What question did this study set out to answer?

The study aims to investigate a genetic cause of refractory pulmonary conditions in a premature infant.

January 23, 2026Open Access

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

LSLea C. SteffesLucile Packard Children's Hospital GAGregory T. AdamsonLucile Packard Children's Hospital KDKyla DunnStanford Health Care

Key Points

The study aims to investigate a genetic cause of refractory pulmonary conditions in a premature infant.
Genetic evaluation was performed on a patient with treatment-resistant pulmonary conditions.
Clinical assessments included diagnostic imaging and surgical interventions for peripheral pulmonary stenosis.
Haplotype analysis was conducted to identify the de novo variant in FGD5.
Identification of a novel heterozygous variant in FGD5 associated with refractory pulmonary conditions.
The child exhibited progressive pulmonary arterial hypertension despite surgical interventions.
Findings suggest a critical role of FGD5 in vascular development and possible implications for treatment strategies.

Abstract

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.

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