Genetic analyses in a cohort of children with pulmonary hypertension

Eur Respir J. 2016 Oct;48(4):1118-1126. doi: 10.1183/13993003.00211-2016. Epub 2016 Sep 1.


The prevalence of germline mutations in paediatric pulmonary hypertension (PH) is poorly documented. The objective of this study was to determine the mutation frequency in PH genes in a paediatric cohort and describe the clinical characteristics of mutation carriers.The study involved 66 index cases with PH: 35 children with idiopathic pulmonary arterial hypertension (IPAH); five children with familial PAH (FPAH); three children with pulmonary veno-occlusive disease (PVOD); and 23 children with PAH associated with congenital heart disease (APAH-CHD).No mutations were found in the 23 children with APAH-CHD. In the 40 children with IPAH or FPAH, 12 mutations were found: five on BMPR2; four on ACVRL1; and three on TBX4. In the three PVOD cases, two carried the EIF2AK4 mutation. Mutation carriers had a more severe disease at diagnosis and more aggressive first-line therapy was required. The three patients with PVOD had a very severe disease at diagnosis and required a lung transplantation.The genetic architecture of paediatric PAH is enriched in ACVRL1 and TBX4 mutations compared to adult PAH, but further studies are required to confirm these results. Childhood-onset PAH in children carrying a mutation in one of the genes tested has a more severe presentation at diagnosis but a similar outcome to that observed in non-carriers.

MeSH terms

  • Activin Receptors, Type II / genetics
  • Adolescent
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Child
  • Child, Preschool
  • Cohort Studies
  • DNA Mutational Analysis
  • Familial Primary Pulmonary Hypertension / diagnosis*
  • Familial Primary Pulmonary Hypertension / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Heart Defects, Congenital / complications
  • Heart Defects, Congenital / diagnosis
  • Heart Defects, Congenital / genetics
  • Hemodynamics
  • Heterozygote
  • Humans
  • Male
  • Mutation
  • Pedigree
  • Pulmonary Veno-Occlusive Disease / complications
  • Pulmonary Veno-Occlusive Disease / diagnosis
  • Pulmonary Veno-Occlusive Disease / genetics
  • T-Box Domain Proteins / genetics
  • Treatment Outcome


  • T-Box Domain Proteins
  • TBX4 protein, human
  • ACVRL1 protein, human
  • Activin Receptors, Type II
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II