ADOPTING ORPHAN DISEASES RARE INTERSTITIAL LUNG DISEASES

adoptingorphandiseaseskapak

FAMILIAL INTERSTITIAL PNEUMONIAS (SP-C/TELOMERE SHORTENING/ABCA3)

Demet Polat Yuluğ1 Eylem Sercan Özgür2

1Mersin University, Faculty of Medicine, Department of Chest Diseases, Mersin, Türkiye
2Mersin University, Faculty of Medicine, Department of Chest Diseases, Mersin, Türkiye

Polat Yulug D, Sercan Ozgur E. Familial Interstitial Pneumonias (SP-C/Telomere Shortening/ABCA3). In: Altinisik G, McCormack FX, editors. Adopting Orphan Diseases: Rare Interstitial Lung Diseases. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.135-145.

ABSTRACT

Familial interstitial pneumonia (FIP) represents one of the most intriguing frontiers in interstitial lung disease, lying at the intersection of clinical heterogeneity, genetic complexity, and therapeutic uncertainty. While idiopathic pulmonary fibrosis (IPF) remains the prototypical phenotype, patients with FIP often defy textbook definitions: presenting earlier, progressing faster, and exhibiting unexpected extrapulmonary manifestations such as macrocytosis or hepatic dysfunction.

Over the past two decades, a paradigm shift has occurred: from recognizing FIP as a clinical curiosity to understanding it as a genetically driven disorder rooted in mutations affecting surfactant homeostasis (e.g., SFTPC, SFTPA1/2, ABCA3) and telomere maintenance (e.g., TERT, TERC, RTEL1, PARN). These mutations not only alter epithelial cell integrity and regenerative capacity but also introduce critical questions about heritability, disease anticipation, and systemic involvement. Remarkably, in many families, these mutations reveal themselves not only through pulmonary fibrosis but through hematologic abnormalities, cryptogenic liver disease, and premature hair graying.

With the advent of accessible genetic sequencing and telomere length assays, FIP has become a diagnostically actionable entity. However, these developments have raised many questions: How frequently should an asymptomatic individual carrying a telomere mutation be monitored? Can standard immunosuppressive regimens be safely administered in patients with short telomeres? Should lung transplantation protocols be fundamentally restructured for this group?

Therapeutic decisions are no longer solely based on radiologic patterns or lung function decline. Instead, they must account for the molecular architecture of the disease. Emerging data suggest that antifibrotic therapies remain effective in patients with telomerase mutations, offering hope where traditional immunosuppression may increase harm. Additionally, lung transplantation, often considered the last resort, requires a nuanced approach in FIP due to heightened risk of complications in telomere syndromes.

In the future, the integration of genetic and clinical data may enable the development of a more predictable, safe, and effective monitoring-treatment model for both patients and asymptomatic individuals at risk. This chapter explores the evolving landscape of FIP, with a focus on gene-specific phenotypes, risk stratification strategies, and the expanding role of precision medicine.

Keywords: Familial interstitial pneumonia; Surfactant protein mutations; Telomere shortening; Interstitial lung disease; Rare interstitial lung diseases; Monogenic fibrosis

