Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2mutations

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2011

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Pfarr Nicole , Szamalek-Hoegel Justyna , Fischer Christine , Hinderhofer Katrin , Nagel Christian , Ehlken Nicola , Tiede Henning , Olschewski Horst , Reichenberger Frank , Ghofrani , Seeger Werner , Grünig Ekkehard

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biomed

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biomed

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01 janvier 2011

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185

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Mutations in the bone morphogenetic protein receptor 2 ( BMPR2 ) gene can lead to idiopathic pulmonary arterial hypertension (IPAH). This study prospectively screened for BMPR2 mutations in a large cohort of PAH-patients and compared clinical features between BMPR2 mutation carriers and non-carriers. Methods Patients have been assessed by right heart catheterization and genetic testing. In all patients a detailed family history and pedigree analysis have been obtained. We compared age at diagnosis and hemodynamic parameters between carriers and non-carriers of BMPR2 mutations. In non-carriers with familial aggregation of PAH further genes/gene regions as the BMPR2 promoter region, the ACVRL1 , Endoglin , and SMAD8 genes have been analysed. Results Of the 231 index patients 22 revealed a confirmed familial aggregation of the disease (HPAH), 209 patients had sporadic IPAH. In 49 patients (86.3% of patients with familial aggregation and 14.3% of sporadic IPAH) mutations of the BMPR2 gene have been identified. Twelve BMPR2 mutations and 3 unclassified sequence variants have not yet been described before. Mutation carriers were significantly younger at diagnosis than non-carriers (38.53 ± 12.38 vs. 45.78 ± 11.32 years, p < 0.001) and had a more severe hemodynamic compromise. No gene defects have been detected in 3 patients with HPAH. Conclusion This study identified in a large prospectively assessed cohort of PAH- patients new BMPR2 mutations, which have not been described before and confirmed previous findings that mutation carriers are younger at diagnosis with a more severe hemodynamic compromise. Thus, screening for BMPR2 mutations may be clinically useful.

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Publié par

biomed

Publié le

01 janvier 2011

Nombre de lectures

185

Langue

English

Pfarret al.Respiratory Research2011,12:99 http://respiratoryresearch.com/content/12/1/99

R E S E A R C HOpen Access Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2mutations 1,2†2†2†2 1 Nicole Pfarr, Justyna SzamalekHoegel, Christine Fischer, Katrin Hinderhofer , Christian Nagel , 1 34 33 3 Nicola Ehlken , Henning Tiede , Horst Olschewski , Frank Reichenberger , Ardeschir HA Ghofrani , Werner Seeger 1* and Ekkehard Grünig

Abstract Background:Mutations in thebone morphogenetic protein receptor 2(BMPR2) gene can lead to idiopathic pulmonary arterial hypertension (IPAH). This study prospectively screened forBMPR2mutations in a large cohort of PAHpatients and compared clinical features betweenBMPR2mutation carriers and noncarriers. Methods:Patients have been assessed by right heart catheterization and genetic testing. In all patients a detailed family history and pedigree analysis have been obtained. We compared age at diagnosis and hemodynamic parameters between carriers and noncarriers ofBMPR2mutations. In noncarriers with familial aggregation of PAH further genes/gene regions as theBMPR2promoter region, theACVRL1,Endoglin, andSMAD8genes have been analysed. Results:Of the 231 index patients 22 revealed a confirmed familial aggregation of the disease (HPAH), 209 patients had sporadic IPAH. In 49 patients (86.3% of patients with familial aggregation and 14.3% of sporadic IPAH) mutations of theBMPR2gene have been identified. TwelveBMPR2mutations and 3 unclassified sequence variants have not yet been described before. Mutation carriers were significantly younger at diagnosis than noncarriers (38.53 ± 12.38 vs. 45.78 ± 11.32 years, p < 0.001) and had a more severe hemodynamic compromise. No gene defects have been detected in 3 patients with HPAH. Conclusion:This study identified in a large prospectively assessed cohort of PAH patients newBMPR2mutations, which have not been described before and confirmed previous findings that mutation carriers are younger at diagnosis with a more severe hemodynamic compromise. Thus, screening forBMPR2mutations may be clinically useful.

Introduction Pulmonary arterial hypertension (PAH) is a rare vascular disorder characterised by increased pulmonary vascular resistance and right heart failure. PAH can be idiopathic (IPAH), heritable (HPAH) or associated with other con ditions (APAH) as connective tissue diseases, congenital heart diseases, portal hypertension, drug or toxin expo sure [1,2]. Heterozygous germline mutations in thebone morphogenetic protein type 2 receptor(BMPR2) have

* Correspondence: ekkehard.gruenig@thoraxklinikheidelberg.de †Contributed equally 1 Centre for Pulmonary Hypertension Thoraxclinic, University of Heidelberg, Heidelberg, Germany Full list of author information is available at the end of the article

been identified as a gene underlying HPAH in approxi mately 10 to 40% of patients with apparently sporadic disease [1,36] and in 58% to 74% of patients with famil ial PAH [1,4,6,7]. In total 298 different mutations in BMPR2have been identified so far in independent patients including those with a known PAH family his tory, sporadic disease and PAH associated with other diseases [1]. In a few PAH patients mutations in other genes participating in the BMPR2 signalling pathway have been identified, asActivin A receptor type IIlike 1 (ACVRL1, also calledALK1) [8],Endoglin[9], and SMAD8[10]. Nevertheless, there is still a small

© 2011 Pfarr et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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