Julien Grynblat, Melanie Eyries, Marine Ambar-Akkaoui, Marilyne Levy, Mathilde Meot, Isabelle Szezepanski, Julien Ranchoup, Alessia Callegari, Julie Karila-Cohen, Caroline Bonnet, Pierre Marijon, Jerome Champ, Florence Coulet, Caroline Ovaert, Frederic Perros, Fabrice Antigny, Pascale Maragnes, Guy Vaksmann, Marc Humbert, Sophie Guiti Malekzadeh Milani, David Montani Damien Bonnet
Hôpital Necker-Enfants malades, AP-HP, Université de Paris Cité, Université Paris-Saclay, Marie Lannelongue Hospital and Bicêtre Hospital, Le Kremlin-Bicêtre. Sorbonne Université, Assistance Publique-Hôpitaux de Paris and Hôpital Pitié-Salpêtrière. Centre Psychiatrique d’Orientation et d’Accueil and GHU Paris-Psychiatry & Neurosciences. CHU Lyon. Seqoia Laboratory. La Timone Hospital and CHU Marseille. Caen University and CHU de CAEN. Hôpital Privé de La Louvière.
France
Resiratory Medicine and Research
Respir Med Res 2026;
DOI: 10.1016/j.resmer.2026.101277
Abstract
Objectives: To determine the prevalence and phenotypes of children with heritable pulmonary arterial hypertension (PAH) and those with pulmonary hypertension (PH) associated with genetic disorders.
Methods: We retrospectively analysed 133 paediatric cases with PAH, with a median age of 6 years.
Results: 83 patients had isolated PAH, 41 had associated congenital heart disease, and 9 had suspected pulmonary veno-occlusive disease. The female/male sex ratio was 1.8/1. Affected genes were BMPR2 [13], SOX17 [10], TBX4 [8], ACVRL1 [9], EIF2AK4 [4], GDF2 [2], BMP10 [1], and KCNK3 [1]. SOX17 variants were more common in children with APAH-CHD (p = 0.01). Additionally, 18% of patients had genetic disorders associated with PH, including Chuvash syndrome (n = 2), incontinentia pigmenti (n = 1), 5 patients with RASopathy (3 Noonan syndromes and 2 neurofibromatosis type 1), Cantu syndrome (n = 1), Alagille syndrome (n = 1), Bourneville tuberous sclerosis (n = 1), mitochondrial diseases (n = 5), Myhre syndrome (n = 1), and chromosomal rearrangements (n = 6). Overall, a significant proportion of patients had either pathogenic variants in known PAH genes or genetic disorders complicated by pulmonary vascular disease.
Conclusion: The prevalence of genetic disorders and heritable PAH in children appears to be higher than previously reported, affecting over half of the paediatric population. This study emphasizes the importance of systematic genetic testing, including next-generation sequencing panels, in apparently idiopathic PAH and newly diagnosed PH patients. Larger genomic sequencing may be necessary to identify novel genes associated with these conditions when initial testing is negative.
Category
Class I. Heritable Pulmonary Hypertension
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes