Alveolar Capillary Dysplasia Research Articles

Long survival of congenital alveolar capillary dysplasia patient with NO inhalation and epoprostenol: Effect of sildenafil, beraprost and bosentan

The case is described herein of a patient with alveolar capillary dysplasia with double-outlet right ventricle and duodenal atresia who survived for a remarkably long time. The newborn girl was born at a gestational age of 36 weeks and weighed 1926 g. One min after delivery the Apgar score was 4. The patient had persistent pulmonary hypertension (PH) and needed nitric oxide inhalation and i.v. epoprostenol all through her life. Although other oral medications for PH were tried, they could not be used in practice because of gastrointestinal complications. The patient died on the 237 th day of life as a result of worsening PH associated with infection.

Loss of Semaphorin-Neuropilin-1 Signaling Causes Dysmorphic Vascularization Reminiscent of Alveolar Capillary Dysplasia

Respiratory diseases of the newborn can arise from the disruption of essential angiogenic pathways. Neuropilin-1 (NRP1), which is a critical receptor implicated in systemic vascular growth and remodeling, binds two distinct ligand families: vascular endothelial growth factor (VEGF) and class 3 semaphorins (SEMA3). Although the function of VEGF-NRP1 interactions in vascular development is well described, the importance of SEMA3-NRP1 signaling in systemic or pulmonary vascular morphogenesis is debated. We sought to characterize the effect of deficient SEMA3-NRP1 signaling on fetal pulmonary vascular development in a mouse model. Temporospatial expression of Nrp1 and Sema3 mRNA and protein during murine fetal lung development was investigated, and the development of the pulmonary vasculature in transgenic mice deficient in Sema3-Nrp1 signaling was examined by histology, immunostaining, and electron microscopy. Loss of Sema3-Nrp1 signaling resulted in acute respiratory distress and high neonatal mortality. Pathohistological examination of mutants revealed immature and atelectatic regions in the lung, severely reduced capillary density, thickened alveolar septa containing centrally located dilated capillaries, hypertensive changes in arteriolar walls, anomalous and misaligned pulmonary veins, and reduced pulmonary surfactant secretion. Notably, many features are reminiscent of the fatal pulmonary disorder alveolar capillary dysplasia. These findings indicate a critical role for Sema3-Nrp1 signaling in fetal pulmonary development, which may have clinical relevance for treatment of various neonatal respiratory disorders, including alveolar capillary dysplasia.

Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.

Mesodermal Pten inactivation leads to alveolar capillary dysplasia-like phenotype

Alveolar capillary dysplasia (ACD) is a congenital, lethal disorder of the pulmonary vasculature. Phosphatase and tensin homologue deleted from chromosome 10 (Pten) encodes a lipid phosphatase controlling key cellular functions, including stem/progenitor cell proliferation and differentiation; however, the role of PTEN in mesodermal lung cell lineage formation remains unexamined. To determine the role of mesodermal PTEN in the ontogeny of various mesenchymal cell lineages during lung development, we specifically deleted Pten in early embryonic lung mesenchyme in mice. Pups lacking Pten died at birth, with evidence of failure in blood oxygenation. Analysis at the cellular level showed defects in angioblast differentiation to endothelial cells and an accompanying accumulation of the angioblast cell population that was associated with disorganized capillary beds. We also found decreased expression of Forkhead box protein F1 (Foxf1), a gene associated with the ACD human phenotype. Analysis of human samples for ACD revealed a significant decrease in PTEN and increased activated protein kinase B (AKT). These studies demonstrate that mesodermal PTEN has a key role in controlling the amplification of angioblasts as well as their differentiation into endothelial cells, thereby directing the establishment of a functional gas exchange interface. Additionally, these mice could serve as a murine model of ACD.

Mice with mesodermal inactivation of Pten ( Mmac1 ; Tep1 ) as models for alveolar capillary dysplasia (ACD)

Mice with mesodermal inactivation of Pten ( Mmac1 ; Tep1 ) as models for alveolar capillary dysplasia (ACD)

A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare developmental lung disorder that is uniformly lethal. Affected infants die within the first few weeks of their life despite aggressive treatment, although a few cases of late manifestation and longer survival have been reported. We have shown previously that mutations and deletions in FOXF1 are a cause of this disorder. Although most of the cases of ACD/MPV are sporadic, there have been infrequent reports of familial cases. We present a family with five out of six children affected with ACD/MPV. DNA analysis identified a missense mutation (c.416G>T; p.Arg139Leu) in the FOXF1 gene that segregated in the three affected siblings tested. The same variant is also present as a de novo mutation in the mother and arose on her paternally derived chromosome 16. The two tested affected siblings share the same chromosome 16 haplotype inherited from their maternal grandfather. Their single healthy sibling has a different chromosome 16 haplotype inherited from the maternal grandmother. The results are consistent with paternal imprinting of FOXF1 in human.

