A disorder of surfactant metabolism without identified genetic mutations.

BACKGROUND: Surfactant metabolism disorders may result in diffuse lung disease in children. CASE PRESENTATION: We report a 3-years-old boy with dry cough, progressive hypoxemia, dyspnea and bilateral ground glass opacities at chest high-resolution computed tomography (HRCT) who had no variants in genes encoding surfactant proteins or transcription factors. Lung histology strongly suggested an abnormality of surfactant protein. A 7-month course of pulse intravenous high-dose methylprednisolone plus oral hydroxychloroquine and azithromycin led to gradual weaning from oxygen and oral steroids, and to improvement of cough and dyspnea. Over the follow-up period, hydroxychloroquine and azithromycin were not withdrawn as cough and dyspnea re-appeared at each attempt and disappeared at re-start. At 6 years of age chest HRCT still appeared unchanged, but clinical symptoms or signs were absent. CONCLUSIONS: In children suspected of inborn errors of pulmonary surfactant metabolism who do not have a recognized genetic mutation, lung biopsy with consistent histology may help physicians to address the definitive diagnosis.

Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the chILD Classification Scheme.

RATIONALE: Children's Interstitial and Diffuse Lung Disease (chILD) is a heterogeneous group of disorders that is challenging to categorize. In previous study, a classification scheme was successfully applied to children 0 to 2 years of age who underwent lung biopsies for chILD. This classification scheme has not been evaluated in children 2 to 18 years of age. OBJECTIVES: This multicenter interdisciplinary study sought to describe the spectrum of biopsy-proven chILD in North America and to apply a previously reported classification scheme in children 2 to 18 years of age. Mortality and risk factors for mortality were also assessed. METHODS: Patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease from 12 North American institutions were included. Demographic and clinical data were collected and described. The lung biopsies were reviewed by pediatric lung pathologists with expertise in diffuse lung disease and were classified by the chILD classification scheme. Logistic regression was used to determine risk factors for mortality. MEASUREMENTS AND MAIN RESULTS: A total of 191 cases were included in the final analysis. Number of biopsies varied by center (5-49 biopsies; mean, 15.8) and by age (2-18 yr; mean, 10.6 yr). The most common classification category in this cohort was Disorders of the Immunocompromised Host (40.8%), and the least common was Disorders of Infancy (4.7%). Immunocompromised patients suffered the highest mortality (52.8%). Additional associations with mortality included mechanical ventilation, worse clinical status at time of biopsy, tachypnea, hemoptysis, and crackles. Pulmonary hypertension was found to be a risk factor for mortality but only in the immunocompetent patients. CONCLUSIONS: In patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease, there were far fewer diagnoses prevalent in infancy and more overlap with adult diagnoses. Immunocompromised patients with diffuse lung disease who underwent lung biopsies had less than 50% survival at time of last follow-up.

Comparative analyses of lung transcriptomes in patients with alveolar capillary dysplasia with misalignment of pulmonary veins and in foxf1 heterozygous knockout mice.

Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a developmental disorder of the lungs, primarily affecting their vasculature. FOXF1 haploinsufficiency due to heterozygous genomic deletions and point mutations have been reported in most patients with ACDMPV. The majority of mice with heterozygous loss-of-function of Foxf1 exhibit neonatal lethality with evidence of pulmonary hemorrhage in some of them. By comparing transcriptomes of human ACDMPV lungs with control lungs using expression arrays, we found that several genes and pathways involved in lung development, angiogenesis, and in pulmonary hypertension development, were deregulated. Similar transcriptional changes were found in lungs of the postnatal day 0.5 Foxf1+/- mice when compared to their wildtype littermate controls; 14 genes, COL15A1, COL18A1, COL6A2, ESM1, FSCN1, GRINA, IGFBP3, IL1B, MALL, NOS3, RASL11B, MATN2, PRKCDBP, and SIRPA, were found common to both ACDMPV and Foxf1 heterozygous lungs. Our results advance knowledge toward understanding of the molecular mechanism of ACDMPV, lung development, and its vasculature pathology. These data may also be useful for understanding etiologies of other lung disorders, e.g. pulmonary hypertension, bronchopulmonary dysplasia, or cancer.

Desquamative interstitial pneumonia in a child related to cigarette smoke.

