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.

FIG. 1.

Approach to genetic diagnosis of children's interstitial lung disease (chILD). Potential genetic mechanisms based upon age of the patient (neonatal to adult, from top to bottom) and phenotypic characteristics (middle) are listed on the right. Arrows point to primary genes to be analyzed; if results of initial studies are negative, arrows on right indicate secondary genetic studies to be considered. Abbreviations: RDS, Respiratory distress syndrome; PPHN, persistent pulmonary hypertension of the newborn; PAP, pulmonary alveolar proteinosis. See text and Table 1 for details on genetic loci.