Persistent Respiratory Distress in the Term Neonate: Genetic Surfactant Deficiency Diseases

Author(s): Jessie E. Magnani, Steven M. Donn*

Journal Name: Current Pediatric Reviews

Volume 16 , Issue 1 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Respiratory distress is one of the most common clinical presentations in newborns requiring admission to a Neonatal Intensive Care Unit (NICU). Many of these infants develop respiratory distress secondary to surfactant deficiency, which causes an interstitial lung disease that can occur in both preterm and term infants. Pulmonary surfactant is a protein and lipid mixture made by type II alveolar cells, which reduces alveolar surface tension and prevents atelectasis.

The etiology of surfactant deficiency in preterm infants is pulmonary immaturity and inadequate production. Term infants may develop respiratory insufficiency secondary to inadequate surfactant, either from exposure to factors that delay surfactant synthesis (such as maternal diabetes) or from dysfunctional surfactant arising from a genetic mutation.

The genetics of surfactant deficiencies are very complex. Some mutations are lethal in the neonatal period, while others cause a wide range of illness severity from infancy to adulthood. Genes that have been implicated in surfactant deficiency include SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD (which encode for surfactant proteins A, B, C, and D, respectively); ABCA3 (crucial for surfactant packaging and secretion); and NKX2 (a transcription factor that regulates the expression of the surfactant proteins in lung tissue).

This article discusses the interplay between the genotypes and phenotypes of newborns with surfactant deficiency to assist clinicians in determining which patients warrant a genetic evaluation.

Keywords: Surfactant, surfactant-associated proteins, respiratory distress, genetics, pulmonary, deficiency, phospholipid.

