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GENETICS: Edited by Coline H.M. van Moorsel

TBX4 variants and pulmonary diseases

getting out of the ‘Box’

Haarman, Meindina G.a; Kerstjens-Frederikse, Wilhelmina S.b; Berger, Rolf M.F.a

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Current Opinion in Pulmonary Medicine: May 2020 - Volume 26 - Issue 3 - p 277-284
doi: 10.1097/MCP.0000000000000678
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In 1927, Nadezhda Alexandrovna Dobrovolskaya-Zavadskaya described a heterozygous mutation in mice that affected both tail length and the sacral vertebrae [1]. This mutation was called brachyury (short tail, Greek) mutation. Later, because of the T(tail)-locus of the gene product, the mutation was renamed into T-Box mutation [2,3]. In 1996, T-Box transcription factor 4 (TBX4) was identified, in a series of other T-Box genes (TBX1–5), as a gene highly expressed during organogenesis [4,5].

This review deepens into the TBX4 gene and its variants in pulmonary diseases, since in the recent years, the spectrum of clinical phenotypes associated with variants of the TBX4 gene [including both mutations and copy number variations (CNVs)] is expanding from bone abnormalities to conditions affecting other organs, especially the lungs. We aim to discuss the current knowledge on the role of TBX4 variants in human lung diseases.

Box 1
Box 1:
no caption available


T-Box genes are DNA-binding transcription factors that play a crucial role during embryogenesis [6]. The TBX4 gene is located on chromosome 17q23.2 and has shown to be important for hindlimb and pelvic development in both animals and humans [5,7,8]. Animal studies have also suggested an important role for TBX4 in the formation of the body wall, development of external genitalia and anorectal development [5,9,10].

In addition, TBX4 is expressed in the lung mesenchyme, already at an early stage during embryogenesis [10]. Together with TBX5, TBX4 regulates the process of lung branching by controlling the expression of the secreted fibroblast growth factor (FGF)10 and activation of FGF10 signalling [11,12]. FGF10 is expressed in the mesenchyme surrounding the distal epithelial tips that mark the site of future bud formation and acts by mainly binding to the FGF receptor 2b [13–15]. FGF10 is involved in the initial production of paired buds of endoderm from the ventral foregut and their eventual outgrowth forming the precursors of the main bronchi [14]. Second, FGF10 induces new bud formation and therefore plays a key role in branching morphogenesis [14,16].

Another important regulatory gene that is affected by TBX4 and TBX5 signalling is canonical wingless-2 (WNT2), a mesenchymal protein that is essential for lung specification [11,17].

Reduction of TBX4 or TBX5 leads to a severe decrease in branching by a loss of expression of both FGF10 and WNT2. This results in a defect of formation of lung lobes and failure of lung lobe separation, eventually leading to a smaller overall lung size [11,18]. Absence of both TBX4 and TBX5 leads to complete branching arrest [19].

In addition, TBX4 and TBX5, via SOX9 and independently of the FGF10 signalling pathway, regulate the condensation of cells to form the cartilage rings of the trachea and bronchi, and also the development of the smooth muscle cells in the trachea [11,20]. Reduction of both TBX4 and TBX5 causes a decreased number of tracheal cartilage rings and can therefore result in tracheomalacia or tracheal stenosis [11]. TBX4 has also been shown to be present in pulmonary veins and arteries, suggesting that pulmonary vessels arise from the surrounding lung mesenchyme [10]. These experimental data, derived from cell and animal studies, indicate rather convincingly that TBX4 plays an important role in foetal development, including both parenchymal and vascular lung development.


Clinical consequences of TBX4 variants in humans were first revealed in 2004, when the association between a spectrum of limb and skeletal abnormalities, known as small patella syndrome (SPS) or ischiocoxopodopatellar syndrome, was identified (Fig. 1) [22]. This syndrome causes aplasia or hypoplasia of the patella and developmental anomalies of the pelvis and feet.

Timeline of the expanding clinical phenotypes of TBX4 variants since the discovery of this gene in 1996. Reproduced with permission from [21].

