Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins (ACDMPV)

Lethal disorder of pulmonary vascular development due to haploinsufficiency of FOXF1 or loss of its lung enhancer at 16q24.1 — classic neonatal and atypical late-presenting forms and contiguous deletions of the FOX cluster

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and evolution of the concept

Alveolar capillary dysplasia was described in 1981 by Janney, Askin and Kuhn in a term newborn whose clinical course corresponded to what was then called persistent fetal circulation syndrome. Autopsy showed a failure of formation and penetration of the alveolar capillaries, with absence of a normal air–blood barrier, and anomalous veins within the bronchovascular bundles; morphometry indicated otherwise mature lungs, which led the authors to propose that distal epithelial and vascular development obey separate control mechanisms [23]. In 1991, Langston systematically associated misalignment of the pulmonary veins with capillary dysplasia, and this finding became part of the histological definition of the entity (according to Szafranski and colleagues, who cite Langston 1991) [7]. In the 1990s the disease was recognised as a cause of PPHN refractory to inhaled nitric oxide and ECMO [24]. Before that, MacMahon (1948) had described as "congenital alveolar dysplasia" three term newborns who breathed well at birth, developed progressive respiratory distress and cyanosis within minutes to hours and died within 2 days, with excess capillary-rich interstitium around scanty alveoli; Sen and colleagues (2004) considered that this entity may be distinct, because patients generally survive longer, do not always have pulmonary hypertension and do not show misaligned veins [11].

Reports of affected siblings followed: three siblings born to Tunisian Jewish first cousins, with pulmonary arterial pressure above systemic pressure and a right-to-left shunt, who died at 4, 11 and 15 days (Shohet 1984); two siblings of Ukrainian Jewish ancestry, who died at 6 weeks and at 43 days (McDonald-McGinn 1992); a boy who deteriorated at 12 hours and died on day 40, with bilateral pelviureteric junction obstruction and cryptorchidism, whose sister was asymptomatic until 6 weeks and had patchy, non-diffuse capillary lesions (Boggs 1994); two siblings with bilateral pelviureteric junction obstruction and hydronephrosis who died before 4 months (Manouvrier-Hanu 1996); two siblings who died at 21 hours and 20 days, one of them with lymphangiectasia, patent ductus arteriosus and severe bilateral hydronephrosis with ureters about 8 cm in diameter (Vassal 1998); and two children of consanguineous Turkish parents, one with tibial agenesis and ectrodactyly (Witters 2001) [11]. In the Boggs review, more than half of the 14 published cases had associated anomalies, mainly genitourinary, gastrointestinal and cardiovascular [11].

Before the gene was identified, the analysis of 23 cases by Sen and colleagues (2004) outlined the natural history and associated anomalies, drew attention to left–right asymmetry and intestinal malrotation, and excluded BMPR2 and the endothelial monocyte-activating polypeptide II gene as candidates; families with affected siblings then led to autosomal recessive inheritance being accepted in some cases, an interpretation that later molecular studies replaced with the dominant model with de novo variants and parental mosaicism [2, 25]. Among the 23 patients in this series, 90% were born at term, 85% were appropriate for gestational age and 82% died in the first month despite intensive treatment; of the 22 available autopsies, 18 (82%) had at least one other major malformation (cardiovascular in 5, gastrointestinal in 4, genitourinary in 4, musculoskeletal in 1), and 5 of these 18 (28%) had abnormal thoracic or abdominal left–right asymmetry [11].

1.2. Molecular discovery

In 2009, Stankiewicz and colleagues identified, by array comparative genomic hybridisation (array CGH), overlapping microdeletions at 16q24.1q24.2 centred on the FOX gene cluster and, subsequently, four de novo inactivating FOXF1 variants in sporadic patients; on an array targeting the region they also found two deletions upstream of FOXF1 that did not include the gene, the first indication of a position effect [1]. The next series from the same group (2013) added 38 non-synonymous variants and identified FOXF1 alterations in 70% (37/53) of the new cases [26]. Between 2013 and 2016 the distal lung enhancer, the deep intronic variant and the strong maternal predominance of the deletions were characterised [7, 27]. The accumulation of more than 200 published cases and access to genetic testing led to recognition of atypical forms, with late presentation or prolonged survival, and of successfully transplanted patients [2, 14, 28].

1.3. Definition and place in classifications

ACDMPV is defined by the combination of histological findings — a reduced number of alveolar capillaries, which lie away from the epithelium, thickened alveolar septa, hypertrophy of the muscular layer of the small arteries with muscularisation of the intra-acinar arterioles and pulmonary veins located within the bronchovascular bundle next to the arteries — and, increasingly, by demonstration of a pathogenic alteration at the FOXF1 locus [2, 14, 18]. The American Thoracic Society (ATS) classification of childhood interstitial lung disease (chILD) places it among the diffuse developmental disorders and, in the 2026 update, among the monogenic diseases usually fatal in the first year without transplantation, alongside surfactant protein B deficiency and ABCA3 deficiency with a null genotype [17, 29]. The aetiological classification proposed by the European chILD-EU registry includes it among the diseases native to the lung parenchyma [5]. In the pulmonary hypertension classification of the 7th World Symposium (WSPH, 2024), developmental lung disorders belong to group 3, and PPHN, although listed in group 1, is treated as a physiological syndrome that includes these diseases [30]. Orphanet classifies the entity simultaneously as a rare genetic disease, a rare respiratory disease and a transplant-related disease [3].

Three entities should be distinguished from the outset. Classic ACDMPV presents in the first hours of life and has diffuse lesions. Atypical ACDMPV has onset after a symptom-free interval of weeks or months, or a less severe neonatal course, and has focal or patchy lesions [14]. The contiguous 16q24.1 deletion syndrome includes FOXF1, FOXC2, FOXL1 and FENDRR and adds severe cardiac malformations, digestive atresias and a single umbilical artery to the lung disease [1, 7].

2. Molecular Genetics and Pathophysiology

2.1. The FOXF1 gene and protein

FOXF1 is located at 16q24.1, about 3.7 Mb from the telomere of the long arm, in a cluster that includes FOXC2 and FOXL1 and, in the opposite orientation and 1.7 kb upstream, the long non-coding RNA (lncRNA) gene FENDRR, with which it probably shares a bidirectional promoter [1, 7]. The gene has two exons; it encodes a transcription factor of the forkhead family, whose DNA-binding domain has a winged helix-turn-helix structure, and is expressed in the lung mesenchyme and vascular endothelium [7, 26]. FOXF1 expression depends on sonic hedgehog (SHH) signalling from the epithelium, through the GLI proteins, and is activated by bone morphogenetic protein 4 (BMP4) [1, 2]. The promoter overlaps a CpG island, has no TATA box and requires enhancers for activity [7]. The 5.5 kb promoter region immediately upstream of the start codon contains several GLI binding sites, partly overlaps, on the opposite strand, the lncRNA FOXF1-AS1 (FENDRR), and the CpG island extends into exon 1 [12].

The 2.6 kb FOXF1 transcript was identified in the placenta and in fetal and adult lung; the protein has a C-terminal transcriptional activation domain and activates the promoters of lung genes such as SFTPB and that of the club cell protein CC10 [12]. In the developing mouse stomach and intestine, Foxf1 and Foxl1 expression depends on Gli2 and Gli3 and is induced by the N-terminal fragment of Shh, through conserved Gli binding sites, which links hedgehog signalling to the digestive malformations of the disease [12].

