Interstitial lung diseases are a heterogeneous group of disorders that are poorly understood at a molecular level.^1,2 The cause is often unknown, and the histologic diagnoses used in adults may represent different disease processes in children.^3-5 For example, cases of desquamative interstitial pneumonitis reported in infants are often more severe and refractory to treatment than those reported in adults.^6,7 Many of these cases probably represent chronic pneumonitis of infancy.^8,9 The lungs in patients with chronic pneumonitis of infancy are characterized by interstitial thickening with mesenchymal cells, rather than by an inflammatory infiltrate, and an alveolar infiltrate with variable amounts of proteinaceous material. A possible genetic basis for desquamative interstitial pneumonitis and chronic pneumonitis of infancy is suggested by reports of familial cases.^6,8,10 We tested the hypothesis that mutations in the gene (SP-C ) encoding surfactant protein C, a hydrophobic, lung-specific protein, were associated with chronic lung disease in an infant with a family history of interstitial lung disease.

Rationale: ABCA3 is a member of the ATP-binding cassette family of proteins that mediate the translocation of a wide variety of substrates, including lipids, across cellular membranes. Mutations in the gene encoding ABCA3 were recently identified in full-term neonates with fatal surfactant deficiency. Objective: To test the hypothesis that ABCA3 mutations are not always associated with fatal neonatal lung disease but are a cause of pediatric interstitial lung disease. Methods: DNA samples were obtained from 195 children with chronic lung disease of unknown etiology. The 30 coding exons of the ABCA3 gene were sequenced in four unrelated children with a referring diagnosis of desquamative interstitial pneumonitis and who were older than 10 years at the time of enrollment. Results: Three of four patients (ages 16, 23, and 11 years) with desquamative interstitial pneumonitis had ABCA3 mutations identified on both alleles. All three had the same missense mutation (E292V) and a second unique mutation. The E292V mutation was not found on 200 control alleles from adults without lung disease, but seven additional patients of the remaining study patients had the E292V mutation on one allele. Immunohistochemical analysis of surfactant protein expression in three patients revealed a specific staining pattern for surfactant protein-B, which was the same pattern observed in several infants with fatal lung disease due to ABCA3 mutations. Conclusion: ABCA3 mutations cause some types of interstitial lung disease in pediatric patients.

▪ Abstract The hydrophobic surfactant proteins, SP-B and SP-C, have important roles in surfactant function. The importance of these proteins in normal lung function is highlighted by the lung diseases associated with abnormalities in their expression. Mutations in the gene encoding SP-B result in severe, fatal neonatal lung disease, and mutations in the gene encoding SP-C are associated with chronic interstitial lung diseases in newborns, older children, and adults. This work reviews the current state of knowledge concerning the lung diseases associated with mutations in the SP-B and SP-C genes, and the potential roles of abnormal SP-B and SP-C expression and genetic variation in these genes in other lung diseases.