In 2013, Kerstjens-Frederikse et al.[23] discovered that mutations in the TBX4 gene or deletions encompassing the TBX4 gene were associated with pulmonary arterial hypertension (PAH) in childhood. Pulmonary hypertension, an increased pulmonary arterial pressure, is a haemodynamic symptom, and its underlying diseases are characterised by a clinical classification (Table 1) [24,25]. PAH is a specific form of PH and is a rare, progressive and often lethal disease of the pulmonary vasculature, characterised by an increased pulmonary vascular resistance, leading to right ventricular failure and eventually death [26,27]. It may be associated with a variety of underlying diseases, including connective tissue diseases, congenital heart diseases, portal hypertension, HIV infection and drugs. In the absence of associated conditions, it is classified as idiopathic PAH (IPAH) or it can be caused by a genetic defect (hereditary PAH; HPAH) (Table 1) [24,25]. In recent years, a progressive number of gene mutations is being been identified as cause for PAH, including mutations in bone morphogenetic protein receptor type II (BMPR2) being the most frequently found gene mutation in both children and adults with PAH [28–30]. Further, mutations in activin receptor-like kinase 1 (ACVRL1), endoglin (ENG), potassium channel subfamily K member 3 (KCNK3), eukaryotic translation initiation factor 2-alpha kinase 4 (EIF2AK4), Caveolin-1 (CAV1) and SMAD9 have currently been identified as associated with the occurrence of PAH, and this list is growing [31–36].

Table 1
Table 1:
Clinical classification of pulmonary hypertension (PH) [24,25]

In the study of Kerstjens-Frederikse et al.[23], genetic analyses in a cohort of 20 children with IPAH revealed deletions at 17q23.2 with an overlapping region harbouring the TBX4 gene in three children with PAH and mental retardation, and an intragenic TBX4 mutation in three children with PAH with normal intelligence. All appeared to have skeletal malformations characteristic for SPS.

Since the discovery of the association between TBX4 variants and paediatric PAH, different cohorts confirmed an enrichment of TBX4 variants in childhood P(A)H. Levy et al.[33] reported three TBX4 truncating mutations in a subgroup of 40 paediatric IPAH/HPAH patients (8%). Zhu et al.[37▪] found in a cohort of 155 patients with paediatric-onset IPAH/HPAH that TBX4 variants were present in a substantial proportion of children (8%). Of these, 5% were pathogenic and likely pathogenic (LP) variants in TBX4, while another 3% were variants of unknown significance (VUS).

In summary, the prevalence of TBX4 variants in children with IPAH/HPAH is estimated 7–8%, which makes TBX4, after BMPR2, the second most frequently affected gene in these children [33,37▪,38].

A lower number of TBX4 variants seemed to be present in the adult population with IPAH/HPAH. Kerstjens-Frederikse et al.[23] in the same study, as previously mentioned, identified two TBX4 variants (one LP, one VUS) in a cohort of 49 adults with IPAH. In a larger cohort of 257 adults with IPAH/HPAH, Zhu et al.[37▪] identified three adult patients with a TBX4 variant (one LP, two VUS) (1.2%). Navas et al.[39] reported a prevalence of 2.4% of TBX4 variants in patients with IPAH/HPAH. In a cohort of 966 adult patients with IPAH/HPAH, Gräf et al.[40] reported that 1.4% of the patients had a TBX4 variant. Finally, in a French cohort, Eyries et al.[38] reported that 2.6% of the patients with IPAH/HPAH had a TBX4 variant, concluding that also in adulthood PAH, TBX4 may be the most frequently mutated gene after BMPR2. In summary, the overall prevalence of TBX4 variants in adults with IPAH/HPAH is estimated around 1.7%.

The reason why TBX4 variants seem to be more frequent in childhood-onset compared with adulthood-onset IPAH/HPAH is insufficiently clear. A detrimental disease course of TBX4-associated HPAH with early decease before reaching adulthood would have explained such phenomenon, however currently available, preliminary outcome data invalidate such speculation. The clinical implications of the presence of TBX4 variants in children with PAH have been scarcely studied. Where BMPR2 mutation carriers have shown to have a worse survival in both children and adults with HPAH when compared with noncarriers, children with TBX4 variants in a Dutch national cohort of 70 children with PAH showed less severe clinical presentation and more favourable survival compared with BMPR2 mutation carriers, similar to nonmutation carriers (own data). Similar findings have been reported by Levy et al.[33] in a French cohort of 66 children with PAH.

Navas et al.[39] confirmed these findings in adults with IPAH/HPAH and showed that patients with a TBX4 variant tended to have a milder clinical presentation compared with patients with IPAH, BMPR2 mutation carriers, KCNK3 mutation carriers and patients with familial PAH without a mutation. Also, survival in patients with a TBX4 variant was better compared with patients with a BMPR2 mutation or a KCNK3 mutation.

Zhu et al.[37▪] reported that HPAH patients carrying a TBX4 variant had a 20-year younger age-of-onset than BMPR2 mutation carriers (mean ± SD: 7.9 ± 9.0 compared with 28.2 ± 15.4, respectively, P < 0.0001). Although the clinical phenotype of PAH in TBX4 variant carriers in general seems to be milder than in BMPR2 mutation carriers, it is not necessarily favourable, and varies from mild/moderate PAH to also more severe forms of PAH, eventually fatal or requiring lung transplantation [37▪].