In mouse models, complete absence of Foxf1 is lethal at embryonic day 8.5 owing to defects of the extraembryonic and lateral mesoderm; Foxf1+/− heterozygotes show abnormal alveolarisation, scarce alveolar capillaries and lymphangiectasia, but not venous misalignment, and half of them have lung Foxf1 levels reduced to 20% of normal, with pulmonary haemorrhage and foregut malformations, whereas the other half are normal [1, 2]. Foxf1+/− mice also have severe structural abnormalities of the gallbladder and reduced expression of Vcam1, integrin alpha-5, PDGF receptor alpha and Hgf, molecules required for adhesion, migration and differentiation of mesenchymal cells [12].

2.2. Long-range regulation: the lung enhancer

The most important regulatory region lies about 270 kb upstream of FOXF1 and contains the lncRNA genes LINC01081 and LINC01082; it was delimited by the smallest region of overlap of the deletions found in patients [2, 7]. In 2013 it was described as a 75 kb region without coding genes, between 332 and 257 kb upstream of the start codon, with sequences conserved in vertebrates, the lncRNAs LINC01081 and LINC01082, a cluster of GLI1, GLI2 and GLI3 binding sites and a CpG island; chromosome conformation capture suggested a chromatin loop between this region and the promoter [12]. Two patients reported in 2014 showed the effect of each component: a 194 kb deletion, located about 272 kb upstream, which preserved FOXF1 and disrupted LINC01081, caused severe neonatal disease and death at 13 days; a 1.5 Mb deletion, 306 kb upstream, which spared LINC01081 and removed part of LINC01082, caused onset at 7 months, with lung FOXF1 expression reduced by 70%; both arose de novo on the maternal chromosome, and silencing of LINC01081 by siRNA in fetal lung fibroblasts reduced the FOXF1 transcript by 14% and 20% [11, 12]. FOXF1 and this enhancer belong to the same topologically associating domain (TAD) of about 400 kb, with FOXF1 at the distal boundary; enhancer–promoter interactions are stronger in fetal lung fibroblasts than in other cell types [7]. Single-nucleus multiomics studies identified four conserved FOXF1 enhancers, some endothelial and self-activating, others mesenchymal and regulated by EBF1 and GLI1, which explains why non-coding deletions, sometimes of only a few kilobases, abolish gene function in the lung [31]. The 1.4 kb intron also has moderate enhancer activity: a 0.8 kb intronic deletion arising de novo on the maternal allele reduced the lung transcript by about 40% and caused the disease [27].

2.3. Tissue and physiological mechanism

FOXF1 haploinsufficiency disrupts development of the pulmonary vascular bed from the embryonic and pseudoglandular stages; the presence of thickened septa and simplified acini with few type 1 pneumocytes indicates that the saccular stage is also affected [2]. In human ACDMPV lungs, single-nucleus RNA and accessible chromatin sequencing demonstrated autonomous functions of FOXF1 in capillary endothelial cells and pericytes, loss of type 2 capillary endothelial cells, increased VEGFA signalling and expansion of COL15A1-expressing systemic bronchial endothelial cells [32]. A mouse carrying the p.(Ser52Phe) variant reproduces the human histology: the mutant protein does not bind chromatin, loses its interaction with STAT3 and reduces Stat3 transcription, with reduced endothelial proliferation [33]. The serotonin transporter is absent in ACDMPV lungs and normal in other causes of neonatal pulmonary hypertension, and is a possible FOXF1 target [2].

Hypoxaemia does not result only from the scarcity of capillaries. Post-mortem ink injections into the pulmonary artery, bronchial arteries and pulmonary veins showed intrapulmonary vascular pathways connecting the systemic and pulmonary circulations and bypassing the capillary bed, forming a right-to-left shunt [34]. The "misaligned veins" are now interpreted as persistent shunt vessels of the developing lung, possibly of bronchial venous origin, as suggested by the presence of valves [2, 18]. The pulmonary hypertension is not explained by postnatal hypoxaemia alone, because the extent of the arterial changes implies a disturbance already present in fetal life, and it persists despite correction of oxygenation by ECMO [2].

2.4. Inheritance and parent-of-origin effect

ACDMPV behaves as an autosomal dominant disorder due to haploinsufficiency, and most cases result from de novo alterations [1, 26]. In the largest collection worldwide, with 141 families, 86 pathogenic variants at the locus were identified: 38 deletions, one complex rearrangement and 47 point variants; in most of the remaining 55 families the DNA was of insufficient quality [7]. Of the 31 deletions with known parental origin, 30 arose de novo on the maternal chromosome 16 (p<4×10⁻⁶), and a later review counted 50 maternal and 3 paternal deletions [7, 35]. Point variants, by contrast, may originate from either parent, including mosaic parents [2, 7]. In the 2013 series, only 4 cases were familial, and in 3 transmission was maternal [11, 26].

This asymmetry led to the hypothesis of non-canonical genomic imprinting of the enhancer, with partial expression of each allele (about 35% and 65%), supported by differential methylation of a CpG island with GLI binding sites in the enhancer [7]. The hypothesis has not been confirmed by all groups: in fetal tissues, including lung and intestine, FOXF1 and FENDRR showed biallelic expression, without allele-specific methylation regions at 16q24.1 [36], and detailed studies in fetal, neonatal and adult lung did not demonstrate imprinting [2]. The 2026 ATS table and the European review describe the inheritance as autosomal dominant, "usually with parental imprinting", which reflects the maternal predominance of the deletions and not a proven imprinting mechanism [5, 17]. The phenotype of maternal uniparental disomy of chromosome 16, which shares pulmonary hypoplasia, heart disease, tracheo-oesophageal fistula, malrotation, renal agenesis and single umbilical artery, has been linked to this parent-of-origin effect [7].

2.5. Spectrum of point variants

About 60% (25/42) of the point variants in the 2013 series lay in the DNA-binding domain, including 88% of the variants in the first exon and 95% of the missense variants; five were located in the second exon [26]. The spectrum includes nonsense, frameshift, in-frame deletion, missense and stop-loss variants [1, 26]. The variants in Table 2.1 were normalised in VariantValidator against the MANE transcript NM_001451.3 [6].

Table 2.1. FOXF1 variants cited in this article (GRCh38; NM_001451.3/NP_001442.2)

The variants published in 2009 followed the 1996 cDNA numbering, which predicted a 354-amino-acid protein with the start codon 75 nucleotides downstream of the current one; the historical descriptions c.150C>A "p.Y50X" and c.1063T>C "p.X355Rext*74" read directly on NM_001451.2 or NM_001451.3 would give p.(Pro50=) and p.(Ser355Pro), and correspond, on the MANE transcript and in ClinVar, to c.225C>A p.(Tyr75Ter) and c.1138T>C p.(Ter380ArgextTer73), the latter with the 73-amino-acid extension described in the original article [1, 6, 12]. The four patients from 2009 with point variants died between 12 hours and 47 days: the carrier of p.(Tyr75Ter) on day 10, with partial atrioventricular canal defect, malrotation, annular pancreas, duodenal stenosis and bilateral hydronephrosis; the carrier of p.(Ter380ArgextTer73) at 47 days, with malrotation and Meckel diverticulum; the carrier of a 1 bp duplication in exon 1 (historical designation 775dupT) at 12 hours, with obstructive renal dysplasia; and a girl with a 2 bp deletion in exon 2 (956delTT) on day 1, with partial anomalous pulmonary venous drainage, congenital short bowel with malrotation, small omphalocele, severe bilateral hydronephrosis, micrognathia and low-set ears [12]. The in-frame duplication c.54_59dup p.(Gly22_Gly23dup), in a tract of 11 glycines whose length varies between species, was inherited from a healthy father and considered probably not pathogenic [7].

