Showing papers on "Alveolar capillary dysplasia published in 2019"

The S52F FOXF1 Mutation Inhibits STAT3 Signaling and Causes Alveolar Capillary Dysplasia.

Abstract: Rationale: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal congenital disorder causing respiratory failure and pulmonary hypertension shortly after birth. There are no effective treatments for ACDMPV other than lung transplant, and new therapeutic approaches are urgently needed. Although ACDMPV is linked to mutations in the FOXF1 gene, molecular mechanisms through which FOXF1 mutations cause ACDMPV are unknown.Objectives: To identify molecular mechanisms by which S52F FOXF1 mutations cause ACDMPV.Methods: 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. Immunohistochemistry, whole-lung imaging, and biochemical methods were used to examine vasculature in Foxf1WT/S52F lungs and identify molecular mechanisms regulated by FOXF1.Measurements and Main Results: FOXF1 mutations were identified in 28 subjects with ACDMPV. Foxf1WT/S52F knock-in mice recapitulated histopathologic findings in ACDMPV infants. The S52F FOXF1 mutation disrupted STAT3-FOXF1 protein-protein interactions and inhibited transcription of Stat3, a critical transcriptional regulator of angiogenesis. STAT3 signaling and endothelial proliferation were reduced in Foxf1WT/S52F mice and human ACDMPV lungs. S52F FOXF1 mutant protein did not bind chromatin and was transcriptionally inactive. Furthermore, we have developed a novel formulation of highly efficient nanoparticles and demonstrated that nanoparticle delivery of STAT3 cDNA into the neonatal circulation restored endothelial proliferation and stimulated lung angiogenesis in Foxf1WT/S52F mice.Conclusions: FOXF1 acts through STAT3 to stimulate neonatal lung angiogenesis. Nanoparticle delivery of STAT3 is a promising strategy to treat ACDMPV associated with decreased STAT3 signaling.

Clinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders.

Abstract: Lethal lung developmental disorders are a rare but important group of pediatric diffuse lung diseases presenting with neonatal respiratory failure. On the basis of histopathological appearance at lung biopsy or autopsy, they have been termed: alveolar capillary dysplasia with misalignment of the pulmonary veins, acinar dysplasia, congenital alveolar dysplasia, and other unspecified primary pulmonary hypoplasias. However, the histopathological continuum in these lethal developmental disorders has made accurate diagnosis challenging, which has implications for recurrence risk. Over the past decade, genetic studies in infants with alveolar capillary dysplasia with misalignment of the pulmonary veins have revealed the causative role of the dosage-sensitive FOXF1 gene and its noncoding regulatory variants in the distant lung-specific enhancer at chromosome 16q24.1. In contrast, the molecular bases of acinar dysplasia and congenital alveolar dysplasia have remained poorly understood. Most recently, disruption of the TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling pathway has been reported in patients with these lethal pulmonary dysplasias. Application of next-generation sequencing techniques, including exome sequencing and whole-genome sequencing, has demonstrated their complex compound inheritance. These data indicate that noncoding regulatory elements play a critical role in lung development in humans. We propose that for more precise lethal lung developmental disorder diagnosis, a diagnostic pathway including whole-genome sequencing should be implemented.

Lung Ultrasound to Assess the Etiology of Persistent Pulmonary Hypertension of the Newborn (LUPPHYN Study): A Pilot Study.

Abstract: Introduction Persistent pulmonary hypertension of the newborn (PPHN) is a neonatal syndrome associated with significant morbidity and mortality that is caused by the failure of postnatal drop in pulmonary vascular resistance. In extreme cases, patients may require extracorporeal membrane oxygenation therapy (ECMO). The aim of this study was to explore lung ultrasound (LUS) patterns in newborns with PPHN requiring ECMO. Patients and methods From January 2014 to January 2018, LUS was performed on patients with PPHN admitted for ECMO treatment. PPHN diagnosis was based on clinical and echocardiographic findings. LUS was performed before patients underwent ECMO cannulation. An underlying diagnosis was made taking into account the patient's complete medical history, excluding LUS information. A blinded physician, unaware of the patient's clinical condition, analyzed the stored ultrasound images. Results were then compared with chest x-ray (CXR) diagnoses. Results Seventeen patients were recruited; 12 were male (70.6%). The median gestational age was 38.7 weeks, with 13 term newborns (76.5%). Twelve were cannulated for VA ECMO, with a median ECMO run of 111.2 h. Six patients (35%) survived. Patients with alveolar capillary dysplasia with misaligned pulmonary veins, fetal ductus arteriosus constriction, or sepsis had normal LUS patterns (A-lines with lung sliding). LUS showed a better sensitivity (88.9%) and specificity (85%) than CXR (55.6 and 77.5%, respectively) in identifying patients with nonparenchymal lung disease. Conclusions LUS can provide essential information to help diagnose the underlying cause of PPHN in an earlier and more effective way than CXR. LUS is suitable for routine utilization in the intensive care unit.

