Correspondence regarding “T-box protein 4 mutation causing pulmonary arterial hypertension and lung disease”: a single-centre case series

To the Editor:

With great interest we read the article “T-box protein 4 mutation causing pulmonary arterial hypertension and lung disease” by Maurac et al. [1]. The authors elegantly demonstrated a case of a female TBX4 mutation carrier presenting with adult-onset pulmonary arterial hypertension (PAH) in combination with bronchial and pulmonary parenchymal abnormalities which could be related to this mutation [1].

This case fits well together with the recent observation made in the French registry of heritable pulmonary hypertension (HPAH) that TBX4 mutations are frequently found in both adult and paediatric PAH cases [2, 3].

Here, we present data on the currently known TBX4 mutation carriers in our institute. The cohort consists of three mutation carriers without PAH, one patient with early PAH and four patients with HPAH. In all but one patient, a diagnosis of PAH was made in adulthood. Four different heterozygous variants in TBX4 were identified in the eight subjects (two families were included in the cohort). All variants were classified as “likely pathogenic” or “pathogenic”, including missense mutations (subject 1, 5 and 8) and frameshift mutations (subject 2, 3, 4, 6 and 7). A targeted gene panel was analysed in our cohort using next generation sequencing. Using this technique only small deletions or insertions were detected. To date, it has not been possible to determine the disease penetrance of TBX4 mutations, due to the low number of known carriers of such mutations [4].

The median age at diagnosis of PAH in our cohort was 31 (interquartile range (IQR) 39) years, while carriers without PAH had a median age of 39 (IQR 20) years. Remarkably, all patients were female and all carriers without PAH were male. All subjects, including the carriers without PAH, had skeletal anomalies on clinical examination, including a sandal gap in all and a small patella in one carrier without PAH and two HPAH patients. Subject demographic and clinical characteristics are shown in table 1. Two carriers without PAH were assessed by echocardiography alone, while six subjects underwent at least one right heart catheterisation (RHC) for diagnostic or research purposes (one carrier without PAH). The systolic pulmonary artery pressure on echocardiography was not measurable in two carriers without PAH because no tricuspid insufficiency could be measured. No other signs of PAH were noticed on echocardiography. In the six subjects in whom RHC was performed, elevated mean pulmonary artery pressures (mPAP) (median 44 mmHg, IQR 66.5 mmHg) and pulmonary vascular resistance indices (median 6.2 WU, IQR 15.1 WU) were demonstrated. However, only four out of six subjects met all criteria for a strict diagnosis of PAH based on the current guidelines [5]. One subject had early signs of PAH including a mPAP of 28 mmHg, but PVR did not exceed the threshold of 3 WU (2.4 WU). All four HPAH patients and the early PAH patient were treated with pulmonary hypertension-targeted therapy, predominantly double combination therapy (table 1).

Noticeably, all subjects with HPAH had a medical history of asthma with a mildly reduced forced expiratory volume in 1 s (median 74% of predicted value, IQR 11%). In addition, median diffusing capacity of the lung for carbon monoxide (D_LCO) was mildly reduced (65% of the predicted value, IQR 11.2%); three out of four HPAH patients had an abnormal D_LCO <70%. High-resolution computed tomography was performed in all subjects except one carrier without PAH and showed a spectrum of findings, including air trapping, interlobular septal thickening, centrilobular ground-glass opacities and small nodules. Tracheal and bronchial diverticulosis was found in all subjects, including the carriers without PAH (figure 1). In addition, all subjects showed irregular bronchial walls with changes in calibres predominantly in the (sub)segmental bronchi. Airway abnormalities were milder in carriers without PAH, but there was no relation between extent of airway abnormalities and severity of haemodynamic compromise in patients.

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FIGURE 1

Bronchial diverticulosis in a pulmonary arterial hypertension patient carrying a TBX4 mutation. Coronal image from high-resolution computed tomography with a maximal intensity projection of 2 mm.

Overall, this small cohort of carriers without PAH and PAH patients carrying a TBX4 mutation may help to get a better understanding of HPAH. Animal studies have shown that TBX4 (in concert with TBX5) is important for lung branching and the formation of cartilage rings in the trachea. This may explain the observation that all TBX4 mutation carriers displayed tracheal diverticulosis and irregularity of the bronchial walls [6]. The lung abnormalities previously observed in TBX4 mutation carriers form a broad clinical spectrum. Neonatal patients have predominantly severe and diffuse features of growth arrest, including acinar dysplasia, while milder features of bronchial abnormalities, including interstitial remodelling, are more common in patients diagnosed post-neonatally, in childhood or as adults [1, 7–9]. Because airway abnormalities were observed in subjects with no signs of pulmonary hypertension and also because the degree of abnormalities on computed tomography was not correlated to the degree of haemodynamic compromise, it remains to be determined whether pulmonary hypertension in TBX4 mutation carriers develops as a consequence of airway abnormalities (placing this form of pulmonary hypertension in group 3 of the diagnostic classification). Alternatively, airway and vascular abnormalities in TBX4 mutation carriers may develop entirely independently.

Further studies are required to better understand phenotypic expression, penetrance (including an apparently much higher penetrance in females) and the optimal treatment approach of TBX4 associated PAH.

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