New Coding in the International Classification of Diseases, Ninth Revision, for Children's Interstitial Lung Disease

The term "children's interstitial lung disease" (chILD) refers to a heterogeneous group of rare and diffuse lung diseases associated with significant morbidity and mortality. These disorders include neuroendocrine cell hyperplasia of infancy, pulmonary interstitial glycogenosis, surfactant dysfunction mutations, and alveolar capillary dysplasia with misalignment of pulmonary veins. Diagnosis can be challenging, which may lead to a delay in recognition and treatment of these disorders. Recently, International Classifications of Diseases, Ninth Revision codes have been added for several of the chILD disorders. The purpose of this article is to give an overview of the chILD disorders and appropriate diagnostic coding.

Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val

De novo heterozygous mutations in HRAS cause Costello syndrome (CS), a condition with high mortality and morbidity in infancy and early childhood due to cardiac, respiratory, and muscular complications. HRAS mutations predicting p.Gly12Val, p.Gly12Asp, and p.Gly12Cys substitutions have been associated with severe, lethal, CS. We report on molecular, clinical, and pathological findings in patients with mutations predicting HRAS p.Gly12Val that were identified in our clinical molecular genetic testing service. Such mutations were identified in four patients. Remarkably, three were deletion/insertion mutations affecting coding nucleotides 35 and 36. All patients died within 6 postnatal weeks, providing further evidence that p.Gly12Val mutations predict a very poor prognosis. High birth weight, polyhydramnios (and premature birth), cardiac hypertrophy, respiratory distress, muscle weakness, and postnatal growth failure were present. Dysmorphism was subtle or non-specific, with edema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares, and low-set ears. Proximal upper limb shortening, a small bell-shaped chest, talipes, and fixed flexion deformities of the wrists were seen. Neonatal atrial arrhythmia, highly suggestive of CS, was also present in two patients. One patient had congenital alveolar dysplasia, and another, born after 36 weeks' gestation, bronchopulmonary dysplasia. A rapidly fatal disease course, and the difficulty of identifying subtle dysmorphism in neonates requiring intensive care, suggest that this condition remains under-recognized, and should enter the differential diagnosis for very sick infants with a range of clinical problems including cardiac hypertrophy and disordered pulmonary development. Clinical management should be informed by knowledge of the poor prognosis of this condition. © 2012 Wiley Periodicals, Inc.

Outcomes of neonates requiring extracorporeal membrane oxygenation for irreversible pulmonary dysplasia

Neonates with an irreversible pulmonary dysplasia such as alveolar capillary dysplasia, surfactant protein deficiency, and pulmonary lymphangiectasis may have a deteriorating clinical course requiring cardiopulmonary support with extracorporeal membrane oxygenation. These neonates are often difficult to distinguish from those with persistent pulmonary hypertension of the newborn. The objective of this study was to identify clinical variables that distinguish infants with irreversible pulmonary dysplasia from those with persistent pulmonary hypertension of the newborn before, and while receiving, extracorporeal membrane oxygenation support. A retrospective analysis of the Extracorporeal Life Support Registry from 2000 to 2010 was performed. A total of 114 extracorporeal membrane oxygenation centers providing data to the Extracorporeal Life Support Registry. All neonates day of life 0-31 reported to the Extracorporeal Life Support Registry with irreversible pulmonary dysplasia and persistent pulmonary hypertension of the newborn were identified. None. Patient demographics, pre-extracorporeal membrane oxygenation variables, and survival were analyzed. Univariate analysis was performed using Student's t test or Fisher's exact test, and variables found to be significant underwent multivariate analysis by logistic regression. Neonates with irreversible pulmonary dysplasia were placed on extracorporeal membrane oxygenation later (day of life 5.3 vs. 3.0, p = .045) and for a longer duration (11.1 vs. 6.8 days, p < .001) than those with persistent pulmonary hypertension of the newborn. Initiation of extracorporeal membrane oxygenation at day of life ≥5 (p = .026) and a duration of extracorporeal membrane oxygenation ≥10 days (p = .003) were independent predictors of irreversible pulmonary dysplasia by multivariate analysis. No differences in demographics, blood gas values, or vascular access were observed. Survival to discharge was significantly lower for neonates with irreversible pulmonary dysplasia (3%) vs. persistent pulmonary hypertension of the newborn (81%, p < .001). Although neonates with irreversible pulmonary dysplasia and persistent pulmonary hypertension of the newborn have similar presentations, those with irreversible pulmonary dysplasia require extracorporeal membrane oxygenation support later in the perinatal period and for a longer duration. For neonates with a diagnosis of persistent pulmonary hypertension of the newborn, irreversible pulmonary dysplasia should be considered when extracorporeal membrane oxygenation is initiated on day of life ≥5 and/or the duration of extracorporeal membrane oxygenation ≥10 days.