Alveolar capillary dysplasia with misalignment of the pulmonary veins and hypoplastic left heart sequence caused by an in frame deletion within FOXF1

Abstract: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a rare, autosomal dominant disorder of interstitial lung development, leading to pulmonary hypertension, and death in infancy. Associated features include malformations of the heart, gastrointestinal tract, and genitourinary system. ACDMPV is caused by heterozygous variants in the FOXF1 gene or microdeletions involving FOXF1. We present a male infant with ACDMPV, hypoplastic left heart sequence (HLHS), duodenal atresia, and imperforate anus due to a de novo, in frame deletion in FOXF1: c.209_214del (p.Thr70_Leu71del). Previous reports have suggested that microdeletions involving FOXF1 are associated with ACDMPV with congenital heart defects, including HLHS, gastrointestinal atresias, and other anomalies; whereas likely pathogenic variants within FOXF1 have not been reported with ACDMPV and HLHS. This is the first patient reported with ACDMPV, HLHS, imperforate anus, and duodenal atresia associated with a likely pathogenic variant in the FOXF1 gene.

Successful lung donation at the age of 6 weeks: Challenges and lessons learned.

Abstract: A clinical case of successful procurement and transplantation of bilateral lungs from 6-week-old infant with sepsis secondary to bacterial meningitis is reported. Forty-one-day-old male infant (height 60 cm, weight 4 kg) died of cerebral edema secondary to Escherichia coli meningitis and bacteremia. Preretrieval assessment included the following: arterial gases; pO2 50.4 kPa (378 mm Hg), pCO2 4.9 kPa (37 mm Hg), on FiO2 100%, PEEP 5 cm H2 O. Fiberoptic bronchoscopy showed no secretions nor mucosal inflammation; CXR revealed clear lung fields and pleural spaces. Inspection revealed dense adhesions in pericardial cavity and purulent left hemithorax effusion (urgent Gram-stain came back as negative) but there was no consolidation in the lung. Good compliance of the lungs on inflation/deflation test was observed. The lungs were retrieved using the technique described. The recipient was a 4-month-old infant with alveolar capillary dysplasia and malaligned pulmonary veins. Implantation of the lungs was performed via bilateral thoracosternotomy on cardiopulmonary bypass, cooling to 30°C. Elective support with nitric oxide was used postoperatively. Two years after the transplantation, the recipient doing well with normal lung function. Lung procurement from a 6-week donor with infectious complications and prolonged ventilation is a challenging undertaking but can be successful and should be attempted whenever possible given the paucity of organs available for pediatric recipients.

A recurrent 8 bp frameshifting indel in FOXF1 defines a novel mutation hotspot associated with alveolar capillary dysplasia with misalignment of pulmonary veins

Abstract: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal lung developmental disease. Affected infants manifest with severe respiratory distress and refractory pulmonary hypertension and uniformly die in the first month of life. Heterozygous point mutations or copy-number variant deletions involving FOXF1 and/or its upstream lung-specific enhancer on 16q24.1 have been identified in the vast majority of ACDMPV patients. We have previously described two unrelated families with a de novo pathogenic frameshift variant c.691_698del (p.Ala231Argfs*61) in the exon 1 of FOXF1. Here, we present a third unrelated ACDMPV family with the same de novo variant and propose that a direct tandem repeat of eight consecutive nucleotides GCGGCGGC within the ~ 4 kb CpG island in FOXF1 exon 1 is a novel mutation hotspot causative for ACDMPV.

A Step toward Treating a Lethal Neonatal Lung Disease. STAT3 and Alveolar Capillary Dysplasia.

