View Abstract

A5627 - BMPR2 Mutation in a 3-Year-Old Female with Severe Pulmonary Hypertension
Author Block: M. Lu1, B. Bartley1, K. S. Gipson1, M. H. Crawley2, B. A. Nelson1, M. Lahoud-Rahme3, O. J. Benavidez3, M. P. Mullen4, T. Kinane1; 1Pediatric Pulmonary Medicine, Massachusetts General Hospital, Boston, MA, United States, 2Laboratory for Molecular Medicine, Massachusetts General Hospital, Boston, MA, United States, 3Pediatric and Congenital Cardiology, Massachusetts General Hospital, Boston, MA, United States, 4Pediatric Cardiology, Boston Children's Hospital, Boston, MA, United States.
INTRODUCTION
Bone morphogenetic protein receptor type 2 (BMPR2) is an important component of transforming growth factor-beta (TGF-β) mediated cell signal transduction. Disruption of BMPR2 and downstream TGF-β signaling leads to a maladaptive pulmonary vascular response to injury resulting in vascular smooth muscle proliferation, small vessel occlusion, and pulmonary arterial hypertension (PAH). While onset and severity of presentation are heterogeneous, patients with BMPR2 mutations may present with marked PAH at a strikingly young age. Here, we report a case of severe PAH in a pediatric patient. Molecular diagnostic testing via next-generation sequencing identified a heterozygous deletion of exon 1 in the BMPR2 gene. This known pathogenic deletion is expected to have a loss-of-function effect, resulting in reduced expression of the BMPR2 protein.
CASE
A 3-year-old female presented to her pediatrician with one week of fatigability and refusal to walk long distances secondary to dyspnea. A chest radiograph demonstrated increased interstitial opacities and prominence of the left mediastinum. CT of the chest showed dilation of the pulmonary arteries with evidence of right ventricular overload but no indication of a pulmonary embolism or parenchymal lung disease. Echocardiogram confirmed the absence of significant structural heart disease and estimated right ventricular pressure of at least 120 mmHg. Cardiac catheterization confirmed the diagnosis of PAH with a severely elevated mean pulmonary arterial pressure of 106 mmHg and pulmonary vascular resistance of 24.2 iWU. There was no family history of cardiopulmonary disorders. Hyper-coagulability work-up was unrevealing, but genetics evaluation returned positive for a pathogenic deletion of exon 1 in the BMPR2 gene.
DISCUSSION
BMPR2 mutations are the predominant cause of familial PAH and comprise a significant proportion of idiopathic PAH. Despite the relatively high prevalence of BMPR2 mutations in pediatric PAH, there is a paucity of information detailing clinical features and prognosis. In adult patients with BMPR2 mutations, an earlier age at diagnosis is associated with a higher risk of hemodynamic compromise and all-cause mortality. Here, we highlight the case of a 3-year-old patient without congenital heart disease or family history of PAH and with a pathogenic deletion of exon 1 in BMPR2 causing severe PAH. A deletion of exon 1 is likely to have significant functional consequences for this molecule resulting in a severe phenotype. Systematic genetic screening for BMPR2 mutations in children with PAH may have significant implications for prognosis, therapy, and familial predictive genetic testing.