INTRODUCTION:
TBX4 mutation cause small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.

METHODS:
We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French PH Network.

RESULTS:
Twenty patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 (0-76) year-old and a female to male ratio of 3. Most of the patients were in NYHA functional class III or IV (70%) with a severe hemodynamic impairment (median pulmonary vascular resistance 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 for carbon monoxide was decreased in all patients. High-resolution computed tomography 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 died and two underwent lung transplantation. One-, three- 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 PAH, and accumulation of cholesterol crystals within the lung parenchyma.

CONCLUSION:
PAH 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.

https://erj.ersjournals.com/content/erj/early/2020/02/06/13993003.02340-2019.full.pdf

Phenotype and outcome of PAH patients carrying a TBX4 mutation

Background/aims Alveolar capillary dysplasia (ACD) is characterised by pulmonary veins misalignment, capillary paucity and alveolar misdevelopment, and caused by FOXF1 mutations only in 40% of cases. Objectives were 1. to identify known and new gene defects and 2. to correlate them with molecular/cellular mechanisms. Methods We recruited a cohort of 23 pathology-confirmed cases. When DNA was available, genome-wide copy number variation was analysed through Array Comparative Genomic Hybridization (aCGH). Mutations were tested by direct sequencing of FOXF1 and candidate genes identified by aCGH; Molecular pathways were analysed by multi-channel immunofluorescence microscopy of ACD cases compared to human fetal/neonatal lung tissue at various development stages. Results Genomic deletions or mutations were identified in 57% of tested cases. Besides FOXF1, two of the genes involved stand out as potential candidates: MEOX2 and TBX4. ACD cases showed a markedly decreased expression of c-kit, a marker expressed in pulmonary small arteries and capillaries in fetal lung controls. In normal fetal lungs FOXF1 and TBX4 were prevalently expressed at the mesenchymal-epithelial border, and MEOX2 in pulmonary vascular smooth muscle cells (PVSMC). Their expression pattern and intensity were altered in all ACD cases, indicating that decreased FOXF-1 and/or its downstream transcription factor TBX4 disrupt lung micro vessel formation and homing to alveolar epithelium, and that a similar phenotype may derive from dysregulated PVSMC proliferation and angiogenesis related to MEOX2 insufficiency. Conclusion Genetic defects affecting the FOXF1 pathway affect the mesenchymal, endothelial and epithelial cross-talk leading to lung developmental disruption, pulmonary hypertension and hypoxic respiratory failure.

https://adc.bmj.com/content/archdischild/99/Suppl_2/A188.2.full.pdf

C Lizama

Papers

PS-210 Alveolar Capillary Dysplasia: A Genetically Determined Disruption Of The Alveolar/mesenchymal Cross-talk Causing Neonatal Hypoxic Failure