Until today, available clinical data do not justify patients with HPAH harbouring a TBX4 variant to be treated differently than patients with other forms of PAH-associated conditions.


After the first discovery of a role for TBX4 variants in the development of PAH, Szafranski et al.[41] described in 2016 a neonate with signs of acinar dysplasia (AcDys), a severe diffuse developmental lung disease, who showed to have a de novo TBX4 mutation. This was the first report suggesting a relation between a TBX4 variant and developmental parenchymal lung disease. Subsequently, in 2019, German et al.[42] described another case of a preterm born neonate with respiratory failure due to a diagnosis of AcDys, harbouring a deletion from chromosome 17q23.2 to 17q23.2 involving 14 genes including TBX4 (Fig. 2). In the same year, Karolak et al.[43▪▪] described a cohort of 26 children with AcDys, congenital alveolar dysplasia (CAD) or other rare pulmonary hypoplasias and reported in 16 children, a TBX4 variant or FGF10 variant. In almost 50% of these cases, the developmental lung disease was accompanied by PH. Suhrie et al.[44] identified pathogenic TBX4 mutations in two cases of infants presenting with respiratory failure. One child had abnormal lung lobulation with marked deficiency in acinar/alveolar development, and eventually deceased. The other child had a lung biopsy that demonstrated areas of the lung with near normal alveolarisation adjacent to regions with deficient alveolar growth, characterised by simplified, cystically dilated alveolar spaces [45].

Lung histopathology of a patient with acinar dysplasia. (a) Lung from the infant's autopsy, showing an immature appearance for gestational age with no saccular structures or alveoli. (b) Higher power demonstrating abnormal acinar structures with abundant intervening mesenchyme (hematoxylin and eosin). Reproduced with permission from [42].

Galambos et al.[46▪▪] subsequently further extended the spectrum of paediatric diffuse parenchymal lung disease associated with TBX4 variants. The authors described a cohort of 19 children with TBX4 variants, including six children with loss of the TBX4 gene due to 17q23 deletions and thirteen children with intragenic mutations. The majority of the children (63%) presented with a biphasic clinical course of neonatal hypoxic respiratory failure and persistent pulmonary hypertension of the neonate (PPHN), which seemed to resolve around the age of 1 month, but followed by chronic PH later in infancy or early childhood. Histopathological assessment was available in seven children and showed mainly signs of severe disruption of all compartments of distal lung development similar to CAD or AcDys, or signs of pulmonary interstitial glycogenosis (PIG). The children with a severe presentation of PPHN in the beginning of their life also showed more severe disruption of the distal lung development compared with children who were diagnosed later in childhood. Some children had prominent interstitial lung disease. This series unequivocally shows that TBX4 variants are not only associated with lethal developmental lung diseases such as AcDys or CAD, but may also present with milder growth abnormallities or nonspecific interstitial lung diseases. Interestingly, a recent case report of Maurac et al.[47▪] suggests that such developmental growth anomalies are not necessarily associated with neonatal presentation. The authors describe a 34-year-old woman presenting with unexplained PAH and right heart failure [47▪]. On x-rays of the feet and the pelvis, the patient showed signs of SPS. Chest computed tomography (CT) revealed peripheral reticular lines, centrilobular nodules, thin-walled cysts in the upper lobes and an appearance resembling diverticula in the trachea and large bronchi. Lung biopsy from the left upper lobe showed densification foci of the lung parenchyma with cholesterol crystals. Although the histopathological abnormalities were not typical for developmental distal lung abnormalities, the tracheal abnormalities in this patient highlight a potential role of TBX4 in a disturbed development of the larger airways [11].

The studies described here strongly suggest that TBX4 variants can be associated with a broad spectrum of lung diseases with a wide age range of clinical presentations. Neonates and infants with TBX4 variants are clearly overrepresented in the reports on parenchymal lung diseases and authors have frequently used the terminology ‘developmental lung disease’. Different classifications for children's interstitial and diffuse lung disease (chILD) have been proposed. The American Thoracic Society published a classification of chILD in 2013 where AcDys, CAD, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) are classified as diffuse developmental disorders, whereas primary pulmonary hypoplasia is classified under growth abnormalities (Table 2) [48,49▪]. The structural changes seen in these diseases are associated with the different stages during lung embryogenesis in which growth arrest occurs; the pseudoglandular (AcDys), canalicular (CAD) and saccular/alveolar (both ACDMPV and primary pulmonary hypoplasia) phase [50▪▪]. Also, PIG, characterised by interstitial expansion due to increased mesenchymal cellularity, is regarded a disease of altered lung development [49▪,51]. Also, other diffuse lung diseases such as chronic neonatal lung disease (i.e. bronchopulmonary dysplasia), or surfactant dysfunction disorders (i.e. nonspecific interstitial pneumonia) are associated with disturbed or disrupted vascular and parenchymal lung development [46▪▪,47▪,48].

