Phenotype and outcome of pulmonary arterial hypertension patients carrying aTBX4mutation

Abstract

IntroductionTBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.MethodsWe report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network.Results20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0–76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2–41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (DLCO) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma.ConclusionPAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

“…Ten newborns presented with PPHN which resolved but recurred later in infancy or childhood [ 34 ]. A report from the National French Registry [ 35 ] concurred these findings of skeletal, heart, and lung developmental anomalies in PAH cases. 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.…”

Potential interactions between the TBX4-FGF10 and SHH-FOXF1 signaling during human lung development revealed using ChIP-seq

“…In support of this notion, homozygous loss of Tbx2 or Tbx4 in mice results in reduced lung branching [12,16]. Heterozygous SNVs in TBX4 and CNV deletions involving TBX4 and TBX2 have been reported also in pediatric and adult patients with pulmonary arterial hypertension (PAH) [17,18], ischiocoxopodopatellar syndrome (MIM# 147891), and developmental delay, heart defects, and limb abnormalities [19]. The observed extrapulmonary anomalies likely result from disruption of the TBX2/TBX4 pathway as these genes are widely expressed, including heart and limbs [20,21].…”

The role of genomics and genetics in pulmonary arterial hypertension

“…Mutations in TBX4 , known for its pivotal role in embryogenesis, present with severe PAH associated with bronchial and parenchymal changes, low DLCO, with or without skeletal abnormalities 118 , and bimodal age of onset 9 . Interestingly, the penetrance of TBX4 mutations for skeletal abnormalities is much higher than for PAH 119 .…”