TBX4 syndrome: a systemic disease highlighted by pulmonary arterial hypertension in its most severe form

Austin, Eric D.; Elliott, C. Gregory

doi:10.1183/13993003.00585-2020

Cited by 9 publications

(7 citation statements)

References 21 publications

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“…Why some patients present with PAH alone, small patella syndrome alone, PAH with small patella syndrome, or PAH with other developmental defects is not understood at this time but may depend on the variant type or the protein location of gene variants, other genetic or epigenetic factors, or other environmental factors affecting the specific transcriptional pathways regulated by TBX4. It is clear that genetic diagnosis of a rare deleterious TBX4 variant or TBX4 -containing microdeletion in pediatric PAH predicts a more complex developmental phenotype ( TBX4 syndrome [ 36 ]). Chest imaging for severe and diffuse features of pulmonary growth arrest, assessment for congenital heart defects, physical examination of hands and feet, and radiological assessment of pelvic areas are recommended.…”

Section: Genetics Of Pediatric Pah—current Knowledgementioning

confidence: 99%

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Welch

Chung

2020

Genes

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Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene–environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

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Section: Genetics Of Pediatric Pah—current Knowledgementioning

confidence: 99%

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Welch

Chung

2020

Genes

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“…Patients with variants in TBX4 are often diagnosed with persistent pulmonary hypertension of the newborn (PPHN), but when diagnosed in late childhood or adulthood, they are usually diagnosed as IPAH. Even these cases could have associated coincidental septal defects or could have an abnormal DLCO or lung abnormalities in their CT scan, being classified as PAH-CHD, PVOD, or PH related to interstitial lung disease [ 39 , 40 ]. Patients carrying pathogenic variants in genes associated with MSD showed a younger age at diagnosis in comparison with the rest of the groups.…”

Section: Discussionmentioning

confidence: 99%

Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry

Cruz‐Utrilla

Gallego

Tenorio

et al. 2022

IJMS

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Background: Pulmonary arterial hypertension (PAH) is a severe and rare disease with an important genetic background. The influence of genetic testing in the clinical classification of pediatric PAH is not well known and genetics could influence management and prognosis. Objectives: The aim of this work was to identify the molecular fingerprint of PH children in the REgistro de pacientes con HIpertensión Pulmonar PEDiátrica (REHIPED), and to investigate if genetics could have an impact in clinical reclassification and prognosis. Methods: We included pediatric patients with a genetic analysis from REHIPED. From 2011 onward, successive genetic techniques have been carried out. Before genetic diagnosis, patients were classified according to their clinical and hemodynamic data in five groups. After genetic analysis, the patients were reclassified. The impact of genetics in survival free of lung transplantation was estimated by Kaplan–Meier curves. Results: Ninety-eight patients were included for the analysis. Before the genetic diagnoses, there were idiopathic PAH forms in 53.1%, PAH associated with congenital heart disease in 30.6%, pulmonary veno-occlusive disease—PVOD—in 6.1%, familial PAH in 5.1%, and associated forms with multisystemic disorders—MSD—in 5.1% of the patients. Pathogenic or likely pathogenic variants were found in 44 patients (44.9%). After a genetic analysis, 28.6% of the cohort was “reclassified”, with the groups of heritable PAH, heritable PVOD, TBX4, and MSD increasing up to 18.4%, 8.2%, 4.1%, and 12.2%, respectively. The MSD forms had the worst survival rates, followed by PVOD. Conclusions: Genetic testing changed the clinical classification of a significant proportion of patients. This reclassification showed relevant prognostic implications.

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“…The development of high-throughput sequencing approaches led to novel causal genes and additional pathways involved in PAH susceptibilities such as pathogenic or likely pathogenic genetic variants in potassium channels [potassium two pore domain channel subfamily K 3 (KCNK3), ATP Binding Cassette Subfamily C Member 8 (ABCC8), transcription factors [T-Box Transcription Factor 4 (TBX4) and SRY-Box Transcription Factor 17 (SOX17) [40][41][42][43][44][45] . Recently, Hodgson et al reported the association of the heterozygous mutations in the gene encoding the growth differentiation factor 2 (GDF2) and in two ligands for the BMPR2, the BMP type 9 and type 10, resulting in BMP9 loss of function and PAH 46 .…”

Section: Genetic and Epigenetic Mechanisms In Pahmentioning

confidence: 99%

The Impact of Sex Chromosomes in the Sexual Dimorphism of Pulmonary Arterial Hypertension

Predescu

Mokhlesi

Predescu

2022

The American Journal of Pathology

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TBX4 syndrome: a systemic disease highlighted by pulmonary arterial hypertension in its most severe form

Abstract: Thoré and co-workers add to our understanding of TBX4-associated pulmonary vascular disease as a precapillary form of pulmonary hypertension (PH), showing that TBX4 mutations may also cause multisystem anomalies concurrent with, or independent of, PH https://bit.ly/2yIqb9v

Cited by 9 publications

References 21 publications

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry

The Impact of Sex Chromosomes in the Sexual Dimorphism of Pulmonary Arterial Hypertension

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