Twins with alveolar capillary dysplasia with misalignment of pulmonary veins: Strategies for diagnosis and management.

We present a case of dichorionic-diamniotic twin females who developed hypoxemic respiratory failure. They were ultimately diagnosed by lung biopsy with alveolar capillary dysplasia with misalignment of pulmonary veins. This case highlights a practical approach to reaching a diagnosis in infants with suspected developmental lung disease.

Megacystis in the First Trimester as an Unreported Sonographic Finding of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins Confirmed by Whole-exome Sequencing.

A pregnant woman was revealed to have fetal univentricular heart and megacystis by a routine first-trimester ultrasound. Chorionic villus sampling with the use of karyotyping and microarray found no causative etiologies. A further investigation with whole-exome sequencing (WES) demonstrated a FOXF1 variant. Autopsy confirmed the prenatal findings, and a histological study of the lungs showed the characteristic features of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). This study indicates that although ultrasound itself has no ability of the identification of pulmonary histological malformations associated with ACDMPV, the early markers of univentricular heart and megacystis might alert clinicians to consider this genetic disorder which is facilitated considerably by the increasingly used WES in prenatal diagnosis.

Clinical Relevance of Rapid FOXF1-Targeted Sequencing in Patients Suspected of Alveolar Capillary Dysplasia With Misalignment of Pulmonary Veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal congenital lung disorder that presents shortly after birth with respiratory failure and therapy-resistant pulmonary hypertension. It is associated with heterozygous point mutations and genomic deletions that involve the FOXF1 gene or its upstream regulatory region. Patients are unresponsive to the intensive treatment regimens and suffer unnecessarily because ACDMPV is not always timely recognized and histologic diagnosis is invasive and time consuming. Here, we demonstrate the usefulness of a noninvasive, fast genetic test for FOXF1 variants that we previously developed to rapidly diagnose ACDMPV and reduce the time of hospitalization.

Case report: High-dose epoprostenol therapy in pediatric patients with pulmonary hypertension and developmental lung disease.

Pulmonary hypertension (PH) with developmental lung disease is a life-threatening disease and accounts for 10%-12% of pediatric PH patients. Administration of specific pulmonary vasodilators to pediatric PH patients has brought about improvement of their long-term prognosis. Intravenous epoprostenol therapy is a gold standard therapy for severe idiopathic pulmonary arterial hypertension (IPAH), but there are few reports demonstrating the efficacy of epoprostenol for pediatric PH patients with developmental lung disease, especially when treating with high doses of epoprostenol. Two cases of pediatric PH patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) and congenital diaphragmatic hernia (CDH) with bronchopulmonary dysplasia (BPD), respectively, treated with epoprostenol above 100 ng/kg/min are presented. In these two cases, severe PH was improved significantly by an aggressive increase of the epoprostenol infusion rate with administration of oral pulmonary vasodilators and appropriate respiratory management, without any significant adverse effects. High-dose epoprostenol therapy may be one of the therapeutic options in pediatric PH patients with developmental lung disease.

Therapeutic Potential of Endothelial Progenitor Cells in Pulmonary Diseases.

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.

Incidence of alveolar capillary dysplasia with misalignment of pulmonary veins in infants with unexplained severe pulmonary hypertension: The roles of clinical, pathological, and genetic testing.

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.

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

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.

Two patients with FOXF1 mutations with alveolar capillary dysplasia with misalignment of pulmonary veins and other malformations: Two different presentations and outcomes.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) describes a group of developmental disorders affecting the lungs with its pulmonary vasculature. Mutations in the FOXF1 gene have been reported in most cases, and extrapulmonary findings were described. We present two patients with ACDMPV and FOXF1 mutations that illustrate the variability in presentation and outcome of their disease. Patient 1 was a full-term infant with imperforate anus and pulmonary hypertension. He required Extracorporeal Membrane Oxygenation on day of life (DOL) 3, and passed away on DOL 13 after no clinical improvement. Postmortem findings were consistent with ACDMPV. FOXF1 testing revealed a heterozygous pathogenic frameshift de novo mutation, c.1057_1078dup, p.(Gly360Valfs*58). Patient 2 is a 6-month-old female, with a small omphalocele. She had intermittent retractions at 1 week of age. She was admitted with pulmonary hypertension at 7 weeks of age. Lung biopsy confirmed ACDMPV. FOXF1 testing revealed a de novo, heterozygous likely pathogenic missense mutation c.253T>C, p.(Phe85Leu]). Our two patients had different presentations, ages of onset, and progression of their disease. Our second patient had patchy lung involvement on biopsy, which may explain the relatively delayed onset and longer survival. ACDMPV is an important consideration for full-term infants with worsening pulmonary hypertension early in life.