An 8-year-old white male was referred to our clinic for a 1-year history of decreased appetite and no weight gain. His entire workup failed to demonstrate cystic fibrosis, or any infectious or immune-related diseases. Chest imaging and clinical picture suggested parenchymal lung disease. Histopathology examination of the video-assisted thoracoscopic biopsy of his lungs showed a desquamative interstitial pneumonia (DIP)-like pattern that resembled that of adult smokers with the same disease. Genes for surfactant proteins B and C and the transporter ABCA3 were all negative. Furthermore, lack of any genetic disorder for surfactant proteins, along with his history of heavy exposure to 10 pack-years of indoor secondhand smoke suggests that this child's DIP is due to secondhand cigarette exposure. He had nearly complete resolution of his symptoms after a year of treatments with pulse steroid and hydroxycholoroquine. To the best of our knowledge this is the first case of cigarette smoke-related DIP reported in a child.

Novel FOXF1 deep intronic deletion causes lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins.

Haploinsufficiency of FOXF1 causes an autosomal dominant neonatally lethal lung disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). We identified novel 0.8-kb deletion within the 1.4-kb intron of FOXF1 in a deceased newborn diagnosed with ACDMPV. The deletion arose de novo on the maternal copy of the chromosome 16, and did not affect FOXF1 minigene splicing tested in lung fibroblasts. However, FOXF1 transcript level in the ACDMPV peripheral lung tissue was reduced by almost 40%. We found that, in an in vitro reporter assay, the FOXF1 intron exhibited moderate transcriptional enhancer activity, correlating with the presence of binding sites for expression regulators CTCF and CEBPB, whereas its truncated copy, which lost major CTCF and CEBPB-binding sites, inhibited the FOXF1 promoter. Our data further emphasize the importance of testing the non-protein coding regions of the genome currently not covered by diagnostic chromosomal microarray analyses or whole-exome sequencing.

An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy.

BACKGROUND: There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and adults. METHODS: A multidisciplinary panel was convened to develop evidence-based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient's or family's quality of life, and death. RESULTS: No controlled clinical trials were identified. Therefore, observational evidence and clinical experience informed judgments. These guidelines: (1) describe the clinical characteristics of neonates and infants (<2 yr of age) with diffuse lung disease (DLD); (2) list the common causes of DLD that should be eliminated during the evaluation of neonates and infants with DLD; (3) recommend methods for further clinical investigation of the remaining infants, who are regarded as having "childhood ILD syndrome"; (4) describe a new pathologic classification scheme of DLD in infants; (5) outline supportive and continuing care; and (6) suggest areas for future research. CONCLUSIONS: After common causes of DLD are excluded, neonates and infants with childhood ILD syndrome should be evaluated by a knowledgeable subspecialist. The evaluation may include echocardiography, controlled ventilation high-resolution computed tomography, infant pulmonary function testing, bronchoscopy with bronchoalveolar lavage, genetic testing, and/or lung biopsy. Preventive care, family education, and support are essential.

Inversion upstream of FOXF1 in a case of lethal alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a congenital malformation that leads to severe pulmonary hypertension and respiratory failure. It has been associated with deletion of, or mutation in, FOXF1 on 16q24.1, a gene encoding a forkhead transcription factor expressed in the mesenchyme of the developing lung. Here we report on the identification of a pericentric inversion on chromosome 16 (p11.2q24.1) in a case of lethal ACDMPV with atrioventricular septal defect and duodenal atresia. Array-CGH indicated that the inversion is balanced, and FISH showed that the q-arm breakpoint occurs 134 ± 10 kb upstream (5'; centromeric) of FOXF1. This is suggestive of cis-regulatory elements located more than 130 kb 5' of FOXF1, and analysis of genome-wide data sets of chromatin modifications in two different cell types suggested that the FOXF1 regulatory domain covers more than 300 kb, and perhaps up to 433 kb, upstream of the gene, but only 3 kb downstream. The 588 kb gene-free region between FOXF1 and the next gene in the centromeric direction, IRF8, is highly conserved between species and divided into two distinct regulatory domains by an insulator element. Another putative insulator occurs just downstream of FOXF1. Our results further strengthen the association between FOXF1 and a spectrum of malformations that include ACDMPV, atrioventricular septal defects, and gastrointestinal atresia. Furthermore, the presented analysis aids in defining the critical genomic region for this syndrome.

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.

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.

Rapid and progressive pulmonary fibrosis in 2 families with DNA repair deficiencies of undetermined etiology.

Known genetic causes of pediatric interstitial lung disease include disorders of surfactant metabolism, telomerase, and DNA repair. We report 4 children from 2 families with rapidly progressive and fatal pulmonary fibrosis. A novel DNA repair defect unrelated to the ataxia-telangiectasia mutated gene was found in 1 child from each family.

