Mary P. Mullen, D. Dunbar Ivy, Nidhy P. Varghese, Abbey J. Winant, Nahir Cortes-Santiago, Sara O. Vargas, Diego Porres, Nicola Maschietto, Paul J. Critser, Russel Hirsch, Catherine M. Avitabile, Rachel K. Hopper, Benkamin S. Frank, Ryan D. Coleman, Pankaj B. Agrawal, Jill A. Madden, Amy E. Roberts, Shane L. Collins, J. Usha Raj, Eric D. Austin, Wendy K. Chung, Steven H. Abman
Boston Children’s Hospital and Harvard Medical School. University of Colorado Denver Anschutz Medical Center and Children’s Hospital Colorado. Texas Children’s Hospital and Baylor College of Medicine. Cincinnati Children’s Hospital and University of Cincinnati College of Medicine. Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine. Stanford University School of Medicine. University of Miami Miller School of Medicine. University of Illinois at Chicago. Vanderbilt University Medical Center.
United States
Journal of Pediatrics
J Pediatr 2024;
DOI: 10.1016/j.jpeds.2024.114422
Abstract
Objective: To characterize clinical, hemodynamic, imaging, and pathologic findings in children with pulmonary arterial hypertension (PAH) and variants in SOX17, a novel risk gene linked to heritable and congenital heart disease-associated PAH.
Study design: We assembled a multi-institutional cohort of children with PAH and SOX17 variants enrolled in the Pediatric Pulmonary Hypertension Network (PPHNet) and other registries. Subjects were identified through exome and PAH gene panel sequencing. Data were collected from registries and retrospective chart review.
Results: We identified 13 children (8 female, 5 male) aged 1.6 to 16 years at diagnosis with SOX17 variants and PAH. Seven patients had atrial septal defects (ASD) and two had patent ductus arteriosus. At diagnostic cardiac catheterization, patients had severely elevated mean pulmonary artery pressure (mean 78, range 47-124 mmHg) and markedly elevated indexed pulmonary vascular resistance (mean 25.9, range 4.9-55 WU*m2). No patients responded to acute vasodilator testing. Catheter and CT angiography imaging demonstrated atypical pulmonary artery anatomy including severely dilated main pulmonary arteries, lack of tapering in third and fourth order pulmonary arteries, tortuous ‘corkscrewing’ pulmonary arteries, and abnormal capillary ‘blush.’ Several children had pulmonary artery stenoses and two had systemic arterial abnormalities. Histologic examination of explanted lungs from three patients disclosed plexiform arteriopathy and extensive aneurysmal dilation of alveolar septal capillaries.
Conclusions: SOX17-associated PAH is a distinctive genetic syndrome characterized by early onset severe PAH, extensive pulmonary vascular abnormalities, and high prevalence of congenital heart disease with intracardiac and interarterial shunts, suggesting a role for SOX17 in pulmonary vascular development.
Category
Class I. Heritable Pulmonary Hypertension
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Genetic Factors Associated with Pulmonary Vascular Disease
Diagnostic Testing for Pulmonary Vascular Disease. Non-invasive Testing
Diagnostic Testing for Pulmonary Vascular Disease. Invasive Testing
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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