A Novel De Novo Pathogenic Variant in FOXF1 in a Newborn with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins.

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.

A Novel De Novo Pathogenic Variant in FOXF1 in a Newborn with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins

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.

Enfermedad pulmonar difusa: causa de hipertensión pulmonar persistente antes del año de vida / Diffuse lung disease: cause of persistent pulmonary hypertension before one year of age

En pediatría, la enfermedad vascular pulmonar es multifactorial y heterogénea. Si bien comparte algunas características con la hipertensión pulmonar en los adultos, hay diferencias en las comorbilidades y condiciones asociadas, la coexistencia de enfermedades genéticas o del desarrollo. Las enfermedades pulmonares intersticiales pueden ser causantes de esta entidad. Una de ellas es la displasia alvéolo-capilar con mal alineamiento de las venas pulmonares, una patología infrecuente pero con 100% de mortalidad, caracterizada por la falla en la formación del tejido pulmonar que da por resultado final la alteración en la difusión de gases. Se describe un caso clínico de una paciente de 5 meses de edad estudiada a partir de sospechar una cardiopatía congénita con hipoxemia persistente, a cuyo diagnóstico se llega por la biopsia pulmonar.

Pulmonary vascular disease in children is multifactorial and heterogeneous. While it shares some features with pulmonary hypertension in adults, there are differences in the associated comorbidities and conditions, the coexistence of genetic or developmental diseases. Interstitial lung diseases may be responsible for this entity. One is alveolar capillary dysplasia with misalignment of pulmonary veins, a rare pathology but with a mortality rate of 100%, characterized by a failure in the formation of lung tissue that eventually results in impaired gas diffusion. We present a 5-month-old patient studied due to suspected congenital heart disease with persistent hypoxemia; diagnosis was made through lung biopsy.

[Diffuse lung disease: cause of persistent pulmonary hypertension before one year of age]. / Enfermedad pulmonar difusa: causa de hipertensión pulmonar persistente antes del año de vida.

Pulmonary vascular disease in children is multifactorial and heterogeneous. While it shares some features with pulmonary hypertension in adults, there are differences in the associated comorbidities and conditions, the coexistence of genetic or developmental diseases. Interstitial lung diseases may be responsible for this entity. One is alveolar capillary dysplasia with misalignment of pulmonary veins, a rare pathology but with a mortality rate of 100%, characterized by a failure in the formation of lung tissue that eventually results in impaired gas diffusion. We present a 5-month-old patient studied due to suspected congenital heart disease with persistent hypoxemia; diagnosis was made through lung biopsy.

En pediatría, la enfermedad vascular pulmonar es multifactorial y heterogénea. Si bien comparte algunas características con la hipertensión pulmonar en los adultos, hay diferencias en las comorbilidades y condiciones asociadas, la coexistencia de enfermedades genéticas o del desarrollo. Las enfermedades pulmonares intersticiales pueden ser causantes de esta entidad. Una de ellas es la displasia alvéolo-capilar con mal alineamiento de las venas pulmonares, una patología infrecuente pero con 100% de mortalidad, caracterizada por la falla en la formación del tejido pulmonar que da por resultado final la alteración en la difusión de gases. Se describe un caso clínico de una paciente de 5 meses de edad estudiada a partir de sospechar una cardiopatía congénita con hipoxemia persistente, a cuyo diagnóstico se llega por la biopsia pulmonar.