16q24.1 microdeletion in a premature newborn: Usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn

Report of a 16q24.1 deletion in a premature newborn, demonstrating the usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn and multiple congenital malformations. Descriptive case report. Genetic department and neonatal intensive care unit of a tertiary care children's hospital. None. We report the case of a preterm male infant, born at 26 wks of gestation. A cardiac malformation and bilateral hydronephrosis were diagnosed at 19 wks of gestation. Karyotype analysis was normal, and a 22q11.2 microdeletion was excluded by fluorescence in situ hybridization analysis. A cesarean section was performed due to fetal distress. The patient developed persistent pulmonary hypertension unresponsive to mechanical ventilation and nitric oxide treatment and expired at 16 hrs of life. An autopsy revealed partial atrioventricular canal malformation and showed bilateral dilation of the renal pelvocaliceal system with bilateral ureteral stenosis and annular pancreas. Array-based comparative genomic hybridization analysis (Agilent oligoNT 44K, Agilent Technologies, Santa Clara, CA) showed an interstitial microdeletion encompassing the forkhead box gene cluster in 16q24.1. Review of the pulmonary microscopic examination showed the characteristic features of alveolar capillary dysplasia with misalignment of pulmonary veins. Some features were less prominent due to the gestational age. Our review of the literature shows that alveolar capillary dysplasia with misalignment of pulmonary veins is rare but probably underreported. Prematurity is not a usual presentation, and histologic features are difficult to interpret. In our case, array-based comparative genomic hybridization revealed a 16q24.1 deletion, leading to the final diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins. It emphasizes the usefulness of array-based comparative genomic hybridization analysis as a diagnostic tool with implications for both prognosis and management decisions in newborns with refractory persistent pulmonary hypertension and multiple congenital malformations.

Misalignment of Lung Vessels and Alveolar Capillary Dysplasia: A Case Report With Autopsy

Misalignment of lung vessels (MLV) with or without alveolar capillary dysplasia (ACD) is a rare cause of idiopathic persistent pulmonary hypertension of the neonate. This report describes a full-term infant with severe and intractable pulmonary hypertension. The patient's condition progressively deteriorated despite high-frequency oscillatory ventilation, infusion of magnesium sulfate, dopamine, and dobutamine to control blood pressure, and nitric oxide inhalation therapy. The infant died at 5 days of age. The diagnosis of MLV with ACD was established by autopsy. Histopathologic analysis revealed a failure of formation and an ingrowth of alveolar capillaries, thickening of the alveolar walls, poor contact of capillaries with alveolar epithelium, small intra-acinar muscularized arterioles, and anomalous pulmonary veins within bronchovascular bundles. The low rate of diagnosis of MLV with or without ACD may be because of the early high mortality rate or patchy involvement in some cases. Increasing awareness of this clinical entity may prevent the use of costly, invasive, and probably ineffective procedures. Short-term improvement after inhalation of nitric oxide does not lead to long-term survival but merely provides time for potential lung transplantation.

Alveolar capillary dysplasia associated with duodenal atresia: Ultrasonographic findings of enlarged, highly echogenic lungs and gastric dilatation in a third‐trimester fetus

We report a case of alveolar capillary dysplasia, wherein duodenal atresia was diagnosed during the third trimester. A 36-year-old mother was referred to our hospital for polyhydramnios at 31 weeks' gestation. Duodenal atresia was suspected from the ultrasonographic findings, which showed gastric dilation. Other findings noted were enlarged, highly echogenic lungs, a spherical heart and an increased lung-thorax transverse area ratio. A male infant was born at 37 weeks' gestation. The findings of serial radiography of the infant's upper gastrointestinal tract were compatible with the diagnosis of duodenal atresia; however, he developed persistent pulmonary hypertension of the newborn eight hours after birth and died at five days of age. The autopsy revealed alveolar capillary dysplasia and duodenal obstruction. We propose that the detection of duodenal atresia should prompt the physician to conduct a thorough ultrasonographic examination to rule out associated anomalies, such as alveolar capillary dysplasia, which can be detected by the presence of highly echogenic lungs.

