Survival Into Adulthood With FOXF1‐Associated Pulmonary Vascular Disease After Neonatal Onset

ABSTRACT

Neonates and infants with FOXF1 mutation develop alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), which is typically considered a uniformly fatal neonatal lung disorder due to marked hypoxemic respiratory failure with severe pulmonary hypertension (PH). Survival beyond infancy is exceedingly rare, with limited reports of FOXF1 genetic abnormalities in older children or adult cases of severe PH. Here, we report the case of a male patient with a pathogenic FOXF1 variant who presented with severe PH in early infancy whose disease stabilized and improved with early and aggressive PH therapy. The patient subsequently died at the age of 30 years, however, due to severe right ventricular failure due to the acute onset of pneumonia. This case highlights that survival into adulthood is feasible in patients with FOXF1‐related pulmonary vascular disease and supports the inclusion of FOXF1 in pulmonary hypertension genetic panels for subjects who develop PH across the lifespan.

1. Case Description

A male patient with a lifelong history of pulmonary hypertension (PH) associated with the diagnosis of chronic lung disease who died at 30 years of age following progressive cardiopulmonary and multi‐organ failure due to the acute onset of pneumonia. He was born at term with an uneventful perinatal course with only routine neonatal care, leading to home discharge shortly after birth without any apparent cardiorespiratory problems. At 7 weeks of age, however, he presented with a 1‐month history of episodic cyanosis and pallor. His initial echocardiogram showed no evidence of congenital heart disease, but there was near‐systemic pulmonary artery pressure with right‐to‐left shunting at the patent foramen ovale (PFO). Cardiac catheterization demonstrated suprasystemic pulmonary pressures and a markedly elevated indexed pulmonary vascular resistance (PVRi) of 28.6 Wood units·m² on room air, which decreased to 6.4 Wood units·m² on inhaled nitric oxide and oxygen, without further response to a calcium channel blocker. He was initially managed on inhaled nitric oxide (iNO) via nasal cannula, which led to clinical stability, but iNO and respiratory support could not be discontinued without marked cyanosis and distress, leading to the initiation of continuous intravenous epoprostenol at 4 months of age with marked improvement and successful weaning from iNO therapy. Details of his course during early infancy have been previously reported (Ivy et al in 1994) [1].

Due to the subsequent development of slowly progressive respiratory distress, tachypnea, pulmonary edema, and cyanosis, he was re‐evaluated at 10 months of age, leading to the possible diagnosis of pulmonary veno‐occlusive disease (PVOD). He also developed several systemic venous thrombi due to the chronic use of a central line for prostacyclin therapy, for which he remained on anticoagulation with warfarin and later transitioned to a direct oral anticoagulant. At 10 years of age, further evaluation that included pulmonary function testing revealed signs of airways obstruction with acute responsiveness to bronchodilator therapy, leading to the initiation of chronic therapy with inhaled corticosteroids and bronchodilators and intermittent oral steroids for respiratory exacerbations. PH‐targeted therapy was sequentially increased throughout his life due to progressive disease. During childhood, he was maintained on intravenous epoprostenol, but bosentan and sildenafil were initiated at 9 and 10 years of age, after these agents became available for therapy in children. Repeat cardiac catheterization at 10 years of age showed a cardiac index of 3.49 L/min/m², PVRi of 14.3 Wood units·m², pulmonary capillary wedge pressure of 6 mmHg and a mean pulmonary artery pressure of 56 mmHg, which decreased to 35 mmHg with increased inspired oxygen. During adolescence and early adulthood, his medications were subsequently transitioned to intravenous treprostinil, tadalafil, and ambrisentan. The PFO was no longer seen by echocardiogram after the age of 10 years. As his PH continued to worsen over time and with advances in genetic testing technology, whole‐exome sequencing was performed in adulthood, which identified a pathogenic heterozygous FOXF1 variant [c.145 C > G; p.(Pro49Ala)] in 2023. Family history was notable for the death of two siblings during infancy. One sibling died on day 1 of life in the setting of oligohydramnios, and another died at 4 months of age with pulmonary vein stenosis and severe pulmonary hypertension. No genetic testing was performed. Despite aggressive PH‐targeted drug therapy, the patient continued to have recurrent PH exacerbations throughout adolescence and adulthood, which were often precipitated by respiratory infections. Cardiac catheterization performed 1 month prior to his death demonstrated severely elevated pulmonary pressures (mean PAP 94 mmHg), PVRi of 16 Wood units·m², cardiac index of 2.9 L/min/m² and severely reduced mixed venous oxygen saturation of 47%. Evaluation for lung transplantation was considered but was precluded by hemodynamic and multi‐organ instability. He died at 30 years of age following refractory hypoxic respiratory failure secondary to pneumonia, which caused severe right ventricular failure and multi‐organ dysfunction. The family chose not to consent to perform an autopsy after his death.

