Hereditary Pulmonary Hypertension Associated with TBX4 Gene Variants in Children: First Description of Four Cases Studies in Russian Federation

Background. Pulmonary arterial hypertension (PAH) is a severe, multifactorial, polygenic group of pulmonary-cardiac diseases. The probable causes of hereditary PAH, especially at onset in childhood, are TBX4 (T-box transcription factor 4) gene variants. There are no reports of PAH cases associated with pathogenic TBX4 variants in the Russian Federation.

Case descriptions. 66 children with pulmonary hypertension (PH) of unknown etiology were examined in the Pediatric Cardiology Department of the Veltischev Institute during the period from 2020 to 2025. Pathogenic variants of genes associated with PAH development were revealed in 43 children via whole-genome sequencing. These genes were BMPR2, EIF2AK4, SOX17, SMAD9, ENG, GDF2, ALK1, KCNK3, and, moreover, there were 4 (9%) cases of TBX4 pathogenic variants (frameshift mutations, missense mutation, and one structural variant — microdeletion 17q23.1q23.2). All cases have shown persistent combination of features: 1) respiratory distress in neonatal period requiring  long-term oxygen support, including the development of oxygen dependence, 2) early onset of pulmonary hypertension, 3) cardiovascular manifestations, 4) skeletal abnormalities, 5) psychomotor retardation. Three variants were accompanied by combination of parenchymal lung damage and broncho-obstructive syndrome; patient with microdeletion had chronic bronchitis. Follow-up has shown that specifically respiratory distress and concomitant respiratory failure determine the disease severity. Pulmonary hypertension onset worsens the clinical picture and prognosis. Pulmonary vasodilators efficacy in case of lung damage is limited.

Conclusion. Pathogenic variants in the TBX4 gene lead to phenotype extending clinical manifestations of isolated hereditary PAH. This phenotype can be considered as a syndrome complex of impaired development, interstitial lung disease, manifested by respiratory distress in neonatal period, heart defects, precapillary pulmonary hypertension, skeletal anomalies, and neurodevelopmental disorders. Patients with TBX4 gene mutations require treatment by a multidisciplinary team of specialists. Such patients should be managed by interdisciplinary team of specialists in specialized medical center for patients with pulmonary hypertension.

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