2.6. Deletions and mechanisms of formation

Deletions range from a few kilobases to several megabases and fall into three types: deletions that remove only FOXF1, deletions that remove FOXF1 and the enhancer, and deletions that remove only the enhancer and leave FOXF1 intact [7]. In 53% (16/30) of the characterised deletions, the junction was mediated by Alu elements, and 85% of 45 sequenced deletions had at least one breakpoint in a retrotransposon, including a hotspot of about 35 kb with the L1PA2 and L1PA3 elements; microhomologies of 7 to 43 base pairs point to replication-based mechanisms (FoSTeS/MMBIR) [1, 7, 41]. Very small deletions have been described, such as a 5 kb deletion removing the paternal allele of FOXF1 and the promoter without affecting FENDRR, and a 151 base-pair deletion in a GC-rich portion of exon 1, which escaped Sanger sequencing and microarray and was found only by genome sequencing [42, 43]. A de novo balanced pericentric inversion, with a breakpoint 123–163 kb upstream of FOXF1, caused the phenotype through a position effect [44].

2.7. Genotype–phenotype correlations

The 2009 study distinguished three groups. Deletions including FOXF1, FOXC2, FOXL1 and MTHFSD were associated in all cases with cardiovascular malformation, from patent ductus arteriosus to tetralogy of Fallot, interrupted aortic arch and hypoplastic left heart syndrome (HLHS), and with digestive atresias (oesophageal, duodenal, anal). Point variants were associated with malrotation or congenital short bowel and, in one case in four, with partial atrioventricular canal defect. Partial or upstream-only deletions had intermediate phenotypes; the only deletion removing FOXC2 and FOXL1 without FOXF1 did not cause lung disease [1]. One example is a boy with a 1.37 Mb de novo deletion at 16q24.1q24.2, including FOXF1, FOXC2 and FOXL1, who died at 3 days from irreversible pulmonary hypertension and cor pulmonale, with hypoplasia of the left ventricle and mitral valve, pulmonary valve atresia, subaortic ventricular septal defect, overriding aorta, atrial septal defect, patent ductus arteriosus, persistent left superior vena cava, obstructive uropathy with hydronephrosis and intestinal malrotation (Yu 2010) [11]. The combination of severe heart disease and single umbilical artery occurred only with deletions affecting FOXF1 and the TAD boundary, which is attributed to loss of FENDRR or dysregulation of neighbouring genes; screening of FOXC2 and FOXL1 in patients with isolated HLHS found no pathogenic variants [7, 42]. Paternal deletions, which are rarer, appear to be associated with more severe extrapulmonary anomalies [35]. In the prenatal cases reviewed, no difference was shown between FOXF1 deletions and enhancer deletions [44].

In the atypical forms, missense, nonsense and frameshift variants and upstream deletions have been described, but not complete deletions or CNVs including FOXC2; the number of cases does not yet allow a firm genotype–phenotype correlation [40]. The p.(Pro49Ala) variant, outside the region where most pathogenic variants cluster, has been proposed as hypomorphic in a patient who survived to the age of 30 [37].

2.8. Penetrance, expressivity and modifiers

In six of eight published families with exon 1 variants, the variant was present in a parent without signs of the disease, including two mosaic parents [2]. In one family, one sibling had the classic form and died, another had an atypical form and survived, and a carrier sister was unaffected [2, 7]. In a four-generation family with the c.881_902dup variant, the proband's healthy mother, with a history of pulmonary arterial hypertension (PAH), carried in trans a regulatory variant in the lung enhancer (rs560517434-A) that increased promoter activity tenfold in vitro, which supports a dosage and compound-inheritance model in which non-coding variants can rescue the lethal phenotype [39]. In adults, FOXF1 variants have been described in PAH with onset at 18 and 25 years with asymptomatic carrier parents, and lung FOXF1 expression correlated with severity in pulmonary hypertension cohorts [37].

2.9. Cases without a FOXF1 alteration, other genes and duplications

The proportion of cases with an identified alteration depends on the selection and methods: 71.4% (15/21) in a French series, 85% (11/13) in a Japanese series with CNV study by MLPA, 90% of pathologically proven cases in another Japanese series and about 80–90% in the review literature [8, 9, 13, 39]. Exome sequencing in FOXF1-negative families found de novo variants in ESRP1, ZMYND11, SLC50A1, MPRIP and DOCK8 and inherited variants in PLXNB2, without proof of causality, and no second consistently associated gene has been identified [7, 18]. Duplications of 16q24.1 including FOXF1 do not cause paediatric lung disease; one of them was accompanied by pyloric stenosis, common mesentery and aplasia of the appendix in a mother and daughter [45].

3. Clinical Spectrum and Manifestations by System

3.1. Classic neonatal form

About 95% of patients are born at term, with normal weight and Apgar score, and most develop symptoms in the first 24 hours: respiratory distress, cyanosis and hypoxaemia due to severe pulmonary hypertension [2]. In the French series of 21 patients born between 2005 and 2017, the mean postmenstrual age at birth was 37.6 weeks, symptoms appeared at a median of 2.5 hours and pulmonary hypertension was documented in 20 [13]. In the North American Pediatric Health Information System (PHIS) database, which gathered 58 newborns admitted between 2016 and 2025, the median gestational age was 38 weeks and the median weight 2883 g; 51.7% were female [16]. Some infants have no extrapulmonary anomalies and suspicion only arises after days, particularly when meconium-stained amniotic fluid points to aspiration syndrome [18, 46].

The typical course is progressive hypoxaemia and refractory pulmonary hypertension despite mechanical ventilation with a fraction of inspired oxygen of 1.0, inhaled nitric oxide and other vasodilators [18]. Nitric oxide increases the arterial partial pressure of oxygen markedly, but the response is not sustained; in the five infants described by Steinhorn, concentrations had to be raised to 80 ppm or more and all died, four after long periods of ECMO [24]. Most die of hypoxaemic respiratory failure days to weeks after presentation, and mortality approaches 100% without transplantation [1, 2]. In the PHIS cohort, 93.1% required invasive ventilation, 63.8% ECMO and 86.2% died [16].

3.2. Extrapulmonary malformations

Anomalies of other organs are present in about 80% of patients in the classic series and in 91% in the PHIS cohort, where cardiovascular anomalies predominated [16, 26]. Intestinal malrotation is the most frequent anomaly in the genetic series, and HLHS with hypoplasia or coarctation of the aortic arch are the most frequent cardiovascular anomalies [1]. Some malformations are detected only at autopsy [25].

