A Novel BMPR2 Variant Gene in Relation with Hereditary Pulmonary Arterial Hypertension Combined with Pulmonary Arteriovenous Malformations

INTRODUCTION

BMPR2 gene belongs to transforming growth factor-beta superfamily. Mutations in this gene are categorized as hereditary pulmonary arterial hypertension (HPAH), a form of group 1 pulmonary hypertension (PH). Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between pulmonary arteries and veins. Concomitant PAVMs and HPAH are most commonly seen in hereditary hemorrhagic telangiectasia (HHT) with endoglin (ENG) or activin A receptor like type 1 (ACVRL1 or ALK1) mutation and rare cases with BMPR2 mutation are reported. Medications for pulmonary arterial hypertension (PAH) may reduce pulmonary vascular resistance (PVR) but increase deoxygenated blood flow to the left side of the heart in patients with PAVMs, which further worsens oxygenation. Conversely, occlusion of PAVMs increases pulmonary arterial pressure (PAP) and exacerbates PAH.

CASE REPORT

A 70-year-old woman was referred to our hospital two years ago for PH. She has been diagnosed with PAVMs in the left lower and right upper zones, treated by coils embolization more than 20 years ago and 6 years ago respectively. Although she has underlying chronic obstructive pulmonary disease, the condition is not contributory to PH development. Her niece has been experiencing dyspnea on exertion in her 40’s and also recognized to have PAH and PAVMs.

The patient has been suffering from breathlessness around the age of 50. At presentation, vital signs were recorded as blood pressure of 146/83 mmHg, pulse rate of 96 beats per minute, respiratory rate of 22 breaths per minute with oxygen saturation around 88-92% while she was breathing the ambient air. On examination, there were no jugular vein engorgement, no pedal edema and no signs of mucocutaneous telangiectatic lesions. The heart sounds were regular without significant heart murmur. A continuous murmur could be heard over right upper lung field. Orthodeoxia was absent. Laboratory tests were unremarkable. Normal sinus rhythm without a strain pattern was noted by the electrocardiogram. Chest radiography showed a tortuous structure in the right upper lung and a cluster of metalic coils in the left lower lung field (Figure 1A). Transthoracic echocardiogram revealed increased sizes of right heart chambers with dilated pulmonary artery up to 49 mm in diameter. Neither left ventricular dysfunction nor valvular heart disease was observed. Pulmonary function test showed mild obstructive ventilatory defect with normal diffusing capacity. Computed tomography (CT) angiogram reported enlarged pulmonary arteries as well as PAVMs in the right upper lobe. There was neither intracranial aneurysm nor vascular malformation on brain CT angiogram. Despite small matched filling defects found by ventilation-perfusion lung scintigraphy, pulmonary artery angiography (PAG) excluded the diagnosis of chronic thromboembolic pulmonary hypertension.

Figure 1.

Chest X-rays (A and B) showed disappearance of pulmonary arteriovenous malformation (PAVM) in right upper lung zone after vascular plug occlusion. The pulmonary artery angiography illustrates PAVM (C) and no residual lesion (D) after vascular plug occlusion. (The white arrows indicate PAVMs, the black arrows indicate vascular plug, the arrowheads indicate previous coil embolization.

Right heart catheterization (RHC) indicated pre-capillary PH (Table 1). Negative vasoreactivity test was disclosed. PAG showed PAVM in the right upper lung. Contrast echocardiogram revealed Grade III intrapulmonary shunt. Furthermore, the molecular genetic testing for BMPR2, ENG, ACVRL1 (or ALK1) and SMAD4 were performed by next generation sequencing (NovaSeq6000, Illumina, USA). A heterozygous BMPR2 mutation with a single nucleotide substitution (G->A transversion) at nucleotide position 1165, which converted a glutamic acid into a lysine residue (c.1165 G->A, p.Glu389Lys) was identified (Table 2). Meanwhile, the patient’s niece was reported with the same BMPR2 mutation.

Table 1. Hemodynamic parameters.

	2 years before PAVM occlusion	Day of PAVM occlusion		6 months after PAVM occlusion
		Before repair	After repair
Cardiac output (L/min)	3.34	3.23		3.28
Mean pulmonary pressure (mmHg)	28	26	31	36
Pulmonary vascular resistance (WU)	4.20	7.11		6.40
Pulmonary arterial wedge pressure (mmHg)	14	3		15
Arterial O2 saturation (SaO2, %)		78	97
Resting arterial O2 saturation (%) by pulse oximetry	90	88		96
Nadir arterial O2 saturation (%) by pulse oximetry	86	84		91

PAVM, pulmonary arteriovenous malformation.

Table 2. Gene test.

Gene	Nucleotide variant	Amino acid changes	Genotype	Clinical importance
BMPR2	c.1165 G>A	p.Glu389Lys	Heterozygous	Likely pathogenic

A, adenine; BMPR2, bone morphogenic protein receptor type 2; G, guanine; Glu, glutamic acid, Lys, lysine.

