Abstract
Mutations in genes critical for surfactant metabolism, including surfactant protein C (SP-C) and ABCA3, are well-recognized causes of interstitial lung disease. Recessive mutations in ABCA3 were first attributed to fatal respiratory failure in full-term neonates, but they are also increasingly being recognized as a cause of respiratory disorders with less severe phenotypes in older children and also adults. Here, we report a 20-month-old boy with interstitial lung disease caused by two distinct ABCA3 mutations. Initial treatment with methylprednisolone was unsuccessful, but the additional administration of hydroxychloroquine was effective. The family history revealed that the patient’s older brother had died of idiopathic interstitial lung disease at 6 months of age, suggesting a genetic etiology of the disease. Sequence analyses of SP-C and ABCA3 genes were performed using DNA samples from the patient himself, his parents, and his brother. These analyses revealed novel compound heterozygous mutations in the coding exons of ABCA3 in both the patient and his brother: c.2741A > G, of paternal origin, and c.3715_3716insGGGGGG, of maternal origin. Conclusion Since ABCA3 mutations seem to be a heterogeneous entity with various phenotypes, we recommend genetic testing for mutations in SP-C and ABCA3 genes to be considered in children with unexplained interstitial lung disease.
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Agrawal A, Hamvas A, Cole FS, Wambach JA, Wegner D, Coghill C, Harrison K, Nogee LM (2012) An intronic ABCA3 mutation that is responsible for respiratory disease. Pediatr Res 71:633–637. doi:10.1038/pr.2012.21
Anandarajan M, Paulraj S, Tubman R (2009) ABCA3 Deficiency: an unusual cause of respiratory distress in the newborn. Ulster Med J 78:51–52
Balasubramanyan N, Murphy A, O'Sullivan J, O'Connell EJ (1997) Familial interstitial lung disease in children: response to chloroquine treatment in one sibling with desquamative interstitial pneumonitis. Pediatr Pulmonol 23:55–61
Bullard JE, Nogee LM (2007) Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein C gene (SFTPC) mutation. Pediatr Res 62:176–179
Bullard JE, Wert SE, Nogee LM (2006) ABCA3 deficiency: neonatal respiratory failure and interstitial lung disease. Semin Perinatol 30:327–334
Clement A, Nathan N, Epaud R, Fauroux B, Corvol H (2010) Interstitial lung diseases in children. Orphanet J Rare Dis 5:22
Cole FS, Hamvas A, Nogee LM (2001) Genetic disorders of neonatal respiratory function. Pediatr Res 50:157–162
Crossno PF, Polosukhin VV, Blackwell TS et al (2010) Identification of early interstitial lung disease in an individual with genetic variations in ABCA3 and SFTPC. Chest 137:969–973
Doan ML, Elidemir O, Dishop MK, Zhang H, Smith EO, Black PG, Deterding RR, Roberts DM, Al-Salmi QA, Fan LL (2009) Serum KL-6 differentiates neuroendocrine cell hyperplasia of infancy from the inborn errors of surfactant metabolism. Thorax 64:677–681
Doan ML, Guillerman RP, Dishop MK, Nogee LM, Langston C, Mallory GB, Sockrider MM, Fan LL (2008) Clinical, radiological and pathological features of ABCA3 mutations in children. Thorax 63:366–373
Flamein F, Riffault L, Muselet-Charlier C et al (2012) Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children. Hum Mol Genet 21:765–775
Gower WA, Wert SE, Ginsberg JS, Golan A, Whitsett JA, Nogee LM (2010) Fatal familial lung disease caused by ABCA3 deficiency without identified ABCA3 mutations. J Pediatr 157:62–68
Johansson J, Curstedt T (1997) Molecular structures and interactions of pulmonary surfactant components. Eur J Biochem 244:675–693
Kaltenborn E, Kern S, Frixel S, Fragnet L, Conzelmann KK, Zarbock R, Griese M (2012) Respiratory syncytial virus potentiates ABCA3 mutation-induced loss of lung epithelial cell differentiation. Hum Mol Genet 21:2793–2806. doi:10.1093/hmg/dds107
Nathan N, Taam RA, Clement A et al (2012) A national internet-linked based database for pediatric interstitial lung diseases: the French network. Orphanet J Rare Dis 7:40
Nathan N, Thouvenin G, Fauroux B, Corvol H, Clement A (2011) Interstitial lung disease: physiopathology in the context of lung growth. Paediatr Respir Rev 12:216–222
Nogee LM (2010) Genetic basis of children’s interstitial lung disease. Pediatr Allergy Immunol Pulmonol 23:15–24
Nogee LM, Dunbar AE 3rd, Wert SE, Askin F, Hamvas A, Whitsett JA (2001) A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 344:573–579
Park SK, Amos L, Rao A, Quasney MW, Matsumura Y, Inagaki N, Dahmer MK (2010) Identification and characterization of a novel ABCA3 mutation. Physiol Genomics 40:94–99
Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M (2004) ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 350:1296–1303
Weaver TE, Conkright JJ (2001) Function of surfactant proteins B and C. Annu Rev Physiol 63:555–578
Weichert N, Kaltenborn E, Hector A, Woischnik M, Schams A, Holzinger A, Kern S, Griese M (2011) Some ABCA3 mutations elevate ER stress and initiate apoptosis of lung epithelial cells. Respir Res 12:4
Wert SE, Whitsett JA, Nogee LM (2009) Genetic disorders of surfactant dysfunction. Pediatr Dev Pathol 12:253–274
Yang HZ, Wang JP, Mi S, Liu HZ, Cui B, Yan HM, Yan J, Li Z, Liu H, Hua F, Lu W, Hu ZW (2012) TLR4 activity is required in the resolution of pulmonary inflammation and fibrosis after acute and chronic lung injury. Am J Pathol 180:275–292. doi:10.1016/j.ajpath.2011.09.019
Yokota T, Matsumura Y, Ban N et al (2007) Heterozygous ABCA3 mutation associated with non-fatal evolution of respiratory distress. Eur J Pediatr 167:691–693
Young LR, Nogee LM, Barnett B, Panos RJ, Colby TV, Deutsch GH (2008) Usual interstitial pneumonia in an adolescent with ABCA3 mutations. Chest 134:192–195
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We thank Ms. Ikuko Hakozaki (Tohoku University) for technical assistance.
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Kitazawa, H., Moriya, K., Niizuma, H. et al. Interstitial lung disease in two brothers with novel compound heterozygous ABCA3 mutations. Eur J Pediatr 172, 953–957 (2013). https://doi.org/10.1007/s00431-013-1977-8
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DOI: https://doi.org/10.1007/s00431-013-1977-8