| 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) (pqac-00000003, pqac-00000007) | ~200 cases reported in 2009 literature; >80% with additional malformations in early series (pqac-00000007) | 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) (pqac-00000005, pqac-00000006, pqac-00000015) | >100 pathogenic SNVs and >70 CNV deletions reported by 2023 review of primary cases (pqac-00000003) | 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 (pqac-00000001, pqac-00000018) | Two de novo maternal chr16 deletions; ~75 kb enhancer region implicated; severity varied with enhancer/LINC01081 involvement (pqac-00000018) | 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 (pqac-00000002, pqac-00000006, pqac-00000007) | Death usually in days to weeks/months; first month emphasized in landmark cohort (pqac-00000007) | 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 (pqac-00000004, pqac-00000006, pqac-00000007) | >80% had additional malformations in early series (pqac-00000007) | 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 (pqac-00000005, pqac-00000004, pqac-00000002) | 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 (pqac-00000005) | 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 (pqac-00000003, pqac-00000008, pqac-00000009, pqac-00000010) | 6 subjects analyzed; 35 cell types identified; 32,300 ACDMPV nuclei profiled; CAP2 reduction correlated with severity (pqac-00000010, pqac-00000008) | 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 (pqac-00000010, pqac-00000008, pqac-00000009, pqac-00000013) | 61 genes downregulated in pericytes; 58.8% of predicted FOXF1 targets validated in integrated analysis (pqac-00000008) | 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 (pqac-00000008, pqac-00000010, pqac-00000011) | FOXF1 RNA absent in CAP1/CAP2 in 3/5 ACDMPV subjects with severe disease (pqac-00000010) | 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 (pqac-00000004, pqac-00000006, pqac-00000018) | Two 2020 neonates had ~1.45 Mb and ~0.7 Mb deletions identified by array CGH; one spared FOXF1 coding region (pqac-00000004) | 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 (pqac-00000015) | 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 (pqac-00000001, pqac-00000004, pqac-00000006) | One atypical patient underwent bilateral lung transplant at 15 months; recent multiomics cohort included transplants at 9 months and 3.5 years (pqac-00000001, pqac-00000002) | 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 (pqac-00000002, pqac-00000007, pqac-00000018) | Severe subjects died at 2–5 weeks in the 2023 cohort; atypical survivors reached 9 months, 15 months, or 3.5 years with transplantation (pqac-00000000, pqac-00000001, pqac-00000002) | 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 (pqac-00000015, pqac-00000018, pqac-00000014, pqac-00000017) | 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) (pqac-00000007, pqac-00000019) | 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 (pqac-00000014, pqac-00000019, pqac-00000020) | Deep targeted sequencing >5000× with ~0.5% VAF detection limit used for mosaicism detection in analogous severe DNM disorders (pqac-00000014) | 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 (pqac-00000009, pqac-00000013) | Rescue described in newborn mice; no human interventional trial identified in gathered evidence (pqac-00000009) | 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.*