Frequency, treatment, and functional outcome in children with hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis is a rare interstitial lung disease and very few data regarding frequency, treatment and outcome exist for children. Children identified with hypersensitivity pneumonia from a Danish national cohort with diffuse interstitial lung disease form the basis of this study focused on disease frequency, treatment, and functional outcome. METHODS: Seventy-three children with clinical and radiological signs of interstitial lung disease verified by lung biopsy were identified over a 12-year period. Histologic material from all cases was reviewed by pathologists from the ChILD Clinical and Research Network, USA. Diagnosis of hypersensitivity pneumonitis was confirmed in 19 cases. MEASUREMENTS AND MAIN RESULTS: Incidence of hypersensitivity pneumonitis was approximately 2/year and with a point prevalence of 4/1,000,000 children. The median (range) number of monthly courses with intravenous methylprednisolone was 15 courses (8-34) in resolved cases, but in the vast majority (92%), mono-therapy with high dose pulse methylprednisolone treatment was not sufficient for acceptable improvement. Lung function, DLco and DLco/VA increased significantly after 3 and 6 months of treatment compared to baseline (P < 0.05). However, without reaching normal values [mean SDS (range) FEV(1) -0.66 (-1.88 to 0.41) and FVC -0.67(-1.94 to 0)]. No mortality was seen. CONCLUSIONS: Incidence and point prevalence of hypersensitivity pneumonitis in Denmark was 2/year and 4/1.000.000 children. High dose intravenous methylprednisolone constituted the basic treatment, but in most cases supplemental anti-inflammatory therapy was necessary. Outcome was acceptable without any mortality. Nevertheless, both lung function and diffusion capacity were in subnormal level though without any clinically functional impact.

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

OBJECTIVE: 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. DESIGN: Descriptive case report. SETTING: Genetic department and neonatal intensive care unit of a tertiary care children's hospital. INTERVENTIONS: None. PATIENT: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

Interstitial lung disease in children.

PURPOSE OF REVIEW: In this review, we discuss the recent advances in our understanding of the cause, pathogenesis, presentation, diagnosis, treatment, and prognosis of interstitial lung disease (ILD) in children. RECENT FINDINGS: The classification of ILD syndromes in children greater than 2 years of age is based largely on adult classification schemes. In children less than 2 years of age, classification has been developed and evaluated pathologically. Entities can be categorized into developmental disorders, growth abnormalities, and surfactant dysfunction disorders based on pathologic findings. Two distinctive entities, neuroendocrine cell hyperplasia of infancy and pulmonary interstitial glycogenosis, present early in life with characteristic findings. These two disorders appear to have a favorable prognosis. Diagnosis of ILD syndromes is based on the summation of history and physical findings and both noninvasive and invasive studies. Newer approaches are being evaluated to decrease the need for lung biopsy. SUMMARY: Children's interstitial lung diseases are rare diffuse lung diseases resulting from a variety of pathogenic processes that include genetic factors, association with systemic disease processes, and inflammatory or fibrotic responses to stimuli. There are unique causes and presentations seen in infancy. Diagnosis in these disorders is made by the summation of clinical, radiologic, and pathologic findings.

Neuroendocrine cell distribution and frequency distinguish neuroendocrine cell hyperplasia of infancy from other pulmonary disorders.

BACKGROUND: The diagnostic gold standard for neuroendocrine cell hyperplasia of infancy (NEHI) is demonstration of increased numbers of neuroendocrine cells (NECs) amid otherwise near-normal lung histology. Typical clinical and radiographic features often are present. However, NECs are also increased after lung injury and in other disorders, which can complicate biopsy specimen interpretation and diagnosis of suspected NEHI. Our objective was to determine whether NEC prominence is specific for the diagnosis of NEHI. METHODS: Bombesin immunoreactivity was quantified in lung biopsy specimens from 13 children with characteristic clinical presentation and imaging appearance of NEHI. The primary comparison group was 13 age-matched patients selected from children with lung disorders that are known to be associated with NEC prominence. RESULTS: Bombesin-immunopositive epithelial area was significantly increased in NEHI compared with other diseases. Patchy bronchiolar inflammation or fibrosis was frequently observed in NEHI, with no direct association between airway histopathology and bombesin-immunopositive area. NEC prominence correlated with severity of small airway obstruction demonstrated on infant pulmonary function testing. Immunohistochemical colocalization of bombesin with Ki67 did not reveal active NEC proliferation. There was wide intra- and intersubject variability in NEC number, which did not relate to radiographic appearance of the region biopsied. CONCLUSIONS: Our findings demonstrate that NEC prominence is a distinguishing feature of NEHI independent of airway injury. The extent of intrasubject variability and potential for overlap with control subjects suggest that clinical-radiologic-pathologic correlation is required for diagnosis and that the abundance of NECs may not fully explain the disease pathogenesis.

