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Refractory Peripheral Pulmonary Stenosis and Severe Pulmonary Arterial Hypertension Associated With a De Novo
Lea C Steffes1, Gregory T Adamson2, Kyla E Dunn3
1Department of Pediatrics, Division of Pediatric Pulmonology, Lucile Salter Packard Children's Hospital Stanford University School of Medicine Palo Alto California USA.
Insights
A novel genetic variant in FGD5 was identified in a patient with treatment-resistant peripheral pulmonary artery stenosis (PPS) and pulmonary arterial hypertension (PAH). This finding suggests FGD5 haploinsufficiency may cause PPS and contribute to PAH, offering new insights into pulmonary vascular diseases.
Area of Science:
- Genetics
- Cardiovascular Biology
- Pediatric Medicine
Background:
- Peripheral pulmonary artery stenosis (PPS) and pulmonary arterial hypertension (PAH) can present as complex, treatment-resistant conditions.
- Understanding the genetic underpinnings of these diseases is crucial for developing effective therapies.
Purpose of the Study:
- To identify potential novel genetic causes of treatment-resistant PPS and progressive PAH.
- To investigate the role of FGD5 in pulmonary vascular development and disease pathogenesis.
Main Methods:
- Case report of a premature infant with bilateral PPS and progressive PAH.
- Comprehensive genetic evaluation including whole-exome sequencing.
- Analysis of a de novo heterozygous variant in the FGD5 gene.
Main Results:
- A de novo heterozygous variant in FGD5 was identified in the patient.
- FGD5 is a critical regulator of VEGF signaling involved in pulmonary vascular development.
- The identified variant suggests FGD5 haploinsufficiency as a potential cause of PPS and PAH.
Conclusions:
- FGD5 haploinsufficiency may disrupt endothelial function, leading to aberrant vascular patterning and contributing to PPS and PAH.
- This study highlights a potential novel genetic etiology for PPS with PAH.
- Comprehensive genetic evaluation is valuable for understanding treatment-resistant pulmonary vascular diseases and guiding personalized medicine.
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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