Pulmonary Hypertension in a 19-Year-Old Patient Due to a Mutation in the Bone Morphogenetic Protein Receptor Gene: A Case Report

Abstract

Pulmonary hypertension (PH) is a chronic disease with a high socio-economic and health burden, often misdiagnosed or diagnosed late due to the absence of specific symptoms, with often fatal outcomes. Despite numerous studies on the disorder, the exact mechanisms of onset are not yet fully understood, and the therapeutic possibilities, although increasing, are still few and not curative. We report the case of an apparently healthy 19-year-old woman who presented with recurrent syncope, dyspnea, and chest pain on exertion. Diagnostic work-up showed severe PH, and genetic analysis revealed a truncating mutation in the bone morphogenetic protein receptor gene 2 as an etiologic factor. Similar mutations in the same gene, inherited in an autosomal-dominant pattern, are already known as the causative factor of PH. Despite the implementation of guideline-directed medical therapy, the clinical situation rapidly deteriorated, and the patient died due to a pulmonary hemorrhage. This case report highlights the importance of early diagnosis, especially at a young age, and the need for treatment by a center specialized in these disorders.

Introduction

Pulmonary hypertension (PH) is a chronic and progressive condition characterized by high blood pressure in the pulmonary arteries. It represents, as defined by the European Society of Cardiology and the Proceedings of the 6th WSPH (World Symposia on Pulmonary Hypertension Association), a hemodynamic state characterized by a resting mean pulmonary artery pressure (PAPm) of ≥ 20 mmHg assessed by a right heart catheterization [1,2]. With a prevalence of about 1%, which varies according to region and age group, it is not a rare disorder and is linked to high social, health, and economic burden [1-4].

The clinical classification, with currently five subgroups, highlights the different pathophysiological mechanisms and consequently the possible therapeutic approaches and has been established with global consensus [1-4].

In the following report, we describe the case of a young female patient with no previously diagnosed medical conditions and who was not taking any medication, who presented to the emergency department with shortness of breath and chest pain on exertion, as well as a history of recurrent syncope, to whom we have diagnosed severe PH. A subsequent work-up at a national center for the diagnosis and treatment of PH revealed a mutation in the bone morphogenetic protein receptor gene 2 (BMPR2), a known gene linked as a causative factor of PH [1,5,6].

Case presentation

We report the case of a 19-year-old woman without known cardiac disease and without other known previously diagnosed medical conditions, who was referred to our hospital because of a two-year history of shortness of breath and angina-like chest pain under moderate exercise. At the time of presentation, she was not taking any medication. As remote personal history is pertinent to the case, we mention two episodes of loss of consciousness: the first one when she was 16 years old during a hike, and the second episode one year later after a sneeze. A medical examination was hence performed with normal blood values and a negative Schellong test.

The day of the hospitalization, she presented to our Emergency Department because of chest pain under light physical strain in association with palpitations and dizziness. The physical examination did not reveal any noteworthy particularities.

Her 12-lead ECG on admission (Figure 1) revealed signs of right heart chamber overload. Laboratory values showed no compatible signs of myocardial necrosis.

Figure 1. Surface 12-lead ECG showing right ventricular overload (hypertrophy/dilatation): right ventricular Sokolow-Lyon index >1.05 mV and downsloping of the ST segment in v1-v4 and in the inferior leads.

Chest X-rays (Figure 2) showed an accentuation of the second left arc of the cardiac shadow (corresponding to the pulmonary artery).

Figure 2. Chest X-rays showing characteristic radiographic signs of PH: right heart enlargement and accentuation of the second left arc (corresponding to the pulmonary artery) of the cardiac silhouette.

PH: Pulmonary hypertension

Trans-thoracic echocardiography in different views (Videos 1-3) revealed a systo-diastolic D-shape of the interventricular septum with ventricular interdependence and dilatation of the right chamber that appears hypertrophic and hypokinetic. Trans-esophageal echocardiography showed neither a patent Botalli duct nor interatrial and interventricular shunts nor anatomical coronary/venous sinus defects. Cardiac magnetic resonance imaging showed a normal pulmonary venous return. The immunological and thrombophilic screening, as well as the HIV, Hepatitis B and C screening, tested negative. Right heart catheterization revealed a PAPm of 108 mmHg, with a mean aortic pressure of 88 mmHg. There was a marked increase in the mean pulmonary vascular resistance (PVR 2429 dynes* sec/cm⁵), which exceeded systemic resistance. The wedge pressure was measured as slightly increased (22 mmHg) secondary to extreme (end-stage) right heart overload in the absence of any other signs of left heart disease. No intracardiac shunts were noted on the oximetry run. A respiratory function test, difficult to execute due to a tendency towards pre-syncope, was compatible with air trapping (RV/TLC 260 % of predicted) and a severe alveolar-capillary diffusion defect (DLCO <40%). Contrast-enhanced lung and abdomen CT revealed multiple areas of ground-glass lung parenchymal change compatible with the underlying PH.