Considering PAH-specific therapy related increase of PAVMs flow and further arterial desaturation as well as PAVMs occlusion related PAH worsening, we did not take any intervention. Diuretic agent was prescribed for elevated left ventricular end-diastolic pressure up to 21 mmHg after fluid challenge at first RHC and the symptoms improved initially. Nevertheless, she experienced progressive exertional dyspnea in the later period of a 2-year follow-up. There was a deterioration of exercise capacity with declination of the six-minute walk distance (6MWD) from 440 to 363 meters and the saturation (Table 1). Follow-up RHC data showed an increase in PVR (Table 1) and PAG demonstrated an obvious growth of PAVM size (Figure 2). Due to deteriorated condition by progressive PAH and PAVM, we decided to occlude the PAVM with vascular plug and prescribe PAH-specific medicine simultaneously. The arterial O2 saturation obviously improved but mean PAP increased soon after PAVM occlusion (Table 1). Sildenafil was then added because PAVM occlusion had unmasked PAH worsening and additionally increased right ventricular afterload.

Figure 2.

Pulmonary angiography demonstrated right upper lung PAVM at initial presentation (A) with obviously increasing size in diameter after 2-year follow up (B), arrows indicate previous coil embolization.

After 6 months of maintenance therapy, symptoms improved further with stable hemodynamics. 6MWD was increased from 363 to 380 meters with resting saturation from 88% to 96% and nadir saturation from 84% to 91%. Furthermore, there was a significant improvement in cardiopulmonary exercise test showing a decrease in minute ventilation/carbon dioxide production slope from 36.85 to 32.34 and an increase in oxygen consumption from 15.395 to 18.31 ml/kg/min. The pulmonary hemodynamics were reassessed as shown in Table 1. No residual PAVM was observed (Figure 1).

DISCUSSION

BMPR2 gene mutation is well-known as the most common genetic cause of PAH over the past decades and associated with 80% of familial PAH and 15-40% of idiopathic PAH cases.⁶ We discovered a new BMPR2 variant (c.1165 G->A, p.Glu389Lys) located in the hot-spot regions where most of the known pathogenic gene mutations were identified. The aberrant genetic sequencing of BMPR2, as a missense mutation, was predicted to be "likely pathogenic" according to 2015 American College of Medical Genetics & Genomics standards & guidance. Besides, the patient’s niece also carries the same gene mutation and has been diagnosed with idiopathic PAH and PAVMs for years. We, herein, speculated that this BMPR2 mutation may be another causal mutation related to PAH and PAVMs. To the best of our knowledge, this novel gene mutation has not been recorded in the past literatures.

We reported a patient with concurrent PAVM and HPAH which may be associated with a new BMPR2 gene mutation. Although approximately 70% of PAVMs are associated with HHT,⁷ about 80% of HHT cases are associated with heterozygous germline mutations of ENG, ACVRL1 and MADH42.¹ Some authors speculated that HHT results from disruption of BMP9 signaling in endothelial cells, primarily due to ACVRL1 or ENG mutation.² Aside from PAVM, our patient did not express other features suggestive of HHT and the mutant genes for HHT were not disclosed. Hence, the diagnosis of HHT is less likely according to Curacao’s criteria.

For early diagnosis with appropriate treatment and to stratify the risk, genetic counselling may be considered in patients diagnosed with idiopathic PAH, familial PAH, pulmonary veno-occlusive disease, and PAH associated with congenital heart disease.⁸ Regarding the cost-effectiveness, genetic testing is more favored for patients with complex presentation, little improvement, PAVM or a family history of PAH in our practice.

Treatment strategies in patients with concomitant PAH and PAVMs should be carefully evaluated. PAH-targeted therapies lower PVR but take the risk of desaturation^3,4 and higher risk of ischemic stroke. Meanwhile, patients may benefit from lower risk of PAVMs rupture and better hemodynamics and exercise capacity. For patients undergoing PAVMs occlusion, PAP was assumed to be elevated⁵ though insignificant PAP change after procedure was also reported.⁹ To predict the hemodynamic consequences of PAVMs occlusion, some experts suggested balloon test occlusion before permanent occlusion of the PAVMs, but other experts proposed opposite opinion.⁹ Indications to treat PAVMs are progressive enlargement, paradoxical embolization, symptomatic hypoxemia, afferent arteries > 3 mm in diameter, transient ischemic attack, stroke, and brain abscess.¹⁰ Severe PAH is deemed as a relative contraindication.¹¹ In the present case, the mean PAP and the pulmonary artery wedge pressure were increased after 6 months of PAVM occlusion and targeted-PAH medical therapy. However, the improvements of exercise capacity and oxygenation were clearly observed. World Health Organization functional class (FC) was also improved from FC III to FC II.

LEARNING POINTS

• So far as we know, this is the first case of concurrent HPAH and PAVM with a gene mutation at nucleotide position 1165.

• Treatment for HPAH and PAVM demonstrated conflicted hemodynamic consequences. Individualized decision making should be performed after thorough evaluation.

• This patient was successfully treated with vascular plug for PAVM and specific medicine for PAH simultaneously.

• Genetic counselling should be considered in patients with complex presentation, little improvement, PAVM or a family history of PAH.

DECLARATION OF CONFLICT OF INTEREST

All the authors declare no conflict of interest.