Showing papers on "Alveolar capillary dysplasia published in 2010"

Genetic Basis of Children's Interstitial Lung Disease

Abstract: Specific genetic causes for children's interstitial lung disease (chILD) have been identified within the past decade. These include deletions of or mutations in genes encoding proteins important in surfactant production and function (SP-B, SP-C, and ABCA3), surfactant catabolism (GM-CSF receptor), as well as transcription factors important for surfactant production (TTF1) or lung development (Fox F1), with heterozygous deletions or loss-of-function mutations of the latter resulting in alveolar capillary dysplasia (ACD) with misalignment of the pulmonary veins. Familial pulmonary fibrosis in adults may result from mutations in genes encoding components of telomerase and SP-A2. While not yet reported in children, the expression of these genes in alveolar type II epithelial cells supports a key role for the disruption of normal homeostasis in this cell type in the pathogenesis of interstitial lung disease. The identification of specific genetic causes for chILD now allows for the possibility of non-invasive diagnosis, and provides insight into basic cellular mechanisms that may allow the development of novel therapies.

Haploinsufficiencies of FOXF1 and FOXC2 genes associated with lethal alveolar capillary dysplasia and congenital heart disease.

Abstract: Neonatal deaths account for about 67% of all deaths during the first year of life in the USA. Genetic defects are important factors contributing to neonatal deaths and congenital anomalies. Here we report on the identification of a 1.37 Mb de novo deletion of chromosome 16q24.1-q24.2 by microarray-based comparative genomic hybridization (aCGH) technique in a newborn boy with lethal severe alveolar capillary dysplasia and multiple congenital anomalies who died of irreversible pulmonary hypertension, respiratory failure and cor pulmonale at three days of age. The phenotypic findings and causal genes (FOXF1 and FOXC2) involved in producing this unusual syndrome are detailed. Our findings independently confirm the results in a previous publication describing multiple patients with similar clinical and genetic observations, and highlight the importance of scanning human genomes at high resolution for identifications of micro-imbalances as pathogenic causes in neonates with unexplained congenital anomalies. (c) 2010 Wiley-Liss, Inc.

Pulmonary interstitial glycogenosis: words of caution

Abstract: Pulmonary interstitial glycogenosis (PIG), an idiopathic form of childhood interstitial lung disease, is being increasingly recognized by pathologists and entering into clinicians’ differential diagnoses for infants who present with respiratory distress in the first few days to weeks of life. The case reports by Lanfranchi et al. [1] and now Castillo et al. [2] in this issue of Pediatric Radiology highlight the clinical contexts in which PIG occurs and suggest associated imaging findings. Lanfranchi and colleagues report a 31-week preterm infant who briefly required CPAP at birth, continued on supplemental oxygen, but then unexpectedly required intubation and mechanical ventilation on day of life 18. The radiographic findings in this case included diffuse reticular opacities with architectural distortion. The case reported by Castillo et al. [2] is that of a term infant with persistent tachypnea and hypoxemia from birth, without need for mechanical ventilation. At 8 weeks of age, in the setting of persistent requirement for supplemental oxygen, a chest CT scan revealed diffuse ground-glass and reticular opacities, interlobular septal thickening, and cystic changes. In both cases, lung biopsies revealed not only pulmonary interstitial glycogenosis, but also deficient alveolarization reflective of poor lung growth. In one case, the authors reported significant clinical improvement after treatment with corticosteroids, although the details of dose, duration, and time to improvement were not reported. In the current report by Castillo et al. [2], the infant gradually improved without reported interventions beyond supportive care. These cases illustrate many emerging themes about PIG as well as questions about this enigmatic disorder. The term PIG was coined by Canakis et al. [3] based on the histological finding of increased glycogen-laden mesenchymal cells in the alveolar interstitium. Although PIG might be an isolated finding in term neonates with interstitial lung disease, diffuse or patchy accumulation of glycogenated mesenchymal cells frequently accompanies other pulmonary conditions. Specifically, PIG is particularly common in conjunction with disorders of deficient lung growth and development, as occurred in both of these case reports. In a recent multi-institutional pathological review of lung biopsies from the Children’s Interstitial Lung Disease (ChILD) Research Network, patchy PIG was present in more than 40% of cases classified as having a lung growth abnormality [4]. This included not only chronic neonatal lung disease resulting from prematurity, but also pulmonary hypoplasia and lung growth abnormalities in the setting of trisomy 21 and severe congenital heart disease. In this study, patchy PIG was also present in 22% of cases classified as vascular disorders masquerading as ILD [4]. Given the settings in which PIG is observed, we have wondered whether PIG directly influences the clinical presentation of these infants, or perhaps is merely a transient inconsequential bystander. Arguments in favor of the latter include: (1) the incidental identification of PIG in congenital lung lesions [4], (2) the often patchy distribution of PIG in infant lung biopsies amid a variety of clinical contexts of altered lung development, and (3) its apparent restriction to lung biopsies from very young infants. Interestingly, in the ChILD Research Network study, PIG G. H. Deutsch Department of Laboratories, Department of Pathology, Seattle Children’s Hospital, Seattle, WA, USA

Expression of angiogenic and vasculogenic proteins in the lung in alveolar capillary dysplasia/misalignment of pulmonary veins: An immunohistochemical study

Abstract: 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 e...

Omphalocele and alveolar capillary dysplasia: a new association.

