Inherited disorders of neonatal lung diseases. (2004)

Although genetic factors are assumed to have a role in the etiology of respiratory distress syndrome (RDS), specific genes underlying this susceptibility are incompletely known. The most promising candidates are the genes coding for the lung-specific protein components of the surfactant. In congenital absence of surfactant protein A in mice, lung mechanics or surfactant homeostasis is normal. However, there is an increased susceptibility to infections. The major surfactant protein A alleles, 6A(2) and 1A(0), are the general high-risk RDS alleles, while the allele 6A(3) carries a decreased risk of RDS. The allele 6A(6) is also over-represented in infants with bronchopulmonary dysplasia. To date, no human infants who lack surfactant protein A have been identified, and the human respiratory phenotype associated with the 1A(0) allele has been demonstrated to be variable, therefore, surfactant protein A polymorphisms are not currently useful for estimation of individual risk of having an affected infant. Surfactant protein B (SP-B) plays an essential role in the structure of tubular myelin. Mutations resulting in an absence of surfactant protein B have been identified. They cause a recessively inherited, progressive respiratory disease. More than 27 loss of function mutations have been identified in the surfactant protein B gene that result in lethal neonatal respiratory failure. Of the several known common variants of the surfactant protein B gene, the most common mutation is 121ins22 that accounts for 60-70% of the mutant cases. Although the frequency of the 121ins2 mutation is rare, the consistent phenotype is exhibited by infants with a homozygous genotype. The clinical presentation in infants homozygous for the 121ins2 mutation is full-term infants who develop respiratory distress within the first 12-24 hours of life. Surfactant replacement therapy fails to reverse this outcome, and without lung transplantation, they expire within the first 1-6 months of life. Surfactant protein B gene mutations may also result in milder phenotypes. These mutations resulting in reduced synthesis of SP-B appear to be family-specific and result in respiratory distress, but sometimes with more gradually progressive or chronic respiratory failure. Surfactant protein C plays a role in the stabilization of surfactant and may also have a role in the intracellular processing of the surfactant complex. Surfactant protein B is important in the intracellular processing and production of surfactant protein C. Although surfactant protein C-deficient mice are viable and survive to adulthood without obvious pulmonary abnormalities, their lung have reduced viscoelasticty. Human respiratory disease in the neonatal period caused by loss-of-function mutations in the surfactant protein C gene has not been identified. However, an autosomal dominant inherited mutation at the surfactant protein C gene causes chronic interstitial lung disease. Surfactant protein D is a member of the collectin family like surfactant protein A, therefore it opsonizes pathogens and enhances their phagocytosis by alveolar macrophages and neutrophils. Unlike surfactant protein A, it does not contribute to lowering surface tension. Surfactant protein D-deficient mice have no respiratory abnormalities at birth, but it causes development of emphysema and predisposition to specific infections. No human infant or child with respiratory distress and mutation in the surfactant protein D gene has been identified.