2. Discussion

FOXF1 is an essential transcription factor for pulmonary vascular development and endothelial homeostasis. Mutations in FOXF1 cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), which is an abnormal lung development disorder defined by the failure of the alveolar‐capillary bed to form properly, resulting in severe pulmonary hypertension with exceedingly high mortality rate in the neonatal period [2, 3]. FOXF1 is also involved in the BMPR‐II signaling pathway, suggesting another role in the pathway of the most common cause of heritable PH [4]. The presented case describes a survival into adulthood in a patient with lifelong PH and FOXF1 mutation, who first presented at 7 weeks of age with severe PH. This case represents the longest known survival in a patient with a pathogenic FOXF1 variant associated with pulmonary vascular disease. Current genomic and transcriptomic data suggest that decreased FOXF1 expression or predicted dysfunction is associated with adult‐onset PH, highlighting that FOXF1‐associated PH extends beyond the classic neonatal ACD/MPV phenotype [5].

The improved survival of this patient into adulthood may be related in part to the missense mutation in the FOXF1 gene. The p.(Pro49Ala) variant is located outside the highly conserved DNA‐binding domain, where most pathogenic variants cluster. Therefore, it is assumed that the location of the variant may preserve partial FOXF1 activity (a hypomorphic effect), potentially contributing to the milder phenotype [5]. The positive acute vasoreactivity on presentation is atypical for classic diffuse ACD/MPV and supports a mitigated, partially preserved pulmonary vascular phenotype. This patient's initial management with inhaled nitric oxide as a bridge to continuous prostacyclin therapy, as reported by Ivy et al. in 1994, and ultimately maintained on a triple‐therapy combination, which allowed for hemodynamic stability for nearly three decades, highlighting the critical importance of early and aggressive PH therapy [1].

A literature review identified three studies reporting FOXF1 mutations in adults. In one report, two separate patients developed pulmonary hypertension at ages 18 and 25 years, respectively, and in both cases, their fathers carried the same FOXF1 variant but were asymptomatic [5]. In another report of a four‐generation family with two adult women carrying a frameshifting FOXF1 variant, one with an adult‐onset heritable PH, and another with neonatal PH and pneumothoraces, which were treated successfully, and a recent echocardiogram was normal [6]. In a separate family, variable expressivity of the FOXF1 missense mutation ranged from an asymptomatic adult mosaic carrier father to two children with severe PH [7]. This variable expressivity is also seen in our patient, as two of his siblings died in infancy. The ages of the adult FOXF1 cases reported in references [6, 7] were not available.

Among the reports of adult cases with FOXF1 mutations, none had persistent pulmonary hypertension beginning in infancy, raising the possibility that FOXF1‐associated pulmonary vascular disease presenting in adulthood may represent a distinct phenotype. Our case provides important insight, as despite presenting early in infancy with persistent pulmonary hypertension, the patient survived into adulthood. This finding challenges the current understanding that early FOXF1‐associated disease is uniformly fatal in pediatric patients.

In a multicenter international study, seven novel or ultra‐rare missense FOXF1 coding variants were identified across three PH cohorts, and FOXF1 expression in explanted lung tissue correlated with disease severity [5].

The identification of a pathogenic FOXF1 variant in adulthood raises an important question: how many patients with idiopathic or BPD‐associated PH have an undetected FOXF1 variant?

Early genetic diagnosis informs family counseling, guides surveillance of carrier relatives, and may, in the future, identify candidates for FOXF1‐targeted therapies that are currently in the preclinical phase [8]. Therefore, we strongly support the inclusion of FOXF1 in all PH genetic panels, particularly for those with severely neonatal‐onset, unexplained, or heritable PH.

This case establishes that survival into adulthood with a pathogenic FOXF1 variant is possible. Factors that may have contributed to improved survival include the type of mutation, preserved pulmonary vasoreactivity, and aggressive PH therapy. As our understanding of the genetic background of PH continues to evolve, retrospective genomic analysis of cases historically classified as idiopathic will be essential to better define the phenotypic spectrum of FOXF1‐related pulmonary vascular disease.

Author Contributions

Khalifah A. Aldawsari: drafting and finalizing the manuscript. Steven H. Abman: editing the manuscript. David Badesch: reviewing. David Dunbar Ivy: editing and supervising the writing process of the manuscript.

Ethics Statement

The consent was obtained from the patient's family for publication.

Conflicts of Interest

The authors declare no conflicts of interest.

Guarantor Statement

All authors accept full responsibility for the integrity and accuracy of the work.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.