Pediatric pulmonary arterial hypertension due to a novel homozygous GDF2 missense variant affecting BMP9 processing and activity.

Pulmonary arterial hypertension (PAH) is a rare and severe disorder characterized by progressive pulmonary vasculopathy. Growth differentiation factor (GDF)2 encodes the pro-protein bone morphogenetic protein (BMP) 9, activated after cleavage by endoproteases into an active mature form. BMP9, together with BMP10, are high-affinity ligands of activin receptor-like kinase 1 (ALK1) and BMP receptor type II (BMPR2). GDF2 mutations have been reported in idiopathic PAH with most patients being heterozygous carriers although rare homozygous cases have been described. The link between PAH occurrence and BMP9 or 10 expression level is still unclear. In this study, we describe a pediatric case of PAH also presenting with telangiectasias and epistaxis. The patient carries the novel homozygous GDF2 c.946A > G mutation, replacing the first arginine of BMP9's cleavage site (R316) by a glycine. We show that this mutation leads to an absence of circulating mature BMP9 and mature BMP9-10 heterodimers in the patient's plasma although pro-BMP9 is still detected at a similar level as controls. In vitro functional studies further demonstrated that the mutation R316G hampers the correct processing of BMP9, leading to the secretion of inactive pro-BMP9. The heterozygous carriers of the variant were asymptomatic, similarly to previous reports, reinforcing the hypothesis of modifiers preventing/driving PAH development in heterozygous carriers.

Milwaukee shoulder syndrome.

Milwaukee shoulder syndrome or rapid destructive arthropathy of the shoulder is a rare form of arthropathy that mainly affects elderly women. It is characterized by a rapid destruction of the glenohumeral joint and the rotator cuff and by an important noninflammatory joint effusion containing hydroxyapatite crystals. Radiography plays an important role in the evaluation of patients with articular disease. However, magnetic resonance imaging is the method of choice for assessing the full extent of osseous, chondral, and soft-tissue involvement.

Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension.

Mutations in the gene encoding bone morphogenetic protein (BMP) receptor type 2 (BMPR-2) have been reported in pulmonary arterial hypertension (PAH), but their functional relevance remains incompletely understood. BMP receptor expression was evaluated in human lungs and in cultured pulmonary artery smooth muscle cells (PASMCs) isolated from 19 idiopathic PAH patients and nine heritable PAH patients with demonstrated BMPR-2 mutations. BMP4-treated PASMCs were assessed for Smad and p38 mitogen-activated protein kinase (MAPK) signalling associated with mitosis and apoptosis. Lung tissue and PASMCs from heritable PAH patients presented with decreased BMPR-2 expression and variable increases in BMPR-1A and BMPR-1B expression, while a less important decreased BMPR-2 expression was observed in PASMCs from idiopathic PAH patients. Heritable PAH PASMCs showed no increased phosphorylation of Smad1/5/8 in the presence of BMP4, which actually activated the p38MAPK pathway. Individual responses varied from one mutation to another. PASMCs from PAH patients presented with an in vitro proliferative pattern, which could be inhibited by BMP4 in idiopathic PAH but not in heritable PAH. PASMCs from idiopathic PAH and more so from heritable PAH presented an inhibition of BMP4-induced apoptosis. Most heterogeneous BMPR-2 mutations are associated with defective Smad signalling compensated for by an activation of p38MAPK signalling, accounting for PASMC proliferation and deficient apoptosis.

[Animal models of pulmonary arterial hypertension]. / Modèles animaux d'hypertension artérielle pulmonaire.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a rare syndrome of fatigue and dyspnoea, caused by increased pulmonary vascular resistance and right heart failure without an identifiable pulmonary or cardiac cause. Despite important recent advances in treatment the condition remains incurable. BACKGROUND: Experimental animal models of PAH rely on hypoxic or monocrotaline injected rodents, the creation of left to right shunts in lambs or piglets, ligation of the ductus arteriosus in newborn lambs, genetically manipulated rodents and tissue culture. Hypoxic pulmonary hypertension is usually only moderate and limited to medial hypertrophy with varying degrees of adventitial change, but may progress to extensive remodelling in some species. Monocrotaline induced pulmonary hypertension is severe with prominent medial hypertrophy, inflammatory adventitial remodelling and, initially, pulmonary oedema and endothelial apoptosis. Pulmonary hypertension induced by shunting remains the most realistic model of PAH but causes only moderate increase in vascular resistance due to medial hypertrophy. Pulmonary hypertension of the newborn is severe but largely vasospastic, with predominant medial hypertrophy. An increasing number of genetically manipulated rodents are becoming available for the investigation of specific signalling pathways. VIEWPOINT: While none of the models has yet reproduced PAH each allows investigation of a specific hypothesis. Recent progress has resulted from genetic manipulation and molecular and cellular approaches. CONCLUSIONS: Animal models of PAH share basic biological abnormalities which, together with the study of lung tissue from patients with severe disease should lead to better understanding of the pathology and therapeutic innovation.