Refractory Peripheral Pulmonary Stenosis and Severe Pulmonary Arterial Hypertension Associated With a De Novo Loss‐of‐Function Variant in FGD5

ABSTRACT

We report a novel genetic variant in a patient with treatment‐resistant peripheral pulmonary artery stenosis (PPS) and progressive pulmonary arterial hypertension (PAH). A premature infant was diagnosed with bilateral PPS requiring multiple surgical reconstructions and interventional procedures with refractory proximal stenoses. Despite adequate anatomic repair preserving nearly all right lung segments, the child developed progressive PAH with elevated pressures in preserved segments out of proportion to residual obstruction. Genetic evaluation revealed a de novo heterozygous variant in FGD5, a critical regulator of VEGF signaling essential for pulmonary vascular development and homeostasis. We propose that FGD5 haploinsufficiency could disrupt endothelial function during development, leading to aberrant vascular patterning. This dysfunction may lead to PPS and ongoing endothelial dysfunction contributing to PAH. This represents a potential novel genetic cause of PPS with PAH, expanding the understanding of critical regulators in pulmonary vascular development and pathology. Comprehensive genetic evaluation in treatment‐resistant pulmonary vascular disease may identify novel mechanisms and eventually guide personalized therapeutic approaches through enhanced genotype‐phenotype correlation.

1. Case Description

Peripheral pulmonary artery stenosis (PPS) is characterized by stenoses of proximal, lobar, segmental, and occasionally subsegmental pulmonary artery (PA) branches [1]. PPS is associated with Williams syndrome (and other elastin and non‐elastin arteriopathies) and Alagille syndrome, but a subset of patients lacks a clear genetic diagnosis [2]. Left untreated, right ventricular (RV) hypertension caused by severe PPS will progress to RV failure [1, 2]. Multi‐level surgical PA reconstruction at experienced centers can improve RV pressures with low mortality rates and durable long‐term outcomes. In the absence of recurrent atresia of many PA segments, it is unusual for patients with surgically repaired PPS to develop pulmonary arterial hypertension (PAH) [1].

We report a case of severe PPS and PAH in a patient with a de novo heterozygous variant in FGD5 (faciogenital dysplasia‐5), a key modulator of vascular endothelial growth factor (VEGF) signaling, representing a possible novel genetic etiology of PAH in the setting of PPS [3, 4].

This case report was written under institutional review board approved protocols, and parental permission was obtained.

The proband was born at 30w3d gestational age via cesarean section due to intrauterine growth restriction. He developed respiratory distress syndrome requiring positive pressure ventilation and was diagnosed with bronchopulmonary dysplasia (BPD) but weaned to room air by 2 months. A cardiac murmur at 6 weeks prompted an echocardiogram and CT angiogram which demonstrated normal intracardiac anatomy, elevated RV pressure, mildly hypoplastic branch pulmonary arteries, and stenoses at multiple lobar and segmental PA takeoffs bilaterally. Genetic testing for Alagille, Williams and Noonan syndromes and a chromosomal microarray were negative.

At an outside hospital, he underwent proximal surgical PA reconstruction, transcatheter balloon angioplasty of distal PA stenoses, and stenting of the proximal and intermediate left PA over multiple procedures during his first 2 years of life. He was referred to our center at age 2.8 years with severe residual anatomic PA disease (Figure 1A). Preoperative catheterization demonstrated atresia of 4 of 8 left PA segments. He underwent bilateral distal surgical PA reconstruction of 7 stenoses in the left PA and twelve stenoses in the right PA systems. Initial lung scan demonstrated 74.73% of flow to the right PA.

Figure 1.

Progressive peripheral pulmonary artery stenosis and PAH in FGD5 haploinsufficiency: angiographic progression and proposed mechanism. (A) Pulmonary angiography demonstrates progressive pulmonary vascular disease before and after bilateral pulmonary artery reconstruction (PAR). Representative angiograms of the right pulmonary artery (RPA) and left pulmonary artery (LPA) are shown pre‐PAR (top row) and 19 months post‐PAR (bottom row). Red arrows indicate sites of stenosis. Pre‐PAR RPA [1]: long segment stenosis to apical and posterior right upper lobe (RUL) [2], stenosis of superior segment RUL [3], stenosis of lateral segment right lower lobe (RLL) [4], long segment stenosis to RLL. Pre‐PAR LPA [1]: stenosis of apicoposterior left upper lobe [2], stenosis of branch to left lower lobe (LLL) [3], stenosis to lingula [4], stenosis of superior segment LLL [5], long segment stenosis to posterior and lateral LLL. (B) Proposed mechanism by which FGD5 haploinsufficiency disrupts pulmonary vascular development leading to pulmonary vascular disease. (C) Expression profile of FGD5 in the developing human lung across epithelial, endothelial, and mesenchymal cell types. Dot plot shows FGD5 expression is nearly exclusive to the endothelial compartment with highest expression in arterial endothelial cells, consistent with its proposed role in arterial development. Dot size represents the percentage of cells expressing FGD5 within each cell type, while color intensity indicates average expression level (log‐normalized). Cell type ACTC + , cardiac muscle alpha actin‐positive; ASCL1 + , achaete‐scute family bHLH transcription factor 1‐positive; AT1, type I alveolar cell; AT2, type II alveolar cell; Cap, capillary; Endo, endothelial; Fibro, fibroblast; GHRL + , ghrelin‐positive; GRIA2 + , glutamate ionotropic receptor AMPA type subunit 2‐positive; Interm, intermediate; MUC16 + , mucin 16‐positive; MUC5AC + , mucin 5AC‐positive; MYL4 + , myosin light chain 4‐positive; Myofibro, myofibroblast; NE, neuroendocrine; OMD + , osteomodulin‐positive; SCG3 + , secretogranin III‐positive; SMC, smooth muscle cell; SMG, submucosal gland.

Follow‐up catheterizations showed sustained surgical result of his right PA with mild residual stenoses of 2 segments, responding to balloon angioplasty. Unfortunately, his left PA developed severe recurrent stenosis of the remaining 4 left lower PA segments, with follow up lung scans demonstrating worsening flow split with 88% of flow to the right PA (Figure 1A).

Recent cardiac catheterization at age 4 years old found central main PA pressures of 70/22/44, no pressure gradient to 9 of 10 right segments, and recurrent stenosis of the superior segment of the right lower PA. The left PA showed ongoing stenosis and hypoplasia of the remaining left lower PA which was treated with stenting (Figure 1A).

Despite an adequate surgical anatomic outcome within 12 of 18 lung segments, the patient developed progressive PAH. On dual pulmonary vasodilator therapy, the estimated total pulmonary vascular resistance was 6.7 WU × m², with systemic RV systolic pressure.

Given refractory PPS and PAH out of proportion to lung segment loss alone, a PAH genetic testing panel was sent. This revealed a maternally‐inherited heterozygous pathogenic variant in the gene encoding surfactant protein B (SFTPB) (c.361delinsGAA, p. Pro121Gluf*95, premature stop‐gain). Given the autosomal recessive inheritance pattern, and lack of clinical symptoms consistent with a surfactantopathy, this was not thought to be explanatory [5]. Whole exome sequencing then revealed a maternally‐inherited heterozygous variant of uncertain significance (VUS) in Myosin Heavy Chain 6 (MYH6) (c.301 G > A, p. Val101Met, missense) and a de novo heterozygous likely pathogenic variant in FGD5 (c.1384_1388del, p. Asn463*, premature stop‐gain).

2. Discussion

We present a case of refractory PPS and PAH in a patient with a novel de novo truncating, predicted loss‐of‐function variant in FGD5. Despite expert surgical reconstruction and interventional procedures, his left‐sided subsegmental vascular disease persisted, an outcome rarely observed at this center given surgical expertise with these procedures [1, 2]. In addition, he developed progressive PAH in preserved lung segments, which again is unusual, suggesting disease extending beyond the focal proximal stenotic lesions, unmasked by the repair [1, 2]. Though his BPD may have contributed, BPD‐related pulmonary hypertension typically improves rather than progresses over time [6]. This unusual persistence and progression in his PVD encouraged a deeper interrogation for a genetic etiology.

