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Compromised alveolar development and pulmonary vascular remodeling are hallmarks of pediatric lung diseases such as bronchopulmonary dysplasia (BPD) and alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Although advances in surfactant therapy, corticosteroids, and antiinflammatory drugs have improved clinical management of preterm infants, those who suffer with severe vascular complications still lack viable treatment options. Paucity of the alveolar capillary network in ACDMPV causes respiratory distress and leads to mortality in a vast majority of infants with ACDMPV. The discovery of endothelial progenitor cells (EPCs) in 1997 brought forth the paradigm of postnatal vasculogenesis and hope for promoting vascularization in fragile patient populations, such as those with BPD and ACDMPV. The identification of diverse EPC populations, both hematopoietic and nonhematopoietic in origin, provided a need to identify progenitor cell–selective markers that are linked to progenitor properties needed to develop cell-based therapies. Focusing on the future potential of EPCs for regenerative medicine, this review will discuss various aspects of EPC biology, beginning with the identification of hematopoietic, nonhematopoietic, and tissue-resident EPC populations. We will review knowledge related to cell surface markers, signature gene expression, and key transcriptional regulators and will explore the translational potential of EPCs for cell-based therapy for BPD and ACDMPV. The ability to produce pulmonary EPCs from patient-derived induced pluripotent stem cells in vitro holds promise for restoring vascular growth and function in the lungs of patients with pediatric pulmonary disorders.

У статті наведено клінічне спостереження дитини 3 місяців з альвеолокапілярною дисплазією, обговорення якого включило термінологічні аспекти, патоморфологічні, діагностичні критерії захворювань, що належать до дифузних порушень розвитку легень. Висвітлено сучасні принципи лікування мальформацій.

Congenital lung disease comes to the attention of the surgical pathologist through lung biopsy or excision of a lung lobe. The two most frequent clinical indications are removal of a mass, often detected antenatally, or investigation of difficulty in ventilation or oxygenation. The diagnostic possibilities in each instance are different. The mass is most commonly a cystic airway malformation, but a limited number of rare neoplasms enters the differential diagnosis. Biopsy in the case of difficulty in ventilation most often shows delayed alveolar development, but surfactant protein disorder and a small number of lethal developmental abnormalities must be excluded. This review offers a conceptual framework to the general histopathologist confronted with such specimens and presents an approach to assessment in order to achieve the maximum information from the specimen. Correlation with clinical features and radiology is vital.

Rationale: Although pulmonary endothelial progenitor cells (EPCs) hold promise for cell-based therapies for neonatal pulmonary disorders, whether EPCs can be derived from pluripotent embryonic stem...

The pulmonary alveolocapillary dysplasia (ACD) with pulmonary vein misalignment (PVM) is a rare condition characterized by a congenital anomaly of the development of the pulmonary parenchyma. We present a case of an 8-month-old infant who died quickly from acute respiratory failure complicating an unknown ACD. We also describe its epidemiological characteristics in infants and we discuss the diagnosis's difficulties. In this case, a pulmonary arterial hypertension was decompensated by an infection. A medico-legal autopsy was performed. As for the Histological examination, it showed the features of ACD/PVM.

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare, lethal condition caused by irregular pulmonary vascular maturation. Almost all cases present in the newborn period with ensuing respiratory decline within a couple days of life, ultimately leading to nearly 100% neonatal mortality. While the gold standard for diagnosis is lung biopsy, the identification of the Forkhead Box F1 (FOXF1) gene as the main genetic cause of ACD/MPV has allowed for a definitive diagnosis to be made without performing a high-risk procedure in a critically-ill neonate. This case report describes an ACD/MPV patient with hyperinsulinemia and refractory hypoglycemia as well as multiple anomalies who was found to have a novel pathogenic variant in the FOXF1 gene, identified via exome with copy number analysis, which results in premature protein termination (NM 001451.2 c.637 dup, p.Val213Glyfs*82). Our patient showcases the importance of early genetic testing to diagnose ACD/MPV given the substantial risk in obtaining a lung biopsy in a patient with hypoxemic respiratory failure, severe pulmonary hypertension, and vasodilator-induced pulmonary edema.

First trimester ultrasound screening is an essential fetal examination performed generally at 11-13 weeks of gestation (WG). However, it does not allow for an accurate description of all fetal organs, partly due to their development in progress. Meanwhile, increased nuchal translucency (INT) is a widely used marker known to be associated with chromosomal deleterious rearrangements. We report on a 14 WG fetus with an association of INT and univentricular congenital heart malformation (CHM) leading to chorionic villous sampling (CVS). Cytogenetic investigations performed using array-Comparative Genomic Hybridization (CGH) and fluorescence in situ hybridization (FISH) demonstrated a 1.17 Mb deletion in 16q24.1 encompassing FOXF1 arisen de novo on maternal inherited chromosome. Fetopathological study confirmed CHM with hypoplastic left heart syndrome (HLHS) associating aortic atresia, mitral stenosis, and left ventricular hypoplasia and revealed in addition specific lung lesions corresponding to alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). This is so far the first case of first trimester prenatal diagnosis of ACDMPV due to the deletion of FOXF1 gene. An interpretation of the complex genomic data generated by ultrasound markers is facilitated considerably by the genotype-phenotype correlations on fetopathological examination.

