Familial pulmonary arterial hypertension leucopenia and atrial septal defect

Other Names: Familial pulmonary arterial hypertension, leucopenia and ASD; Familial PAH, leucopenia and ASD

Pulmonary arterial hypertension is a progressive disorder characterized by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs. Pulmonary arterial hypertension is one form of a broader condition known as pulmonary hypertension. Pulmonary hypertension occurs when most of the very small arteries throughout the lungs narrow in diameter, which increases the resistance to blood flow through the lungs. To overcome the increased resistance, blood pressure increases in the pulmonary artery and in the right ventricle of the heart, which is the chamber that pumps blood into the pulmonary artery. Ultimately, the increased blood pressure can damage the right ventricle of the heart.

The term "heritable PAH" (HPAH) includes familial PAH (PAH that occurs in two or more family members) and simplex PAH (i.e., a single occurrence in a family) when a pathogenic variant has been identified.

Cause

Most heritable PAH (75%) is caused by a pathogenic variant in BMPR2; pathogenic variants in other genes (i.e., ACVRL1, KCNK3, CAV1, SMAD9, BMPR1B) are considerably less common (1%-3%).

Inheritance

Autosomal dominant pattern, a 50/50 chance.

HPAH is inherited in an autosomal dominant manner.

Risk factors

PAH develops across all ages, and the lifetime risk of developing PAH with a BMPR2 pathogenic variation in a male is 14%, whereas in a female it is 42%. (The penetrance of pathogenic variants in ACVRL1, KCNK3, CAV1, SMAD9, and BMPR1B is unknown.) If a parent of a proband has a pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%; however, because of the reduced penetrance of BMPR1B pathogenic variants, the risk to a sib of developing PAH is approximately 10% (50% x ~20%). Similarly, each child of an affected individual is at a 50% risk of inheriting the mutated allele; however, because of reduced penetrance the risk to offspring who inherit a BMPR2 pathogenic variant of developing PAH is approximately 10% (50% x ~20%).

Signs and symptoms

HPAH has identical symptoms, signs, and histology as PAH of unknown cause. Symptoms: dyspnea, fatigue, chest pain, palpitation, syncope, or edema Signs (abnormal findings on physical examination) including: Accentuation of the pulmonic component of the second heart sound Right ventricular heave or cardiac murmur such as tricuspid regurgitation resulting from right ventricular dilatation. Signs of right ventricular failure such as increased venous pressure, edema, or hepatomegaly (later in the course)

Diagnosis

Clinical testing to confirm PAH and distinguish from other forms of PH:

• Electrocardiography (ECG) may reveal changes suggestive of right atrial or right ventricular hypertrophy or strain. In individuals with PH associated with cardiac causes (Group 2 PH), ECG may reveal additional changes.
• Pulmonary function testing
• Chest radiography
• Echocardiography
• Cardiac catheterization
• Lung histopathology
• Chest CT

Molecular testing approaches can include serial single-gene testing or the use of a multigene panel. Perfusion lung scanning

Treatment

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Selexipag (Brand name: Uptravi) For use of Uptravi (Selexipag) Tablets, 200, 400, 600, 800, 1000, 1200, 1400, and 1600 mcg for treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.