[1]
Nogee LM. Interstitial lung disease in newborns. Semin Fetal Neonatal Med 2017; 22(4): 227-33.
[http://dx.doi.org/10.1016/j.siny.2017.03.003] [PMID: 28363760]
[2]
Ketko AK, Donn SM. Surfactant-associated proteins: structure, function and clinical implications. Curr Pediatr Rev 2014; 10(2): 162-7.
[http://dx.doi.org/10.2174/157339631130900006] [PMID: 25088270]
[3]
Halliday HL. The fascinating story of surfactant. J Paediatr Child Health 2017; 53(4): 327-32.
[http://dx.doi.org/10.1111/jpc.13500] [PMID: 28271629]
[4]
Hallman M. The surfactant system protects both fetus and newborn. Neonatology 2013; 103(4): 320-6.
[http://dx.doi.org/10.1159/000349994] [PMID: 23736009]
[5]
Nkadi PO, Merritt TA, Pillers DA. An overview of pulmonary surfactant in the neonate: genetics, metabolism, and the role of surfactant in health and disease. Mol Genet Metab 2009; 97(2): 95-101.
[http://dx.doi.org/10.1016/j.ymgme.2009.01.015] [PMID: 19299177]
[6]
Lamberska T, Settelmayerova E, Smisek J, Luksova M, Maloskova G, Plavka R. Oropharyngeal surfactant can improve initial stabilisation and reduce rescue intubation in infants born below 25 weeks of gestation. Acta Paediatr 2018; 107(1): 73-8.
[http://dx.doi.org/10.1111/apa.14060] [PMID: 28871620]
[7]
Olivier F, Nadeau S, Bélanger S, et al. Efficacy of minimally invasive surfactant therapy in moderate and late preterm infants: A multicentre randomized control trial. Pediatric & Child Health 2017; 22(3): 120-4.
[8]
Boggaram V. Regulation of lung surfactant protein gene expression. Front Biosci 2003; 8(8): d751-64.
[http://dx.doi.org/10.2741/1062] [PMID: 12700056]
[9]
Wang Y, Kuan PJ, Xing C, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet 2009; 84(1): 52-9.
[http://dx.doi.org/10.1016/j.ajhg.2008.11.010] [PMID: 19100526]
[10]
Aneja MK, Rudolph C. Gene therapy of surfactant protein B deficiency. Curr Opin Mol Ther 2006; 8(5): 432-8.
[PMID: 17078385]
[11]
Wilder MA. Surfactant protein B deficiency in infants with respiratory failure. J Perinat Neonatal Nurs 2004; 18(1): 61-7.
[http://dx.doi.org/10.1097/00005237-200401000-00006] [PMID: 15027668]
[12]
Barnett RC, Lin X, Barravecchia M, et al. Featured Article: Electroporation-mediated gene delivery of surfactant protein B (SP-B) restores expression and improves survival in mouse model of SP-B deficiency. Exp Biol Med (Maywood) 2017; 242(13): 1345-54.
[http://dx.doi.org/10.1177/1535370217713000] [PMID: 28581337]
[13]
Avital A, Hevroni A, Godfrey S, et al. Natural history of five children with surfactant protein C mutations and interstitial lung diseases 2014; 49(121): 1097-5.
[http://dx.doi.org/10.1002/ppul.22971]
[14]
Gower WA, Nogee LM. Candidate gene analysis of the surfactant protein D gene in pediatric diffuse lung disease. J Pediatr 2013; 163(6): 1778-80.
[http://dx.doi.org/10.1016/j.jpeds.2013.06.063] [PMID: 23932215]
[15]
Gonçalves JP, Pinheiro L, Costa M, Silva A, Gonçalves A, Pereira A. Novel ABCA3 mutations as a cause of respiratory distress in a term newborn. Gene 2014; 534(2): 417-20.
[http://dx.doi.org/10.1016/j.gene.2013.11.015] [PMID: 24269975]
[16]
Connors TD, Van Raay TJ, Petry LR, Klinger KW, Landes GM, Burn TC. The cloning of a human ABC gene (ABC3) mapping to chromosome 16p13.3. Genomics 1997; 39(2): 231-4.
[http://dx.doi.org/10.1006/geno.1996.4500] [PMID: 9027511]
[17]
AlAnazi A, Epaud R, Heena H, de Becdelievre A, Miqdad AM, Fanen P. The most frequent ABCA3 nonsense mutation -p.Tyr1515* (Y1515X) causing lethal neonatal respiratory failure in a term neonate. Ann Thorac Med 2017; 12(3): 213-5.
[http://dx.doi.org/10.4103/atm.ATM_386_16] [PMID: 28808495]
[18]
Yamano G, Funahashi H, Kawanami O, et al. ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells. FEBS Lett 2001; 508(2): 221-5.
[http://dx.doi.org/10.1016/S0014-5793(01)03056-3] [PMID: 11718719]
[19]
Peca D, Cutrera R, Masotti A, Boldrini R, Danhaive O. ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system. Biochem Soc Trans 2015; 43(5): 913-9.
[http://dx.doi.org/10.1042/BST20150100] [PMID: 26517903]
[20]
Henderson LB, Melton K, Wert S, et al. Large ABCA3 and SFTPC deletions resulting in lung disease. Ann Am Thorac Soc 2013; 10(6): 602-7.
[http://dx.doi.org/10.1513/AnnalsATS.201306-170OC] [PMID: 24024739]
[21]
Wambach JA, Casey AM, Fishman MP, et al. Genotype-phenotype correlations for infants and children with ABCA3 deficiency. Am J Respir Crit Care Med 2014; 189(12): 1538-43.
[http://dx.doi.org/10.1164/rccm.201402-0342OC] [PMID: 24871971]
[22]
Attarian SJ, Leibel SL, Yang P, et al. Mutations in the thyroid transcription factor gene NKX2-1 result in decreased expression of SFTPB and SFTPC. Pediatr Res 2018; 84(3): 419-25.
[http://dx.doi.org/10.1038/pr.2018.30] [PMID: 29538355]
[23]
Guazzi S, Price M, De Felice M, Damante G, Mattei M-G, Di Lauro R. Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity. EMBO J 1990; 9(11): 3631-9.
[http://dx.doi.org/10.1002/j.1460-2075.1990.tb07574.x] [PMID: 1976511]
[24]
Hamvas A, Deterding RR, Wert SE, et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest 2013; 144(3): 794-804.
[http://dx.doi.org/10.1378/chest.12-2502] [PMID: 23430038]
[25]
Nattes E, Lejeune S, Carsin A, et al. Heterogeneity of lung disease associated with NK2 homeobox 1 mutations. Respir Med 2017; 129: 16-23.
[http://dx.doi.org/10.1016/j.rmed.2017.05.014] [PMID: 28732825]
[26]
Chung C, Kim T, Kim M, et al. Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis. Proc Natl Acad Sci USA 2013; 110(19): 7732-7.
[http://dx.doi.org/10.1073/pnas.1220603110] [PMID: 23620511]
[27]
Donn SM, Sinha SK. Pulmonary diagnostics. Semin Fetal Neonatal Med 2017; 22(4): 200-5.
[http://dx.doi.org/10.1016/j.siny.2017.03.006] [PMID: 28389088]
[28]
Hermansen CL, Lorah KN. Respiratory distress in the newborn. Am Fam Physician 2007; 76(7): 987-94.
[PMID: 17956068]
[29]
Kuzniewicz MW, Puopolo KM, Fischer A, et al. A quantitative, risk-based approach to the management of neonatal early-onset sepsis. JAMA Pediatr 2017; 171(4): 365-71.
[http://dx.doi.org/10.1001/jamapediatrics.2016.4678] [PMID: 28241253]
[30]
Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T. Artificial surfactant therapy in hyaline-membrane disease. Lancet 1980; 1(8159): 55-9.
[http://dx.doi.org/10.1016/S0140-6736(80)90489-4] [PMID: 6101413]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 1
Year: 2020
Page: [17 - 25]
Pages: 9
DOI: 10.2174/1573396315666190723112916

Article Metrics

PDF: 33
HTML: 6
EPUB: 1
PRC: 1