Interstitial lung disease in children (chILD) is rare and encompasses more than 200 entities, with new especially genetic causes being discovered. Several classifications have been proposed, and there is considerable overlap with entities which present in adult life. Presentation may be shortly after birth with acute respiratory distress and in infancy and childhood either with a primary respiratory presentation or with systemic symptoms such as poor feeding and failure to thrive. Newborn acute presentations are usually due either to a mutation in one of the surfactant protein (Sp) genes or the alveolar capillary dysplasia (ACD)-congenital alveolar dysplasia (CAD) spectrum. The latter usually progress rapidly to extracorporeal membrane oxygenation, and early lung biopsy is advisable to prevent prolonged futile treatment being offered. Outside the newborn period, a staged protocol for investigation is proposed. This starts with a computed tomography scan, which confirms or otherwise the presence of chILD, and occasionally can lead to a specific diagnosis. In particular in settings where there is a high burden of infection, infective mimics of chILD need to be excluded. The next investigations aim to try to move from pattern recognition to specific diagnoses, both genetic and environmental. The speed of progression to lung biopsy will depend on the clinical state of the child, and the biopsy itself may suggest a hunt for a new underlying cause, such as immunodeficiency. Specific genetic causing chILD includes mutations in SpB and SpC and processing genes (thyroid transcription factor-1 [TTF-1] and adenosine triphosphate-binding cassette subfamily A) (the last three can present at any time in the life course); genes involved in Sp catabolism (granulocyte-macrophage colony factor receptor A and B genes), an increasing number implicated in the ACD-CAD spectrum, and other non-Sp related genes such as Filamin-A and integrin genes. Environmental causes are also important and vary across the world. Vaping has been implicated as causing a large number of chILDs, and a vaping history is essential in any young person with an unusual respiratory illness. Medications, both prescribed and over-the-counter such as oily laxatives, are also causes of chILD. There are important conditions of unknown cause presenting in early childhood. Neuroendocrine cell hyperplasia of infancy (NEHI) and pulmonary interstitial glycogenosis generally have a good prognosis, and are probably best considered as part of a spectrum of pulmonary dysmaturity syndromes, in some of which underlying gene mutations have been detected, for example, TTF-1 for NEHI. Pulmonary alveolar proteinosis is an example of an umbrella description, which may present at any age, and has a number of underlying causes with different specific treatments, underscoring the need to move from pattern recognition to specific diagnoses. chILDs have important implications for adult physicians; there may be late as yet poorly described sequelae of the disease or its treatment in adult life; there may be genetic implications for the wider family; and there may be late chILD relapses. Smooth transition to adult services is essential for all chILD survivors, with pediatric and adult chest physicians working closely together.

Neonatal lung biopsy guides important medical decisions when the diagnosis is not clear from prior clinical assessment, imaging, or genetic testing. Common scenarios that lead to biopsy include severe acute respiratory distress in a term neonate, pulmonary hypertension disproportionate to that expected for gestational age or known cardiac anomalies, and assessment of suspected genetic disorder based on clinical features or genetic variant of unknown significance. The differential diagnosis includes genetic developmental disorders, genetic surfactant disorders, vascular disorders, acquired infection, and meconium aspiration. This article describes pathologic patterns in the neonatal lung and correlation with molecular abnormalities, where appropriate.

A patient with alveolar capillary dysplasia has survived more than 56 months with medical therapy. Intrauterine exposure to metformin potentially modified the severity of disease. In combination with other agents, endothelin receptor antagonists and amlodipine have been key medications in lowering pulmonary arterial pressure and managing right heart failure. (Level of Difficulty: Beginner.), Graphical abstract, A patient with alveolar capillary dysplasia has survived more than 56 months with medical therapy. Intrauterine exposure to metformin potentially…

A newborn infant patient presented with persistent pulmonary hypertension. For right ventricular decompression, the ductus arteriosus was kept open by prostaglandin E1 infusion and was stented at the age of 4 weeks during heart catheterization. The child was weaned from mechanical ventilation, since pulmonary functions were adequate. A small atrial septal defect was identified and closed in cardiac catheterization laboratory to decrease preductal hypoxemia. Diagnostic workup led to the diagnosis of alveolar capillary dysplasia with misalignment of the pulmonary veins. Suprasystemic pulmonary arterial hypertension with persisting nitric oxide dependency remained the leading symptoms. The child underwent bilateral lung transplantation at the age of 28 months. He is well at the age of 44 months.

This is a case report of a successful single-lobe lung transplantation for pulmonary hypertension secondary to alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV). A 6-year-old boy underwent living-donor single-lobe transplantation with the right lower lobe from his 31-year-old mother. The pretransplantation graft size matching was acceptable: the estimated graft forced vital capacity (FVC) was 96.5% of the recipient's predicted FVC, and the graft size measured by computed tomography (CT) volumetry was 166% of the recipient's chest cavity volume. Right pneumonectomy followed by implantation was performed under cardiopulmonary bypass (CPB). The pulmonary arterial pressure was significantly decreased to 31/12 mm Hg immediately after transplantation, and the first PaO2 /FiO2 in the intensive-care unit (ICU) was 422 mm Hg. Lung perfusion scintigraphy showed 97.5% perfusion to the right implanted lung 3 months after transplantation. Chest CT showed a mass rapidly growing in the native left upper lobe 6 months after transplantation, which was diagnosed as posttransplant lymphoproliferative disorder (PTLD) by a CT-guided biopsy. After immunosuppressant reduction and six courses of chemotherapy with rituximab, he underwent native left upper lobectomy for salvage lung resection 13 months after transplantation. Seven months after lobectomy, he has returned to normal school life without any sign of tumor recurrence.

