SOX17-Associated Pulmonary Hypertension in Children: A Distinct Developmental and Clinical Syndrome.

Objective: To characterize clinical, hemodynamic, imaging, and pathologic findings in children with pulmonary arterial hypertension (PAH) and variants in SRY-box transcription factor 17 (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 1.6-16 years at diagnosis with SOX17 variants and PAH. Seven patients had atrial septal defects and 2 had patent ductus arteriosus. At diagnostic cardiac catheterization, patients had severely elevated mean pulmonary artery (PA) 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 computed tomography angiography imaging demonstrated atypical PA 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 PA stenoses and 2 had systemic arterial abnormalities. Histologic examination of explanted lungs from 3 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.