Table 3.1. Extrapulmonary malformations associated with ACDMPV

3.3. Atypical late-presenting form

The St. Louis series (1998–2016) described six infants with atypical ACDMPV who underwent bilateral lung transplantation. None had progressive neonatal respiratory failure: three had mild respiratory distress treated with nasal cannula oxygen, and three had no respiratory symptoms at birth and presented with hypoxaemia and pulmonary hypertension at 2–3 months [14]. Triggers were respiratory infections, dehydration from diarrhoea and travel to altitude; one infant had abdominal distension and dysmotility on the third day of life, with an echocardiogram without pulmonary hypertension on day 20, and cardiorespiratory arrest on day 67 [14]. Computed tomography (CT) showed ground-glass opacity and septal thickening in five, and three had a reduction in pulmonary vascular resistance with nitric oxide at catheterisation [14]. The latest presentation described was at 7 months [15, 18]. The 2026 ATS guideline stresses that, of the six atypical transplanted patients, five had symptoms in the first three months [17].

Table 3.2. Atypical forms and forms with prolonged survival with individual data

3.4. Survival beyond infancy

Prolonged survival without transplantation is exceptional. One atypical patient was alive at 38 months on oral vasodilators and oxygen, and at least one child diagnosed genetically in the neonatal period stabilised on vasodilators until 2.5 years [2, 18]. The longest survival is that of a man with the p.(Pro49Ala) variant, presenting at 7 weeks with an indexed pulmonary vascular resistance of 28.6 Wood units·m² that fell to 6.4 with nitric oxide and oxygen; he was treated with intravenous epoprostenol from 4 months and, later, with bosentan, sildenafil, treprostinil, tadalafil and ambrisentan, and died at 30 years from pneumonia with right ventricular failure [37]. Two siblings of this patient had died in infancy, one with oligohydramnios on the first day and another at 4 months with pulmonary vein stenosis [37].

3.5. Prematurity, twins and prenatal presentation

The disease also occurs in preterm infants: a newborn of 29 weeks and 850 g, with growth restriction, had respiratory distress within minutes, was treated with surfactant because of an ultrasound pattern of respiratory distress syndrome and died within 48 hours; the diagnosis was made at autopsy [51]. Monozygotic twins with de novo variants on the maternal allele and dichorionic twin girls diagnosed by biopsy have been described [36, 52]. Prenatally, the findings of 16q24.1 deletions are non-specific: increased nuchal translucency and cystic hygroma at 11–12 weeks and cardiac, renal and intestinal malformations from about 20 weeks, sometimes with hydrops and single umbilical artery [44]. A fetus with suspected posterior urethral valves treated with vesicoamniotic shunting had the c.203dup variant, and first-trimester megacystis has been described as an ultrasound sign [38, 48].

3.6. Natural history and treated disease

The published series mix natural history and disease treated with maximal support. In the structured review of 165 patients published between 2018 and 2025, which includes atypical forms, mean survival without transplantation was 7 months and that of the ten transplanted patients 81 months, with six alive at the time of publication; these are means of published cases, subject to selection bias [19]. In the Extracorporeal Life Support Organization (ELSO) registry for 2000–2010, survival to discharge of newborns with irreversible lung dysplasias treated with ECMO was 3%, compared with 81% in PPHN [53].

4. Clinical Recognition and Red Flags

4.1. In the newborn

Suspicion should arise in any term or late preterm newborn with hypoxaemia and pulmonary hypertension without an evident cause — without diaphragmatic hernia, severe meconium aspiration, sepsis, respiratory distress syndrome or heart disease to explain it — and, in particular, when the response to nitric oxide is absent or transient [2, 18, 24]. The summary of product characteristics of inhaled nitric oxide in the European Union states that newborns who cannot be weaned after 4 days should undergo careful diagnostic investigation for other diseases [54]. The presence of associated malformations — malrotation, duodenal or anal atresia, HLHS, hydronephrosis, posterior urethral valves or single umbilical artery — reinforces the suspicion [1, 47]. In the Australian series of 1982–2000, ACD was found at autopsy in all six newborns with severe idiopathic PPHN who died in the neonatal period, all treated with ECMO [55].

4.2. During ECMO

In the ELSO registry, irreversible lung dysplasias were distinguished from PPHN by later ECMO initiation (day 5.3 versus 3.0) and longer duration (11.1 versus 6.8 days); initiation on day 5 or later and a duration of 10 days or more were independent predictors [53]. The 2026 review recommends strongly considering a genetic test that includes CNVs, such as genome sequencing, in term newborns who progress to ECMO without another confirmed diagnosis [18]. Lung ultrasound before cannulation showed a normal pattern, with A-lines and pleural sliding, in newborns with ACDMPV, as in fetal ductal constriction and sepsis; this pattern suggests non-parenchymal disease [56].

4.3. In the infant and child

The atypical form should be considered in any infant with hypoxaemia and idiopathic pulmonary hypertension, including those with a CT pattern of interstitial disease, and even after the neonatal period [14]. Red flags are pulmonary hypertension disproportionate to the initial findings and poorly responsive to therapy, decompensation precipitated by respiratory infections, dehydration or altitude, and a neonatal history of transient tachypnoea or brief oxygen therapy [14, 15, 40]. A family history of neonatal deaths from "persistent pulmonary hypertension" or "meconium aspiration" should be sought: in a Japanese family, the first child was wrongly diagnosed with meconium aspiration syndrome and the diagnosis was only made at the autopsy of the third [46]. In an adult or adolescent with unexplained or heritable pulmonary hypertension, especially if it began in childhood, FOXF1 should be included in the genetic panel [37].

4.4. In the prenatal period

There are no specific prenatal signs [2]. The combination of increased nuchal translucency or cystic hygroma with cardiac, renal or intestinal malformations, or vesicoamniotic shunting for suspected urinary obstruction with other anomalies, should lead to 16q24.1 deletion and ACDMPV being included in counselling, with microarray analysis [38, 44]. There is no newborn screening for the disease.

4.5. Urgent signs

Urgency arises from the combination of refractory hypoxaemia with haemodynamic instability. In the atypical forms, anaesthetic induction and intubation may trigger bradycardia and pulseless electrical activity, as in the Tower case, in which the arrest occurred during catheterisation [40]. In the St. Louis series, one infant had cardiorespiratory arrest as the first presentation [14].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Histological criteria

Histological diagnosis requires the constellation of findings and not an isolated finding. The criteria used in the reference series are deficient alveolar capillarisation (fewer capillaries, lying away from the alveolar epithelium), pulmonary veins located next to the small arteries within the same bronchovascular bundle, sharing the adventitia, and medial hypertrophy of the small arteries and arterioles; deficient lobular development with reduced alveolarisation and lymphangiectasia are frequent findings [2, 14]. The lungs are bulky, up to three times the expected weight, with thickened septa and an epithelium of hyperplastic cuboidal type 2 pneumocytes [2]. CD31 immunohistochemistry highlights the reduction and displacement of the capillaries [2]. Glomeruloid vessels have been described [15].

In the classic form the lesions are diffuse; in the atypical forms they are focal or patchy, and all explants in the St. Louis series had areas with normal capillaries, so a single biopsy may not show the disease [14]. For this reason it is recommended to take more than one sample [2]. Histological diagnosis identifies the disease but not the gene, and normal FOXF1 sequencing does not exclude the disease [4].