Background: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a lethal congenital lung disorder associated with heterozygous variants in the FOXF1 gene or its regulatory region. Patients with ACD/MPV unnecessarily undergo invasive and expensive treatments while awaiting a diagnosis. The aim of this study was to reduce the time to diagnose ACD/MPV by developing a targeted next-generation sequencing (NGS) panel that detects FOXF1 variants. Methods: A FOXF1-targeted NGS panel was developed for detection of mutations and large genomic alterations and used for retrospective testing of ACD/MPV patients and controls. Results were confirmed with Sanger sequencing and SNP array analysis. Results: Each amplicon of the FOXF1-targeted NGS panel was efficiently sequenced using DNA isolated from blood or cell lines of 15 ACD/MPV patients and 8 controls. Moreover, testing of ACD/MPV patients revealed six novel and six previously described pathogenic or likely pathogenic FOXF1 alterations. Conclusion: We successfully designed a fast and reliable targeted genetic test to detect variants in the FOXF1 gene and its regulatory region in one run. This relatively noninvasive test potentially prevents unnecessary suffering for patients and reduces the use of futile and expensive treatments like extra-corporeal membrane oxygenation. Impact: FOXF1-targeted NGS potentially prevents ACD/MPV patients from unnecessary suffering and expensive treatments.FOXF1-targeted NGS potentially reduces the number of misdiagnosis in ACD/MPV patients.Retrospective testing of ACD/MPV patients using FOXF1-targeted NGS revealed six novel pathogenic or likely pathogenic variants.

Alveolar capillary dysplasia with misalignment of the pulmonary veins is an uncommon disorder that affects the lung vasculature development in the neonatal period and leads to pulmonary hypertension. We describe two patients with alveolar capillary dysplasia associated with left-sided obstructive heart defects with two different genetic variants. Our cases highlight the importance of early recognition of this disease in the setting of persistent and supra-systemic pulmonary hypertension despite surgical correction of the associated lesions. Identification of these cases will facilitate the development of a multidisciplinary approach and provide guidance to the affected families.

This study aimed to explore the value of synchrotron-based phase-contrast microcomputed tomography (micro-CT) in pulmonary vascular pathobiology. The microanatomy of the lung is complex with intricate branching patterns. Tissue sections are therefore difficult to interpret. Recruited intrapulmonary bronchopulmonary anastomoses (IBAs) have been described in several forms of pulmonary hypertension, including alveolar capillary dysplasia with misaligned pulmonary veins (ACD/MPV). Here, we examine paraffin-embedded tissue using this nondestructive method for high-resolution three-dimensional imaging. Blocks of healthy and ACD/MPV lung tissue were used. Pulmonary and bronchial arteries in the ACD/MPV block had been preinjected with dye. One section per block was stained, and areas of interest were marked to allow precise beam-alignment during image acquisition at the X02DA TOMCAT beamline (Swiss Light Source). A ×4 magnifying objective coupled to a 20-µm thick scintillating material and a sCMOS detector yielded the best trade-off between spatial resolution and field-of-view. A phase retrieval algorithm was applied and virtual tomographic slices and video clips of the imaged volumes were produced. Dye injections generated a distinct attenuation difference between vessels and surrounding tissue, facilitating segmentation and three-dimensional rendering. Histology and immunohistochemistry post-imaging offered complementary information. IBAs were confirmed in ACD/MPV, and the MPVs were positioned like bronchial veins/venules. We demonstrate the advantages of using synchrotron-based phase-contrast micro-CT for three-dimensional characterization of pulmonary microvascular anatomy in paraffin-embedded tissue. Vascular dye injections add additional value. We confirm intrapulmonary shunting in ACD/MPV and provide support for the hypothesis that MPVs are dilated bronchial veins/venules.

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.

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 Foxf1(WT/S52F) lungs and identify molecular mechanisms regulated by FOXF1. Measurements and Main Results: FOXF1 mutations were identified in 28 subjects with ACDMPV. Foxf1(WT/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 Foxf1(WT/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 Foxf1(WT/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.

Pediatric pulmonary hypertension (PPH) is a multifactorial disease with diverse etiologies and presenting features. Pulmonary hypertension (PH), defined as elevated pulmonary artery pressure, is the presenting feature for several pulmonary vascular diseases. It is often a hidden component of other lung diseases, such as cystic fibrosis and bronchopulmonary dysplasia. Alterations in lung development and genetic conditions are an important contributor to pediatric pulmonary hypertensive disease, which is a distinct entity from adult PH. Many of the causes of pediatric PH have prenatal onset with altered lung development due to maternal and fetal conditions. Since lung growth is altered in several conditions that lead to PPH, therapy for PPH includes both pulmonary vasodilators and strategies to restore lung growth. These strategies include optimal alveolar recruitment, maintaining physiologic blood gas tension, nutritional support, and addressing contributing factors, such as airway disease and gastroesophageal reflux. The outcome for infants and children with PH is highly variable and largely dependent on the underlying cause. The best outcomes are for neonates with persistent pulmonary hypertension (PPHN) and reversible lung diseases, while some genetic conditions such as alveolar capillary dysplasia are lethal. © 2021 American Physiological Society. Compr Physiol 11:2135-2190, 2021.

