Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry

Abstract

Background: Pulmonary arterial hypertension (PAH) is a severe and rare disease with an important genetic background. The influence of genetic testing in the clinical classification of pediatric PAH is not well known and genetics could influence management and prognosis. Objectives: The aim of this work was to identify the molecular fingerprint of PH children in the REgistro de pacientes con HIpertensión Pulmonar PEDiátrica (REHIPED), and to investigate if genetics could have an impact in clinical reclassification and prognosis. Methods: We included pediatric patients with a genetic analysis from REHIPED. From 2011 onward, successive genetic techniques have been carried out. Before genetic diagnosis, patients were classified according to their clinical and hemodynamic data in five groups. After genetic analysis, the patients were reclassified. The impact of genetics in survival free of lung transplantation was estimated by Kaplan–Meier curves. Results: Ninety-eight patients were included for the analysis. Before the genetic diagnoses, there were idiopathic PAH forms in 53.1%, PAH associated with congenital heart disease in 30.6%, pulmonary veno-occlusive disease—PVOD—in 6.1%, familial PAH in 5.1%, and associated forms with multisystemic disorders—MSD—in 5.1% of the patients. Pathogenic or likely pathogenic variants were found in 44 patients (44.9%). After a genetic analysis, 28.6% of the cohort was “reclassified”, with the groups of heritable PAH, heritable PVOD, TBX4, and MSD increasing up to 18.4%, 8.2%, 4.1%, and 12.2%, respectively. The MSD forms had the worst survival rates, followed by PVOD. Conclusions: Genetic testing changed the clinical classification of a significant proportion of patients. This reclassification showed relevant prognostic implications.

Pulmonary Hypertension and Hypothyroidism—Still an Important Clinical Coincidence in Paediatric Population, an Endocrinologist’s Point of View

“…Moreover, there is a hypothesis of a possible common genetic background of the diseases, as thyroid anomalies seem to be associated with BMPR2 mutations (bone morphogenetic protein receptor type II gene), a well described genetic cause of PAH [ 1 , 24 , 29 , 30 , 31 ]. In a report regarding analysis of BMPR2 mutations in both adult and paediatric patients with IPAH, there were five novel mutations found in 4 of 66 adults (6%) and in 1 of 75 children (1%) [ 29 ].…”

Pulmonary arterial hypertension related to congenital heart disease with a left-to-right shunt: phenotypic spectrum and approach to management

“…More recently, a role for pathogenetic polymorphisms in PAH-CHD has been suggested: BMPR2 mutations were identified in 6% of adults and children with PAH-CHD (mainly Eisenmenger syndrome or post-repair), although the role of BMPR2 in PAH-CHD remains unclear ( 17 ). An increased prevalence of mutations in the SRY-Box Transcription Factor 17 gene ( SOX-17 ) and T-box transcription factor gene ( TBX4 ) has been identified in patients who developed PAH after ventricular septal defect repair and patients with pre-tricuspid shunts and Eisenmenger physiology ( 18 – 20 ). Other genes ( ABCC8 and SMAD1 ) have been described in patients with PAH associated with a small/coincidental defect ( 18 ).…”

“…An increased prevalence of mutations in the SRY-Box Transcription Factor 17 gene ( SOX-17 ) and T-box transcription factor gene ( TBX4 ) has been identified in patients who developed PAH after ventricular septal defect repair and patients with pre-tricuspid shunts and Eisenmenger physiology ( 18 – 20 ). Other genes ( ABCC8 and SMAD1 ) have been described in patients with PAH associated with a small/coincidental defect ( 18 ). Genetic factors may explain the variability in the development of PVD in patients with pre-tricuspid shunts, in whom the increased pulmonary blood flow alone is deemed insufficient for the development of PVD ( 21 ).…”

Genes in pediatric pulmonary arterial hypertension and the most promising BMPR2 gene therapy

“…Etiologically, according to the Pediatric Pulmonary Hypertension Network (PPHN), nationwide Netherlands PH Service, TOPP (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) registry, and REHIPED ( REgistro depacientes con HIpertensión Pulmonar PEDiátrica ), childhood-onset PAH has a higher proportion of idiopathic PAH (IPAH) and PAH associated with congenital heart disease (PAH-CHD), with PAH-CHD constituting nearly 30.6%–60% of children with PAH, and IPAH and heritable PAH (HPAH) comprising about 23%–53.1% and 5%–18.4%, respectively ( van Loon et al, 2011 ; Barst et al, 2012 ; Abman et al, 2022 ; Cruz-Utrilla et al, 2022 ). In addition, according to the PPHN, the majority of PAH in children were characterized by Eisenmenger syndrome in 10%; systemic-to-pulmonary shunts, excluding Eisenmenger syndrome, in 26%; and post-operative PAH in 25% ( Abman et al, 2022 ).…”

“…Although at least nine genes are associated with childhood-onset PAH nowadays, BMPR2 has been identified by a body of evidence as the major risk PAH gene, and approximately 50%–80% of HPAH and 10%–40% of IPAH are thought to be driven by BMPR2 mutations; thus, restoring BMPR2 expression to cure PAH seems to be the most reasonable and important approach of genetic therapy ( Zhu et al, 2018a ; Rosenzweig et al, 2019 ; Zhu et al, 2019 ; Ivy and Frank, 2021 ; Rai et al, 2021 ; Cruz-Utrilla et al, 2022 ). In addition, restoration of BMPR2 expression using gene therapy has shown promising results in animal models under research settings.…”