Fetal lung interstitial tumor (FLIT): A proposed newly recognized lung tumor of infancy to be differentiated from cystic pleuropulmonary blastoma and other developmental pulmonary lesions.

The differential diagnosis of congenital lung lesions includes a variety of pulmonary malformations, and uncommon or rare neoplasms such as the pleuropulmonary blastoma (PPB) and congenital peribronchial myofibroblastic tumor (CPMT). Although most of the congenital lesions have a predominantly cystic appearance, the exceptions of a more solid process are the type 3 congenital cystic adenomatoid or pulmonary airway malformation (CCAM-CPAM) and the CPMT. The clinical and pathologic features of a unique solid or mixed solid/cystic lung mass composed of immature interstitial mesenchyme in association with irregular airspace-like structures mimicking abnormal incompletely developed lung are presented in this report of 10 infants (7 males, 3 females) whose tumor-like lesions were detected in the prenatal period to 3 months of age (median, 1-day old). A lobectomy was done in all 10 infants and 1 infant received adjuvant chemotherapy. One of the surgical resections occurred as an ex utero, antenatal procedure because of fetal ascites. There have been no reported recurrences in those patients with greater than 12 months of follow-up ranging from 15 to 182 months (9 cases). Because of the morphologic resemblance of this mass-like lesion to fetal lung at 20 to 24 weeks gestation (as though any further pulmonary development was arrested in these localized lesions), we are proposing the designation of fetal lung interstitial tumor (FLIT) whose pathogenetic relationship, if any, to type 1 (cystic) pleuropulmonary blastoma remains uncertain to date.

Evaluation and management of pulmonary disease in ataxia-telangiectasia.

SUMMARY: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ATM gene, resulting in faulty repair of breakages in double-stranded DNA. The clinical phenotype is complex and is characterized by neurologic abnormalities, immunodeficiencies, susceptibility to malignancies, recurrent sinopulmonary infections, and cutaneous abnormalities. Lung disease is common in patients with A-T and often progresses with age and neurological decline. Diseases of the respiratory system cause significant morbidity and are a frequent cause of death in the A-T population. Lung disease in this population is thought to exhibit features of one or more of the following phenotypes: recurrent sinopulmonary infections with bronchiectasis, interstitial lung disease, and lung disease associated with neurological abnormalities. Here, we review available evidence and present expert opinion on the diagnosis, evaluation, and management of lung disease in A-T, as discussed in a recent multidisciplinary workshop. Although more data are emerging on this unique population, many recommendations are made based on similarities to other more well-studied diseases. Gaps in current knowledge and areas for future research in the field of pulmonary disease in A-T are also outlined.

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.

Pulmonary arterial medial smooth muscle thickness in sudden infant death syndrome: an analysis of subsets of 73 cases.

UNLABELLED: Previous studies addressing pulmonary artery morphology have compared cases of sudden infant death syndrome (SIDS) to controls but none have compared demographic profiles, exposure to potentially hypoxic risk factors and other pathologic variables in SIDS cases grouped according to pulmonary artery medial smooth muscle thickness. AIMS: To compare the relative medial thickness (RMT) in alveolar wall arteries (AW) in SIDS cases with that in age-matched controls and 2. Compare demographic, clinical, and pathologic characteristics among three subsets of SIDS cases based upon alveolar wall (AW) RMT. Retrospective morphometric planimetry of all muscularized arteries in standardized right apical lung sections in 73 SIDS cases divided into three groups based on increasing AW RMT as well as 19 controls age-matched to 19 of the SIDS cases. SIDS and age-matched control cases did not differ with respect to AW RMT or other demographic variables. The SIDS group with the thickest AW RMT had significantly more males and premature birth than the other groups, but the groups did not differ for known clinical risk factors that would potentially expose them to hypoxia. Pathologic variables, including pulmonary inflammation, gastric aspiration, intra-alveolar siderophages, cardiac valve circumferences, and heart and liver weights, were not different between groups. Age was not significantly correlated with RMT of alveolar wall and pre-acinar arteries but was significant at p = .018 for small intra-acinar arteries. The groups were different for RMT of small pre-acinar and intra-acinar arteries, which increased with increasing AW RMT. Statistical differences should not necessarily be equated with clinical importance, however future research incorporating more quantified historical data is recommended.

A novel presentation of diffuse lung disease caused by congenital hypothyroidism.

A term infant was born with respiratory distress, and subsequent imaging, histopathologic, and hormonal studies confirmed congenital hypothyroidism. This report is intended to alert pediatricians to the possibility of congenital hypothyroidism as a cause of respiratory symptoms of unknown cause in neonates with respiratory distress.