Retrospective evaluation of neonates with fatal congenital lung malformation: A single center 15-year forensic autopsy experience.

Congenital lung malformation (CLM) is a leading cause of infant mortality. Clinical methods for diagnosing CLM mainly rely on computed tomography, magnetic resonance imaging, ultrasonography, and Doppler. However, forensic identification of the cause of death in neonates is challenging. Unequivocal classification criteria for CLM are missing as its forensic identification is ambiguous. Therefore, we aimed to analyze neonatal death cases at our center to assist in identifying those with congenital lung malformation. This retrospective study identified and classified the causes of deaths of neonates autopsied between January 2008 and April 2023. All cases born alive and died within 28 days with a clear time of death were selected, and forensic experts reviewed their records. The manner, cause of death, and other characteristics were noted and discussed. This retrospective study reveals a steady increase in autopsy cases from 2008 to 2015, attributed to improved parental consent, heightened awareness of autopsy importance, and enhanced medical resources. However, a subsequent decline post-2015 is observed, potentially influenced by advancements in medical technology and prenatal examination protocols. The top causes of neonatal mortality include respiratory diseases, asphyxia, congenital dysplasia, and fetal distress. Congenital lung malformations, particularly bronchopulmonary malformations, constitute a significant portion of congenital anomalies. This study underscores the importance of standardized autopsies and histopathological examinations in diagnosing and understanding CLM. Future research should focus on expanding case collections and elucidating the genetic basis of CLM to improve forensic management and outcomes.

Pulmonary Hypertension in Developmental Lung Diseases.

Diverse genetic developmental lung diseases can present in the neonatal period with hypoxemic respiratory failure, often associated with with pulmonary hypertension. Intractable hypoxemia and lack of sustained response to medical management should increase the suspicion of a developmental lung disorder. Genetic diagnosis and lung biopsy are helpful in establishing the diagnosis. Early diagnosis can result in optimizing management and redirecting care if needed. This article reviews normal lung development, various developmental lung disorders that can result from genetic abnormalities at each stage of lung development, their clinical presentation, management, prognosis, and differential diagnoses.

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.

Learning from cystic fibrosis: How can we start to personalise treatment of Children's Interstitial Lung Disease (chILD)?

Cystic fibrosis (CF) is a monogenic disorder cause by mutations in the CF Transmembrane Regulator (CFTR) gene. The prognosis of cystic fibrosis has been transformed by the discovery of highly effective modulator therapies (HEMT). Treatment has changed from reactive therapy dealing with complications of the disease to pro-active correction of the underlying molecular functional abnormality. This has come about by discovering the detailed biology of the different CF molecular sub-endotypes; the development of biomarkers to assess response even in mild disease or young children; the performance of definitive large randomised controlled trials in patients with a common mutation and the development of in vitro testing systems to test efficacy in those patients with rare CFTR mutations. As a result, CF is now an umbrella term, rather than a specific diagnostic label; we have moved from clinical phenotypes to molecular subendotypes. Children's Interstitial Lung Diseases (chILDs) comprise more than 200 entities, and are a diverse group of diseases, for an increasing number of which an underlying gene mutation has been discovered. Many of these entities are umbrella terms, such as pulmonary alveolar proteinosis or hypersensitivity pneumonitis, for each of which there are multiple and very different endotypes. Even those chILDs for which a specific gene mutation has been discovered comprise, as with CF, different molecular subendotypes likely mandating different therapies. For most chILDs, current treatment is non-specific (corticosteroids, azithromycin, hydroxychloroquine). The variability of the different entities means that there is little evidence for the efficacy of any treatment. This review considers how some of the lessons of the success story of CF are being applied to chILD, thus opening the opportunities for truly personalised medicine in these conditions. Advances in knowledge in the molecular biology of surfactant protein C and Adenosine triphosphate binding cassette subfamily A member 3 (ABCA3), and the possibilities of discovering novel therapies by in vitro studies will especially be highlighted.

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.

Extracorporeal Membrane Oxygenation (ECMO) for suspected neonatal genetic diagnoses with cardiorespiratory failure.

Recent data describe an increasing use of extracorporeal membrane oxygenation (ECMO) in neonates with various clinical conditions besides primary respiratory or cardiac diagnoses. Infants with underlying genetic disorders characterized by cardiopulmonary failure pose unique management challenges. When pathognomonic dysmorphic features for common genetic diagnoses are not present, the prognosis is uncertain at best when determining ECMO candidacy. Lengthy turnaround times of genetic testing often delay definitive diagnosis during the ECMO course. Clinical management pathways to guide practice and evidence to support the use of ECMO in rare genetic conditions are lacking. The decision to initiate ECMO is daunting but may be of benefit if the subsequent genetic diagnosis is non-lethal. In lethal genetic cases warranting discontinuation of care, the time spent on ECMO may still be advantageous as a bridge to diagnosis while allowing for parental bonding with the terminally ill infant. Diagnostic confirmation may also facilitate the attainment of closure for these parents. Here, we report our experience providing ECMO to three neonates presenting with cardiorespiratory failure and later diagnosed with rare genetic syndromes. We share the challenges faced, lessons learned, and outcomes of these critically ill neonates.

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.

Variants in FGF10 cause early onset of severe childhood interstitial lung disease: A detailed description of four affected children.

INTRODUCTION: Fibroblast growth factor 10 (FGF10) is a signaling molecule with a well-established role for lung branching morphogenesis. Rare heterozygous, deleterious variants in the FGF10 gene are known causes of the lacrimo-auriculo-dento-digital (LADD) syndrome and aplasia of lacrimal and salivary glands. Previous studies indicate that pathogenic variants in FGF10 can cause childhood Interstitial Lung Disease (chILD) due to severe diffuse developmental disorders of the lung, but detailed reports on clinical presentation and follow-up of affected children are lacking. METHODS: We describe four children with postnatal onset of chILD and heterozygous variants in FGF10, each detected by exome or whole genome sequencing. RESULTS: All children presented with postnatal respiratory failure. Two children died within the first 2 days of life, one patient died at age of 12 years due to right heart failure related to severe pulmonary hypertension (PH) and one patient is alive at age of 6 years, but still symptomatic. Histopathological analysis of lung biopsies from the two children with early postpartum demise revealed diffuse developmental disorder representing acinar dysplasia and interstitial fibrosis. Sequential biopsies of the child with survival until the age of 12 years revealed alveolar simplification and progressive interstitial fibrosis. DISCUSSION: Our report extends the phenotype of FGF10-related disorders to early onset chILD with progressive interstitial lung fibrosis and PH. Therefore, FGF10-related disorder should be considered even without previously described syndromic stigmata in children with postnatal respiratory distress, not only when leading to death in the neonatal period but also in case of persistent respiratory complaints and PH.