alveolar capillary endothelial–pericyte network secondarily prevents normal alveolar epithelial maturation. Rapid combined coding, CNV, and regulatory-region testing—integrated with expert pathology—offers the best diagnostic approach, while bilateral lung transplantation remains the only implemented definitive therapy for the rare patient who can be stabilized long enough to receive it.

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Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

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Output Format

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV)

Executive summary

Evidence framework

1. Disease information

Definition and classification

Identifiers and synonyms

Data provenance

2. Etiology, risks, protective factors, and gene–environment interaction

Primary causal factors

Genetic risk factors

Environmental and demographic risks

Gene–environment interaction

3. Phenotypes

Core pulmonary and cardiovascular phenotype

Extrapulmonary manifestations

Quality of life

4. Genetic and molecular information

Causal gene

Variant interpretation

Regulatory and epigenetic architecture

Chromosomal abnormalities

5. Environmental information

6. Mechanism and pathophysiology

Upstream-to-downstream causal chain

2023 single-cell multiomics advance

Suggested ontology annotations

Immune, metabolic, and tissue-injury components

Advanced technology gaps

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population characteristics

Epidemiology

Inheritance

10. Diagnostics

When to suspect ACDMPV

Clinical evaluation

Molecular testing algorithm

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment and current applications

Supportive and pharmacological treatment

Lung transplantation

Experimental therapy

13. Prevention