FGD5 encodes a critical regulator of VEGF signaling essential for normal pulmonary vascular development and angiogenesis [3, 4]. Heterozygous stop‐gain variants have been reported in patients with conotruncal heart defects but have not been previously reported in patients with PPS or PAH [7, 8]. By regulating VEGFR2 trafficking and retention within endosomal compartments, FGD5 sustains VEGF‐driven endothelial cell migration, angiogenic sprouting, and vascular network formation. Loss of FGD5 disrupts endothelial cytoskeletal organization and directed cell movement, leading to defective vessel branching and impaired angiogenic remodeling (Figure 1B) [3, 4].

In mice, biallelic loss of FGD5 is embryonic lethal due to severe vascular defects [9]. Fetal human lung single‐cell RNA sequencing data reveals FGD5 is nearly exclusively expressed in endothelial cells, with highest expression in arterial endothelial cells (Figure 1C), appropriately positioning it as a key regulator of pulmonary arterial development and homeostasis [10].

We propose that FGD5 haploinsufficiency could result in disrupted endothelial cell migration and angiogenic sprouting leading to aberrant vascular patterning and focal stenoses of the pulmonary arteries, explaining the PPS phenotype. In the more distal vasculature, impaired VEGF signaling may result in defective angiogenesis and ongoing endothelial dysfunction, contributing to PAH development. This is supported by the role of KDR (encoding VEGFR2) variants in PAH and complex cardiopulmonary phenotypes, highlighting the critical role of VEGF signaling in human pulmonary vascular disease (PVD) [7, 11]. Additional studies are needed to fully elucidate FGD5's contribution to PVD with careful interrogation of proximal and distal pulmonary arterial vascular changes.

Two additional heterozygous variants were identified but deemed non‐contributory: a pathogenic SFTPB frameshift variant (due to autosomal recessive inheritance, lack of surfactantopathy symptoms, and predicted loss‐of‐function rather than a dominant toxic gain‐of‐function mechanism) and a MYH6 missense VUS (due to minimal lung MYH6 expression and association with isolated cardiac defects not pulmonary disease) [5, 12, 13]. Both variants were maternally inherited from an unaffected mother.

This case highlights the importance of comprehensive genetic evaluation in patients with unexplained, treatment‐resistant multi‐level pulmonary vascular pathology [14, 15]. It suggests FGD5 as a potential novel genetic cause of severe PPS with PAH, expanding our mechanistic understanding of critical regulators in human pulmonary vascular development. Furthermore, our center has identified other PAH‐causing variants (KDR and BMPR2) in patients with subsegmental PVD with progressive PAH out of proportion to residual obstruction, raising suspicion for a pulmonary vascular “overlap syndrome”. These genetic diagnoses may help predict distal vascular pathology in surgical patients, as demonstrated by this case, where the underlying intrinsic PAH became apparent only after proximal repair.

Going forward, enhanced genotype/phenotype correlation in patients with multi‐level PVD may inform personalized surgical and therapeutic approaches and identify novel therapeutic targets through deeper understanding of disease natural history and developmental mechanisms.

Author Contributions

Lea C. Steffes wrote the initial manuscript with constructive edits and subspecialty expertise contributed by Gregory T. Adamson, Kyla E. Dunn, and Jeffrey A. Feinstein. Gregory T. Adamson helped with figure development.

Ethics Statement

Report approved through Stanford Institutional Review Board protocol number 12338. Written informed consent was obtained from parental guardian.

Conflicts of Interest

The authors declare no conflicts of interest.

Guarantor

Lea C. Steffes serves as the Guarantor for this manuscript and takes responsibility for the integrity of the work as a whole.

Steffes L. C., Adamson G. T., Dunn K. E., and Feinstein J. A., “Refractory Peripheral Pulmonary Stenosis and Severe Pulmonary Arterial Hypertension Associated With a De Novo Loss‐of‐Function Variant in FGD5 ,” Pulmonary Circulation 16 (2026): 1‐4. 10.1002/pul2.70250.