5.2. Genetic testing: what the guidelines recommend

The 2013 ATS guideline suggested, as a weak recommendation, testing for FOXF1 deletions and variants in newborns with chILD syndrome, respiratory failure and refractory pulmonary hypertension, citing that up to 40% of these newborns had alterations of the gene [29]. The 2026 ATS update changed the method: it recommends (strong recommendation, very low certainty of evidence) rapid and broad genetic testing in infants and children under 2 years with chILD syndrome and respiratory failure when potentially fatal diseases are being considered, naming SFTPB, ABCA3 and FOXF1; rapid means preliminary results within 7 days of sampling, and broad means exome or genome, excluding single-gene tests and panels [17]. The same guideline suggests that genetic testing should precede biopsy (conditional) and be performed after biopsy when histology suggests monogenic disease (conditional) [17]. The divergence between the two editions lies in the choice of test — gene-targeted in 2013, exome or genome in 2026 — and in the sequence between genetics and biopsy.

5.3. Limitations of the tests

The 2026 ATS guideline requires CNV detection methods, because deletions are frequent in ACDMPV, and warns that the exome may miss the non-coding deletions upstream of FOXF1 [17]. Trio testing detects de novo variants, which are common in this gene [17]. Routine microarray and exome do not cover the deep intronic regions [27]. The very GC-rich regions of exon 1 may hide small deletions that escape Sanger sequencing and microarray and appear only on hybridisation-free genome sequencing [43]. Low-level parental mosaicism, with allele fractions between 0.03% and 19%, escapes the usual diagnostic methods and requires ultrasensitive techniques such as blocker displacement amplification or droplet digital PCR [10]. Exome and genome results depend on the phenotype communicated to the laboratory, may generate variants of uncertain significance (VUS) and incidental findings, and sensitivity is not 100% [18]. Even with comprehensive methods, 10–15% of histologically proven cases remain without a genetic explanation [8, 9].

Targeted alternatives have been developed: a next-generation sequencing panel specific to FOXF1 and the regulatory region, which detects variants and large alterations in a single assay from blood, and its rapid clinical application in Rotterdam [57, 58]. In the Japanese series, sequencing of the coding exon followed by multiplex ligation-dependent probe amplification (MLPA) of the exons and the upstream region identified point variants in 46% and CNVs in 38% [9]. Rapid genome sequencing allowed diagnosis in 2–3 days in a case of atypical ACDMPV and is proposed as a comprehensive, non-invasive approach to severe neonatal respiratory failure [40, 59]. Preliminary results of rapid exome or genome usually arrive in 5–7 days [18].

5.4. Lung biopsy

Biopsy remains indicated when there is clinical urgency and genetic testing is not feasible, is inconclusive or will not arrive in time, or to allow an informed decision (strong recommendation of the 2026 ATS guideline) [17]. In a centre with an early-biopsy strategy, 6 of 7 cases were diagnosed in life, with a median of 6.5 days between admission and biopsy; all survived the procedure [60]. In the Netherlands, 25 open lung biopsies during ECMO gave a classifying diagnosis in 52%, led to withdrawal of ECMO in six newborns with ACDMPV and had few haemorrhagic complications [61]. In London, among 506 children referred for ECMO, 15 (3%) underwent open biopsy, which contributed to the decision in all newborns; there was one non-fatal haemorrhagic complication [62]. The Dutch review recommends biopsy before starting ECMO or, if already started, in the first week, with more than one sample [2].

5.5. Imaging and complementary investigations

Echocardiography confirms pulmonary hypertension and excludes structural heart disease; catheterisation documents pressures and resistances, but carries increased risk in severely ill infants [2, 30]. The chest radiograph is non-specific (diffuse opacification, pneumothoraces) [2]. CT shows ground-glass opacity with interlobular septal thickening, a pattern included in the imaging table of the 2026 ATS guideline, which suggests CT in the initial assessment (conditional recommendation) [17]. CT angiography does not diagnose the disease, because it does not show the peripheral capillaries [2]. In the review of 165 patients, imaging served to exclude other causes of hypoxaemia, and the final diagnosis required genetic or histological confirmation [19]. Pulmonary angiography may show rapid filling of the pulmonary veins before the contrast passes through the capillary bed [60]. The assessment should include abdominal and renal ultrasound for associated malformations [4].

5.6. Algorithm

Table 5.1. Diagnostic approach when ACDMPV is suspected

5.7. Genetic report and interpretation

The report should state the gene, the transcript and version (NM_001451.3), the HGVS description, zygosity, origin (de novo or inherited) and the classification according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria, and, for CNVs, the coordinates, the genes included (FOXF1, FENDRR, FOXC2, FOXL1) and whether the enhancer is included [7, 40]. In the Tower case, the last-exon frameshift variant was classified as pathogenic because it escapes nonsense-mediated decay with loss-of-function variants described downstream (PVS1), is absent from gnomAD (PM2) and is de novo (PS2) [40]. In-frame variants in the glycine tract require caution, because they may be benign [7].

5.8. Prenatal and preimplantation diagnosis

In families with a known variant or deletion, fetal testing by chorionic villus sampling or amniocentesis allows diagnosis, and preimplantation genetic testing (PGT) has been used in a family with high-level maternal mosaicism [2, 63]. Without a known alteration, diagnosis depends on finding a 16q24.1 deletion on microarray in a fetus with malformations; definitive confirmation of the lung disease is histological [44]. Reduced fetal lung volume on magnetic resonance imaging and ultrasound is associated with several diffuse developmental lung disorders, including ACDMPV, but is not specific [2].

5.9. Autopsy

Many diagnoses are still made at autopsy [2, 14]. Autopsy with lung histology and preservation of tissue for DNA are essential for counselling, as shown by the Japanese family in which the diagnosis was only made at the third death, and the familial case resolved thirty years later by genome sequencing of archived autopsy tissue [43, 46].

6. Differential Diagnosis

The differential of ACDMPV is that of hypoxaemic respiratory failure in the term newborn with pulmonary hypertension and, later, that of pulmonary hypertension in the infant with or without interstitial disease. The acquired causes — transient tachypnoea, respiratory distress syndrome, meconium aspiration, sepsis and pneumonia, congenital diaphragmatic hernia, pulmonary hypoplasia secondary to renal or skeletal anomalies — generally respond to supportive treatment or have an identifiable cause [18]. Absence of a sustained response, inability to wean from nitric oxide and the need for prolonged ECMO point towards the genetic diseases [53, 54].

Table 6.1. Differential diagnosis of ACDMPV

Three differentials deserve comment. Surfactant disorders can mimic ACDMPV in the severely ill newborn, but the radiograph and CT show diffuse parenchymal involvement, whereas in ACDMPV lung ultrasound may be normal and the hypoxaemia depends mainly on the circulation [18, 56]; both appear in the same recommendation for rapid and broad genetic testing in the 2026 ATS guideline and share the indication for early referral for transplantation [17]. Acinar dysplasia and congenital alveolar dysplasia form a histological continuum of lethal developmental lung disorders with ACDMPV; the same patient may have findings of ACD and of acinar dysplasia, and the distinction is relevant for recurrence risk because TBX4 and FGF10 have compound inheritance [60, 64]. In the atypical forms, pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis are the most difficult differentials, because they also combine hypoxaemia, pulmonary hypertension and CT abnormalities; in the Tower case, rapid genome sequencing was requested to test EIF2AK4 and FOXF1 simultaneously [14, 40]. Sildenafil is not recommended in pulmonary veno-occlusive disease because of the risk of pulmonary oedema, which reinforces the importance of the distinction [67].