Background: Pulmonary hypertension (PH) is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the FOXF1 gene. Although the loss of alveolar microvasculature causes PH in patients with ACDMPV, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy. Methods: We used echocardiography, RV catheterization, immunostaining, and biochemical methods to examine lung and heart remodeling and RV output in Foxf1 WT/S52F mice carrying the S52F Foxf1 mutation (identified in patients with ACDMPV). The ability of Foxf1 WT/S52F mutant embryonic stem cells to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a nonintegrating Stat3 expression vector was used to improve neonatal pulmonary angiogenesis in Foxf1 WT/S52F mice and determine its effects on PH and RV hypertrophy. Results: Foxf1 WT/S52F mice developed PH and RV hypertrophy after birth. The severity of PH in Foxf1 WT/S52F mice directly correlated with mortality, low body weight, pulmonary artery muscularization, and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse embryonic stem cells carrying the S52F Foxf1 mutation were used to produce chimeras through blastocyst complementation and to demonstrate that Foxf1 WT/S52F embryonic stem cells have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying Stat3 cDNA protected Foxf1 WT/S52F mice from RV hypertrophy and PH, improved survival, and decreased fibrotic lung remodeling. Conclusions: Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.

Background Alveolar capillary dysplasia (ACD) is a rare cause of severe pulmonary hypertension and respiratory failure in neonates. The onset of ACD is usually preceded by a short asymptomatic period. The condition is refractory to all available therapies as it irreversibly affects development of the capillary bed in the lungs. The diagnosis of ACD is based on histopathological evaluation of lung biopsy or autopsy tissue or genetic testing of FOXF1 on chromosome 16q24.1. Here, we describe the first two Polish patients with ACD confirmed by histopathological and genetic examination. Case presentation The patients were term neonates with high Apgar scores in the first minutes of life. They both were diagnosed prenatally with heart defects. Additionally, the first patient presented with omphalocele. The neonate slightly deteriorated around 12th hour of life, but underwent surgical repair of omphalocele followed by mechanical ventilation. Due to further deterioration, therapy included inhaled nitric oxide (iNO), inotropes and surfactant administration. The second patient was treated with prostaglandin E1 since birth due to suspicion of aortic coarctation (CoA). After ruling out CoA in the 3rd day of life, infusion of prostaglandin E1 was discountinued and immediately patient’s condition worsened. Subsequent treatment included re-administration of prostaglandin E1, iNO and mechanical ventilation. Both patients presented with transient improvement after application of iNO, but died despite maximized therapy. They were histopathologically diagnosed post-mortem with ACD. Array comparative genomic hybridization in patient one and patient two revealed copy-number variant (CNV) deletions, respectively, ~ 1.45 Mb in size involving FOXF1 and an ~ 0.7 Mb in size involving FOXF1 enhancer and leaving FOXF1 intact. Conclusions Both patients presented with a distinct course of ACD, extra-pulmonary manifestations and response to medications. Surgery and ceasing of prostaglandin E1 infusion should be considered as potential causes of this variability. We further highlight the necessity of thorough genetic testing and histopathological examination and propose immunostaining for CD31 and CD34 to facilitate the diagnostic process for better management of infants with ACD.

Background Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare disorder of pulmonary vascular abnormality with persistent pulmonary hypertension of the newborn. The symptom usually presents within hours after birth, leading to an early demise. Heterozygous de novo point mutations and genomic deletions of the FOXF1 (forkhead box F1) gene or its upstream enhancer have been identified in most patients with ACD/MPV. Most cases of ACD/MPV are sporadic; however, familial cases are also reported in 10% of patients. Case presentation We herein report a case of familial ACD/MPV that showed unusual glomeruloid proliferation of endothelial cells. In this family, three of the four siblings died within two to 3 days after birth because of persistent pulmonary hypertension and respiratory failure. Only the second child remains alive and healthy. An autopsy was performed for the third and fourth children, resulting in a diagnosis of ACD/MPV based on the characteristic features, including misalignment of smaller pulmonary veins and lymphangiectasis. In both of these children, glomeruloid endothelial proliferation of vessels was noted in the interlobular septa. The vessels were immunohistochemically positive for D2–40, CD31, Factor VIII, and ERG, suggestive of differentiation for both lymphatic and blood vessels. Conclusions Unusual glomeruloid endothelial proliferation was observed in a familial ACD/MPV case. This histologic feature has not been described previously in ACD/MPV or any other pulmonary disease. Although the histogenesis of this histologic feature is unclear, this finding may suggest that ACD/MPV is a compound vascular and lymphovascular system disorder that exhibits various histologic features.

