Clinical heterogeneity of Pulmonary Arterial Hypertension associated with variants in TBX4


Hernandez-Gonzalez I, Tenorio J, Palomino-Doza J, Martinez Meñaca A, Morales Ruiz R, Lago-Docampo M, Valverde Gomez M, Gomez Roman J, Enguita Valls AB, Perez-Olivares C, Valverde D, Gil Carbonell J, Garrido-Lestache Rodríguez-Monte E, Del Cerro MJ, Lapunzina P, Escribano-Subias P.

PLoS One. 2020 Apr 29;15(4):e0232216. doi: 10.1371/journal.pone.0232216. eCollection 2020.

PMID: 32348326 Free PMC Article

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Background: The knowledge of hereditary predisposition has changed our understanding of Pulmonary Arterial Hypertension. Genetic testing has been widely extended and the application of Pulmonary Arterial Hypertension specific gene panels has allowed its inclusion in the diagnostic workup and increase the diagnostic ratio compared to the traditional sequencing techniques. This is particularly important in the differential diagnosis between Pulmonary Arterial Hypertension and Pulmonary Venoocclusive Disease.

Methods: Since November 2011, genetic testing is offered to all patients with idiopathic, hereditable and associated forms of Pulmonary Arterial Hypertension or Pulmonary Venoocclusive Disease included in the Spanish Registry of Pulmonary Arterial Hypertension. Herein, we present the clinical phenotype and prognosis of all Pulmonary Arterial Hypertension patients with disease-associated variants in TBX4.

Results: Out of 579 adults and 45 children, we found in eight patients from seven families, disease-causing associated variants in TBX4. All adult patients had a moderate-severe reduction in diffusion capacity. However, we observed a wide spectrum of clinical presentations, including Pulmonary Venoocclusive Disease suspicion, interstitial lung disease, pulmonary vascular abnormalities and congenital heart disease.

Conclusions: Genetic testing is now essential for a correct diagnosis work-up in Pulmonary Arterial Hypertension. TBX4-associated Pulmonary Arterial Hypertension has marked clinical heterogeneity. In this regard, a genetic study is extremely useful to obtain an accurate diagnosis and provide appropriate management.


Fig 1. Family 1 pedigree.

Fig 2. Patient 1 Multidetector Computed Tomography. Subtle emphysema radiological pattern with peripheral distribution (red arrows).

Fig 3. Patient 1 lung biopsy. Pulmonary artery without significative lesions (arrow).

Fig 4. Patient 1 lung biopsy. Peripheral area. A septum is shown (arrow) with a vein without significant changes. Note the granuloma and giant cells with prominent intracytoplasmic cholesterol clefts (arrowhead).

Fig 5. Patient 1 lung biopsy. Masson Trichrome staining showing an emphysematous change with muscle cell hyperplasia (arrow).

Fig 6. Patient 1 lung biopsy. Masson Trichrome staining showing pulmonary fibrosis (arrow) near the airway. Note also muscle cell hyperplasia (arrowhead).

Fig 7. Family 2 pedigree.

Fig 8. Multidetector Computed Tomography patients 3 and 4. (A) Patient 3 interlobular septal thickening (red arrow) (B) Patient 3 ground grass pattern (yellow arrow) (C) Patient 4 mediastinal lymphadenopathies (green arrow) (D) Patient 4 interlobular septal thickening (red arrows).

Fig 9. Patient 3 explanted lung tissue. Typical PAH findings, without venous or venular lesions. (A) Vascular structure with glomeruloid morphology. 10X view H&E stain. (B) Artery intimal thickening (arrow). 4X view H&E stain. (C) Lung parenchyma with emphysema signs with dilated alveolar spaces and incomplete alveolar septa (star), increase in vascularization and capillary dilation (blue arrow) and artery medial hypertrophy (green arrow). 4X view H&E stain. (D) Artery intimal thickening (arrow). 10X view H&E stain. (E) Artery medial hypertrophy (green arrow) (F) Dilated alveolar spaces (star). 4X view H&E stain.

Fig 10. Family 3 pedigree.

Fig 11. Family 4 pedigree.

Fig 12. Multidetector Computed Tomography patient 5.

Hypertrophy in mammary (green arrows), phrenic (red arrows) and bronchial arteries (blue arrows).
Fig 13. Family 5 pedigree.
Fig 14. SNP microarray validation of detected deletion through NGS in patients 7 and 8.
Fig 15. Family 6 pedigree.
Fig 16. Family 7 pedigree.
Fig 17. Patient 8 chest X-ray at 4 months.
Fig 18. Comparison of different copy number variants reported.