7. Treatment and Risk Management Strategies

7.1. Principles

There is no treatment that corrects the lung lesion and no drug approved for ACDMPV; there is no randomised clinical trial or society guideline dedicated exclusively to this disease, and the evidence is observational [4, 19]. Supportive treatment is that of PPHN: cardiorespiratory stabilisation, mechanical ventilation and pulmonary vasodilators, which may improve saturation in the short term but require successive escalation, until the hypoxaemia becomes fatal [2]. There are three central decisions and they depend on early diagnosis: starting or continuing ECMO, referring for lung transplantation and moving to palliative care [17, 18]. The 2026 ATS guideline recommends (strong, very low certainty) early referral for transplant assessment in monogenic diseases with a predictably poor prognosis, among which it includes ACDMPV, and suggests (conditional) referral of children with chILD on mechanical ventilation, on ECMO or with progressive pulmonary hypertension; in diseases usually fatal within the first year, transplantation or palliative care are the options available [17].

7.2. Ventilatory support and pulmonary vasodilators

Most patients need immediate intubation and ventilation; rarely, supplemental oxygen suffices for a time [2]. Inhaled nitric oxide, milrinone, sildenafil and epoprostenol are used to reduce pulmonary vascular resistance [2]. The drugs and doses in Table 7.1 come from the official labels, because the guidelines consulted do not set doses for ACDMPV; off-label uses are indicated.

Table 7.1. Supportive drugs used in ACDMPV

The WSPH 2024 paediatric task force notes that PAH therapies are common in infants with developmental lung disorders, but are not approved by the FDA or the EMA for this group and their effects on outcomes are uncertain; it proposes confirming precapillary pulmonary hypertension, excluding post-capillary components such as pulmonary vein stenosis and left ventricular diastolic dysfunction, treating the lung disease first and starting monotherapy with serial reassessment [30]. The atypical forms have pharmacologically reversible components: three infants in the St. Louis series reduced their pulmonary vascular resistance with nitric oxide, and all were treated with vasodilators until transplantation [14]. In the trial of intravenous sildenafil in 59 newborns with PPHN (NCT01720524), which did not include ACDMPV as a specific population, the treatment failure rate was 27.6% with sildenafil and nitric oxide versus 20.0% with placebo and nitric oxide, without a significant difference, and serious adverse effects were more frequent with sildenafil (24.1% versus 6.7%) [69, 74].

7.3. Extracorporeal membrane oxygenation and paracorporeal devices

ECMO stabilises newborns at risk of death when the diagnosis is unclear, but the great majority of patients with ACDMPV cannot be weaned; it is invasive, has complications and high costs [2]. In the PHIS cohort, ECMO was used in 72.0% of non-survivors and in 12.5% of survivors [16]. In the review of 165 cases, it was used in 45 patients and is proposed when medical therapy and ventilation are insufficient [19]. The Dutch review recommends biopsy before ECMO or before a second run, and accepts ECMO as a bridge to transplantation in patients with a mild phenotype [2]. An experience with ECMO in three newborns with rare genetic syndromes highlighted that ECMO can serve as a bridge to diagnosis and allow parental bonding, but that there are no clinical pathways or evidence to guide its use in these diseases [75]. In the 2026 ATS guideline, ECMO and mechanical ventilation at the time of transplantation were associated with higher in-hospital mortality after transplantation in infants [17].

For prolonged support, the St. Louis group transferred children from ECMO to a pumpless paracorporeal lung assist device, an oxygenator interposed between the pulmonary artery and the left atrium: four patients aged 23 days to 23 months, two with ACD, were supported for 44±29 days; three were extubated, a 9-month-old infant with ACD was transplanted after 5 days and two died on the waiting list [76, 77]. The group published recommendations for this device, which includes ACD among its indications [78].

7.4. Lung transplantation

Bilateral lung transplantation is the only curative option [4, 19]. By 2018, seven transplanted patients had been described in the USA, all with an atypical phenotype, with 5-year survival of 56%, comparable to that of infants transplanted for other indications [2]. In the St. Louis series, the six atypical infants were transplanted between 4 and 20 months; three were alive at 5–16 years, two after retransplantation for chronic graft dysfunction, and lung function ranged from normal to severe obstruction due to bronchiolitis obliterans [14]. A 5-month-old girl transplanted with lungs from a 6-week-old donor, with normal growth 6 years later, and a 6-year-old boy with a living-donor lobar transplant (his mother's right lower lobe), complicated by post-transplant lymphoproliferative disorder treated with reduced immunosuppression, rituximab and lobectomy, who returned to normal school life, have been described [79, 80]. No transplantation with prolonged survival has been described in the classic form, because of its severity and the median waiting time of about 2 months for suitable organs; 5-year survival after lung transplantation in infants is about 50–60%, and half of the families counselled decline transplantation [18]. In infants up to 2 years, the median time between listing and death on the list was 36 days (4–259) [17]. The extrapulmonary involvement associated with FOXF1 weighs in the assessment of candidacy [17].

7.5. Palliative care and decisions to limit treatment

As the disease is usually fatal and the diagnosis is often made at autopsy, palliative care and counselling on recurrence are part of routine management [4]. In several series, histological confirmation led to withdrawal of active treatment on grounds of futility [2, 60, 61]. A rapid genetic diagnosis can also change management in the opposite direction: in the Tower case, identification of an atypical form led to the discussion of palliative care being abandoned and intensive treatment being continued, with discharge after 67 days [40]. The 2026 ATS guideline stresses that referral for transplantation does not imply transfer and allows families to talk with the teams, and that some decline transfer after that conversation [17].

7.6. Associated malformations and surgery

The associated malformations sometimes require surgery, but the Dutch review recommends that lung biopsy be performed before surgical interventions for the associated anomalies when lung disease is suspected [2]. The severity of the lung disease and that of the associated malformations should be considered together in the decision to treat [2].

7.7. Regulatory status

No medicine has an indication for ACDMPV in the USA or the European Union. The supportive medicines have their own indications, which do not coincide with their use in this disease.

Table 7.2. Regulatory status of supportive drugs

7.8. Available evidence

Table 7.3. Studies with treatment data in ACDMPV and PPHN

These data do not allow comparisons between studies: they are retrospective series, with different populations and periods, and the mean survival figures of the structured review come from published cases, biased towards diagnosed cases with a longer course [19]. The studies do not provide confidence intervals for the survival outcomes. The only randomised trial was conducted in unselected PPHN, and was negative [69]. A ClinicalTrials.gov search on 1 November 2026 identified no therapeutic trial targeting ACDMPV or FOXF1 [74].