Alveolar Capillary Dysplasia

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare, fatal developmental lung disorder of neonates and infants. This review aims to address recent findings in the etiology and genetics of ACD/MPV and to raise awareness of this poorly known disease, which may also present as milder, unclassified forms. Successively discussed are what is known about the epidemiology, pathogenesis, pathophysiology, diagnostic indicators and approaches, genetic testing, treatment, and cases of delayed onset. The review concludes with suggestions for future directions to answer the many unknowns about this disorder.

Paediatric Interstitial Lung Disease: Classification and Definitions

Classifications of interstitial (diffuse) lung disease in adults and children have undergone significant revision in recent years, with advances in our understanding of new entities and the biology and prognostic significance of certain histologic patterns. The contributions of the European Respiratory Society Task Force on Interstitial Lung Disease in Children and the North American Children's Interstitial Lung Disease Group are reviewed, and a clinicopathologic classification of paediatric diffuse lung disease is summarized. Clinical characteristics and histologic definitions are also presented for selected entities within this classification, specifically, acinar dysgenesis, congenital alveolar dysplasia, alveolar capillary dysplasia with misalignment of pulmonary veins, abnormalities of alveolar growth, pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia of infancy, surfactant dysfunction disorders, obliterative bronchiolitis, hypersensitivity pneumonitis, and immunologic disorders. More uniform application of this diagnostic terminology in the future will allow more meaningful comparisons of different patient populations, radiologic-pathologic correlation, and development of disease-specific therapeutic strategies.

Analysis of FOXF1 and the FOX gene cluster in patients with VACTERL association

VACTERL association, a relatively common condition with an incidence of approximately 1 in 20,000 –35,000 births, is a non-random association of birth defects that includes vertebral defects (V), anal atresia (A), cardiac defects (C), tracheo-esophageal fistula (TE), renal anomalies (R) and limb malformations (L). Although the etiology is unknown in the majority of patients, there is evidence that it is causally heterogeneous. Several studies have shown evidence for inheritance in VACTERL, implying a role for genetic loci. Recently, patients with component features of VACTERL and a lethal developmental pulmonary disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), were found to harbor deletions or mutations affecting FOXF1 and the FOX gene cluster on chromosome 16q24. We investigated this gene through direct sequencing and high-density SNP microarray in 12 patients with VACTERL association but without ACD/MPV. Our mutational analysis of FOXF1 showed normal sequences and no genomic imbalances affecting the FOX gene cluster on chromosome 16q24 in the studied patients. Possible explanations for these results include the etiologic and clinical heterogeneity of VACTERL association, the possibility that mutations affecting this gene may occur only in more severely affected individuals, and insufficient study sample size.

Collagen IV contributes to nitric oxide-induced angiogenesis of lung endothelial cells

Nitric oxide (NO) mediates endothelial angiogenesis via inducing the expression of integrin α(v)β(3). During angiogenesis, endothelial cells adhere to and migrate into the extracellular matrix through integrins. Collagen IV binds to integrin α(v)β(3), leading to integrin activation, which affects a number of signaling processes in endothelial cells. In the present study, we evaluated the role of collagen IV in NO-induced angiogenesis. We found that NO donor 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (NOC-18) causes increases in collagen IV mRNA and protein in lung endothelial cells and collagen IV release into the medium. Addition of collagen IV into the coating of endothelial culture increases endothelial monolayer wound repair, proliferation, and tube formation. Inhibition of collagen IV synthesis using gene silencing attenuates NOC-18-induced increases in monolayer wound repair, cell proliferation, and tube formation as well as in the phosphorylation of focal adhesion kinase (FAK). Integrin blocking antibody LM609 prevents NOC-18-induced increase in endothelial monolayer wound repair. Inhibition of protein kinase G (PKG) using the specific PKG inhibitor KT5823 or PKG small interfering RNA prevents NOC-18-induced increases in collagen IV protein and mRNA and endothelial angiogenesis. Together, these results indicate that NO promotes collagen IV synthesis via a PKG signaling pathway and that the increase in collagen IV synthesis contributes to NO-induced angiogenesis of lung endothelial cells through integrin-FAK signaling. Manipulation of collagen IV could be a novel approach for the prevention and treatment of diseases such as alveolar capillary dysplasia, severe pulmonary arterial hypertension, and tumor invasion.