Video 1. Apical four-chamber view showing a severely dilated right ventricle that appears hypertrophic and hypokinetic.

Download video file ^{(90.1KB, mp4)}

Video 2. Parasternal long axis (PLAX) view showing a dilated right ventricle and interventricular septal flattening .

Download video file ^{(84.8KB, mp4)}

Video 3. Parasternal short axis (PSAX) view showing systolic flattening of the interventricular septum (so-called D-shape) with ventricular interdependence and dilatation of the right chamber .

Download video file ^{(92.4KB, mp4)}

The patient was then transferred to a Swiss specialist center for the continuation of care. A DNA genetic analysis of the blood was performed, which detected a truncating mutation in the BMPR2 gene. This mutation was considered pathogenic. The definitive diagnosis was therefore that of a heritable pulmonary arterial hypertension. In consideration of the seriousness of the case and according to the indications of the ESC guidelines on PH [1], the patient was placed on the benefit of a triple therapy composed of 5-PDE-inhibitor (tadalafil), a cell-proliferation inhibitor and endothelia receptor antagonist (macitentan), and a vasodilator (treprostinil).

Unfortunately, despite this treatment, the clinical course did not show any significant clinical improvements, for example, in terms of the functional class of dyspnea or the cardiac index.

The clinical course was then complicated by the onset of cough in association with major hemoptysis. A detailed blood test for coagulation showed no significant abnormalities. The angiographic examination documented the presence of tortuous pathological circles in the districts of the right bronchial artery, which are selectively excluded by embolization. Pulmonary bronchoscopy confirmed the efficacy of the treatment. The clinical course was then again complicated by a second episode of major hemoptysis of multifactorial origin (hypovolemic, hypoxemic, or hemorrhagic shock), resulting in a cardiac arrest and the death of the patient.

Discussion

Pulmonary arterial hypertension is a complex, multifactorial condition characterized by progressive impairment of pulmonary circulation and high morbidity and mortality. The case described shows multiple characteristic aspects of PH. The most prominent is, unfortunately, the often fatal outcome of this disease. Secondly, the delayed diagnosis, which complicates an already difficult therapeutic approach that actually only includes therapies aimed at alleviating symptoms, slows down disease progression and improves quality of life.

Since the beginning of the new millennium, the deepening of the pathophysiological mechanisms has gained momentum. Multiple genes have been linked to PH onset, with BMPR2 being the most extensively investigated with the largest literature [1,6-8].

The better understanding of the molecular and genetic mechanisms underlying the disease has profoundly changed the pathophysiological model [9,10], highlighting how vascular remodeling results from the complex interaction between genetic predisposition, endothelial dysfunction, alterations in cellular signaling pathways, inflammation, and metabolic dysregulation.

We also believe it is important to underline how, despite the progress that has been made in recent years, the exact pathophysiological mechanism has not yet been fully understood, and therefore, multiple gaps in our knowledge still remain. For example, the exact mutation of the patient, discovered thorough genetic analysis, has, to the best of our knowledge, never been described in the literature, but similar mutations in the same gene, inherited in an autosomal-dominant pattern, are already known as the causative factor of PH, which is why we assumed the link between the patient’s truncating mutation in the BMPR2 gene and the onset of PH.

In this context, the role of the BMPR2 gene has taken on central relevance, not only as the primary genetic susceptibility factor but also as a crucial focal point in the regulation of pulmonary vascular homeostasis. The characterization of the BMP/TGF-β signaling pathway has opened up new therapeutic perspectives aimed not only at vasodilation but also at modulating the biological processes responsible for disease progression [9,10]. 

The lack of certain knowledge mentioned above also poses an obstacle to a screening strategy for mutation carriers. There is in fact currently no accepted screening consensus for evaluating PH in such family members [1]. A strategy currently accepted by experts is to subject the family members to yearly screening through echocardiography and with periodic clinical monitoring, including assessment of symptoms, measurement of cardiac biomarkers (NT-proBNP), respiratory function testing to measure carbon monoxide diffusion capacity, and assessment of exercise capacity via the six-minute walk test, when indicated.

Although PH is a chronic and progressive condition, advancements in treatment have significantly improved outcomes [5].

Conclusions

In conclusion, PH is a chronic and often fatal disease for which treatment is still limited today. Despite the significant advances mentioned above, numerous challenges remain. A better understanding of the determinants of the penetrance of genetic mutations, the identification of reliable biomarkers for early diagnosis and monitoring of therapeutic response, and the development of personalized medicine strategies are needed.

It is important for individuals with PH to work closely with healthcare professionals specialized in the condition, to develop a personalized treatment plan and receive ongoing monitoring, with the prospect of significantly improving the quality of life and survival.