Abstract
Aims: To determine the role of surfactant-related gene anomalies in neonatal/infantile interstitial lung disease.
Methods: 22 infants >32weeks/< 1year with unexplained progressive alveolar/interstitial lung disease. SP-B, SP-C and ABCA3 sequencing. Optical (OM) and electronical (EM) microscopy of biopsy/autopsy lung tissue. Surfactant proteins immunofluorescence.
Results: 13/22 infants (59.1%) had lamellar bodies (LB) ultrastructural abnormalities suggesting genetic surfactant deficiency. Eleven infants (50.0%) carried ABCA3 mutations.
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-Five (22.7%) had bi-allelic mutations (2 homozygote frameshift, 3 double heterozygote missense), showing small, dense LB with 1-2 denser cores and no normal LB on EM.
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-Five (22.7%) had a single mutation (four missense, one intron), showing a mix of small and normal LB plus multivesicular bodies (MVB) on EM. On immunofluorescence, one had cytoplasmic mislocation of TTF-1 despite normal TTF-1 gene sequence, one had altered cleavage of proSP-B into SP-B, and one had reduced/misplaced alveolar capillaries.
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-One infant (4.5%) carried a heterozygote SP-C mutation, plus a synonymous ABCA3 mutation, showing large, empty LB lacking normal surfactant layers on EM.
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-One infant (4.5%) with normal LB + MVB had a heterozygote SP-B mutation.
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-One infant (4.5%) with small dense LB (similar to homozygote ABCA3 mutants) had no mutation identified.
In the 9 remaining infants (40.9%), one had alveolar proteinosis, one had COX-deficiency, one had Niemann-Pick C disease, two had idiopathic pulmonary fibrosis, four remained cryptogenetic.
Conclusions: ABCA3 mutations are the most frequent abnormality. Although EM is indicative in most (92%) cases, molecular mechanisms are elusive in >50% of cases, likely involving complex, multiple surfactant-related gene interactions.
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Peca, D., Boldrini, R., Petrini, S. et al. 496 Mutations of Surfactant-Related Genes Sp-B, Sp-C and Abca3 in Unexplained Aleolar/Interstitial Lung Disease in Newborn and Infants. Pediatr Res 68 (Suppl 1), 254 (2010). https://doi.org/10.1203/00006450-201011001-00496
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DOI: https://doi.org/10.1203/00006450-201011001-00496