Table 2
Table 2:
Classification scheme for paediatric diffuse lung disease [48]

ChILD is a complex spectrum of disorders with a high variety in clinical phenotypes for which the associated pathophysiology is insufficiently understood. Therefore, although the notable role of TBX4 in embryonic development may be tempting, the term ‘developmental lung disease’ as a common denominator in the phenotypical spectrum of TBX4-associated lung diseases should be used with caution.

The reason for the variety in clinical presentation in patients carrying a TBX4 variant remains unclear. It has been hypothesised that the type of mutation may determine both phenotype and its severity, but currently, there does not seem to be a pattern when comparing all described different mutations [41,46▪▪,50▪▪]. Genetic modifiers – coding or noncoding – may play a role in the variability of the phenotype. Karolak et al. demonstrated that all infants with developmental lung disease with either a TBX4 variant or FGF10 variant also harboured at least one noncoding mutation in BCAS3 (microtubule associated cell migration factor), which has overlap with the predicted regulatory elements that have been identified in the human foetal lung fibroblast cell line [43▪▪,52]. However, children with deletions of chromosome 17q23.2, harbouring both TBX4 and BCAS3, do not necessarily present with lung disease or PAH [45]. Karolak et al.[53] recently published a case report on an infant with PIG, harbouring both a TBX4 variant and a CTNNB1 mutation (associated with intellectual disability and neurodevelopmental abnormalities). The authors state that a heterozygous TBX4 variant alone may not be sufficient to cause lung disease and suggest that mixed phenotypes may be due to complex compound inheritance [54]. In addition, environmental and maternal/pregnancy-related factors may also influence the severity of the clinical phenotype [55].


Characterising chILD is difficult especially in neonates [48]. Symptoms are nonspecific and neonatal presentation will complicate the diagnostic process. For a long time, lung biopsy for histopathological analyses has been the ultimate diagnostic, limited by high procedural risks and often low diagnostic yield. Genetic testing is gaining ground due to the identification of an increasing number of genetic causes for several interstitial lung diseases [48]. The presence of a certain mutation can have profound effects for clinical decision making: the dismal prognosis of a FOXF1 mutation causing ACDMPV will affect treatment decisions in a neonate dependent on intensive ventilatory support and will avoid the otherwise required lung biopsy [50▪▪]. Standard testing for TBX4 variants in neonates with respiratory insufficiency has been proposed: Vincent et al.[50▪▪] proposed to screen infants with AcDys, CAD or other lung hypoplasias on TBX4 variants when there is a family history of PAH. However, as long as the prevalence and incidence of TBX4 variants in neonates and the consequences in terms of treatment strategies are not defined, the role of standard testing on TBX4 variants is unclear.


During the most recent World Symposium on Pulmonary Hypertension in 2018, the clinical classification of PH was updated [25]. In this classification, unexplained PAH-associated TBX4 mutations are assigned to group 1 PAH (HPAH). The Pediatric Task Force introduced in Group 3: PH due to lung diseases and/or hypoxia, a subclass ‘PH associated with developmental lung disease’, in order to accommodate neonatal PH (other than PPHN) in the classification. Now, as TBX4 variants are frequently associated with developmental lung diseases, the appropriate classification of an infant or child with a TBX4 variant and PH becomes more complicated and may be hazardous. This forces the diagnosing physician to a meticulous assessment of any lung disease and, if present, its causal role in the presence of PH. This is obviously a challenging task in small infants, but crucial in defining optimal treatment strategy.


Animal studies have demonstrated an important role of the TBX4 gene in the embryonic development of limbs and tail mesoderm, the lung mesenchyme and the genital papilla [5,9]. The clinical phenotype of TBX4 variants in humans has expanded from bone disorders to vascular and parenchymal lung diseases and is likely to expand further. The enrichment of TBX4 variants in PAH justifies inclusion of this gene in genetic analyses in patients with PAH. Further, TBX4 variants have shown to contribute to diffuse lung diseases, especially but not exclusively in neonates, and seems to be multifaced. Importantly, the exact genotype-phenotype correlations have to be further ‘unboxed’.



Financial support and sponsorship

This work was supported by the Sebald Fund.

Conflicts of interest

There are no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest


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    lung disease; pulmonary arterial hypertension; T-Box factor 4

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