The term 'interstitial lung disease' (ILD) refers to a group of disorders involving both the airspaces and tissue compartments of the lung, and these disorders are more accurately termed diffuse lung diseases. Although rare, they are associated with significant morbidity and mortality, with the prognosis depending upon the specific diagnosis. The major categories of ILD in children that present in the neonatal period include developmental disorders, growth disorders, surfactant dysfunction disorders, and specific conditions of unknown etiology unique to infancy. Whereas lung histopathology has been the gold standard for the diagnosis of ILD, as many of the disorders have a genetic basis, non-invasive diagnosis is feasible, and characteristic clinical and imaging features may allow for specific diagnosis in some circumstances. The underlying mechanisms, clinical, imaging, and lung pathology features and outcomes of ILD presenting in newborns are reviewed with an emphasis on genetic mechanisms and diagnosis.

Key Clinical Message Alveolar capillary dysplasia (ACD) is a rare condition with variable presentation and clinical course. Clinicians should consider this diagnosis in neonates presenting with nonlethal congenital gastrointestinal malformation, a period of well‐being after birth then unremitting hypoxemia and refractory pulmonary hypertension. Lung biopsy and FOXF1 gene testing may help in diagnosis.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is an autosomal dominant, fatal developmental disorder of the lungs, with a mortality rate of about 100%. ACD/MPV is caused by mutations in FOXF1. Herein, we describe a newborn boy with ACD/MPV carrying a novel pathogenic variant of FOXF1. The patient developed respiratory distress and severe pulmonary hypertension on the first day of life. Despite aggressive cardiorespiratory management, including veno-venous extracorporeal membrane oxygenation, his condition deteriorated rapidly, and he died within the first month of his life. Lung histology showed the characteristic features of ACD/MPV at autopsy. Sequence analysis of FOXF1 from genomic DNA obtained from autopsied lung tissue revealed that the patient was heterozygous for a novel missense variant (c.305T>C; p.Leu102Pro). Further analysis of both parents confirmed the de novo occurrence of the variant. To the best of our knowledge, this is the first report of genetically confirmed ACD/MPV in Korea.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare but fatal lung disorder, which causes persistent pulmonary hypertension of the newborn (PPHN) and which is unresponsive to treatment. We report the case of two siblings, both of whom died a few hours after birth because of severe pulmonary failure. Post-mortem histology confirmed ACD/MPV as the cause of death in both cases, and genetic analysis identified the same 16p13.3 deletion. ACD/MPV can occur suddenly in apparently healthy newborns after a regular pregnancy, and always leads to death. Nevertheless, an autopsy is not always performed after the death of an infant. For these reasons ACD/MPV represents a challenge for diagnosis and therapeutic management with medicolegal implications. Prenatal assessment of ACD/MPV is very difficult, and it should be suspected when irreversible and persistent fetal circulation occurs rapidly in newborns. An early diagnosis during pregnancy would facilitate adequate counselling regarding treatment and prognosis. When death occurs, a complete autopsy with histological and genetic investigations is recommended in order to define the exact cause of death, and potentially inform appropriate genetic counselling of family members who could be affected by hereditary disorders.

Genomic medicine is of increasing importance in all medical specialties, including pediatric pulmonology. Lung manifestations commonly observed in the pediatric pulmonary clinic are often multifactorial in origin, but phenotypes, including neonatal respiratory distress, interstitial lung disease, bronchiectasis, pulmonary fibrosis, vascular abnormalities, and pneumothorax, have a strong association to certain genetic conditions, and a genetic differential diagnosis should be considered in these patients. This chapter discusses the clinical features and radiological findings of several childhood onset genetic conditions with significant respiratory involvement. Conditions reviewed include surfactant deficiencies, brain-lung-thyroid syndrome, pulmonary alveolar proteinosis, primary ciliary dyskinesia, immune deficiencies, short telomere syndromes, Hermansky Pudlak syndrome, alveolar capillary dysplasia, pulmonary arterial hypertension, hereditary hemorrhagic telangiectasia, connective tissue disorders, and Birt-Hogg-Dube syndrome.

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.

We present a male infant with alveolar capillary dysplasia without misalignment of pulmonary veins, hyperinflammation, megalocornea and macrosomia/macrocephaly at birth. Whole-exome sequencing revealed a homozygous 2bp-insertion in the latent transforming growth factor-beta binding protein 2 (LTBP2) (c.278_279dup, p.(Ser94Glyfs*187)). So far, LTBP2-variants have been frequently reported with an eye-restricted phenotype including primary congenital glaucoma and megalocornea/microspherphakia and ectopia lentis with/without secondary glaucoma. Hitherto reported systemic phenotypes showed, among others, features as tall stature, finger anomalies, high-arched palate and cardiovascular anomalies. The main pathophysiological finding of our patient was an alveolar capillary dysplasia (with pulmonary arterial hypertension and right ventricular impairment but without misalignment of pulmonary veins) resulting in almost continuous oxygen demand and prolonged dependence on mechanical ventilation. He died of respiratory failure at the age of seven months. This patient may extend the LTBP2-related phenotype with resulting diagnostic implications.

