Knowledge on rare diseases and orphan drugs

Prevalence of PAH, in all of its forms, is estimated around 5/1,000,000.

Most forms of PAH develop in adults, and in rare cases in children; women are twice as likely as men to be affected. Initial symptoms include dyspnea, syncope, chest pain, palpitations and pedal edema. Precordial signs include loud and palpable second heart sound, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation. 70% of patients present with severe heart failure. More rarely, abdominal distension, clubbing of digits and Raynaud phenomenon (predominantly in females) are observed. Hemoptysis has also been reported.

PAH is caused by vascular remodeling of pulmonary arteries leading to widespread obliteration of the smallest arteries; sufficient occlusion of these vessels increases the resistance to pulmonary blood flow and a compensating increased pressure in the right ventricle. Mutations in BMPR2 gene (2q33) and also in ACVRL1(12q13), Endoglin(9q34), CAV1 (7q31), KCNK3(2p23),Smad9 (13q12) and TBX4 (17q21) have been described in heritable PAH. Mutations in PAH predisposing genes were identified in patients with idiopathic and/or familial form of PAH and in PAH associated with intake of drugs or toxins. Patients carrying a mutation in PAH predisposing gene, and those displaying a familial form of the disease (with or without mutations identified), are grouped under the term heritable PAH.

Chest X-ray reveals an enlarged pulmonary artery and lung hyper perfusion and ECG shows right ventricular strain and hypertrophy. Echocardiography allows an estimate of pulmonary artery systolic pressure and detects cardiac disease. Right-heart catheterization is essential to establish the diagnosis. PAH is diagnosed when resting mean pulmonary artery pressure is >25mmHg and a normal Pulmonary capillary wedge pressure.

Rarer forms of pulmonary hypertension include pulmonary veno-occlusive disease /pulmonary capillary hemangiotosis (PVOD /PCH). Differential diagnoses include asthma, chronic obstructive pulmonary disease, hypoplastic left heart syndrome, chronic thromboembolic pulmonary hypertension and complete atrio-ventricular canal - left heart obstruction.

Pregnancy is considered to be associated with a high rate of mortality (30-50%) in PAH patients. Prenatal genetic testing could be considered in cases of heritable PAH.

Genetic counseling and testing have to be proposed to patients with idiopathic or heritable form of PAH (transmitted as an autosomal dominant disease with an incomplete penetrance) and to patients displaying drug-or toxin-induced PAH.

Management includes general measures (aggressive management of respiratory tract infections, annual influenza vaccination, family planning) and medical therapy (oxygen, anticoagulants, diuretics, digoxin). Calcium channel blockers are indicated only in patients with acute vasodilator response to Nitric oxide during right heart catheterization. Endothelin receptor agonists (ambrisentan), prostanoids (epoprostenol) and phosphodiestrease inhibitors (sildenafill) have been used. Lung transplantation is the last option for resistant patients.

Prognosis varies between different forms, but is generally poor; the mean survival rate after diagnosis is <3 years. However, early therapeutic intervention may lead to better survival.

Last update: January 2015 - Expert reviewer(s): Pr David MONTANI