SUMMARY
Although respiratory distress syndrome (RDS) is predominantly associated with functional immaturity of the surfactant system in preterm neonates, mutations in genes regulating surfactant metabolism may play an important role in the pathogenesis of severe and treatment-resistant RDS in term infants. This literature review aims to summarize the characteristics of surfactant-related gene mutations associated with RDS in term neonates and to evaluate their diagnostic significance. Available evidence indicates that pathogenic variants in SFTPB, SFTPC, ABCA3, and NKX2-1 may impair surfactant synthesis, intracellular processing, transport, and function, resulting in severe neonatal respiratory failure and interstitial lung disease later in life. SFTPD variants are better regarded as potential modifiers of RDS susceptibility and severity rather than established causes of monogenic surfactant dysfunction. Early genetic panel testing can facilitate a definitive diagnosis, improve prognostic assessment, guide individualized treatment decisions, and support appropriate genetic counselling for affected families. In the future, gene replacement, messenger RNA–based therapy, and protein replacement approaches may provide new opportunities for the targeted treatment of inherited surfactant disorders.
Keywords: respiratory distress syndrome, pulmonary surfactant, term neonates, surfactant dysfunction, SFTPB, ABCA3, genetic testing

---

REFERENCES

1. Wang J, Fan J, Zhang Y, Huang L, et al. ABCA3 gene mutations shape the clinical profiles of severe unexplained respiratory distress syndrome in late preterm and term infants // Transl Pediatr. 2021 Feb;10(2):350-358. doi: 10.21037/tp-20-283
2. Somaschini M, Presi S, Ferrari M, Vergani B, et al. Surfactant proteins gene variants in premature newborn infants with severe respiratory distress syndrome // J Perinatol. 2018 Apr;38(4):337-344. doi: 10.1038/s41372-017-0018-2
3. Mikolajcikova S, Lasabova Z, Holubekova V, Skerenova M, et al. The Common Haplotype GATGACA in Surfactant-Protein B Gene Is Protective for Respiratory Distress Syndrome in Preterm Neonates // Front Pediatr. 2022; 10:851042. doi: 10.3389/fped.2022.851042
4. Nogee LM, Ryan RM. Genetic Testing for Neonatal Respiratory Disease // Children (Basel). 2021 Mar 11;8(3):216. doi: 10.3390/children8030216
5. Овсянников Д.Ю., Жесткова М.А., Стрельникова В.А., Аверин А.П. и др. Генетические дисфункции системы сурфактанта у детей: результаты многоцентрового исследования // Доктор.Ру. 2023;22(3):22–31. doi: 10.31550/1727-2378-2023-22-3-22-31
6. Caldeira I, Fernandes-Silva H, Machado-Costa D, Correia-Pinto J, et al. Developmental Pathways Underlying Lung Development and Congenital Lung Disorders // Cells. 2021 Nov 2;10(11):2987. doi: 10.3390/cells10112987
7. Бойцова Е.В., Овсянников Д.Ю., Макаренко Е.В., Карпенко М.А. Современные представления о развитии и нарушениях развития легких у детей // Детская медицина Северо-Запада. 2021;9(3):c.19–30
8. Possmayer F, Zuo YY, Veldhuizen RAW, Petersen NO. Pulmonary Surfactant: A Mighty Thin Film // Chem Rev. 2023 Dec 13;123(23):13209-13290. doi: 10.1021/acs.chemrev.3c00146
9. Ji J, Sun L, Luo Z, Zhang Y, et al. Potential Therapeutic Applications of Pulmonary Surfactant Lipids in the Host Defence Against Respiratory Viral Infections // Front. Immunol. 2021;12:730022. doi: 10.3389/fimmu.2021.730022
10. Liu D., Wang J., Xu Z, Chen X, et al. Phagocytosis: strategies for macrophages to hunt Mycobacterium tuberculosis // One Health Adv. 2024;2:32. doi: 10.1186/s44280-024-00065-9
11. Özer EA, Demirel G, Tüzün F. Türk Neonatoloji Derneği Term Yenidoğanda Solunum Sıkıntısı Tanı, Tedavi ve Korunma Rehberi. Ankara: Güneş Tıp Kitabevleri; 2021, 90 s
12. Rogulska J, Wróblewska-Seniuk K, Śmigiel R, Szydłowski J, et al. Diagnostic Challenges in Neonatal Respiratory Distress-Congenital Surfactant Metabolism Dysfunction Caused by ABCA3 Mutation // Diagnostics (Basel). 2022 Apr 26;12(5):1084. doi: 10.3390/diagnostics12051084
13. Nevel RJ, Brennan SK, Wambach JA. Genetic disorders of surfactant metabolism // NeoReviews. 2025;26(5):e328–e338. doi:10.1542/neo.26-5-014
14. Dunbar AE 3rd, Wert SE, Ikegami M, Whitsett JA, et al. Prolonged survival in hereditary surfactant protein B (SP-B) deficiency associated with a novel splicing mutation // Pediatr Res. 2000 Sep;48(3):275-82. doi: 10.1203/00006450-200009000-00003
15. Lu J, Willis AC, Reid KB. Purification, characterization and cDNA cloning of human lung surfactant protein D // Biochem J. 1992;284(Pt 3):795–802. doi: 10.1042/bj2840795
16. Cedzyński M, Świerzko AS. Collectins and ficolins in neonatal health and disease // Front Immunol. 2023;14:1328658. doi: 10.3389/fimmu.2023.1328658
17. Anciuc-Crauciuc M, Cucerea MC, Tripon F, Crauciuc GA, et al. Descriptive and Functional Genomics in Neonatal Respiratory Distress Syndrome: From Lung Development to Targeted Therapies // Int J Mol Sci. 2024 Jan 4;25(1):649. doi: 10.3390/ijms25010649
18. Anciuc-Crauciuc M, Cucerea MC, Crauciuc GA, Tripon F, et al. Evaluation of the Copy Number Variants and Single-Nucleotide Polymorphisms of ABCA3 in Newborns with Respiratory Distress Syndrome-A Pilot Study // Medicina (Kaunas). 2024 Feb 29;60(3):419. doi: 10.3390/medicina60030419
19. Amatya S, Ye M, Yang L, Gandhi CK, et al. Single Nucleotide Polymorphisms Interactions of the Surfactant Protein Genes Associated With Respiratory Distress Syndrome Susceptibility in Preterm Infants // Front Pediatr. 2021 Oct 4;9:682160. doi: 10.3389/fped.2021.682160
20. Peers de Nieuwburgh M, Wambach JA, Griese M, Danhaive O. Towards personalized therapies for genetic disorders of surfactant dysfunction // Semin Fetal Neonatal Med. 2023 Dec;28(6):101500. doi: 10.1016/j.siny.2023.101500
21. Cooney AL, Wambach JA, Sinn PL, McCray PB Jr. Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction // Front Genome Ed. 2022 Jan 14;3:785829. doi: 10.3389/fgeed.2021.785829