Clinical, Histopathological, and Molecular Diagnostics in Lethal Lung Developmental Disorders

Abstract

Lethal lung developmental disorders are a rare but important group of pediatric diffuse lung diseases presenting with neonatal respiratory failure. On the basis of histopathological appearance at lung biopsy or autopsy, they have been termed: alveolar capillary dysplasia with misalignment of the pulmonary veins, acinar dysplasia, congenital alveolar dysplasia, 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 alveolar capillary dysplasia with misalignment of the pulmonary veins have revealed the causative role of the dosage-sensitive FOXF1 gene and its noncoding regulatory variants in the distant lung-specific enhancer at chromosome 16q24.1. In contrast, the molecular bases of acinar dysplasia and congenital alveolar dysplasia 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, has demonstrated their complex compound inheritance. These data indicate that noncoding regulatory elements play a critical role in lung development in humans. We propose that for more precise lethal lung developmental disorder diagnosis, a diagnostic pathway including whole-genome sequencing should be implemented.

Keywords: acinar dysplasia; alveolar dysplasia; pulmonary hypoplasia.

Figure 1.

(A) Schematic representation of histologic phases of human lung development, with proposed time of lung growth arrest in particular disorders (adapted by permission from Reference 83). (B) Autopsy of lung from an individual with a deletion on 17q23.1-q23.2 encompassing TBX4 is composed predominantly of conducting airways, in the spectrum of acinar dysplasia. (C) Autopsy of lung from an infant with an intragenic deletion at 17q23.2 displays more numerous distal acinar tubules diagnostic of congenital alveolar dysplasia. (D) An infant who died at 5 days of life with dysplastic ears, digits, and a family history of lacrimo-auriculo-dento-digital syndrome has more mature-appearing lung but reduced alveolar spaces, consistent with pulmonary hypoplasia. (E) Lung biopsy from an infant with a FOXF1 mutation showing the characteristic features of alveolar capillary dysplasia with misalignment of the pulmonary veins, including veins (V) malpositioned next to pulmonary arteries (arrows), which exhibit marked medial thickening and dilated lymphatics (asterisk) (Movat pentachrome stain to highlight the vasculature). Scale bars: B–D, 200 μm; E, 25 μm.

Figure 2.

Diagnostic algorithm in infants with lethal lung developmental disorder (LLDD). Proposed algorithm includes sample collection, histopathological evaluation, and genetic testing. *Next-generation sequencing (NGS) panel including FOXF1 (the list of the available genetic tests can be found at: https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=FOXF1). ACDMPV = alveolar capillary dysplasia with misalignment of the pulmonary veins; AcDys = acinar dysplasia; ALSG = aplasia of lacrimal and salivary glands; array CGH = array comparative genomic hybridization; CAD = congenital alveolar dysplasia; ES = exome sequencing; FFPE = formalin-fixed paraffin-embedded; FGF10 = fibroblast growth factor 10; FGFR2 = fibroblast growth factor receptor 2; FOXF1 = forkhead box F1; LADD syndrome = lacrimo-auriculo-dento-digital syndrome; PAH = pulmonary arterial hypertension; Sanger seq = Sanger sequencing; TBX4 = T-box transcription factor TBX4; WGS = whole-genome sequencing.