A novel association of alveolar capillary dysplasia, atypical duodenal atresia, and subglottic stenosis

Alveolar capillary dysplasia (ACD), which is a rare and lethal congenital pulmonary anomaly found in newborns, begins its onset or causes deterioration of the infant's condition some time after birth. Various congenital anomalies in combination with ACD have been reported, except for subglottic stenosis. Therefore, we aim to report a novel association in a case of ACD with the combination of atypical duodenal atresia and subglottic stenosis. The male infant was scheduled for duodeno-duodenostomy because a double-bubble sign was observed on a chest radiograph. He arrived at the operating theater without any symptoms. After induction of general anesthesia, although mask ventilation was performed without difficulties throughout the entire procedure, oxygen saturation values of the upper and lower extremities dissociated after several attempts of intubation. Surgery was canceled because of instability of the respiratory condition. Respiratory insufficiency worsened progressively, and the infant died at 5days of age. An autopsy confirmed ACD and revealed cartilaginous subglottic stenosis, which had made intubation difficult. This report highlights the hazards of the onset and worsening of ACD, and the importance of thorough echocardiography before surgery when atypical duodenal atresia is suspected. Anesthesiologists should also be prepared for the difficulty of intubation.

Expression of Angiogenic and Vasculogenic Proteins in the Lung in Alveolar Capillary Dysplasia/Misalignment of Pulmonary Veins: An Immunohistochemical Study

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, universally fatal developmental disorder of the lung affecting both the parenchyma and the vasculature. Its cause remains incompletely understood; the occurrence of familial cases has suggested a genetic abnormality. While several candidate genes have been studied previously, the affected pathway(s) have not yet been fully defined. The expression patterns of 8 gene products (endothelial nitric oxide synthase-3, fetal liver kinase-1, hypoxia inducible factor 1α, Von Hippel Lindau protein, 3 vascular endothelial growth factors [VEGF147, VEGFC1, and VEGFA20], and activin receptor-like kinase 1), all known to have a role in vascular development in the lung, were studied in 13 ACD/MPV and 17 control lungs by immunohistochemistry to further address the underlying molecular abnormality. Expression was graded with regard to degree and extent for multiple components of the lung parenchyma and pulmonary vasculature for each antibody. Statistical analyses of the data using the Mann-Whitney test revealed only a few significant differences (P ≤ 0.05) in degree of expression between ACD/MPV and control lung samples and do not clearly implicate one of these genes in ACD/MPV.

Review of genetic factors in intestinal malrotation

Intestinal malrotation is well covered in the surgical literature from the point of view of operative management, but few reviews to date have attempted to provide a comprehensive examination of the topic from the point of view of aetiology, in particular genetic aetiology. Following a brief overview of molecular embryology of midgut rotation, we present in this article instances of and case reports and case series of intestinal malrotation in which a genetic aetiology is likely. Autosomal dominant, autosomal recessive, X-linked and chromosomal forms of the disorder are represented. Most occur in syndromic form, that is to say, in association with other malformations. In many instances, recognition of a specific syndrome is possible, one of several examples discussed being the recently described association of intestinal malrotation with alveolar capillary dysplasia, due to mutations in the forkhead box transcription factor FOXF1. New advances in sequencing technology mean that the identification of the genes mutated in these disorders is more accessible than ever, and paediatric surgeons are encouraged to refer to their colleagues in clinical genetics where a genetic aetiology seems likely.

Omphalocele and alveolar capillary dysplasia: A new association

First report of an infant with coexistent omphalocele and alveolar capillary dysplasia. Descriptive case report. Neonatal intensive care unit of a tertiary care children's hospital. We describe a term infant with omphalocele and respiratory insufficiency attributable to pulmonary hypertension. The patient was placed on extracorporeal membrane oxygenation, but the pulmonary hypertension persisted. After 10 days on extracorporeal membrane oxygenation, a lung biopsy was performed. It showed alveolar capillary dysplasia. Because of the lethal prognosis, extracorporeal membrane oxygenation was withdrawn and the patient expired. This is the first description of an association between omphalocele and alveolar capillary dysplasia. In newborns with omphalocele who have severe respiratory insufficiency and pulmonary hypertension, alveolar capillary dysplasia should be considered.