Abstract
Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene–environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.
Highlights
Pulmonary arterial hypertension (PAH) is a rare disease with an estimated prevalence of4.8–8.1 cases/million for pediatric-onset [1] and 15–50 cases/million for adult-onset disease [2].Pathogenic changes in the pulmonary vasculature—including endothelial dysfunction, aberrant cell proliferation, and vasoconstriction—give rise to the clinical consequences of increased pulmonary vascular pressures, increased vascular resistance, heart failure, and premature death [3]
While prenatal and early postnatal influences on lung growth and development can contribute to the development of PAH across the lifespan, early developmental influences play a prominent role in pediatric-onset PAH in which patients frequently have complex comorbidities such as congenital heart disease (APAH-CHD), Down syndrome, congenital diaphragmatic hernia (CDH), and other developmental lung diseases, including persistent pulmonary hypertension of the newborn (PPHN) [7,14,15]
Variants in BMPR2 are causal in ~6.5–7% of both pediatricand adult-onset PAH; most of the cases are forms of PAH (FPAH) or idiopathic PAH (IPAH), rarely PAH associated with other diseases (APAH) [11,22], and no occurrences in PPHN have been reported to date [23]
Summary
Pulmonary arterial hypertension (PAH) is a rare disease with an estimated prevalence of. Pediatric PAH differs from the adult-onset disease in several important aspects, including sex bias, clinical presentation, etiology, and response to therapy [7,8,9]. Indicate that the frequency of pediatric-onset PAH is similar for females and males, suggesting less dependence on sex-specific factors in children. While prenatal and early postnatal influences on lung growth and development can contribute to the development of PAH across the lifespan, early developmental influences play a prominent role in pediatric-onset PAH in which patients frequently have complex comorbidities such as congenital heart disease (APAH-CHD), Down syndrome, congenital diaphragmatic hernia (CDH), and other developmental lung diseases, including persistent pulmonary hypertension of the newborn (PPHN) [7,14,15].
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