Referanslar

  1. Wijsenbeek M, Cottin V. Spectrum of fibrotic lung diseases. N Engl J Med. 2020;383(10):958-68. [Crossref]  [PubMed]
  2. Borie R, Kannengiesser C, Antoniou K, Bonella F, Crestani B, Fabre A, et al. European Respiratory Society statement on familial pulmonary fibrosis. Eur Respir J. 2023;61(3):2201383. [Crossref]  [PubMed]
  3. Zhang D, Newton CA. Familial Pulmonary Fibrosis: Genetic Features and Clinical Implications. Chest. 2021;160(5):1764- [Crossref]  [PubMed]  [PMC]
  4. Hughes EW. Familial interstitial pulmonary fibrosis. Thorax. 1964;19(10):515-25. [Crossref]  [PubMed]  [PMC]
  5. Ding D, Gao R, Xue Q, Luan R, Yang J. Genomic Fingerprint Associated with Familial Idiopathic Pulmonary Fibrosis: A Review. Int J Med Sci. 2023;20(3):329-45. [Crossref]  [PubMed]  [PMC]
  6. Natalini JG, England BR, Baker JF, Dellaripa PF, Bolster MB, Ascherman DP, et al. Associations between shortened telomeres and rheumatoid arthritis-associated interstitial lung disease among U.S. Veterans. Respir Med. 2022;201:106943. [Crossref]  [PubMed]  [PMC]
  7. Doyle TJ, Juge PA, Peljto AL, Lundström SL, Mathai SC, Glaser SM, et al. Short peripheral blood leukocyte telomere length in rheumatoid arthritis-interstitial lung disease. Thorax. 2024;79(2):182-85. [Crossref]  [PubMed]  [PMC]
  8. Abbasi A, Chen C, Gandhi CK, Duru N, Luna-Rivero C, Figueroa J, et al. SNP and SNP-SNP Interactions of Surfactant Protein Genes in IPF and HP. Front Immunol. 2022;13:842745.
  9. Raghu G, Chen SY, Hou Q, Yeh WS, Collard HR. Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur Respir J. 2016;48(1):179- [Crossref]  [PubMed]
  10. Hodgson U, Laitinen T, Tukiainen P. Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland. Thorax. 2002;57(4):338-42. [Crossref]  [PubMed]  [PMC]
  11. Fernandez BA, Fox G, Bhatia R, Sala CF, Boctor N, Edwards M, et al. A Newfoundland cohort of familial and sporadic idiopathic pulmonary fibrosis patients. Respir Res. 2012;13(1):64. [Crossref]  [PubMed]  [PMC]
  12. Garcia-Sancho C, Buendia-Roldan I, Fernandez-Plata MR, Navarro C, Ramirez R, Gonzalez-Perez MI, et al. Familial pulmonary fibrosis is the strongest risk factor for idiopathic pulmonary fibrosis. Respir Med. 2011;105(12):1902-07. [Crossref]  [PubMed]
  13. Hortense AB, Santos MKD, Wada D, Perim F, Rocha Júnior RS, Salge JM, et al. Familial pulmonary fibrosis: a heterogeneous spectrum of presentations. J Bras Pneumol. 2019;45(5):e20180079. [Crossref]  [PubMed]  [PMC]
  14. Mathai SK, Humphries S, Kropski JA, Blackwell TS, Powers J, Han MK, et al. MUC5B variant is associated with visually and quantitatively detected preclinical pulmonary fibrosis. Thorax. 2019;74(12):1131-39. [Crossref]  [PubMed]  [PMC]
  15. Salisbury ML, Hewlett JC, Ding G, Markin CR, Douglas KN, Carrino JA, et al. Development and progression of radiologic abnormalities in individuals at risk for familial interstitial lung disease. Am J Respir Crit Care Med. 2020;201(10):1230-39. [Crossref]  [PubMed]
  16. Hunninghake GM, Quesada-Arias LD, Carmichael NE, et al. Interstitial lung disease in relatives of patients with pulmonary fibrosis. Am J Respir Crit Care Med. 2020;201(10):1240-48. [Crossref]  [PubMed]
  17. Putman RK, Hatabu H, Araki T, Gudmundsson G, Gao W, Nishino M, et al. Association between interstitial lung abnormalities and all-cause mortality. JAMA. 2016;315(7):672- [Crossref]  [PubMed]
  18. Nureki SI, Tomer Y, Venosa A, Katzen J, Russo SJ, Jamil S, et al. Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis. J Clin Invest. 2018;128(9):4008-24. [Crossref]  [PubMed]
  19. Sutton RM, Bittar HT, Sullivan DI, Silva AG, Bahudhanapati H, Parikh AH, et al. Rare surfactant-related variants in familial and sporadic pulmonary fibrosis. Hum Mutat. 2022;43(12):2091-101. [Crossref]  [PubMed]  [PMC]
  20. Campo I, Zorzetto M, Mariani F, Kadija Z, Morbini P, Dore R, et al. A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant. Respir Res. 2014;15(1):43. [Crossref]  [PubMed]  [PMC]
  21. Katzen J, Wagner BD, Venosa A, Kopp M, Tomer Y, Russo SJ, et al. An SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung fibrosis. JCI Insight. 2019;4(6):e126125. [Crossref]  [PubMed]  [PMC]
  22. Chen R, Zhang K, Chen H, Zhao X, Wang J, Li L, et al. Telomerase deficiency causes alveolar stem cell senescence-associated low-grade inflammation in lungs. J Biol Chem. 2015;290(52):30813-29. [Crossref]  [PubMed]
  23. Zhang D, Zhou Z, Abu-Hijleh M, Batra K, Xing C, Garcia CK. Homozygous rare PARN missense mutation in familial pulmonary fibrosis. Am J Respir Crit Care Med. 2019;199(6):797-99. [Crossref]  [PubMed]
  24. Kannengiesser C, Borie R, Menard C, Nathan N, Cottin V, Nunes H, et al. Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis. Eur Respir J. 2015;46(2):474-85. [Crossref]  [PubMed]
  25. Stanley SE, Gable DL, Wagner CL, Duggal P, Willeford E, Brown EE, et al. Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. Sci Transl Med. 2016;8(351):351ra107. [Crossref]  [PubMed]  [PMC]
  26. Krauss E, Gehrken G, Drakopanagiotakis F, Kairalla RA, Polychronopoulos VS, Tzouvelekis A, et al. Clinical characteristics of patients with familial idiopathic pulmonary fibrosis (f-IPF). BMC Pulm Med. 2019;19(1):130. [Crossref]  [PubMed]  [PMC]
  27. Jaula H, Mattila L, Lappi-Blanco E, Salonen J, Vähänikkilä H, Ahvenjärvi L, et al. Clinical, radiological and histopathological features of patients with familial pulmonary fibrosis. Respir Res. 2024;25(1):239. [Crossref]  [PubMed]  [PMC]
  28. Papiris SA, Tsirigotis P, Kannengiesser C, Borie R, Crestani B, Nunes H, et al. Myelodysplastic syndromes and idiopathic pulmonary fibrosis: a dangerous liaison. Respir Res. 2019;20(1):182. [Crossref]  [PubMed]  [PMC]
  29. Molina-Molina M, Borie R. Clinical implications of telomere dysfunction in lung fibrosis. Curr Opin Pulm Med. 2018;24(5):440-444. [Crossref]  [PubMed]
  30. Phillips-Houlbracq M, Mal H, Cottin V, Le Pavec J, Thabut G, Picard C, et al. Determinants of survival after lung transplantation in telomerase-related gene mutation carriers: a retrospective cohort. Am J Transplant. 2021;22(4):1236- [Crossref]  [PubMed]
  31. Alder JK, Sutton RM, Iasella CJ, Han X, He J, Rosen CJ, et al. Lung transplantation for idiopathic pulmonary fibrosis enriches for individuals with telomere-mediated disease. J Heart Lung Transplant. 2021;41(5):654-63. [Crossref]  [PubMed]  [PMC]
  32. Southern BD, Gadre SK. Telomeropathies in intersti tial lung disease and lung transplant recipients. J Clin Med.2025;14(5):1496. [Crossref]  [PubMed]  [PMC]
  33. Hannan SJ, Iasella CJ, Sutton RM, Popescu ID, Koshy R, Burke R, et al. Lung transplant recipients with telomere-mediated pulmonary fibrosis have increased risk for hematologic complications. Am J Transplant. 2023;23(10):1590-602. [Crossref]  [PubMed]  [PMC]
  34. Hercher L. Discouraging elective genetic testing of minors: a norm under siege in a new era of genomic medicine. Cold Spring Harb Perspect Med. 2020;10(7):a036657. [Crossref]  [PubMed]  [PMC]
  35. van der Vis JJ, van der Smagt JJ, van Batenburg AA, van Es HW, Grutters JC, van Moorsel CHM, et al. Pulmonary fibrosis in non-mutation carriers of families with short telomere syndrome gene mutations. Respirology.2021;26(12):1160-70. [Crossref]  [PubMed]
  36. van Moorsel CHM, van der Vis JJ, Grutters JC. Genetic disorders of the surfactant system: focus on adult disease. Eur Respir Rev. 2021;30(161):200085. [Crossref]  [PubMed]  [PMC]
  37. Kropski JA, Pritchett JM, Zoz DF, Blumhagen RZ, Wheeler S, Edwards MG, et al. Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease. Am J Respir Crit Care Med. 2015;191(4):417-26. [Crossref]  [PubMed]
  38. Rosas IO, Ren P, Avila NA, Chow CK, Franks TJ, Travis WD, et al. Early interstitial lung disease in familial pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176(7):698705. [Crossref]  [PubMed]
  39. Newton CA, Batra K, Torrealba J, Kozlitina J, Glazer CS, Khera A, et al. Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive. Eur Respir J. 2016;48(6):1710-20. [Crossref]  [PubMed]  [PMC]
  40. Bennett D, Mazzei MA, Squitieri NC, Andrei F, Sani S, Fossi A, et al. Familial pulmonary fibrosis: clinical and radiological characteristics and progression analysis in different high-resolution CT patterns. Respir Med. 2017;126:75-83. [Crossref]  [PubMed]
  41. Alder JK, Cogan JD, Brown AF, Anderson CJ, Lawson WE, Lansdorp PM, et al. Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLoS Genet.2011;7(3):e1001352. [Crossref]  [PubMed]  [PMC]
  42. Justet A, Klay D, Porcher R, Bringel V, Menard C, Thabut G, et al. Safety and efficacy of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and carrying a telomere-related gene mutation. Eur Respir J.2021;57(5):2003198. [Crossref]  [PubMed]
  43. Dressen A, Abbas AR, Cabanski C, Reeder J, Ramamoorthy A, Lahouel K, et al. Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study. Lancet Respir Med. 2018;6(8):603-14. [Crossref]
  44. Newton CA, Zhang D, Oldham JM, Kozlitina J, Ma SF, Martinez FJ, et al. Telomere length and use of immunosuppressive medications in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2019;200(3):336-47. [Crossref]  [PubMed]
  45. Adegunsoye A, Morisset J, Newton CA, Oldham JM, Fernández Pérez ER, Haynes S, et al. Leukocyte telomere length and mycophenolate therapy in chronic hypersensitivity pneumonitis. Eur Respir J. 2021;57(3):2002872. [Crossref]  [PubMed]  [PMC]
  46. Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022;205(9):e18-e47. [Crossref]  [PubMed]
  47. Hurley K, Ozaki M, Philippot Q, Cottin V, Maher TM, Molina-Molina M, et al. A roadmap to precision treatments for familial pulmonary fibrosis. EBioMedicine. 2024;104:105135. [Crossref]  [PubMed]  [PMC]