7.9. Research and developments in the last twelve months

All targeted therapies are at the preclinical stage. The compound TanFe (transcellular activator of nuclear FOXF1 expression), a small molecule of the nitrile group, prevents binding of FOXF1 to the ubiquitin ligase HECTD1 and stabilises the protein; given to pregnant mice, it completely prevented postnatal mortality of Foxf1+/− pups and increased angiogenesis in vascular organoids derived from induced pluripotent stem cells of a patient with a FOXF1 deletion [81]. Nanoparticles carrying STAT3 cDNA restored endothelial proliferation in the mouse with the p.(Ser52Phe) variant, and polyethylenimine–polyethylene glycol nanoparticles carrying FOXF1 (npFOXF1) showed no toxicity after a single intravenous dose in 14-day-old mice [33, 82]. The 2026 review acknowledges that there are obstacles to overcome before clinical application [18].

Between November 2025 and October 2026 the following were published: the 2026 ATS guideline, with the recommendation of rapid and broad genetic testing and early referral for transplantation [17]; the largest North American multicentre cohort, with mortality of 86.2% [16]; a structured review of 165 patients [19]; the case of survival to 30 years with the p.(Pro49Ala) variant [37]; genome-based detection of a 151 base-pair deletion in exon 1, invisible to conventional methods [43]; a prenatal presentation as posterior urethral valves [38]; a presentation at 7 months [15]; a European Respiratory Journal review on pulmonary hypertension in genetic syndromes that includes ACDMPV [83]; and a Clinics in Perinatology review on genetic respiratory diseases with hypoxaemic failure [18]. All are observational studies, reviews or guidelines; there were no regulatory applications, opinions or authorisations.

7.10. Special situations

In anaesthesia and invasive procedures, induction and intubation may precipitate pulmonary hypertensive crises with bradycardia and arrest, as happened in the Tower case during catheterisation, and risk factors for unplanned escalation during catheterisation include age under 1 year [30, 40]. Nitric oxide should not be withdrawn abruptly, because of the risk of rebound pulmonary hypertension [68]. In survivors with a central catheter for prostacyclin, venous thrombosis required long-term anticoagulation [37]. In transplanted patients, bronchiolitis obliterans, chronic graft dysfunction and post-transplant lymphoproliferative disorder determine the prognosis [14, 80]. Pregnancy and transition to adulthood arise only in the rare survivors; the sources consulted describe no pregnancies in patients with ACDMPV.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

The recurrence risk depends on the mechanism identified and on parental testing. About 10% of cases are familial [1, 46]. When the alteration arises de novo and the parents are negative, the risk for siblings is low, 1% to 5%, but not zero, because of germline mosaicism [18]. As new mutations on the maternal allele appear to be transmitted recurrently more often and almost all deletions arise on the maternal chromosome, it has been accepted that the risk may be higher than in other sporadic diseases, and possible epigenetic regulation could increase it further [7, 44]. When a parent is a non-mosaic carrier, the risk is 50% for each child, with incomplete penetrance and variable expressivity [2, 39]. When a parent is mosaic, the risk depends on the fraction of germ cells carrying the alteration: in a mother with 36% mosaicism in blood, 44% of the embryos studied by PGT had the deletion [63].

Table 8.1. Counselling according to the result of family testing

8.2. Parental testing and cascade testing

Trio testing detects de novo variants and guides counselling [17]. In 18 families with an apparently de novo variant or one of uncertain origin, high-sensitivity techniques identified parental mosaicism in four (22%), with allele fractions between 0.03% and 19% in blood and, in one family, between less than 0.03% and 0.65% in tissues derived from the three germ layers [10]. In the mother with high-level mosaicism, the allele fraction was 36% in blood, 19% in saliva, 18% in buccal cells, 15% in urine, 19% in nail and 27% in hair, and the deletion had arisen on the chromosome 16 that the mother inherited from her father [63]. Maternal somatic mosaicism with recurrence in siblings and paternal mosaicism for an enhancer deletion with three affected children have been described [46, 84]. In relatives carrying a pathogenic variant, the 2026 review on adult survival proposes surveillance, given the occurrence of PAH in adulthood in carriers [37, 39]. It is also recommended to exclude in the parents a balanced rearrangement involving 16qter when the child has a terminal or complex deletion [1].

8.3. Prenatal and preimplantation diagnosis

With the familial alteration known, chorionic villus sampling or amniocentesis allow prenatal diagnosis, and in vitro fertilisation with PGT has been applied successfully in a family with high-level mosaicism [2, 63]. In the Japanese family with paternal mosaicism, the genetic basis was only clarified after the death of the fourth child, and PGT and prenatal diagnosis could not be offered in time [46]. Early diagnosis allows counselling on prognosis and planning of delivery in an experienced centre, although the postnatal course should be observed because it differs between patients [2].

8.4. Counselling regarding minors and content of the consultation

Testing of asymptomatic minor siblings in a family with a known variant may be justified by the variability of presentation, which includes late forms and PAH in adults, and should be discussed in a genetics clinic [14, 37]. The consultation should address the lethality of the classic form, the existence of atypical forms, the limitations of the tests, the recurrence risk adjusted to parental testing, the reproductive options and bereavement support resources [18, 21].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and what each figure measures

Frequency estimates depend on histological diagnosis and are therefore minimum values. In Manitoba (Canada), Al-Hathlol and colleagues found two cases among 226 neonatal autopsies over ten years, with 170,000 births and 340 neonatal deaths, corresponding to an incidence of about 1/100,000 (according to Slot and colleagues, who cite Al-Hathlol 2000) [2]. Orphanet records a birth prevalence of 1–9/100,000 in Canada, with a mean of 1.2/100,000, and a point prevalence below 1/1,000,000, which are mutually compatible because the disease is lethal in the neonatal period [4]. In the Netherlands, 20 patients diagnosed at two centres since 1993 for 4.3 million live births correspond to about 1/200,000, with probable underdiagnosis owing to a lack of autopsies [2]. These figures measure birth incidence of confirmed cases, not population prevalence.

9.2. Frequency in at-risk populations

The frequency among newborns with severe pulmonary hypertension is much higher. In Japan, about 30% (10/30) of infants with severe unexplained pulmonary hypertension had ACDMPV [8]. At a Canadian centre, four of eight newborns who required ECMO for acute hypoxaemic failure had ACD [60]. In the United Kingdom, among 173 newborns treated with ECMO over three years, there were nine irreversible lung dysplasias, five of them ACD [66]. In Australia, all six newborns with severe idiopathic PPHN who died in the neonatal period had ACD [55]. In the systematic review of ECMO in PPHN, ACDMPV accounted for 0.1% of survivors and 4.4% of deaths [85]. The 2013 ATS guideline cited that up to 40% of newborns with hypoxaemia and severe pulmonary hypertension due to ACD-MPV had FOXF1 deletions or variants [29].

9.3. Geography and populations

The available series come from the USA (Houston, St. Louis, the PHIS cohort with 60.3% white and 28.4% Hispanic patients), Europe (France, the Netherlands, Spain, Poland, Italy, Belgium), Japan, Australia and Hong Kong [2, 7–9, 13, 14, 16, 19, 36, 38, 55, 84]. No founder variants have been described; the disease is dominated by de novo alterations, and the recurrence of deletions at retrotransposon-rich hotspots does not reflect a founder effect [41]. The sources consulted present no data from Portugal or Brazil; a parental mosaicism series included collaborators from Porto, without frequency data [10].

