PA is markedly decreased in children with PAH. Accelerometer output correlated with clinical disease severity markers and may predict outcome. We showed an exciting potential of PA as a meaningful endpoint for clinical trials in pediatric PAH, although its clinical utility and prognostic value need to be further validated.

Objective: To describe the prevalence of pulmonary arterial hypertension (PAH) associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype correlations and outcome. Study design: Seventy children diagnosed with idiopathic PAH (IPAH), heritable PAH (HPAH), PAH associated with congenital heart disease (CHD) with coincidental shunt (PAH-CHD group 3), PAH after closure of a cardiac shunt (PAH-CHD group 4), or PAH associated with other non-cardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9 and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations (CNVs). Results: Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n=7, TBX4 n=8, ACVRL1 n=1, KCNK3 n=1, EIF2AK4 n=2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and Cobalamin C deficiency). In another 16 children (23%) genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome and various CNVs). Survival rates differed between groups and was most favorable in TBX4 variant carriers. Conclusions: Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk stratified care management in pediatric PAH.

IntroductionTreatment strategies in paediatric pulmonary arterial hypertension (PAH) have evolved over the last years, but survival is still poor. Recently, in adults with severe PAH, upfront triple combination therapy (uTCT) from diagnosis has been reported to show significant clinical improvement and excellent long-term outcome. This retrospective, observational study aimed to assess the efficacy of uTCT in paediatric PAH.MethodsChildren diagnosed with PAH between 2010 and 2019 and started with uTCT were included. World Health Organization Functional Class (WHO-FC), haemodynamics, echocardiography, six-minute walking distance, and serum level of N-terminal-Pro-Brain-Natriuretic-Peptide were assessed at baseline, after three and 6 months and at last available follow-up. Events were defined as death, lung transplantation or Potts shunt.ResultsTwenty-one children (median age 4.8 years (2.5–12.8), 57% females) were included. All children except one were in WHO-FC III or IV (28% and 67%, respectively). After 3 months, one child had died and one child had received a Potts shunt. The remaining 19 children showed clinical and echocardiographic improvement, which persisted at 6 months. Children with idiopathic and heritable PAH showed one-, two-, and three-year transplant-free survival estimates of 100%, 94%, and 87%, albeit 47% of them receiving a Potts shunt during follow-up.ConclusionsChildren with severe PAH, but not pulmonary veno-occlusive disease, improved significantly with uTCT and showed beneficial up to 3-year survival rates, albeit 47% of them receiving a Potts shunt during follow-up. The role of a Potts shunt in conjunction to uTCT in paediatric PAH needs to be further established.

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