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Clinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders
Lethal lung developmental disorders (LLDD) are rare but an important group of pediatric diffuse lung disease (chILD) presenting with neonatal respiratory failure. Based on histopathological appearance at lung biopsy or autopsy, they have been termed: alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV), acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD), and other unspecified primary pulmonary hypoplasias. However, the histopathological continuum in these lethal developmental disorders has made accurate diagnosis challenging, which has implications for recurrence risk. Over the past decade, genetic studies in infants with ACDMPV have revealed the causative role of the dosage-sensitive FOXF1 gene and its non-coding regulatory variants in the distant lung-specific enhancer at chromosome 16q24.1. In contrast, the molecular bases of AcDys and CAD have remained poorly understood. Most recently, disruption of the TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling pathway has been reported in patients with these lethal pulmonary dysplasias. Application of next generation sequencing techniques, including exome sequencing and whole genome sequencing (WGS) has demonstrated their complex compound inheritance. These data indicate that non-coding regulatory elements play a critical role in lung development in humans. We propose that for more precise LLDD diagnosis, a diagnostic pathway including WGS should be implemented.