Rationale Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare congenital malformation in neonates that results in severe respiratory distress and pulmonary hypertension. ACD/MPV is caused by mutations in the FOXF1 gene. Herein, a new case of a girl with ACD/MPV carrying a novel pathogenic variant of FOXF1 was reported. Patient concerns A 3-month-old Chinese girl was admitted to the hospital presenting a complaint of cyanosis for 10 days and respiratory distress for 2 days. The history of foreign body inhalation was denied. Diagnoses Blood routine, liver and kidney function, electrolytes, type B natriuretic peptide, electrocardiogram, cardiac computed tomography (CT), and echocardiography were done after admission. Dysplasia of the alveolar and the left upper pulmonary vein was displayed through cardiac CT. Echocardiography showed atrial septal defect, tricuspid valve malformation, and pulmonary hypertension. Sequence analysis of FOXF1 from genomic deoxyribonucleic acid (DNA) revealed that the patient was heterozygous for a novel missense variant (c.418 C>T, p.Pro140Gly). Furthermore, genetic analysis of both parents confirmed the de novo occurrence of the variant. Conservation analysis showed that the locus was highly conserved across species. Then, ACD/MPV was a clinical diagnosis. Interventions After admission, nasal catheter oxygen inhalation, cefazoxime sodium, furosemide diuretic, milrinone lactate, and Bosentan were given to the patient. Outcomes After 6 days of hospitalization, the patient's condition did not improved, the parents gave up treatment and discharged. The patient died half a month after discharge. Lessons ACD/MPV is a rare congenital malformation with a poor prognosis. A new de novo mutation of FOXF1 was found in our case. Non-invasive methods such as DNA sequencing and FOXF1 analysis are helpful in the clinical diagnosis of ACD/MPV especially in early infants with respiratory distress and pulmonary hypertension.

Background Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare and fatal disorder that occurs in the developing fetal lungs; at birth, infants exhibit an oxygenation disorder accompanied by severe pulmonary hypertension (PH) and have a very short life span. ACDMPV is definitively diagnosed by pathological findings, and infants born with unexplained severe PH may not be properly diagnosed without a biopsy or autopsy. Methods Japanese infants with unexplained severe PH were enrolled in this study. Genetic analyses were performed on DNA extracted from peripheral blood leukocytes. Sanger sequencing or next-generation sequencing was performed by coding exons and introns for FOXF1 in all samples. For individuals without pathogenic exonic variants, multiplex ligation-dependent probe amplification was performed to identify copy number variations (CNVs) in exons, introns, and in the upstream region of FOXF1. Results This study included 30 infants who were diagnosed over the course of nine years. Four individuals had the pathogenic variations on the exon 1 of FOXF1, including two frameshift and two missense variations. Pathogenic CNVs were found in another five individuals. Conclusion In the pathologically proven ACDMPV patients, the ratios of cases with exonic variations, CNVs, and no genetic findings were reported as 45%, 45% and 10%, respectively. We estimate that about 30% (10 (9 + 1) out of 30) of individuals with unexplained severe PH had ACDMPV.

Introduction.Failure of the vascular pulmonary remodeling at birth often manifests as pulmonary hypertension (PHT) and is associated with a variety of neonatal lung disorders including a uniformly fatal developmental disorder known as alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV). Serum serotonin regulation has been linked to pulmonary vascular function and disease, and serotonin transporter (SERT) is thought to be one of the key regulators in these processes. We sought to find evidence of a role that SERT plays in the neonatal respiratory adaptation process and in the pathomechanism of ACD/MPV.Methods.We used histology and immunohistochemistry to determine the timetable of SERT protein expression in normal human fetal and postnatal lungs and in cases of newborn and childhood PHT of varied etiology. In addition, we tested for a SERT gene promoter defect in ACD/MPV patients.Results.We found that SERT protein expression begins at 30 weeks of gestation, increases to term, and stays high postnatally. ACD/MPV patients had diminished SERT expression without SERT promoter alteration.Conclusion.We concluded that SERT/serotonin pathway is crucial in the process of pulmonary vascular remodeling/adaptation at birth and plays a key role in the pathobiology of ACD/MPV.

Contains fulltext : 170587.pdf (Publisher’s version ) (Closed access) BACKGROUND: Open lung biopsy can help differentiate between reversible and irreversible lung disease and may guide therapy. To assess the risk-benefit ratio of this procedure in pediatric extracorporeal membrane oxygenation (ECMO) patients, we reviewed data of all patients who underwent an open lung biopsy during ECMO in one of the two pediatric ECMO centers in a nationwide study in the Netherlands. RESULTS: In nineteen neonatal and six pediatric patients (0-15.5years), twenty-five open lung biopsies were performed during the study period. In 13 patients (52%), a classifying diagnosis of underlying lung disease could be made. In another nine patients (36%), specific pathological abnormalities were described. In three patients (12%), only nonspecific abnormalities were described. The histological results led to withdrawal of ECMO treatment in 6 neonates with alveolar capillary dysplasia/misalignment of pulmonary veins (24%) and in another 6 patients, corticosteroids were started (24%). All patients survived the biopsy procedure. Hemorrhagic complications were rare. CONCLUSION: An open lung biopsy during an ECMO run in neonates and children is a safe procedure with a minimum risk for blood loss and biopsy-related death. It can be very useful in diagnosing the underlying pathology and can guide cessation of ECMO treatment and thereby avoid continuation of futile treatment, especially in neonatal patients. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Diagnostic study.

