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Hemodynamic and genetic analysis in children with idiopathic, heritable, and congenital heart disease associated pulmonary arterial hypertension

Nicole Pfarr12, Christine Fischer1, Nicola Ehlken2, Tabea Becker-Grünig2, Vanesa López-González3, Matthias Gorenflo4, Alfred Hager5, Katrin Hinderhofer1, Oliver Miera6, Christian Nagel2, Dietmar Schranz7 and Ekkehard Grünig2*

Author Affiliations

1 Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany

2 Centre of Pulmonary Hypertension Thoraxclinic, University Hospital Heidelberg, Amalienstrasse 5, 69126, Heidelberg, Germany

3 Unidad de Genética Médica, Servicio de Pediatría, Hospital Universitario Virgen de La Arrixaca, Murcia, Spain

4 Department of Paediatric Cardiology, University of Heidelberg, Heidelberg, Germany

5 Department of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum München, Technische Universität München, Munich, Germany

6 German Heart Center, Berlin, Germany

7 Department of Paediatric Cardiology, University of Giessen, Giessen, Germany

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Respiratory Research 2013, 14:3  doi:10.1186/1465-9921-14-3

Published: 9 January 2013



Aim of this prospective study was to compare clinical and genetic findings in children with idiopathic or heritable pulmonary arterial hypertension (I/HPAH) with children affected with congenital heart defects associated PAH (CHD-APAH).


Prospectively included were 40 consecutive children with invasively diagnosed I/HPAH or CHD-APAH and 117 relatives. Assessment of family members, pedigree analysis and systematic screening for mutations in TGFß genes were performed.


Five mutations in the bone morphogenetic protein type II receptor (BMPR2) gene, 2 Activin A receptor type II-like kinase-1 (ACVRL1) mutations and one Endoglin (ENG) mutation were found in the 29 I/HPAH children. Two mutations in BMPR2 and one mutation in ACVRL1 and ENG, respectively, are described for the first time. In the 11 children with CHD-APAH one BMPR2 gene mutation and one Endoglin gene mutation were found. Clinical assessment of relatives revealed familial aggregation of the disease in 6 children with PAH (HPAH) and one CHD-APAH patient. Patients with mutations had a significantly lower PVR.


Mutations in different TGFß genes occurred in 8/29 (27.6%) I/HPAH patients and in 2/11 (18.2%) CHD-APAH patients and may influence the clinical status of the disease. Therefore, genetic analysis in children with PAH, especially in those with I/HPAH, may be of clinical relevance and shows the complexity of the genetic background.

Pulmonary hypertension; Congenital heart disease; Genetics; Children; Bone morphogenetic protein receptor 2