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Diagnosis of pulmonary hypertension ‘Outside of the box’: hereditary pulmonary arterial hypertension with the TBX4 gene Cover

Diagnosis of pulmonary hypertension ‘Outside of the box’: hereditary pulmonary arterial hypertension with the TBX4 gene

Open Access
|May 2025

References

  1. Lau EMT, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension. Nature Reviews. Cardiology. 2017;14(10): 603–614. doi:10.1038/nrcardio.2017.84
  2. Kerstjens-Frederikse WS, Bongers EM, Roofthooft MT, Leter EM, Douwes JM, Van Dijk A, et al. TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension. Journal of Medical Genetics. 2013;50(8): 500–506. doi:10.1136/jmedgenet-2012-101152
  3. Anani AR, Van Kalsbeek D, El-Kersh K. Don’t forget the knees: novel TBX4 gene mutation associated with pulmonary arterial hypertension. Chest. 2024;166(4): A5978–A5979. doi:10.1016/j.chest.2024.06.3539
  4. Li P, Lan W, Li J, Zhang Y, Xiong Q, Ye J, et al. Identification and functional evaluation of a novel TBX4 mutation underlies small patella syndrome. International Journal of Molecular Sciences. 2022;23(4): 2075. doi:10.3390/ijms23042075
  5. Uchida K, Yoshida Y, Kodo K, Yamagishi H. Roles of Tbx4 in the Lung Mesenchyme for Airway and Vascular Development. In: Nakanishi, T., Baldwin, H., Fineman, J., Yamagishi, H. (eds) Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension. Springer, Singapore. https://doi.org/10.1007/978-981-15-1185-1_8; p. 79–81.
  6. Austin ED, Elliott CG. TBX4 syndrome: a systemic disease high-lighted by pulmonary arterial hypertension in its most severe form. European Respiratory Journal. 2020;55(5): 2000585. doi:10.1183/13993003.00585-2020
  7. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M et al. ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Oxford University Press, Oxford, United Kingdom. Eur Heart J. 2022 Oct 11;43(38):3618-3731.
  8. Sitbon O, Humbert M, Jaïs X, Ioos V, Hamid AM, Provencher S, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111(23): 3105–3111. doi:10.1161/CIRCULATIONAHA.104.488486
  9. Tonelli AR, Alnuaimat H, Mubarak K. Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension. Respiratory Medicine. 2010;104(4): 481–496. doi:10.1016/j.rmed.2009.11.015
  10. Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA 3rd, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. New England Journal of Medicine. 2001;345(5): 319–324. doi:10.1056/NEJM200108023450502
  11. Maldonado-Velez G, Mickler EA, Cook TG, Aldred MA. Loss of Tbx4 Affects Postnatal Lung Development and Predisposes to Pulmonary Hypertension. bioRxiv [Preprint]. 2024 Sep 22:2024.09.18.613783. doi: 10.1101/2024.09.18.613783. Update in: Am J Respir Cell Mol Biol. 2025 Mar 19. doi: 10.1165/rcmb.2024-0459OC. PMID: 39345561; PMCID: PMC11429984.
  12. Haarman MG, Kerstjens-Frederikse WS, Berger RMF. The ever-expanding phenotypical spectrum of human TBX4 mutations: from toe to lung. European Respiratory Journal. 2019;54(2): 1901504. doi:10.1183/13993003.01504-2019
  13. Karolak JA, Gambin T, Szafranski P, Stankiewicz P. Potential interactions between the TBX4-FGF10 and SHH-FOXF1 signaling during human lung development revealed using ChIP-seq. Respiratory Research. 2021;22(1): 26. doi:10.1186/s12931-021-01617-y
  14. Lago Docampo M, Gunthur D, Cao A, Wang L, Cheawsamoot C, Mondejar G et al.; (2024). TBX4 deletion in IPSC results in vascular smooth muscle cells with impaired contractility, and apoptosis resistance that induce EndoMT. Coronado Bridge: linking novel extra-thoracic disease mechanisms with PAH. American Thoracic Society; San Diego, CA ; A6804-A6804. 10.1164/ajrccm-conference.2024.209.1_MeetingAbstracts.A6804.
  15. Hernandez-Gonzalez I, Tenorio J, Palomino-Doza J, Martinez Meñaca A, Morales Ruiz R, Lago-Docampo M, et al. Clinical heterogeneity of pulmonary arterial hypertension associated with variants in TBX4. Plos One. 2020;15(4): e0232216. doi:10.1371/journal.pone.0232216
  16. Gräf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W, et al. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nature Communications. 2018;9(1): 1416. doi:10.1038/s41467-018-03672-4
  17. Morrell NW, Aldred MA, Chung WK, Elliott CG, Nichols WC, Soubrier F, et al. Genetics and genomics of pulmonary arterial hypertension. European Respiratory Journal. 2019;53(1): 1801899. doi:10.1183/13993003.01899-2018
  18. Austin ED, Phillips JA III, Loyd JE. Heritable Pulmonary Arterial Hypertension Overview. 2002 Jul 18 [updated 2020 Dec 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301658.
  19. Hjalmarsson C, Radegran G, Bjorklund E, Hjalmarsson A, Nisell M, Papageorgiou J et al.; Prognostic significance of positive vasoreactivity test in pulmonary arterial hypertension is affected by age. The Journal of Heart and Lung Transplantation. 2024;43(4): S407. doi:10.1016/j.healun.2024.02.1305
  20. Carpenter NJ. Genetic anticipation. Neurologic Clinics. 1994;12(4): 683–697. doi:10.1016/S0733-8619(18)30071-9
DOI: https://doi.org/10.2478/pneum-2025-0006 | Journal eISSN: 2247-059X | Journal ISSN: 2067-2993
Language: English
Page range: 36 - 41
Published on: May 6, 2025
In partnership with: Paradigm Publishing Services
Publication frequency: Volume open

© 2025 Anca Trifoi, Andrei Neagu, Georgiana Olaru-Lego, Roxana Enache, Ioan Mircea Coman, Tudor Constantinescu, published by Romanian Society of Pneumology
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.