The literature review provides current information on risk factors, clinical features, advanced diagnostic capabilities, prognosis diffuse disorders of growth and development of lung like interstitial lung disease specific to early childhood. Diffuse disorders of growth and development in children assigned to interstitial disease, due to the fact that along with anatomical defects of the lung, there is a significant increase in the interstitial tissue. Diffuse lung development disorders - acinar dysplasia, congenital alveolar dysplasia, and alveolar capillary dysplasia with misalignment of pulmonary veins is a rare condition, clinically manifested in the first hours of life, severe RDS infants, have a poor prognosis. Early diagnosis is essential for determining the management plan and prognosis of the disease. Diffuse lung disorders of growth occur in different states: bronchopulmonary dysplasia, pulmonary pathology in the neonatal period as in full-term baby so, chromosomal anomalies (trisomy 21 chromosome) and congenital heart diseases at chromosomal anomalies, and without them, congenital defects of other organs. Growth disorders formed as prenatally and postnatally and reflective of abnormalities of alveolarization. Pathology and radiology interpretation often noted the presence of emphysematous changes in these cases. The severity of the clinical course, complications, prognosis can vary in different forms. Lung growth disorders are risk factors for recurrent respiratory diseases and contribute to their chronic course.

Summary Background Heterozygous mutations in the FOXF1 transcription factor gene are implicated in alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a developmental disorder of the lungs classically presenting with pulmonary hypertension and early demise. Evidence has suggested haploinsufficiency and partial paternal imprinting. We present a family with several affected members with an extremely variable phenotype. Patients The index patient presented several hours after birth with severe pulmonary hypertension. She is now 3-years old, thriving on maximal pulmonary hypertension therapy, chronic steroids, and oxygen. One of the patient's siblings died at 16 days with pulmonary hypertension and an annular pancreas, consistent with classical ACDMPV. Methods Whole exome sequencing was performed in the index case. The identified variant was confirmed by Sanger sequencing, and tested in the remaining family members. Parental origin was determined by PCR amplification and cloning, sequencing, and identification of adjacent single nucleotide polymorphisms. Echocardiography was performed in the asymptomatic carriers. Results Whole exome analysis revealed a novel, predictably pathogenic heterozygous missense mutation, g.chr16:86544406 C>A NM_001451, c.C231A, p.F77L, in the FOXF1 gene. The mutation arose in the father, de novo, early postzygotically, with 70% somatic mosaicism in the blood, on the grandpaternal chromosome. It was also present in the proband's asymptomatic sister, found to have partial anomalous pulmonary venous return. Conclusion FOXF1 mutations may have an extremely variable phenotype, possibly as a result of somatic mosaicism and complex gene regulation including unorthodox imprinting of the gene locus. The prolonged survival of the proband suggests the need for aggressive treatment. Pediatr Pulmonol. © 2016 Wiley Periodicals, Inc.

Persistent pulmonary hypertension of the newborn (PPHN) is the most common neonatal form and mostly reversible after a few days with improvement of the underlying pulmonary condition. When pulmonary hypertension (PH) persists despite adequate treatment, the severity of parenchymal lung disease should be assessed by chest CT. Pulmonary vein stenosis may need to be ruled out by cardiac catheterisation and lung biopsy, and genetic workup is necessary when alveolar capillary dysplasia is suspected. In PPHN, optimisation of the cardiopulmonary situation including surfactant therapy should aim for preductal SpO2between 91% and 95% and severe cases without post-tricuspid-unrestrictive shunt may receive prostaglandin E1 to maintain ductal patency in right heart failure. Inhaled nitric oxide is indicated in mechanically ventilated infants to reduce the need for extracorporal membrane oxygenation (ECMO), and sildenafil can be considered when this therapy is not available. ECMO may be indicated according to the ELSO guidelines. In older preterm infant, where PH is mainly associated with bronchopulmonary dysplasia (BPD) or in term infants with developmental lung anomalies such as congenital diaphragmatic hernia or cardiac anomalies, left ventricular diastolic dysfunction/left atrial hypertension or pulmonary vein stenosis, can add to the complexity of the disease. Here, oral or intravenous sildenafil should be considered for PH treatment in BPD, the latter for critically ill patients. Furthermore, prostanoids, mineralcorticoid receptor antagonists, and diuretics can be beneficial. Infants with proven or suspected PH should receive close follow-up, including preductal/postductal SpO2measurements, echocardiography and laboratory work-up including NT-proBNP, guided by clinical improvement or lack thereof.

Childhood interstitial lung disease (chILD) consists of a large, heterogeneous group of individually rare disorders. chILD demonstrates major differences in disease etiology, natural history, and management when compared with the adult group. It occurs primarily secondary to an underlying developmental or genetic abnormality affecting the growth and maturity of the pediatric lung. They present with different clinical, radiologic, and pathologic features. In this pictorial review article, we will divide chILD into those more prevalent in infancy and those not specific to infancy. We will use a case based approach to discuss relevant imaging findings including modalities such as radiograph and computed tomography in a wide variety of pathologies.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare neonatal lung disease with fatal outcome. Typically, respiratory symptoms present in the first 24 hours of life and patients die within the neonatal period. Atypical, delayed clinical presentations and/or longer survival have also been reported. Here, we studied the clinicopathologic relationship of ACD/MPV by examining 16 cases of ACD/MPV, focusing on atypical features. Based on the presence of diffuse vs. focal/patchy ACD/MPV histopathologic changes, we divided the cases into classic and nonclassic pathology groups. MPV was found in all ACD/MPV. Ten of 16 cases exhibited classic diffuse abnormalities, while 6 of 16 had a nonclassic focal/patchy distribution. However, among 7 patients with atypical clinical features, only 2 had nonclassic pathology, while 4 out of 9 clinically typical cases had nonclassic ACD/MPV pathology. Marked intrapulmonary aberrant arteriovenous vessels were present in all atypical cases. In conclusion, clinical presentation is not always correlated with histopathology in ACD/MPV. Atypical ACD/MPV should be suspected in any infants with fulminant pulmonary hypertension. Abnormal pulmonary veins and aberrant intraseptal vessels are the most important clues for diagnosis. Additional studies are needed for further elucidation of diagnostic histological criteria of atypical ACD/MPV and to explore its pathogenesis.