Abstract: OBJECTIVE: First report of an infant with coexistent omphalocele and alveolar capillary dysplasia DESIGN: Descriptive case report SETTING: Neonatal intensive care unit of a tertiary care children's hospital PATIENT: 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 CONCLUSIONS: 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

Misplaced pulmonary arteries in an adult patient with pulmonary hypertension

Abstract: Misalignment of pulmonary vessels, with or without alveolar capillary dysplasia, is a rare cause of persistent pulmonary hypertension in the newborn. The prognosis is poor, with virtually all patients succumbing to unremitting hypoxaemic respiratory failure and death during the newborn period. We report the CT and histological findings of misplaced pulmonary arteries in a previously healthy young adult patient who presented with pulmonary arterial hypertension. Contiguous high-resolution spiral CT angiography showed small pulmonary arteries coursing within the interlobular septa and enlarged central pulmonary arteries. Surgical lung biopsy demonstrated anomalous muscularised pulmonary arteries in the interlobular septa. This is, to our knowledge, the first report of misplaced pulmonary arteries presenting in an adult patient and may represent a forme fruste of the neonatal vascular anomaly. A possible association with pulmonary arterial hypertension is also suggested in this case.

Summary of "Genomic and genetic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations".

Abstract: The gastrointestinal (GI) tract develops from the embryonic endoderm (which gives rise to the epithelium) and the visceral mesoderm (which gives rise to the muscularis propria and the mesenchyme). GI development is characterised by multiple, complicated cell-fate decisions along the anterior-posterior, radial, leftright, and cranio-caudal axes. When 1 or more of these goes awry, intestinal malrotation (incidence 1:500) and other GI malformations ensue and are a frequent component of congenital syndromes. In particular, foregut malformations, such as tracheoesophageal fistulae (incidence 1:5000–3000 live births) or duodenal atresias (1:6000 live births), and hindgut malformations, such as anal atresias, are relatively frequent causes of morbidity in the pediatric population. However, no candidate transcription factor has been associated with these clinical syndromes. Using a cohort of patients with oesophageal atresia/tracheoesophageal fistula and/or alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), Stankiewicz and colleagues performed an array of comparative genomic hybridisation screens to detect copy number variation of candidate genes based on their known role in foregut development (lungs are foregut derivatives). Their results point to the FOX cluster (FOXF1, FOXC2, FOXL1) on chromosome 16 as a potential hotspot for deletions and mutations associated with GI malformations, as well as cardiac and urogenital defects. Indeed, Forkhead genes and, in particular, FOXF1 have previously been shown in both vertebrates and invertebrates to play an essential role in the development of the GI tract (1–9). FOXF1 is an important transcription factor expressed in the visceral mesoderm from late gastrula into adulthood (3,8). Although FOXF1 is expressed throughout the length of the GI tract in mice, it has been shown to play a role in foregut (lung, gallbladder) and heart development (the heart derives from the visceral mesoderm) (10–12).

[Alveolar capillary dysplasia: a case report and review of literature].

Abstract: OBJECTIVE To report a newborn infant who died of alveolar capillary dysplasia (ACD). The literature on about 20 cases of ACD was reviewed. METHODS A retrospective review of records of infants from Medline with a diagnosis of ACD was carried out. RESULTS The case was a newborn female infant who developed respiratory distress 5 hours after an uncomplicated delivery. She died at the fourth day after birth despite full ventilatory support. The lung autopsy provided a diagnosis of ACD. In the 21 infants, 7 were male and 14 were female; 19 infants were born full-term and 2 were born pre-term. The birth weight of 19 infants and Apgar score of 15 infants were normal; 16 infants developed progressing tachypnea and cyanosis within 24 hours of age, 5 developed cyanosis at 1 day to 19 days. Echocardiography demonstrated a right to left shunt in the hearts of all the 21 infants, and pulmonary hypertension in 20 infants. Twenty infants were treated with conventional mechanical ventilation, 7 infants with high-frequency oscillatory ventilation and 12 infants with extracorporeal membrane oxygenation (ECMO). Fourteen infants were also treated with inhaled nitric oxide therapy and 4 with exogenous surfactant. Diagnostic open lung biopsy was performed in 6 infants. The chest radiography showed normal findings in 3 infants, pneumothoraces in 9 infants, reticular markings, granular, patchy or diffuse opacity in lungs of 7 infants, and decreased pulmonary vascular markings in two infants. All the 21 infants died; 8 of them died within 10 days of age, 7 within 30 days of age, and one died at the age of 4 months who was the longest survivor. Fourteen infants were associated with congenital malformations, such as cardiovascular, gastrointestinal, and genitourinary systems, including one infant associated with chromosomal abnormalities, two infants of familial genetic predisposition. CONCLUSIONS At present, ACD is still a disease with poor prognosis, significant medical expenses and no specific treatment. When respiratory failure or persistent pulmonary hypertension (PPHN) is persistent after routine treatment in an infant, ACD should be highly suspected and conventional open-lung biopsy should be preformed to confirm the diagnosis.

Alveolar Capillary Dysplasia Associated with Omphalocoele

Abstract: Alveolar capillary dysplasia (ACD) is a rare and universally fatal form of persistent pulmonary hypertension of the newborn (PPHN) We report a case of a newborn male baby with a moderate sized omphalocoele who developed respiratory distress 10 hours after birth He deteriorated and succumbed shortly afterwards despite maximal ventilatory support and inhaled nitric oxide ACD was diagnosed at postmortem examination, and the association of ACD with omphalocoele and gut malrotation has not been reported We suggest including ACD in the differential diagnosis of refractory PPHN in a newborn even with the presence of other risk factors for respiratory failure