Genotypes and Phenotypes: Making Progress Toward a Precision Medicine Approach in Pediatric Pulmonary Hypertension

Abstract

Pediatric pulmonary hypertension (PH) is a heterogeneous disease that includes etiologies related to growth and development that are unique to children. Recent pediatric registry studies have characterized diverse phenotypes even within recognized PH subtypes, including PH associated with congenital heart disease and developmental lung disease. Advances in genetics are resulting in increased understanding of the genetic basis for PH, with recent discoveries such as TBX4 mutations specific for pediatric-onset pulmonary arterial hypertension (PAH) and SOX17 related to congenital heart disease-associated PAH. In addition to potential genetic underpinnings, PAH risk and clinical presentation in children with congenital heart disease may vary by cardiac condition, such as single-ventricle physiology or transposition of the great arteries. Growth and development of the pulmonary vasculature likely plays a role in all pediatric PH, which is highlighted by the disruption of normal lung growth in patients with PH related to prematurity and developmental lung disease. These diverse pediatric genotypes and phenotypes underscore a need for an individualized approach to diagnose and treat the complex pediatric PH population. Magnetic resonance imaging (MRI) is increasingly being used to improve clinical characterization of PH in children, with recent identification of specific MRI biomarkers associated with PH severity and outcomes. While much progress has been made, additional understanding of the important genetic causes and developmental concepts in pediatric PH is needed to develop a precision medicine approach to diagnosis and treatment of children with PH.

Opportunities and challenges of pharmacotherapy for pulmonary arterial hypertension in children

“…Pediatric PAH differs from adult PAH because a strong component of it relates to the growth and development of the pulmonary vasculature. The phenotypes of pediatric PAH are different, driven by prenatal and postnatal factors, and sometimes with several phenotypes presenting at the same time (e.g., trisomy 21 + congenital heart disease + obstructive sleep apnea) 3 . Proper recognition of these phenotypes is key when deciding on specific personalized treatments for each individual patient 4 …”