There is a wide differential diagnosis of early onset respiratory distress especially in term babies, and interstitial lung disease (chILD) is a rare but important consideration in this context. chILD manifesting immediately after birth is usually related to mutations in surfactant protein genes, or conditions related to the Congenital Acinar Dysplasia -Alveolar capillary dysplasia - Congenital Alveolar Dysplasia (CAD-ACD) spectrum. There is currently no specific treatment for these conditions, and management is supportive. Prognosis is very poor in most of these babies if onset is early, with relentless respiratory deterioration unless transplanted. Ideally, the diagnosis is made on genetic analysis, but this may be time-consuming and complex in CAD-ACD spectrum, so lung biopsy may be needed to avoid prolonged and futile treatment being instituted. Milder forms with prolonged survival have been reported. Early onset, less severe chILD is usually related to neuroendocrine cell hyperplasia of infancy (NEHI), pulmonary interstitial glycogenosis (PIG) and less severe disorders of surfactant proteins. PIG and NEHI are not specific entities, but are pulmonary dysmaturity syndromes, and there may be a number of underlying genetic and other cause. If the child is stable and thriving, many will not be subject to lung biopsy, and slow improvement and weaning of supplemental oxygen can be anticipated. Where possible, a precise genetic diagnosis should be made in early onset cHILD allow for genetic counselling. chILD survivors and their families have complex respiratory and other needs, and co-ordinated, multi-disciplinary support in the community is essential.

ObjectiveAlveolar capillary dysplasia (ACD) is one of the causes of pulmonary hypertension. Its diagnosis is histological but new pathogenetic data have emerged. The aim of this study was to describe a French cohort of patients with ACD to improve the comprehension and the diagnosis of this pathology which is probably underdiagnosed.MethodsA retrospective observational study was conducted in French hospitals. Patients born between 2005 and 2017, whose biological samples were sent to the French genetic reference centres, were included. Clinical, histological and genetic data were retrospectively collected.ResultsWe presented a series of 21 patients. The mean of postmenstrual age at birth was 37.6 weeks. The first symptoms appeared on the median of 2.5 hours. Pulmonary hypertension was diagnosed in 20 patients out of 21. Two cases had prolonged survival (3.3 and 14 months). Histological analysis was done on lung tissue from autopsy (57.1% of cases) or from percutaneous biopsy (28.6%). FOXF1 was found abnormal in 15 patients (71.4%): 8 deletions and 7 point mutations. Two deletions were found by chromosomal microarray.ConclusionThis study is one of the largest clinically described series in literature. It seems crucial to integrate genetics early into diagnostic support. We propose a diagnostic algorithm for helping medical teams to improve diagnosis of this pathology.

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.

The postnatal management of asymptomatic antenatally detected congenital lung malformations (CLM) has been controversial. The aim of this project is to report the clinical outcome of a non-operative approach to management of CLMs detected antenatally. The medical records of all children with CLM detected antenatally, born between 1999 and 2014 and referred to the Royal Children’s Hospital, Melbourne were reviewed. 113 patients were identified with a median follow up period of 7.9 years. Chest x-rays performed in the first year were available for review. No abnormality was detected in 31 overall and only 2 of those who ultimately had resection. In the neonatal period, 2 infants died prior to surgery (hydrops/prematurity) and 6 had resection of which 1, who had alveolar capillary dysplasia, died. Beyond infancy, 17 became symptomatic of whom 13 had resection (mass effect 3, infection in CLM 10) and 5 were managed conservatively. 88 remained asymptomatic of whom 11 had elective resection (parent request 2, recurrent cough, not related to CLM 2, mass effect 3, not specified 4) and 77/113 (68%) managed conservatively. There has been 1 death in this group unrelated to CLM. No malignancies were identified. In conclusion, a non-operative approach provides a safe and effective strategy for the management of antenatally detected CLMs with excellent medium to long term clinical outcome.

Contains fulltext : 196066.pdf (Publisher’s version ) (Open Access) Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal disorder mainly involving the vascular development of the lungs. Since its first description, significant achievements in research have led to a better understanding of the underlying molecular mechanism of ACD/MPV and genetic studies have identified associations with genomic alterations in the locus of the transcription factor FOXF1. This in turn has increased the awareness among clinicians resulting in over 200 cases reported so far, including genotyping of patients in most recent reports. Collectively, this promoted a better stratification of the patient group, leading to new perspectives in research on the pathogenesis. Here, we provide an overview of the clinical aspects of ACD/MPV, including guidance for clinicians, and review the ongoing research into the complex molecular mechanism causing this severe lung disorder.