Abstract: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a rare lethal lung developmental disorder in which the majority of affected infants present with neonatal respiratory failure and severe pulmonary hypertension that is refractory to treatment (1, 2). Pathologically, the disease is characterized by a paucity of distal capillaries and the presence of “misaligned” veins—pulmonary veins located within the same bronchovascular sheath as the pulmonary artery and airway (2). Recently, it has been shown that these misaligned veins are actually anastomotic shunt vessels (3). Most affected infants also have abnormalities in other organ systems, including the cardiac, gastrointestinal, and genitourinary systems (2, 4). Over the past several years, children with milder forms of ACDMPV who present later and survive longer with anti–pulmonary hypertensive therapies have been increasingly recognized, although the prognosis is still poor, with lung transplantation being the only available long-term therapy (5, 6). A breakthrough in understanding the cause of ACDMPV came with the discovery that genic deletions of and mutations in the FOXF1 (forkhead box F1) gene account for the majority of ACDMPV cases (7). FOXF1 is a transcription factor essential for vascular development. Homozygous foxf1-null mice are embryonic lethal because of abnormal vascular development of the allantois and yolk sac (8). Haploinsufficient foxf1 mice recapitulate some of the features of ACDMPV, with affected animals having lung hypoplasia and reduced angiogenesis, abnormal gall bladder morphogenesis, and increased (but not universal) perinatal mortality. Interestingly the pathology of foxf1 mice does not include findings of misaligned pulmonary veins, as seen in the human disorder (8). Haploinsufficiency is the presumed mechanism for FOXF1mutations causing human lung disease, as disease results from monoallelic gene deletions and null (nonsense and frameshift) mutations (4, 7). Regulation of FOXF1 is complex, as disease-associated mutations are clustered within the DNA-binding domain of FOXF1, and deletions in the 59 untranslated region involving two long noncoding RNAs also result in the phenotype of ACDMPV (9). In this issue of the Journal, Pradhan and colleagues (pp. 1045– 1056) expand our knowledge of the molecular mechanisms by which FOXF1 mutations cause disease and offer a glimmer of hope for treatment for this universally fatal disorder (10). They selected for study a mutation identified in an infant with ACDMPV that resulted in the substitution of phenylalanine for S52F (serine in codon 52). The S52F mutation is located within an evolutionary conserved, frequently mutated, computationally predicted SH2binding domain important for interactions with the protein STAT3 (signal transducer and activator of transcription 3). The authors demonstrated that the S52F-FOXF1 protein did not bind STAT3 in vitro, indicating the importance of the serine at position 52 in the interaction of FOXF1 and STAT3, although several other FOXF1 mutations within another computationally predicted SH2 binding domain (Y284A, I285Q, S291*) did not disrupt FOXF1’s interaction with STAT3. They then used CrispR/Cas9 to generate a mouse model with one allele expressing the S52F mutation. Perinatal mortality was increased in the wild type (WT)/S52F mice, although, similar to foxf1 mice, it was not uniformly lethal, and the reasons some WT/S52F pups survive remains unclear. However, this murine model largely recapitulates the histopathology of the human phenotype, including pulmonary hypoplasia, misaligned pulmonary veins, pulmonary arterial hypertrophy, and alveolar simplification. Furthermore, decreased transcription of both the FOXF1 and STAT3 genes, as well as decreased transcription of additional downstream target genes important in endothelial cell proliferation and angiogenesis, was observed in the lungs of WT/S52F mice. Finally, they used nanoparticles to deliver STAT3 complementary DNA intravascularly into newborn WT/S52F mice and demonstrated efficient targeting of lung endothelial cells with increased STAT3 protein and phosphorylation, increased expression of endothelial cell markers indicating improved angiogenesis, improved alveogenesis, and decreased inflammation. Whether there was increased survival or improved lung function in treated mice was unaddressed. Although ACDMPV is a rare disease, with the recognition of the causative role of FOXF1 mutations and deletions, clinical genetic testing is now routinely available, allowing for noninvasive diagnosis. As a result, the number of identified cases has increased dramatically in recent years, as exemplified by the additional 28 cases included in the report (10). Could delivery of STAT3 complementary DNA using nanoparticles, which are being used in clinical trials for human malignancies, be used to treat human infants with ACDMPV? There are several important potential limitations and barriers to this approach. First, it is not clear how many other FOXF1mutations disrupt interactions with STAT3 and are associated with decreased STAT3 signaling, as the authors’ data with respect to several other mutations indicated that they did not interfere with FOXF1–STAT3 interactions. Interestingly, decreased phosphorylated STAT3 was observed in human lung tissue from an infant with an unrelated FOXF1 frameshift mutation downstream of the first STAT3 consensus binding sequence. Augmenting STAT3 signaling might thus be an effective approach for some FOXF1 mutations, as well as an approach that could be applied to augment other downstream signaling critical for angiogenesis. A more practical barrier is that ACDMPV usually arises as a sporadic disorder due to de novo mutations (4, 9). Although familial cases are recognized and prenatal diagnosis has been performed (11), these cases are the exceptions. Most infants present after birth with respiratory failure and persistent pulmonary hypertension, which may result from other disease mechanisms. Even if the diagnosis is suspected initially, confirmatory genetic studies may take several weeks, and affected infants may die before a diagnosis is confirmed. By the time the diagnosis is established for surviving infants, secondary lung damage from oxygen toxicity and ventilator-induced This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern (dgern@thoracic.org).

Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV): A Case Series

Abstract: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a disorder affecting the development of the lungs and their blood vessels. The disorder affects the millions of small air sacs (alveoli) in the lungs and the tiny blood vessels (capillaries) in the alveoli. It is through these alveolar capillaries that inhaled oxygen enters the bloodstream for distribution throughout the body and carbon dioxide leaves the bloodstream to be exhaled.