Interstitial Lung Disease in Childhood: Clinical and Genetic Aspects

Abstract

Interstitial lung disease (ILD) in childhood is a heterogeneous group of rare pulmonary conditions presenting chronic respiratory disorders. Many clinical features of ILD still remain unclear, making the treatment strategies mainly investigative. Guidelines may provide physicians with an overview on the diagnosis and therapeutic directions. However, the criteria used in different clinical studies for the classification and diagnosis of ILDs are not always the same, making the development of guidelines difficult. Advances in genetic testing have thrown light on some etiologies of ILD, which were formerly classified as ILDs of unknown origins. The need of genetic testing for unexplained ILD is growing, and new classification criteria based on the etiology should be adopted to better understand the disease. The purpose of this review is to give an overview of the clinical and genetic aspects of ILD in children.

The biology of the ABCA3 lipid transporter in lung health and disease

“…Many of these mutations are clustered within the first and forth luminal loops as well as in the cytosolic domains, particularly within or adjacent to the second nucleotide-binding domain (NBD2). As previously stated, the presence of a combination of Type I (trafficking) and Type II (lipid pump) variants as compound heterozygous mutations appears to increase the disease severity in children as evidenced by the parents of these children having only one of the mutations and being asymptomatic without apparent respiratory disease (Kitazawa et al, 2013; Wambach et al, 2014; Flamein et al, 2012; Goncalves et al, 2014; Kitazawa and Kure, 2015). While ABCA3 -associated lung disease is believed to be inherited in an autosomal recessive manner requiring mutations on both alleles, monoallelic ABCA3 mutations in infants with surfactant deficiency and in children and adults with IPF/DPLD are also common (Shulenin et al, 2004; Agrawal et al, 2012; Peca et al, 2015; Wambach et al, 2012; Naderi et al, 2014).…”

“…Finally, Type III mutations are compound heterozygotes (having both Type I and Type II mutations) and frequently exhibit a more severe phenotype. The most prevalent ABCA3 mutation in humans, E292V, is a Type II missense substitution producing an IPF/DPLD phenotype in children and adult patients that is often found in a compound heterozygous state with other Type I or II mutations (Garmany et al, 2008; Matsumura et al, 2008; Wambach et al, 2014; Kitazawa and Kure, 2015) (Fig. 3).…”

Rare disease heralded by pulmonary manifestations

“…[57] In the presence of hepatosplenomegaly, the differential diagnosis of ILD in a toddler would be infectious diseases such as HIV and CMV,[58] Langerhans cell histiocytosis,[58] lysinuric protein intolerance,[9] granulomatous disease such as sarcoidosis,[510] and lysosomal storage disorders (Gaucher disease and Niemann–Pick disease). [511]…”

Current Developments in Interstitial Lung Disease

“…Different susceptibility genes are found to be associated with each subset of ILD, suggesting the presence of heterogeneity in ILD. 8 , 9 Another review article in this section, presented by Yamashita, focuses on the role of lymphangiogenesis in the restoration process of damaged lung tissues, which can contribute to the development of IIP and other lung diseases. Lymphangiogenesis has different types of localized functions within each disorder of the IIP group, corresponding to the heterogeneity of lesions in terms of inflammation and fibrosis.…”