Phenotype characterisation of TBX4 mutation and deletion carriers with neonatal and paediatric pulmonary hypertension

Abstract

Rare variants in the T-box transcription factor 4 gene (TBX4) have recently been recognised as an emerging cause of paediatric pulmonary hypertension (PH). Their pathophysiology and contribution to persistent pulmonary hypertension in neonates (PPHN) are unknown. We sought to define the spectrum of clinical manifestations and histopathology associated with TBX4 variants in neonates and children with PH.We assessed clinical data and lung tissue in 19 children with PH, including PPHN, carrying TBX4 rare variants identified by next-generation sequencing and copy number variation arrays.Variants included six 17q23 deletions encompassing the entire TBX4 locus and neighbouring genes, and 12 likely damaging mutations. 10 infants presented with neonatal hypoxic respiratory failure and PPHN, and were subsequently discharged home. PH was diagnosed later in infancy or childhood. Three children died and two required lung transplantation. Associated anomalies included patent ductus arteriosus, septal defects, foot anomalies and developmental disability, the latter with a higher prevalence in deletion carriers. Histology in seven infants showed abnormal distal lung development and pulmonary hypertensive remodelling.TBX4 mutations and 17q23 deletions underlie a new form of developmental lung disease manifesting with severe, often biphasic PH at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects, neurodevelopmental disability and other anomalies.

The ever-expanding phenotypical spectrum of human TBX4 mutations: from toe to lung

“…In the current issue of the European Respiratory Journal, GALAMBOS et al [15] describe a selected series of 19 patients, collected from different institutions over the world, presenting with pulmonary hypertension and carrying different TBX4 variations, including mutations and deletions, and a variety of developmental lung disorders. With that the authors further define the ever-expanding spectrum of clinical manifestations and pulmonary histopathology associated with human TBX4 variations.…”

Pediatric Pulmonary Hypertension on the World Stage: Do We Need Separate Neonatal Guidelines?

“…2 Most importantly, pediatric PH is intrinsically linked to issues of lung growth and development, including many prenatal and early postnatal influences. 7,8,[12][13][14][15][16] Pediatric PH often presents in the immediate neonatal period, which led to its own specific disease classification in Group 1 disease as PPHN. 2 The Pediatric Task Force further emphasized that PPHN represents a syndrome that is composed of specific diseases, ranging from its most common form as a transient disease after birth of term or near-term infants to more severe forms that include diverse developmental lung diseases and specific genetic disorders (Tables 1 and 2).…”

“…These diseases include genetic abnormalities of lung development, such as alveolar capillary dysplasia (due to genetic mutations of the FOXF1 gene), surfactant protein gene mutations (such as surfactant protein C, ABCA3, and others), and more recently, abnormalities of the TBX4 gene. 12 These developmental lung diseases often present during the early postnatal period and are frequently associated with severe PH with marked growth abnormalities of the distal lung ( Figure 1). These disorders commonly present clinically in infants who are born at term or near-term gestation, with the clinical presentation of hypoxemic respiratory failure and severe PPHN physiology that is characterized by profound hypoxemia and elevated pulmonary vascular resistance leading to extrapulmonary shunting of blood across the ductus arteriosus and/or foramen ovale.…”

A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report

“…Ballif et al, 2010 described seven individuals with developmental delay, microcephaly, heart defects, limb abnormalities, and hearing loss [25]. Other patients with this deletion have also presented pulmonary arterial hypertension (PAH) and/or ischiocoxopodopatellar syndrome (MIM# 147891) [26][27][28][29]. Most recently, we and others have identified the heterozygous 17q23.1q23.2 CNV deletion in a series of individuals with lethal lung developmental disorders (LLDDs), including acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD), and other forms of primary pulmonary hypoplasia (PH) [30][31][32].…”