9.4. Special populations

The disease occurs in preterm infants, in monozygotic and dichorionic twins and in association with trisomy 21 and sirenomelia, which means the diagnosis should not be excluded because of prematurity or another chromosomal anomaly [36, 51, 52, 86, 87]. In adults with unexplained PAH, FOXF1 may explain some cases [37].

9.5. Reference networks and associations

The European reference network for rare respiratory diseases is ERN-LUNG [20]. The ACD Association brings together families of affected children, promotes research and offers bereavement resources and support groups [21]. The chILD Foundation supports families of children with interstitial and diffuse lung disease [22]. The European chILD-EU registry collects data and samples on rare childhood lung diseases [5].

10. Illustrative Clinical Case

Tower and colleagues (2023) described a 22-month-old Hispanic boy, born at 38 weeks with appropriate weight, who had respiratory failure at birth requiring intubation and admission to neonatal intensive care, treated as presumed sepsis with hypoxaemic respiratory failure and hyperbilirubinaemia; he was discharged at 2 weeks in room air and grew normally, with mild speech delay and a heart murmur. The paternal grandparents were first cousins [40].

At 22 months he presented with months of palpitations and sweating and days of irritability, tiredness, pallor, dyspnoea and oliguria; he had tachycardia, periorbital oedema and crackles. Haemoglobin was 6.5 g/dL owing to iron deficiency, and B-type natriuretic peptide 8368 pg/mL (normal <100). The radiograph showed cardiomegaly, asymmetric right-sided interstitial opacities and pleural effusion; CT angiography showed dilatation of the right heart chambers and pulmonary arteries with scattered ground-glass opacity; the echocardiogram revealed right ventricular systolic dysfunction and a tricuspid regurgitation gradient compatible with severe pulmonary hypertension. He received milrinone 0.5 mcg/kg/min [40].

On the third day, anaesthetic induction for catheterisation triggered bradycardia and pulseless electrical activity; after resuscitation, pulmonary pressures were suprasystemic and fell markedly with intravenous epoprostenol at 20 ng/kg/min, to which nitric oxide, sildenafil and ambrisentan were added. The right pulmonary oedema progressed, and high-resolution CT showed marked septal thickening in the right middle and lower lobes, raising the differential between pulmonary veno-occlusive disease, pulmonary capillary haemangiomatosis and ACD; biopsy was declined because of the risk. A second episode of pulseless electrical activity led to venoarterial ECMO, discontinued after 3 days because of circuit thrombi, and to balloon atrial septostomy. A transition to palliative care was discussed [40].

Rapid genome sequencing of the patient and parents, requested to study EIF2AK4 and FOXF1, identified after 2 laboratory days the de novo heterozygous variant NM_001451.3:c.1070_1080del p.(His357ArgfsTer50) in the last exon of FOXF1, confirmed by Sanger sequencing within 2 weeks and classified as pathogenic (PVS1, PM2, PS2); low-level parental mosaicism was not excluded [6, 40]. The diagnosis of atypical ACD, with focal lung involvement and a response to vasodilators, changed the goals towards intensive treatment and possible referral for transplantation. After pneumonia, bilateral pneumothoraces and prolonged ventilation, catheterisation on day 52 showed only mildly increased pulmonary vascular resistance and a response to nitric oxide and nicardipine. He was discharged on day 67; more than 30 months later he remained on oxygen, sildenafil, bosentan, amlodipine, digoxin, spironolactone and furosemide, had been weaned off subcutaneous treprostinil and had not needed transplantation, with one readmission for respiratory syncytial virus and rhinovirus [40].

The case illustrates three points: the atypical form may manifest after an apparently resolved neonatal period; rapid genome sequencing can replace biopsy in an unstable patient; and genetic diagnosis can point towards treating rather than limiting treatment. The combination of several vasodilators, ECMO and septostomy are the management described in the report and not routine procedures; in the classic form, the guidelines and series point to an early decision between transplantation and palliative care [2, 17]. Figure 1 of the article shows CT before and after vasodilators, with heterogeneous septal thickening and oedema more marked in the right lung (https://pmc.ncbi.nlm.nih.gov/articles/PMC10815270/).

11. Prognosis and Long-term Follow-up

11.1. Prognosis

In the classic form, mortality approaches 100% without transplantation, and death usually occurs in the first month [1, 2]. In-hospital mortality was 86.2% in the PHIS cohort of 58 newborns, and survival to discharge was 3% in newborns with irreversible lung dysplasias treated with ECMO in the ELSO registry [16, 53]. In the review of 165 published cases, mean survival was 7 months without transplantation and 81 months in the ten transplanted patients [19]. In the French series, only 2 of 21 patients had prolonged survival, of 3.3 and 14 months [13]. 1- and 5-year survival of transplanted infants with the atypical form was similar to that of patients transplanted for other indications, and 5-year survival of the seven North American transplanted patients described up to 2018 was 56% [2, 14]. Median survival after paediatric lung transplantation in an international registry is 5.3 years, and 6.4 years in infants [14]. Prolonged survival without transplantation has been described in atypical and hypomorphic forms, up to 30 years [37, 40].

Factors associated with a better outcome are late onset, focal lesions, vasodilator response and, possibly, variants outside the DNA-binding domain; contiguous deletions with severe heart disease and diffuse forms have the worst prognosis [1, 14, 37]. Carriers of a variant may develop PAH in adulthood [37, 39].

11.2. Surveillance

There are no surveillance protocols specific to ACDMPV, and there are no guidelines on the frequency of follow-up catheterisation in paediatric pulmonary hypertension [30]. Table 11.1 brings together the investigations used in the sources for survivors, transplanted patients and carriers.

Table 11.1. Surveillance of survivors, transplanted patients and carriers

12. Summary and Final Considerations

Alveolar capillary dysplasia with misalignment of the pulmonary veins is a disorder of pulmonary vascular development caused by FOXF1 haploinsufficiency, whether through point variants or through deletions that remove the gene or its distal lung enhancer at 16q24.1. Most alterations arise de novo, deletions almost always occur on the maternal chromosome 16, and parental mosaicism and incomplete penetrance make counselling less straightforward than for a sporadic disease. In the classic form, a term newborn develops within hours hypoxaemia with pulmonary hypertension that responds only transiently to nitric oxide and ECMO, often with intestinal malrotation, heart disease or urinary malformations, and mortality approaches 100% without transplantation. The atypical forms, with late onset and focal lesions, may reach lung transplantation, with results comparable to those of other indications, and some hypomorphic variants allow prolonged survival.

Diagnosis is now based on rapid exome or genome sequencing, preferably as a trio and with CNV analysis, as the ATS has recommended since 2026, with the caveat that non-coding deletions, GC-rich regions and mosaicism may escape the usual methods; lung biopsy keeps its place when genetics will not arrive in time, bearing in mind that a single sample may not show patchy lesions. Failure to wean from nitric oxide after 4 days, the need for prolonged ECMO without another cause and disproportionate pulmonary hypertension in an infant are the clinical entry points. Treatment is supportive and there is no targeted therapy outside the laboratory; the essential decisions are early referral for transplantation or a move to palliative care, supported by rapid diagnosis and parental testing, which define the recurrence risk and the options for prenatal and preimplantation diagnosis.

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